Research progress of epithelial membrane protein 2 in tumor invasion and metastasis_West China Medical Journal

Authors：

 ZHANG Yu

Sichuan Clinical Research Center for Radiation and Therapy / Department of Oncology, Mianyang Central Hospital, Mianyang, Sichuan 621000, P. R. China;

Corresponding author：

ZHANG Yu, Email: 543703371@qq.com

Keywords：

Epithelial membrane protein 2; tumor metastasis; target

DOI：

10.7507/1002-0179.202307060

Video：

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Epithelial membrane protein (EMP) 2 is one of the seven proteins in the EMP gene family and is a tissue-specific transmembrane protein. Recent studies have shown that it exhibits different expression patterns in different tumor tissues and exhibits differentiated manifestations in the invasion and metastasis of different tumors, such as promoting or inhibiting them. Based on these characteristics, progress has been made in the field of anti EMP2 therapy, such as the development of monoclonal antibodies, which may bring new avenues for cancer treatment. Based on this, this article reviews the research progress of EMP2 in tumor invasion and metastasis, in order to provide ideas for determining new tumor targets.

Citation： ZHANG Yu. Research progress of epithelial membrane protein 2 in tumor invasion and metastasis. West China Medical Journal, 2023, 38(12): 1940-1943. doi: 10.7507/1002-0179.202307060 Copy

