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{{Infobox_gene}}
{{Infobox_gene}}
'''[[Cluster of differentiation]] 97''' is a [[protein]] also known as '''BL-Ac[F2]''' encoded by the ''ADGRE5'' [[gene]].<ref name="pmid7636245">{{cite journal | vauthors = Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ, Hoovers JM, Hartmann E, Strauss M, van Lier RA | title = Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain | journal = Journal of Immunology | volume = 155 | issue = 4 | pages = 1942–50 | date = Aug 1995 | pmid = 7636245 | pmc =  | doi =  }}</ref><ref name="pmid8786105">{{cite journal | vauthors = Hamann J, Hartmann E, van Lier RA | title = Structure of the human CD97 gene: exon shuffling has generated a new type of seven-span transmembrane molecule related to the secretin receptor superfamily | journal = Genomics | volume = 32 | issue = 1 | pages = 144–7 | date = Feb 1996 | pmid = 8786105 | pmc =  | doi = 10.1006/geno.1996.0092 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CD97 CD97 molecule| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=976| accessdate = }}</ref><ref>{{cite journal|last1=Hamann|first1=J|last2=Aust|first2=G|last3=Araç|first3=D|last4=Engel|first4=FB|last5=Formstone|first5=C|last6=Fredriksson|first6=R|last7=Hall|first7=RA|last8=Harty|first8=BL|last9=Kirchhoff|first9=C|last10=Knapp|first10=B|last11=Krishnan|first11=A|last12=Liebscher|first12=I|last13=Lin|first13=HH|last14=Martinelli|first14=DC|last15=Monk|first15=KR|last16=Peeters|first16=MC|last17=Piao|first17=X|last18=Prömel|first18=S|last19=Schöneberg|first19=T|last20=Schwartz|first20=TW|last21=Singer|first21=K|last22=Stacey|first22=M|last23=Ushkaryov|first23=YA|last24=Vallon|first24=M|last25=Wolfrum|first25=U|last26=Wright|first26=MW|last27=Xu|first27=L|last28=Langenhan|first28=T|last29=Schiöth|first29=HB|title=International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.|journal=Pharmacological Reviews|date=April 2015|volume=67|issue=2|pages=338–67|pmid=25713288|doi=10.1124/pr.114.009647|pmc=4394687}}</ref> CD97 is a member of the [[adhesion-GPCRs|adhesion GPCR]] family.<ref name="isbn1-4419-7912-3">{{cite book | author = Stacey M, Yona S | title = Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology) | publisher = Springer | location = Berlin | year = 2011 | pages = | isbn = 1-4419-7912-3 }}</ref><ref>{{cite journal|last1=Langenhan|first1=T|last2=Aust|first2=G|last3=Hamann|first3=J|title=Sticky signaling--adhesion class G protein-coupled receptors take the stage.|journal=Science signaling|date=21 May 2013|volume=6|issue=276|pages=re3|pmid=23695165|doi=10.1126/scisignal.2003825}}</ref>
'''[[Cluster of differentiation]] 97''' is a [[protein]] also known as '''BL-Ac[F2]''' encoded by the ''ADGRE5'' [[gene]].<ref name="pmid7636245">{{cite journal | vauthors = Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ, Hoovers JM, Hartmann E, Strauss M, van Lier RA | title = Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain | journal = Journal of Immunology | volume = 155 | issue = 4 | pages = 1942–50 | date = Aug 1995 | pmid = 7636245 | pmc =  | doi =  }}</ref><ref name="pmid8786105">{{cite journal | vauthors = Hamann J, Hartmann E, van Lier RA | title = Structure of the human CD97 gene: exon shuffling has generated a new type of seven-span transmembrane molecule related to the secretin receptor superfamily | journal = Genomics | volume = 32 | issue = 1 | pages = 144–7 | date = Feb 1996 | pmid = 8786105 | pmc =  | doi = 10.1006/geno.1996.0092 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CD97 CD97 molecule| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=976| accessdate = }}</ref><ref>{{cite journal|last1=Hamann|first1=J|last2=Aust|first2=G|last3=Araç|first3=D|last4=Engel|first4=FB|last5=Formstone|first5=C|last6=Fredriksson|first6=R|last7=Hall|first7=RA|last8=Harty|first8=BL|last9=Kirchhoff|first9=C|last10=Knapp|first10=B|last11=Krishnan|first11=A|last12=Liebscher|first12=I|last13=Lin|first13=HH|last14=Martinelli|first14=DC|last15=Monk|first15=KR|last16=Peeters|first16=MC|last17=Piao|first17=X|last18=Prömel|first18=S|last19=Schöneberg|first19=T|last20=Schwartz|first20=TW|last21=Singer|first21=K|last22=Stacey|first22=M|last23=Ushkaryov|first23=YA|last24=Vallon|first24=M|last25=Wolfrum|first25=U|last26=Wright|first26=MW|last27=Xu|first27=L|last28=Langenhan|first28=T|last29=Schiöth|first29=HB|title=International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.|journal=Pharmacological Reviews|date=April 2015|volume=67|issue=2|pages=338–67|pmid=25713288|doi=10.1124/pr.114.009647|pmc=4394687}}</ref> CD97 is a member of the [[adhesion-GPCRs|adhesion GPCR]] family.<ref name="isbn1-4419-7912-3">{{cite book | author = Stacey M, Yona S | title = Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology) | publisher = Springer | location = Berlin | year = 2011 | pages = | isbn = 978-1-4419-7912-4 }}</ref><ref>{{cite journal|last1=Langenhan|first1=T|last2=Aust|first2=G|last3=Hamann|first3=J|title=Sticky signaling--adhesion class G protein-coupled receptors take the stage.|journal=Science Signaling|date=21 May 2013|volume=6|issue=276|pages=re3|pmid=23695165|doi=10.1126/scisignal.2003825}}</ref>
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing [[GAIN domain|(GAIN)]] domain.<ref name="pmid22333914">{{cite journal | vauthors = Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT | title = A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis | journal = The EMBO Journal | volume = 31 | issue = 6 | pages = 1364–78 | date = Mar 2012 | pmid = 22333914 | pmc = 3321182 | doi = 10.1038/emboj.2012.26 }}</ref>
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing [[GAIN domain|(GAIN)]] domain.<ref name="pmid22333914">{{cite journal | vauthors = Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT | title = A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis | journal = The EMBO Journal | volume = 31 | issue = 6 | pages = 1364–78 | date = Mar 2012 | pmid = 22333914 | pmc = 3321182 | doi = 10.1038/emboj.2012.26 }}</ref>