1.	Steeg PS. Targeting metastasis. Nat Rev Cancer, 2016, 16(4): 201-218.
2.	Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer, 2006, 6(6): 449-458.
3.	Ganesh K, Massagué J. Targeting metastatic cancer. Nat Med, 2021, 27(1): 34-44.
4.	Brosnan JA, Iacobuzio-Donahue CA. A new branch on the tree: next-generation sequencing in the study of cancer evolution. Semin Cell Dev Biol, 2012, 23(2): 237-242.
5.	Bacac M, Stamenkovic I. Metastatic cancer cell. Annu Rev Pathol, 2008, 3: 221-247.
6.	Hosseini H, Obradović MMS, Hoffmann M, et al. Early dissemination seeds metastasis in breast cancer. Nature, 2016, 540(7634): 552-558.
7.	Harper KL, Sosa MS, Entenberg D, et al. Mechanism of early dissemination and metastasis in Her2⁺ mammary cancer. Nature, 2016, 540(7634): 588-592.
8.	Hu Z, Curtis C. Looking backward in time to define the chronology of metastasis. Nat Commun, 2020, 11(1): 3213.
9.	Ben-Porath I, Kozak CA, Benvenisty N. Chromosomal mapping of Tmp ( Emp1), Xmp ( Emp2), and Ymp ( Emp3), genes encoding membrane proteins related to PMP22. Genomics, 1998, 49(3): 443-447.
10.	Wadehra M, Sulur GG, Braun J, et al. Epithelial membrane protein-2 is expressed in discrete anatomical regions of the eye. Exp Mol Pathol, 2003, 74(2): 106-112.
11.	Wright MD, Tomlinson MG. The ins and outs of the transmembrane 4 superfamily. Immunol Today, 1994, 15(12): 588-594.
12.	Stipp CS, Kolesnikova TV, Hemler ME. Functional domains in tetraspanin proteins. Trends Biochem Sci, 2003, 28(2): 106-112.
13.	Jetten AM, Suter U. The peripheral myelin protein 22 and epithelial membrane protein family. Prog Nucleic Acid Res Mol Biol, 2000, 64: 97-129.
14.	Ben-Porath I, Benvenisty N. Characterization of a tumor-associated gene, a member of a novel family of genes encoding membrane glycoproteins. Gene, 1996, 183(1/2): 69-75.
15.	Qin Y, Fu M, Takahashi M, et al. Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma. J Biol Chem, 2014, 289(20): 13974-13985.
16.	Taylor V, Suter U. Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family. Gene, 1996, 175(1/2): 115-120.
17.	Wadehra M, Iyer R, Goodglick L, et al. The tetraspan protein epithelial membrane protein-2 interacts with beta1 integrins and regulates adhesion. J Biol Chem, 2002, 277(43): 41094-41100.
18.	Wadehra M, Su H, Gordon LK, et al. The tetraspan protein EMP2 increases surface expression of class I major histocompatibility complex proteins and susceptibility to CTL-mediated cell death. Clin Immunol, 2003, 107(2): 129-136.
19.	Wadehra M, Goodglick L, Braun J. The tetraspan protein EMP2 modulates the surface expression of caveolins and glycosylphosphatidyl inositol-linked proteins. Mol Biol Cell, 2004, 15(5): 2073-2083.
20.	Wadehra M, Forbes A, Pushkarna N, et al. Epithelial membrane protein-2 regulates surface expression of alphavbeta3 integrin in the endometrium. Dev Biol, 2005, 287(2): 336-345.
21.	Wadehra M, Dayal M, Mainigi M, et al. Knockdown of the tetraspan protein epithelial membrane protein-2 inhibits implantation in the mouse. Dev Biol, 2006, 292(2): 430-441.
22.	Morales SA, Mareninov S, Wadehra M, et al. FAK activation and the role of epithelial membrane protein 2 (EMP2) in collagen gel contraction. Invest Ophthalmol Vis Sci, 2009, 50(1): 462-469.
23.	Chung LK, Pelargos PE, Chan AM, et al. Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas. Brain Tumor Pathol, 2018, 35(1): 1-9.
24.	Freije WA, Castro-Vargas FE, Fang Z, et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res, 2004, 64(18): 6503-6510.
25.	Qin Y, Takahashi M, Sheets K, et al. Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme. J Neurooncol, 2017, 134(1): 29-40.
26.	Ganguly D, Fan M, Yang CH, et al. The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma. Oncotarget, 2018, 9(31): 22095-22112.
27.	Kao J, Salari K, Bocanegra M, et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One, 2009, 4(7): e6146.
28.	Li Y, Wang Y. Bioinformatics analysis of gene expression data for the identification of critical genes in breast invasive carcinoma. Mol Med Rep, 2017, 16(6): 8657-8664.
29.	Ma XJ, Dahiya S, Richardson E, et al. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res, 2009, 11(1): R7.
30.	Watson MA, Ylagan LR, Trinkaus KM, et al. Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clin Cancer Res, 2007, 13(17): 5001-5009.
31.	Fu M, Maresh EL, Helguera GF, et al. Rationale and preclinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer. Mol Cancer Ther, 2014, 13(4): 902-915.
32.	Obermayr E, Sanchez-Cabo F, Tea MK, et al. Assessment of a six gene panel for the molecular detection of circulating tumor cells in the blood of female cancer patients. BMC Cancer, 2010, 10: 666.
33.	Christgen M, Geffers R, Kreipe H, et al. IPH-926 lobular breast cancer cells are triple-negative but their microarray profile uncovers a luminal subtype. Cancer Sci, 2013, 104(12): 1726-1730.
34.	Chen Q, Yao L, Burner D, et al. Epithelial membrane protein 2: a novel biomarker for circulating tumor cell recovery in breast cancer. Clin Transl Oncol, 2019, 21(4): 433-442.
35.	Murlidhar V, Reddy RM, Fouladdel S, et al. Poor prognosis indicated by venous circulating tumor cell clusters in early-stage lung cancers. Cancer Res, 2017, 77(18): 5194-5206.
36.	El-Ghlban S, AbouElnour ES, El-Torgoman AEAE, et al. Gene expression of epithelial membrane protein 2 gene and β1-Integrin gene in patients with breast cancer. Biochem Biophys Rep, 2019, 22: 100708.
37.	Fu M, Maresh EL, Soslow RA, et al. Epithelial membrane protein-2 is a novel therapeutic target in ovarian cancer. Clin Cancer Res, 2010, 16(15): 3954-3963.
38.	Fu M, Rao R, Sudhakar D, et al. Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src. PLoS One, 2011, 6(5): e19945.
39.	Gordon LK, Kiyohara M, Fu M, et al. EMP2 regulates angiogenesis in endometrial cancer cells through induction of VEGF. Oncogene, 2013, 32(46): 5369-5376.
40.	Kiyohara MH, Dillard C, Tsui J, et al. EMP2 is a novel therapeutic target for endometrial cancer stem cells. Oncogene, 2017, 36(42): 5793-5807.
41.	Habeeb O, Goodglick L, Soslow RA, et al. Epithelial membrane protein-2 expression is an early predictor of endometrial cancer development. Cancer, 2010, 116(20): 4718-4726.
42.	Tang M, Liu RY, Zhou C, et al. EMP2re-expressioninhibits growth and enhances radiosensitivity in nasopharyngeal carcinoma. Tumour Biol, 2017, 39(3): 1010428317695972.
43.	Wang M, Li S, Zhang P, et al. EMP2 acts as a suppressor of melanoma and is negatively regulated by mTOR-mediated autophagy. J Cancer, 2019, 10(16): 3582-3592.
44.	Wang YW, Li WM, Wu WJ, et al. Epithelial membrane protein 2 is a prognostic indictor for patients with urothelial carcinoma of the upper urinary tract. Am J Pathol, 2013, 183(3): 709-719.
45.	Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature, 2019, 575(7782): 299-309.
46.	Shimazaki K, Lepin EJ, Wei B, et al. Diabodies targeting epithelial membrane protein 2 reduce tumorigenicity of human endometrial cancer cell lines. Clin Cancer Res, 2008, 14(22): 7367-7377.