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== Signaling ==
== Signaling ==
Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt.<ref name="ReferenceC">{{cite journal | vauthors = Becker S, Wandel E, Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G | title = Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions | journal = PLOS ONE | volume = 5 | issue = 1 | pages = e8507 | date = 13 January 2010 | pmid = 20084281 | doi = 10.1371/journal.pone.0008507 | pmc=2801611}}</ref> Furthermore, ectopic CD97 expression facilitated RhoA activation through binding of Gα12/13 as well as induced Ki67 expression and phosphorylated ERK and Akt through enhancing lysophosphatidic acid receptor 1 (LPAR1) signaling.<ref>{{cite journal | vauthors = Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K | title = LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells | journal = Cancer Research | volume = 71 | issue = 23 | pages = 7301–11 | date = Dec 2011 | pmid = 21978933 | doi = 10.1158/0008-5472.CAN-11-2381 }}</ref><ref name="Ward Y 2012">{{cite journal | vauthors = Ward Y, Lake R, Martin PL, Killian K, Salerno P, Wang T, Meltzer P, Merino M, Cheng SY, Santoro M, Garcia-Rostan G, Kelly K | title = CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model | journal = Oncogene | volume = 32 | issue = 22 | pages = 2726–38 | date = May 2013 | pmid = 22797060 | doi = 10.1038/onc.2012.301 }}</ref> Lysophosphatidylethanolamine (LPE; a plasma membrane component) and lysophosphatidic acid (LPA) use heterodimeric LPAR1–CD97 to drive G<sub>i/o</sub> protein–phospholipase C–inositol 1,4,5-trisphosphate signaling and induce [Ca2+] in breast cancer cells.<ref>{{cite journal | vauthors = Park SJ, Lee KP, Kang S, Chung HY, Bae YS, Okajima F, Im DS | title = Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells | journal = Cellular Signalling | volume = 25 | issue = 11 | pages = 2147–54 | date = Nov 2013 | pmid = 23838008 | doi = 10.1016/j.cellsig.2013.07.001 }}</ref>
Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt.<ref name="ReferenceC">{{cite journal | vauthors = Becker S, Wandel E, Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G | title = Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions | journal = PLOS ONE | volume = 5 | issue = 1 | pages = e8507 | date = 13 January 2010 | pmid = 20084281 | doi = 10.1371/journal.pone.0008507 | pmc=2801611}}</ref> Furthermore, ectopic CD97 expression facilitated RhoA activation through binding of Gα12/13 as well as induced Ki67 expression and phosphorylated ERK and Akt through enhancing lysophosphatidic acid receptor 1 (LPAR1) signaling.<ref name="ReferenceD">{{cite journal | vauthors = Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K | title = LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells | journal = Cancer Research | volume = 71 | issue = 23 | pages = 7301–11 | date = Dec 2011 | pmid = 21978933 | doi = 10.1158/0008-5472.CAN-11-2381 }}</ref><ref name="Ward Y 2012">{{cite journal | vauthors = Ward Y, Lake R, Martin PL, Killian K, Salerno P, Wang T, Meltzer P, Merino M, Cheng SY, Santoro M, Garcia-Rostan G, Kelly K | title = CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model | journal = Oncogene | volume = 32 | issue = 22 | pages = 2726–38 | date = May 2013 | pmid = 22797060 | doi = 10.1038/onc.2012.301 | hdl = 10261/116503 }}</ref> Lysophosphatidylethanolamine (LPE; a plasma membrane component) and lysophosphatidic acid (LPA) use heterodimeric LPAR1–CD97 to drive G<sub>i/o</sub> protein–phospholipase C–inositol 1,4,5-trisphosphate signaling and induce [Ca2+] in breast cancer cells.<ref>{{cite journal | vauthors = Park SJ, Lee KP, Kang S, Chung HY, Bae YS, Okajima F, Im DS | title = Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells | journal = Cellular Signalling | volume = 25 | issue = 11 | pages = 2147–54 | date = Nov 2013 | pmid = 23838008 | doi = 10.1016/j.cellsig.2013.07.001 }}</ref>


== Function ==
== Function ==
In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation.<ref>{{cite journal | vauthors = Leemans JC, te Velde AA, Florquin S, Bennink RJ, de Bruin K, van Lier RA, van der Poll T, Hamann J | title = The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense | journal = Journal of Immunology | volume = 172 | issue = 2 | pages = 1125–31 | date = Jan 2004 | pmid = 14707087 | doi=10.4049/jimmunol.172.2.1125}}</ref> Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Mice lacking CD97 or its ligand CD55 have twice as many granulocytes as wild-type mice possibly due to enhanced granulopoiesis.<ref>{{cite journal | vauthors = Veninga H, Hoek RM, de Vos AF, de Bruin AM, An FQ, van der Poll T, van Lier RA, Medof ME, Hamann J | title = A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e24431 | date = 2011 | pmid = 21984892 | doi = 10.1371/journal.pone.0024431 | pmc=3184942}}</ref> Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes.<ref>{{cite journal | vauthors = Hamann J, Veninga H, de Groot DM, Visser L, Hofstra CL, Tak PP, Laman JD, Boots AM, van Eenennaam H | title = CD97 in leukocyte trafficking | journal = Advances in Experimental Medicine and Biology | volume = 706 | pages = 128–37 | date = 2010 | pmid = 21618832 }}</ref> Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism.<ref>{{cite journal | vauthors = Veninga H, de Groot DM, McCloskey N, Owens BM, Dessing MC, Verbeek JS, Nourshargh S, van Eenennaam H, Boots AM, Hamann J | title = CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism | journal = Journal of Leukocyte Biology | volume = 89 | issue = 3 | pages = 413–21 | date = Mar 2011 | pmid = 21169517 | doi = 10.1189/jlb.0510280 }}</ref> Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.<ref>{{cite journal | vauthors = Capasso M, Durrant LG, Stacey M, Gordon S, Ramage J, Spendlove I | title = Costimulation via CD55 on human CD4+ T cells mediated by CD97 | journal = Journal of Immunology | volume = 177 | issue = 2 | pages = 1070–7 | date = Jul 2006 | pmid = 16818763 | doi=10.4049/jimmunol.177.2.1070}}</ref><ref>{{cite journal | vauthors = Abbott RJ, Spendlove I, Roversi P, Fitzgibbon H, Knott V, Teriete P, McDonnell JM, Handford PA, Lea SM | title = Structural and functional characterization of a novel T cell receptor co-regulatory protein complex, CD97-CD55 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 30 | pages = 22023–32 | date = Jul 2007 | pmid = 17449467 | doi = 10.1074/jbc.M702588200 }}</ref>
In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation.<ref>{{cite journal | vauthors = Leemans JC, te Velde AA, Florquin S, Bennink RJ, de Bruin K, van Lier RA, van der Poll T, Hamann J | title = The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense | journal = Journal of Immunology | volume = 172 | issue = 2 | pages = 1125–31 | date = Jan 2004 | pmid = 14707087 | doi=10.4049/jimmunol.172.2.1125}}</ref> Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Mice lacking CD97 or its ligand CD55 have twice as many granulocytes as wild-type mice possibly due to enhanced granulopoiesis.<ref>{{cite journal | vauthors = Veninga H, Hoek RM, de Vos AF, de Bruin AM, An FQ, van der Poll T, van Lier RA, Medof ME, Hamann J | title = A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e24431 | date = 2011 | pmid = 21984892 | doi = 10.1371/journal.pone.0024431 | pmc=3184942}}</ref> Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes.<ref>{{Cite book | vauthors = Hamann J, Veninga H, de Groot DM, Visser L, Hofstra CL, Tak PP, Laman JD, Boots AM, van Eenennaam H | title = CD97 in leukocyte trafficking | journal = Advances in Experimental Medicine and Biology | volume = 706 | pages = 128–37 | date = 2010 | pmid = 21618832 | doi = 10.1007/978-1-4419-7913-1_11 | isbn = 978-1-4419-7912-4 }}</ref> Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism.<ref>{{cite journal | vauthors = Veninga H, de Groot DM, McCloskey N, Owens BM, Dessing MC, Verbeek JS, Nourshargh S, van Eenennaam H, Boots AM, Hamann J | title = CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism | journal = Journal of Leukocyte Biology | volume = 89 | issue = 3 | pages = 413–21 | date = Mar 2011 | pmid = 21169517 | doi = 10.1189/jlb.0510280 }}</ref> Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.<ref>{{cite journal | vauthors = Capasso M, Durrant LG, Stacey M, Gordon S, Ramage J, Spendlove I | title = Costimulation via CD55 on human CD4+ T cells mediated by CD97 | journal = Journal of Immunology | volume = 177 | issue = 2 | pages = 1070–7 | date = Jul 2006 | pmid = 16818763 | doi=10.4049/jimmunol.177.2.1070}}</ref><ref>{{cite journal | vauthors = Abbott RJ, Spendlove I, Roversi P, Fitzgibbon H, Knott V, Teriete P, McDonnell JM, Handford PA, Lea SM | title = Structural and functional characterization of a novel T cell receptor co-regulatory protein complex, CD97-CD55 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 30 | pages = 22023–32 | date = Jul 2007 | pmid = 17449467 | doi = 10.1074/jbc.M702588200 }}</ref>


Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. The expression of CD97 on macrophage and the abundant presence of its ligand CD55 on fibroblast-like synovial cells suggest that the CD97-CD55 interaction is involved in the recruitment and/or retention of macrophages into the synovial tissue in rheumatoid arthritis.<ref>{{cite journal | vauthors = Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP | title = Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue | journal = Arthritis and Rheumatism | volume = 42 | issue = 4 | pages = 650–8 | date = Apr 1999 | pmid = 10211878 | doi = 10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S }}</ref> CD97 antibodies and lack of CD97 or CD55 in mice reduced synovial inflammation and joint damage in collagen- and K/BxN serum transfer-induced arthritis.<ref>{{cite journal | vauthors = Kop EN, Adriaansen J, Smeets TJ, Vervoordeldonk MJ, van Lier RA, Hamann J, Tak PP | title = CD97 neutralisation increases resistance to collagen-induced arthritis in mice | journal = [[Arthritis Research & Therapy]] | volume = 8 | issue = 5 | pages = R155 | date = 2006 | pmid = 17007638 | doi = 10.1186/ar2049 | pmc=1779430}}</ref><ref>{{cite journal | vauthors = Hoek RM, de Launay D, Kop EN, Yilmaz-Elis AS, Lin F, Reedquist KA, Verbeek JS, Medof ME, Tak PP, Hamann J | title = Deletion of either CD55 or CD97 ameliorates arthritis in mouse models | journal = Arthritis and Rheumatism | volume = 62 | issue = 4 | pages = 1036–42 | date = Apr 2010 | pmid = 20131275 | doi = 10.1002/art.27347 }}</ref> In brain tissue, CD97 is undetectable in normal white matter, and expression of CD55 is fairly restricted to the endothelium. In pre-active lesion, increased expression of CD55 in endothelial cells and robust CD97 expression on infiltrating leukocytes suggest a possible role of both molecules in immune cell migration through the blood-brain barrier.<ref>{{cite journal | vauthors = Visser L, de Vos AF, Hamann J, Melief MJ, van Meurs M, van Lier RA, Laman JD, Hintzen RQ | title = Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis | journal = Journal of Neuroimmunology | volume = 132 | issue = 1–2 | pages = 156–63 | date = Nov 2002 | pmid = 12417446 | doi=10.1016/s0165-5728(02)00306-5}}</ref> Additionally, soluble N-terminal fragment (NTF)s of CD97 are detectable in the serum of patients with rheumatoid arthritis and multiple sclerosis.<ref>{{cite journal | vauthors = Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP | title = Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue | journal = Arthritis and Rheumatism | volume = 42 | issue = 4 | pages = 650–8 | date = Apr 1999 | pmid = 10211878 | doi = 10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S }}</ref>
Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. The expression of CD97 on macrophage and the abundant presence of its ligand CD55 on fibroblast-like synovial cells suggest that the CD97-CD55 interaction is involved in the recruitment and/or retention of macrophages into the synovial tissue in rheumatoid arthritis.<ref name="ReferenceE">{{cite journal | vauthors = Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP | title = Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue | journal = Arthritis and Rheumatism | volume = 42 | issue = 4 | pages = 650–8 | date = Apr 1999 | pmid = 10211878 | doi = 10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S }}</ref> CD97 antibodies and lack of CD97 or CD55 in mice reduced synovial inflammation and joint damage in collagen- and K/BxN serum transfer-induced arthritis.<ref>{{cite journal | vauthors = Kop EN, Adriaansen J, Smeets TJ, Vervoordeldonk MJ, van Lier RA, Hamann J, Tak PP | title = CD97 neutralisation increases resistance to collagen-induced arthritis in mice | journal = [[Arthritis Research & Therapy]] | volume = 8 | issue = 5 | pages = R155 | date = 2006 | pmid = 17007638 | doi = 10.1186/ar2049 | pmc=1779430}}</ref><ref>{{cite journal | vauthors = Hoek RM, de Launay D, Kop EN, Yilmaz-Elis AS, Lin F, Reedquist KA, Verbeek JS, Medof ME, Tak PP, Hamann J | title = Deletion of either CD55 or CD97 ameliorates arthritis in mouse models | journal = Arthritis and Rheumatism | volume = 62 | issue = 4 | pages = 1036–42 | date = Apr 2010 | pmid = 20131275 | doi = 10.1002/art.27347 }}</ref> In brain tissue, CD97 is undetectable in normal white matter, and expression of CD55 is fairly restricted to the endothelium. In pre-active lesion, increased expression of CD55 in endothelial cells and robust CD97 expression on infiltrating leukocytes suggest a possible role of both molecules in immune cell migration through the blood-brain barrier.<ref>{{cite journal | vauthors = Visser L, de Vos AF, Hamann J, Melief MJ, van Meurs M, van Lier RA, Laman JD, Hintzen RQ | title = Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis | journal = Journal of Neuroimmunology | volume = 132 | issue = 1–2 | pages = 156–63 | date = Nov 2002 | pmid = 12417446 | doi=10.1016/s0165-5728(02)00306-5}}</ref> Additionally, soluble N-terminal fragment (NTF)s of CD97 are detectable in the serum of patients with rheumatoid arthritis and multiple sclerosis.<ref name="ReferenceE"/>


Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 in colonic enterocytes strengthens E-cadherin-based adherens junctions to maintain lateral cell-cell contacts and regulates the localization and degradation of β-catenin through glycogen synthase kinase-3β (GSK-3β) and Akt signaling.<ref name="ReferenceC"/> Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation.<ref>{{cite journal | vauthors = Hsiao CC, Chen HY, Chang GW, Lin HH | title = GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation | journal = FEBS Letters | volume = 585 | issue = 2 | pages = 313–8 | date = Jan 2011 | pmid = 21156175 | doi = 10.1016/j.febslet.2010.12.005 }}</ref> CD97 is expressed at the sarcoplasmic reticulum and the peripheral sarcolemma in skeletal muscle. However, lack of CD97 only affects the structure of the sarcoplasmic reticulum, but not the function of skeletal muscle.<ref name="ReferenceA"/> In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.<ref name="ReferenceB"/>
Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 in colonic enterocytes strengthens E-cadherin-based adherens junctions to maintain lateral cell-cell contacts and regulates the localization and degradation of β-catenin through glycogen synthase kinase-3β (GSK-3β) and Akt signaling.<ref name="ReferenceC"/> Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation.<ref>{{cite journal | vauthors = Hsiao CC, Chen HY, Chang GW, Lin HH | title = GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation | journal = FEBS Letters | volume = 585 | issue = 2 | pages = 313–8 | date = Jan 2011 | pmid = 21156175 | doi = 10.1016/j.febslet.2010.12.005 }}</ref> CD97 is expressed at the sarcoplasmic reticulum and the peripheral sarcolemma in skeletal muscle. However, lack of CD97 only affects the structure of the sarcoplasmic reticulum, but not the function of skeletal muscle.<ref name="ReferenceA"/> In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.<ref name="ReferenceB"/>


== Clinical significance ==
== Clinical significance ==
CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases.<ref>{{cite journal | vauthors = Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C | title = CD97: a dedifferentiation marker in human thyroid carcinomas | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1798–806 | date = May 1997 | pmid = 9135025 }}</ref> CD97 is expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells.<ref>{{cite journal | vauthors = Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C | title = CD97: a dedifferentiation marker in human thyroid carcinomas | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1798–806 | date = May 1997 | pmid = 9135025 }}</ref><ref>{{cite journal | vauthors = Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M | title = CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas | journal = American Journal of Clinical Pathology | volume = 118 | issue = 5 | pages = 699–707 | date = Nov 2002 | pmid = 12428789 | doi = 10.1309/A6AB-VF3F-7M88-C0EJ }}</ref><ref>{{cite journal | vauthors = Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G | title = Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues | journal = The American Journal of Pathology | volume = 161 | issue = 5 | pages = 1657–67 | date = Nov 2002 | pmid = 12414513 | doi = 10.1016/S0002-9440(10)64443-4 | pmc=1850798}}</ref><ref>{{cite journal | vauthors = Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C | title = Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 14 | issue = 1 | pages = 108–19 | date = Jan 2005 | pmid = 15668483 }}</ref><ref>{{cite journal | vauthors = Safaee M, Clark AJ, Oh MC, Ivan ME, Bloch O, Kaur G, Sun MZ, Kim JM, Oh T, Berger MS, Parsa AT | title = Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e62765 | date = 2013 | pmid = 23658650 | doi = 10.1371/journal.pone.0062765 | pmc=3637305}}</ref><ref name="Liu JK 2014">{{cite journal | vauthors = Liu JK, Lubelski D, Schonberg DL, Wu Q, Hale JS, Flavahan WA, Mulkearns-Hubert EE, Man J, Hjelmeland AB, Yu J, Lathia JD, Rich JN | title = Phage display discovery of novel molecular targets in glioblastoma-initiating cells | journal = Cell Death and Differentiation | volume = 21 | issue = 8 | pages = 1325–39 | date = Aug 2014 | pmid = 24832468 | doi = 10.1038/cdd.2014.65 | pmc=4085538}}</ref><ref>{{cite journal | vauthors = Safaee M, Fakurnejad S, Bloch O, Clark AJ, Ivan ME, Sun MZ, Oh T, Phillips JJ, Parsa AT | title = Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells | journal = PLOS ONE | volume = 10 | issue = 2 | pages = e0111532 | date = 2015 | pmid = 25714433 | doi = 10.1371/journal.pone.0111532 | pmc=4340952}}</ref> In addition, enhanced CD97 expression has been found at the invasion front of tumors,<ref>{{cite journal | vauthors = Wobus M, Huber O, Hamann J, Aust G | title = CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway | journal = Molecular Carcinogenesis | volume = 45 | issue = 11 | pages = 881–6 | date = Nov 2006 | pmid = 16929497 | doi = 10.1002/mc.20262 }}</ref> suggesting a possible role in tumor migration/invasion,<ref>{{cite journal | vauthors = Safaee M, Clark AJ, Oh MC, Ivan ME, Bloch O, Kaur G, Sun MZ, Kim JM, Oh T, Berger MS, Parsa AT | title = Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e62765 | date = 2013 | pmid = 23658650 | doi = 10.1371/journal.pone.0062765 | pmc=3637305}}</ref><ref>{{cite journal | vauthors = Wobus M, Huber O, Hamann J, Aust G | title = CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway | journal = Molecular Carcinogenesis | volume = 45 | issue = 11 | pages = 881–6 | date = Nov 2006 | pmid = 16929497 | doi = 10.1002/mc.20262 }}</ref> and correlated with a poorer clinical prognosis.<ref name="Liu JK 2014"/><ref>{{cite journal | vauthors = Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G | title = Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues | journal = The American Journal of Pathology | volume = 161 | issue = 5 | pages = 1657–67 | date = Nov 2002 | pmid = 12414513 | doi = 10.1016/S0002-9440(10)64443-4 | pmc=1850798}}</ref><ref>{{cite journal | vauthors = Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C | title = Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 14 | issue = 1 | pages = 108–19 | date = Jan 2005 | pmid = 15668483 }}</ref><ref>{{cite journal | vauthors = Wu J, Lei L, Wang S, Gu D, Zhang J | title = Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma | journal = Journal of Biomedicine & Biotechnology | volume = 2012 | pages = 587672 | date = 2012 | pmid = 22547928 | doi = 10.1155/2012/587672 | pmc=3324160}}</ref><ref>{{cite journal | vauthors = He Z, Wu H, Jiao Y, Zheng J | title = Expression and prognostic value of CD97 and its ligand CD55 in pancreatic cancer | journal = Oncology Letters | volume = 9 | issue = 2 | pages = 793–797 | date = Feb 2015 | pmid = 25624904 | doi = 10.3892/ol.2014.2751 | pmc=4301556}}</ref> Interestingly, CD97 has isoform-specific functions in some tumors. For instance, the small EGF(1,2,5) isoform promoted tumor invasion and metastasis in gastric carcinoma;<ref>{{cite journal | vauthors = Liu D, Trojanowicz B, Ye L, Li C, Zhang L, Li X, Li G, Zheng Y, Chen L | title = The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma | journal = PLOS ONE | volume = 7 | issue = 6 | pages = e39989 | date = 2012 | pmid = 22768192 | doi = 10.1371/journal.pone.0039989 | pmc=3386904}}</ref> the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.<ref>{{cite journal | vauthors = Liu D, Trojanowicz B, Radestock Y, Fu T, Hammje K, Chen L, Hoang-Vu C | title = Role of CD97 isoforms in gastric carcinoma | journal = International Journal of Oncology | volume = 36 | issue = 6 | pages = 1401–8 | date = Jun 2010 | pmid = 20428763 }}</ref>
CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases.<ref name="ReferenceF">{{cite journal | vauthors = Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C | title = CD97: a dedifferentiation marker in human thyroid carcinomas | journal = Cancer Research | volume = 57 | issue = 9 | pages = 1798–806 | date = May 1997 | pmid = 9135025 }}</ref> CD97 is expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells.<ref name="ReferenceF"/><ref>{{cite journal | vauthors = Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M | title = CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas | journal = American Journal of Clinical Pathology | volume = 118 | issue = 5 | pages = 699–707 | date = Nov 2002 | pmid = 12428789 | doi = 10.1309/A6AB-VF3F-7M88-C0EJ }}</ref><ref name="ReferenceG">{{cite journal | vauthors = Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G | title = Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues | journal = The American Journal of Pathology | volume = 161 | issue = 5 | pages = 1657–67 | date = Nov 2002 | pmid = 12414513 | doi = 10.1016/S0002-9440(10)64443-4 | pmc=1850798}}</ref><ref name="ReferenceH">{{cite journal | vauthors = Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C | title = Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 14 | issue = 1 | pages = 108–19 | date = Jan 2005 | pmid = 15668483 }}</ref><ref name="ReferenceI">{{cite journal | vauthors = Safaee M, Clark AJ, Oh MC, Ivan ME, Bloch O, Kaur G, Sun MZ, Kim JM, Oh T, Berger MS, Parsa AT | title = Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e62765 | date = 2013 | pmid = 23658650 | doi = 10.1371/journal.pone.0062765 | pmc=3637305}}</ref><ref name="Liu JK 2014">{{cite journal | vauthors = Liu JK, Lubelski D, Schonberg DL, Wu Q, Hale JS, Flavahan WA, Mulkearns-Hubert EE, Man J, Hjelmeland AB, Yu J, Lathia JD, Rich JN | title = Phage display discovery of novel molecular targets in glioblastoma-initiating cells | journal = Cell Death and Differentiation | volume = 21 | issue = 8 | pages = 1325–39 | date = Aug 2014 | pmid = 24832468 | doi = 10.1038/cdd.2014.65 | pmc=4085538}}</ref><ref>{{cite journal | vauthors = Safaee M, Fakurnejad S, Bloch O, Clark AJ, Ivan ME, Sun MZ, Oh T, Phillips JJ, Parsa AT | title = Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells | journal = PLOS ONE | volume = 10 | issue = 2 | pages = e0111532 | date = 2015 | pmid = 25714433 | doi = 10.1371/journal.pone.0111532 | pmc=4340952}}</ref> In addition, enhanced CD97 expression has been found at the invasion front of tumors,<ref name="ReferenceJ">{{cite journal | vauthors = Wobus M, Huber O, Hamann J, Aust G | title = CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway | journal = Molecular Carcinogenesis | volume = 45 | issue = 11 | pages = 881–6 | date = Nov 2006 | pmid = 16929497 | doi = 10.1002/mc.20262 }}</ref> suggesting a possible role in tumor migration/invasion,<ref name="ReferenceI"/><ref name="ReferenceJ"/> and correlated with a poorer clinical prognosis.<ref name="Liu JK 2014"/><ref name="ReferenceG"/><ref name="ReferenceH"/><ref>{{cite journal | vauthors = Wu J, Lei L, Wang S, Gu D, Zhang J | title = Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma | journal = Journal of Biomedicine & Biotechnology | volume = 2012 | pages = 1–7 | date = 2012 | pmid = 22547928 | doi = 10.1155/2012/587672 | pmc=3324160}}</ref><ref>{{cite journal | vauthors = He Z, Wu H, Jiao Y, Zheng J | title = Expression and prognostic value of CD97 and its ligand CD55 in pancreatic cancer | journal = Oncology Letters | volume = 9 | issue = 2 | pages = 793–797 | date = Feb 2015 | pmid = 25624904 | doi = 10.3892/ol.2014.2751 | pmc=4301556}}</ref> CD97 has isoform-specific functions in some tumors. For instance, the small EGF(1,2,5) isoform promoted tumor invasion and metastasis in gastric carcinoma;<ref>{{cite journal | vauthors = Liu D, Trojanowicz B, Ye L, Li C, Zhang L, Li X, Li G, Zheng Y, Chen L | title = The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma | journal = PLOS ONE | volume = 7 | issue = 6 | pages = e39989 | date = 2012 | pmid = 22768192 | doi = 10.1371/journal.pone.0039989 | pmc=3386904}}</ref> the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.<ref>{{cite journal | vauthors = Liu D, Trojanowicz B, Radestock Y, Fu T, Hammje K, Chen L, Hoang-Vu C | title = Role of CD97 isoforms in gastric carcinoma | journal = International Journal of Oncology | volume = 36 | issue = 6 | pages = 1401–8 | date = Jun 2010 | pmid = 20428763 | doi = 10.3892/ijo_00000625 }}</ref>


Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.<ref>{{cite journal | vauthors = Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M, Aust G | title = Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion | journal = The American Journal of Pathology | volume = 169 | issue = 5 | pages = 1802–11 | date = Nov 2006 | pmid = 17071601 | doi = 10.2353/ajpath.2006.060006 | pmc=1780199}}</ref> Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.<ref>{{cite journal | vauthors = Lu YY, Sweredoski MJ, Huss D, Lansford R, Hess S, Tirrell DA | title = Prometastatic GPCR CD97 is a direct target of tumor suppressor microRNA-126 | journal = ACS Chemical Biology | volume = 9 | issue = 2 | pages = 334–8 | date = Feb 2014 | pmid = 24274104 | doi = 10.1021/cb400704n | pmc=3944050}}</ref> CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.<ref name="Ward Y 2012"/><ref>{{cite journal | vauthors = Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K | title = LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells | journal = Cancer Research | volume = 71 | issue = 23 | pages = 7301–11 | date = Dec 2011 | pmid = 21978933 | doi = 10.1158/0008-5472.CAN-11-2381 }}</ref> It has been shown that CD97 regulates localization and degradation of β-catenin.<ref name="ReferenceC"/> GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes.<ref>{{cite journal | vauthors = Wong NA, Pignatelli M | title = Beta-catenin--a linchpin in colorectal carcinogenesis? | journal = The American Journal of Pathology | volume = 160 | issue = 2 | pages = 389–401 | date = Feb 2002 | pmid = 11839557 | doi=10.1016/s0002-9440(10)64856-0 | pmc=1850660}}</ref><ref>{{cite journal | vauthors = Takahashi-Yanaga F, Sasaguri T | title = GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy | journal = Cellular Signalling | volume = 20 | issue = 4 | pages = 581–9 | date = Apr 2008 | pmid = 18023328 | doi = 10.1016/j.cellsig.2007.10.018 }}</ref> Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone.<ref>{{cite journal | vauthors = Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G | title = Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues | journal = The American Journal of Pathology | volume = 161 | issue = 5 | pages = 1657–67 | date = Nov 2002 | pmid = 12414513 | doi = 10.1016/S0002-9440(10)64443-4 | pmc=1850798}}</ref><ref>{{cite journal | vauthors = Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C | title = Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 14 | issue = 1 | pages = 108–19 | date = Jan 2005 | pmid = 15668483 }}</ref><ref>{{cite journal | vauthors = Park JW, Zarnegar R, Kanauchi H, Wong MG, Hyun WC, Ginzinger DG, Lobo M, Cotter P, Duh QY, Clark OH | title = Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines | journal = Thyroid | volume = 15 | issue = 3 | pages = 222–31 | date = Mar 2005 | pmid = 15785241 | doi = 10.1089/thy.2005.15.222 }}</ref> Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress.
Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.<ref>{{cite journal | vauthors = Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M, Aust G | title = Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion | journal = The American Journal of Pathology | volume = 169 | issue = 5 | pages = 1802–11 | date = Nov 2006 | pmid = 17071601 | doi = 10.2353/ajpath.2006.060006 | pmc=1780199}}</ref> Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.<ref>{{cite journal | vauthors = Lu YY, Sweredoski MJ, Huss D, Lansford R, Hess S, Tirrell DA | title = Prometastatic GPCR CD97 is a direct target of tumor suppressor microRNA-126 | journal = ACS Chemical Biology | volume = 9 | issue = 2 | pages = 334–8 | date = Feb 2014 | pmid = 24274104 | doi = 10.1021/cb400704n | pmc=3944050}}</ref> CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.<ref name="Ward Y 2012"/><ref name="ReferenceD"/> It has been shown that CD97 regulates localization and degradation of β-catenin.<ref name="ReferenceC"/> GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes.<ref>{{cite journal | vauthors = Wong NA, Pignatelli M | title = Beta-catenin--a linchpin in colorectal carcinogenesis? | journal = The American Journal of Pathology | volume = 160 | issue = 2 | pages = 389–401 | date = Feb 2002 | pmid = 11839557 | doi=10.1016/s0002-9440(10)64856-0 | pmc=1850660}}</ref><ref>{{cite journal | vauthors = Takahashi-Yanaga F, Sasaguri T | title = GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy | journal = Cellular Signalling | volume = 20 | issue = 4 | pages = 581–9 | date = Apr 2008 | pmid = 18023328 | doi = 10.1016/j.cellsig.2007.10.018 }}</ref> Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone.<ref name="ReferenceG"/><ref name="ReferenceH"/><ref>{{cite journal | vauthors = Park JW, Zarnegar R, Kanauchi H, Wong MG, Hyun WC, Ginzinger DG, Lobo M, Cotter P, Duh QY, Clark OH | title = Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines | journal = Thyroid | volume = 15 | issue = 3 | pages = 222–31 | date = Mar 2005 | pmid = 15785241 | doi = 10.1089/thy.2005.15.222 }}</ref> Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress.


== References ==
== References ==
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{{G protein-coupled receptors}}
{{G protein-coupled receptors}}


[[Category:G protein coupled receptors]]
[[Category:G protein-coupled receptors]]

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Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene.[1][2][3][4] CD97 is a member of the adhesion GPCR family.[5][6] Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[7]

CD97 is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle cells as well as their malignant counterparts.[8][9][10][11][12][13] In the case of CD97 the N-terminal domains consist of alternatively spliced epidermal growth factor (EGF)-like domains. Alternative splicing has been observed for this gene and three variants have been found.[3] The N-terminal fragment of CD97 contains 3-5 EGF-like domains in human and 3-4 EGF-like domains in mice.[14]

Ligands

Decay accelerating factor (DAF/CD55), a regulatory protein of the complement cascade, interacts with the first and second EGF-like domains of CD97;[15] chondroitin sulfate B with the fourth EGF-like domain;[16] α5β1 and αvβ3 integrins with an RGD downstream the EGF-like domains;[17] and CD90 (Thy-1) with the GAIN domain.[18] N-glycosylation of CD97 within the EGF domains is crucial for CD55 binding.[19]

Signaling

Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt.[20] Furthermore, ectopic CD97 expression facilitated RhoA activation through binding of Gα12/13 as well as induced Ki67 expression and phosphorylated ERK and Akt through enhancing lysophosphatidic acid receptor 1 (LPAR1) signaling.[21][22] Lysophosphatidylethanolamine (LPE; a plasma membrane component) and lysophosphatidic acid (LPA) use heterodimeric LPAR1–CD97 to drive Gi/o protein–phospholipase C–inositol 1,4,5-trisphosphate signaling and induce [Ca2+] in breast cancer cells.[23]

Function

In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation.[24] Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Mice lacking CD97 or its ligand CD55 have twice as many granulocytes as wild-type mice possibly due to enhanced granulopoiesis.[25] Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes.[26] Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism.[27] Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.[28][29]

Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. The expression of CD97 on macrophage and the abundant presence of its ligand CD55 on fibroblast-like synovial cells suggest that the CD97-CD55 interaction is involved in the recruitment and/or retention of macrophages into the synovial tissue in rheumatoid arthritis.[30] CD97 antibodies and lack of CD97 or CD55 in mice reduced synovial inflammation and joint damage in collagen- and K/BxN serum transfer-induced arthritis.[31][32] In brain tissue, CD97 is undetectable in normal white matter, and expression of CD55 is fairly restricted to the endothelium. In pre-active lesion, increased expression of CD55 in endothelial cells and robust CD97 expression on infiltrating leukocytes suggest a possible role of both molecules in immune cell migration through the blood-brain barrier.[33] Additionally, soluble N-terminal fragment (NTF)s of CD97 are detectable in the serum of patients with rheumatoid arthritis and multiple sclerosis.[30]

Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 in colonic enterocytes strengthens E-cadherin-based adherens junctions to maintain lateral cell-cell contacts and regulates the localization and degradation of β-catenin through glycogen synthase kinase-3β (GSK-3β) and Akt signaling.[20] Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation.[34] CD97 is expressed at the sarcoplasmic reticulum and the peripheral sarcolemma in skeletal muscle. However, lack of CD97 only affects the structure of the sarcoplasmic reticulum, but not the function of skeletal muscle.[13] In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.[17]

Clinical significance

CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases.[35] CD97 is expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells.[35][36][37][38][39][40][41] In addition, enhanced CD97 expression has been found at the invasion front of tumors,[42] suggesting a possible role in tumor migration/invasion,[39][42] and correlated with a poorer clinical prognosis.[40][37][38][43][44] CD97 has isoform-specific functions in some tumors. For instance, the small EGF(1,2,5) isoform promoted tumor invasion and metastasis in gastric carcinoma;[45] the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.[46]

Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.[47] Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.[48] CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.[22][21] It has been shown that CD97 regulates localization and degradation of β-catenin.[20] GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes.[49][50] Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone.[37][38][51] Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress.

References

  1. ↑ Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ, Hoovers JM, Hartmann E, Strauss M, van Lier RA (Aug 1995). "Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain". Journal of Immunology. 155 (4): 1942–50. PMID 7636245.
  2. ↑ Hamann J, Hartmann E, van Lier RA (Feb 1996). "Structure of the human CD97 gene: exon shuffling has generated a new type of seven-span transmembrane molecule related to the secretin receptor superfamily". Genomics. 32 (1): 144–7. doi:10.1006/geno.1996.0092. PMID 8786105.
  3. ↑ 3.0 3.1 "Entrez Gene: CD97 CD97 molecule".
  4. ↑ Hamann, J; Aust, G; Araç, D; Engel, FB; Formstone, C; Fredriksson, R; Hall, RA; Harty, BL; Kirchhoff, C; Knapp, B; Krishnan, A; Liebscher, I; Lin, HH; Martinelli, DC; Monk, KR; Peeters, MC; Piao, X; Prömel, S; Schöneberg, T; Schwartz, TW; Singer, K; Stacey, M; Ushkaryov, YA; Vallon, M; Wolfrum, U; Wright, MW; Xu, L; Langenhan, T; Schiöth, HB (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–67. doi:10.1124/pr.114.009647. PMC 4394687. PMID 25713288.
  5. ↑ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN 978-1-4419-7912-4.
  6. ↑ Langenhan, T; Aust, G; Hamann, J (21 May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling. 6 (276): re3. doi:10.1126/scisignal.2003825. PMID 23695165.
  7. ↑ Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT (Mar 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal. 31 (6): 1364–78. doi:10.1038/emboj.2012.26. PMC 3321182. PMID 22333914.
  8. ↑ van Pel M, Hagoort H, Hamann J, Fibbe WE (Aug 2008). "CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells". Haematologica. 93 (8): 1137–44. doi:10.3324/haematol.12838. PMID 18603564.
  9. ↑ Eichler W, Hamann J, Aust G (Nov 1997). "Expression characteristics of the human CD97 antigen". Tissue Antigens. 50 (5): 429–38. doi:10.1111/j.1399-0039.1997.tb02897.x. PMID 9389316.
  10. ↑ Jaspars LH, Vos W, Aust G, Van Lier RA, Hamann J (Apr 2001). "Tissue distribution of the human CD97 EGF-TM7 receptor". Tissue Antigens. 57 (4): 325–31. doi:10.1034/j.1399-0039.2001.057004325.x. PMID 11380941.
  11. ↑ Aust G, Wandel E, Boltze C, Sittig D, Schütz A, Horn LC, Wobus M (Apr 2006). "Diversity of CD97 in smooth muscle cells". Cell and Tissue Research. 324 (1): 139–47. doi:10.1007/s00441-005-0103-2. PMID 16408199.
  12. ↑ Veninga H, Becker S, Hoek RM, Wobus M, Wandel E, van der Kaa J, van der Valk M, de Vos AF, Haase H, Owens B, van der Poll T, van Lier RA, Verbeek JS, Aust G, Hamann J (Nov 2008). "Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration". Journal of Immunology. 181 (9): 6574–83. doi:10.4049/jimmunol.181.9.6574. PMID 18941248.
  13. ↑ 13.0 13.1 Zyryanova T, Schneider R, Adams V, Sittig D, Kerner C, Gebhardt C, Ruffert H, Glasmacher S, Hepp P, Punkt K, Neuhaus J, Hamann J, Aust G (2014). "Skeletal muscle expression of the adhesion-GPCR CD97: CD97 deletion induces an abnormal structure of the sarcoplasmatic reticulum but does not impair skeletal muscle function". PLOS ONE. 9 (6): e100513. doi:10.1371/journal.pone.0100513. PMC 4065095. PMID 24949957.
  14. ↑ Gordon S, Hamann J, Lin HH, Stacey M (Sep 2011). "F4/80 and the related adhesion-GPCRs". European Journal of Immunology. 41 (9): 2472–6. doi:10.1002/eji.201141715. PMID 21952799.
  15. ↑ Hamann J, Stortelers C, Kiss-Toth E, Vogel B, Eichler W, van Lier RA (May 1998). "Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97". European Journal of Immunology. 28 (5): 1701–7. doi:10.1002/(SICI)1521-4141(199805)28:05<1701::AID-IMMU1701>3.0.CO;2-2. PMID 9603477.
  16. ↑ Hamann J, Vogel B, van Schijndel GM, van Lier RA (Sep 1996). "The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF)". The Journal of Experimental Medicine. 184 (3): 1185–9. doi:10.1084/jem.184.3.1185. PMC 2192782. PMID 9064337.
  17. ↑ 17.0 17.1 Wang T, Ward Y, Tian L, Lake R, Guedez L, Stetler-Stevenson WG, Kelly K (Apr 2005). "CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells". Blood. 105 (7): 2836–44. doi:10.1182/blood-2004-07-2878. PMID 15576472.
  18. ↑ Wandel E, Saalbach A, Sittig D, Gebhardt C, Aust G (Feb 2012). "Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells". Journal of Immunology. 188 (3): 1442–50. doi:10.4049/jimmunol.1003944. PMID 22210915.
  19. ↑ Wobus M, Vogel B, Schmücking E, Hamann J, Aust G (Dec 2004). "N-glycosylation of CD97 within the EGF domains is crucial for epitope accessibility in normal and malignant cells as well as CD55 ligand binding". International Journal of Cancer. 112 (5): 815–22. doi:10.1002/ijc.20483. PMID 15386373.
  20. ↑ 20.0 20.1 20.2 Becker S, Wandel E, Wobus M, Schneider R, Amasheh S, Sittig D, Kerner C, Naumann R, Hamann J, Aust G (13 January 2010). "Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions". PLOS ONE. 5 (1): e8507. doi:10.1371/journal.pone.0008507. PMC 2801611. PMID 20084281.
  21. ↑ 21.0 21.1 Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K (Dec 2011). "LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells". Cancer Research. 71 (23): 7301–11. doi:10.1158/0008-5472.CAN-11-2381. PMID 21978933.
  22. ↑ 22.0 22.1 Ward Y, Lake R, Martin PL, Killian K, Salerno P, Wang T, Meltzer P, Merino M, Cheng SY, Santoro M, Garcia-Rostan G, Kelly K (May 2013). "CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model". Oncogene. 32 (22): 2726–38. doi:10.1038/onc.2012.301. hdl:10261/116503. PMID 22797060.
  23. ↑ Park SJ, Lee KP, Kang S, Chung HY, Bae YS, Okajima F, Im DS (Nov 2013). "Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells". Cellular Signalling. 25 (11): 2147–54. doi:10.1016/j.cellsig.2013.07.001. PMID 23838008.
  24. ↑ Leemans JC, te Velde AA, Florquin S, Bennink RJ, de Bruin K, van Lier RA, van der Poll T, Hamann J (Jan 2004). "The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense". Journal of Immunology. 172 (2): 1125–31. doi:10.4049/jimmunol.172.2.1125. PMID 14707087.
  25. ↑ Veninga H, Hoek RM, de Vos AF, de Bruin AM, An FQ, van der Poll T, van Lier RA, Medof ME, Hamann J (2011). "A novel role for CD55 in granulocyte homeostasis and anti-bacterial host defense". PLOS ONE. 6 (10): e24431. doi:10.1371/journal.pone.0024431. PMC 3184942. PMID 21984892.
  26. ↑ Hamann J, Veninga H, de Groot DM, Visser L, Hofstra CL, Tak PP, Laman JD, Boots AM, van Eenennaam H (2010). CD97 in leukocyte trafficking. Advances in Experimental Medicine and Biology. 706. pp. 128–37. doi:10.1007/978-1-4419-7913-1_11. ISBN 978-1-4419-7912-4. PMID 21618832.
  27. ↑ Veninga H, de Groot DM, McCloskey N, Owens BM, Dessing MC, Verbeek JS, Nourshargh S, van Eenennaam H, Boots AM, Hamann J (Mar 2011). "CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism". Journal of Leukocyte Biology. 89 (3): 413–21. doi:10.1189/jlb.0510280. PMID 21169517.
  28. ↑ Capasso M, Durrant LG, Stacey M, Gordon S, Ramage J, Spendlove I (Jul 2006). "Costimulation via CD55 on human CD4+ T cells mediated by CD97". Journal of Immunology. 177 (2): 1070–7. doi:10.4049/jimmunol.177.2.1070. PMID 16818763.
  29. ↑ Abbott RJ, Spendlove I, Roversi P, Fitzgibbon H, Knott V, Teriete P, McDonnell JM, Handford PA, Lea SM (Jul 2007). "Structural and functional characterization of a novel T cell receptor co-regulatory protein complex, CD97-CD55". The Journal of Biological Chemistry. 282 (30): 22023–32. doi:10.1074/jbc.M702588200. PMID 17449467.
  30. ↑ 30.0 30.1 Hamann J, Wishaupt JO, van Lier RA, Smeets TJ, Breedveld FC, Tak PP (Apr 1999). "Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue". Arthritis and Rheumatism. 42 (4): 650–8. doi:10.1002/1529-0131(199904)42:4<650::AID-ANR7>3.0.CO;2-S. PMID 10211878.
  31. ↑ Kop EN, Adriaansen J, Smeets TJ, Vervoordeldonk MJ, van Lier RA, Hamann J, Tak PP (2006). "CD97 neutralisation increases resistance to collagen-induced arthritis in mice". Arthritis Research & Therapy. 8 (5): R155. doi:10.1186/ar2049. PMC 1779430. PMID 17007638.
  32. ↑ Hoek RM, de Launay D, Kop EN, Yilmaz-Elis AS, Lin F, Reedquist KA, Verbeek JS, Medof ME, Tak PP, Hamann J (Apr 2010). "Deletion of either CD55 or CD97 ameliorates arthritis in mouse models". Arthritis and Rheumatism. 62 (4): 1036–42. doi:10.1002/art.27347. PMID 20131275.
  33. ↑ Visser L, de Vos AF, Hamann J, Melief MJ, van Meurs M, van Lier RA, Laman JD, Hintzen RQ (Nov 2002). "Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis". Journal of Neuroimmunology. 132 (1–2): 156–63. doi:10.1016/s0165-5728(02)00306-5. PMID 12417446.
  34. ↑ Hsiao CC, Chen HY, Chang GW, Lin HH (Jan 2011). "GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation". FEBS Letters. 585 (2): 313–8. doi:10.1016/j.febslet.2010.12.005. PMID 21156175.
  35. ↑ 35.0 35.1 Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C (May 1997). "CD97: a dedifferentiation marker in human thyroid carcinomas". Cancer Research. 57 (9): 1798–806. PMID 9135025.
  36. ↑ Aust G, Steinert M, Schütz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M (Nov 2002). "CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas". American Journal of Clinical Pathology. 118 (5): 699–707. doi:10.1309/A6AB-VF3F-7M88-C0EJ. PMID 12428789.
  37. ↑ 37.0 37.1 37.2 Steinert M, Wobus M, Boltze C, Schütz A, Wahlbuhl M, Hamann J, Aust G (Nov 2002). "Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues". The American Journal of Pathology. 161 (5): 1657–67. doi:10.1016/S0002-9440(10)64443-4. PMC 1850798. PMID 12414513.
  38. ↑ 38.0 38.1 38.2 Mustafa T, Eckert A, Klonisch T, Kehlen A, Maurer P, Klintschar M, Erhuma M, Zschoyan R, Gimm O, Dralle H, Schubert J, Hoang-Vu C (Jan 2005). "Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas". Cancer Epidemiology, Biomarkers & Prevention. 14 (1): 108–19. PMID 15668483.
  39. ↑ 39.0 39.1 Safaee M, Clark AJ, Oh MC, Ivan ME, Bloch O, Kaur G, Sun MZ, Kim JM, Oh T, Berger MS, Parsa AT (2013). "Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients". PLOS ONE. 8 (4): e62765. doi:10.1371/journal.pone.0062765. PMC 3637305. PMID 23658650.
  40. ↑ 40.0 40.1 Liu JK, Lubelski D, Schonberg DL, Wu Q, Hale JS, Flavahan WA, Mulkearns-Hubert EE, Man J, Hjelmeland AB, Yu J, Lathia JD, Rich JN (Aug 2014). "Phage display discovery of novel molecular targets in glioblastoma-initiating cells". Cell Death and Differentiation. 21 (8): 1325–39. doi:10.1038/cdd.2014.65. PMC 4085538. PMID 24832468.
  41. ↑ Safaee M, Fakurnejad S, Bloch O, Clark AJ, Ivan ME, Sun MZ, Oh T, Phillips JJ, Parsa AT (2015). "Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells". PLOS ONE. 10 (2): e0111532. doi:10.1371/journal.pone.0111532. PMC 4340952. PMID 25714433.
  42. ↑ 42.0 42.1 Wobus M, Huber O, Hamann J, Aust G (Nov 2006). "CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway". Molecular Carcinogenesis. 45 (11): 881–6. doi:10.1002/mc.20262. PMID 16929497.
  43. ↑ Wu J, Lei L, Wang S, Gu D, Zhang J (2012). "Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma". Journal of Biomedicine & Biotechnology. 2012: 1–7. doi:10.1155/2012/587672. PMC 3324160. PMID 22547928.
  44. ↑ He Z, Wu H, Jiao Y, Zheng J (Feb 2015). "Expression and prognostic value of CD97 and its ligand CD55 in pancreatic cancer". Oncology Letters. 9 (2): 793–797. doi:10.3892/ol.2014.2751. PMC 4301556. PMID 25624904.
  45. ↑ Liu D, Trojanowicz B, Ye L, Li C, Zhang L, Li X, Li G, Zheng Y, Chen L (2012). "The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma". PLOS ONE. 7 (6): e39989. doi:10.1371/journal.pone.0039989. PMC 3386904. PMID 22768192.
  46. ↑ Liu D, Trojanowicz B, Radestock Y, Fu T, Hammje K, Chen L, Hoang-Vu C (Jun 2010). "Role of CD97 isoforms in gastric carcinoma". International Journal of Oncology. 36 (6): 1401–8. doi:10.3892/ijo_00000625. PMID 20428763.
  47. ↑ Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M, Aust G (Nov 2006). "Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion". The American Journal of Pathology. 169 (5): 1802–11. doi:10.2353/ajpath.2006.060006. PMC 1780199. PMID 17071601.
  48. ↑ Lu YY, Sweredoski MJ, Huss D, Lansford R, Hess S, Tirrell DA (Feb 2014). "Prometastatic GPCR CD97 is a direct target of tumor suppressor microRNA-126". ACS Chemical Biology. 9 (2): 334–8. doi:10.1021/cb400704n. PMC 3944050. PMID 24274104.
  49. ↑ Wong NA, Pignatelli M (Feb 2002). "Beta-catenin--a linchpin in colorectal carcinogenesis?". The American Journal of Pathology. 160 (2): 389–401. doi:10.1016/s0002-9440(10)64856-0. PMC 1850660. PMID 11839557.
  50. ↑ Takahashi-Yanaga F, Sasaguri T (Apr 2008). "GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy". Cellular Signalling. 20 (4): 581–9. doi:10.1016/j.cellsig.2007.10.018. PMID 18023328.
  51. ↑ Park JW, Zarnegar R, Kanauchi H, Wong MG, Hyun WC, Ginzinger DG, Lobo M, Cotter P, Duh QY, Clark OH (Mar 2005). "Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines". Thyroid. 15 (3): 222–31. doi:10.1089/thy.2005.15.222. PMID 15785241.

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