1. Steeg PS. Targeting metastasis. Nat Rev Cancer, 2016, 16(4): 201-218.
2. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer, 2006, 6(6): 449-458.
3. Ganesh K, Massagué J. Targeting metastatic cancer. Nat Med, 2021, 27(1): 34-44.
4. Brosnan JA, Iacobuzio-Donahue CA. A new branch on the tree: next-generation sequencing in the study of cancer evolution. Semin Cell Dev Biol, 2012, 23(2): 237-242.
5. Bacac M, Stamenkovic I. Metastatic cancer cell. Annu Rev Pathol, 2008, 3: 221-247.
6. Hosseini H, Obradović MMS, Hoffmann M, et al. Early dissemination seeds metastasis in breast cancer. Nature, 2016, 540(7634): 552-558.
7. Harper KL, Sosa MS, Entenberg D, et al. Mechanism of early dissemination and metastasis in Her2⁺ mammary cancer. Nature, 2016, 540(7634): 588-592.
8. Hu Z, Curtis C. Looking backward in time to define the chronology of metastasis. Nat Commun, 2020, 11(1): 3213.
9. Ben-Porath I, Kozak CA, Benvenisty N. Chromosomal mapping of Tmp ( Emp1), Xmp ( Emp2), and Ymp ( Emp3), genes encoding membrane proteins related to PMP22. Genomics, 1998, 49(3): 443-447.
10. Wadehra M, Sulur GG, Braun J, et al. Epithelial membrane protein-2 is expressed in discrete anatomical regions of the eye. Exp Mol Pathol, 2003, 74(2): 106-112.
11. Wright MD, Tomlinson MG. The ins and outs of the transmembrane 4 superfamily. Immunol Today, 1994, 15(12): 588-594.
12. Stipp CS, Kolesnikova TV, Hemler ME. Functional domains in tetraspanin proteins. Trends Biochem Sci, 2003, 28(2): 106-112.
13. Jetten AM, Suter U. The peripheral myelin protein 22 and epithelial membrane protein family. Prog Nucleic Acid Res Mol Biol, 2000, 64: 97-129.
14. Ben-Porath I, Benvenisty N. Characterization of a tumor-associated gene, a member of a novel family of genes encoding membrane glycoproteins. Gene, 1996, 183(1/2): 69-75.
15. Qin Y, Fu M, Takahashi M, et al. Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma. J Biol Chem, 2014, 289(20): 13974-13985.
16. Taylor V, Suter U. Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family. Gene, 1996, 175(1/2): 115-120.
17. Wadehra M, Iyer R, Goodglick L, et al. The tetraspan protein epithelial membrane protein-2 interacts with beta1 integrins and regulates adhesion. J Biol Chem, 2002, 277(43): 41094-41100.
18. Wadehra M, Su H, Gordon LK, et al. The tetraspan protein EMP2 increases surface expression of class I major histocompatibility complex proteins and susceptibility to CTL-mediated cell death. Clin Immunol, 2003, 107(2): 129-136.
19. Wadehra M, Goodglick L, Braun J. The tetraspan protein EMP2 modulates the surface expression of caveolins and glycosylphosphatidyl inositol-linked proteins. Mol Biol Cell, 2004, 15(5): 2073-2083.
20. Wadehra M, Forbes A, Pushkarna N, et al. Epithelial membrane protein-2 regulates surface expression of alphavbeta3 integrin in the endometrium. Dev Biol, 2005, 287(2): 336-345.
21. Wadehra M, Dayal M, Mainigi M, et al. Knockdown of the tetraspan protein epithelial membrane protein-2 inhibits implantation in the mouse. Dev Biol, 2006, 292(2): 430-441.
22. Morales SA, Mareninov S, Wadehra M, et al. FAK activation and the role of epithelial membrane protein 2 (EMP2) in collagen gel contraction. Invest Ophthalmol Vis Sci, 2009, 50(1): 462-469.
23. Chung LK, Pelargos PE, Chan AM, et al. Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas. Brain Tumor Pathol, 2018, 35(1): 1-9.
24. Freije WA, Castro-Vargas FE, Fang Z, et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res, 2004, 64(18): 6503-6510.
25. Qin Y, Takahashi M, Sheets K, et al. Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme. J Neurooncol, 2017, 134(1): 29-40.
26. Ganguly D, Fan M, Yang CH, et al. The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma. Oncotarget, 2018, 9(31): 22095-22112.
27. Kao J, Salari K, Bocanegra M, et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One, 2009, 4(7): e6146.
28. Li Y, Wang Y. Bioinformatics analysis of gene expression data for the identification of critical genes in breast invasive carcinoma. Mol Med Rep, 2017, 16(6): 8657-8664.
29. Ma XJ, Dahiya S, Richardson E, et al. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res, 2009, 11(1): R7.
30. Watson MA, Ylagan LR, Trinkaus KM, et al. Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clin Cancer Res, 2007, 13(17): 5001-5009.
31. Fu M, Maresh EL, Helguera GF, et al. Rationale and preclinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer. Mol Cancer Ther, 2014, 13(4): 902-915.
32. Obermayr E, Sanchez-Cabo F, Tea MK, et al. Assessment of a six gene panel for the molecular detection of circulating tumor cells in the blood of female cancer patients. BMC Cancer, 2010, 10: 666.
33. Christgen M, Geffers R, Kreipe H, et al. IPH-926 lobular breast cancer cells are triple-negative but their microarray profile uncovers a luminal subtype. Cancer Sci, 2013, 104(12): 1726-1730.
34. Chen Q, Yao L, Burner D, et al. Epithelial membrane protein 2: a novel biomarker for circulating tumor cell recovery in breast cancer. Clin Transl Oncol, 2019, 21(4): 433-442.
35. Murlidhar V, Reddy RM, Fouladdel S, et al. Poor prognosis indicated by venous circulating tumor cell clusters in early-stage lung cancers. Cancer Res, 2017, 77(18): 5194-5206.
36. El-Ghlban S, AbouElnour ES, El-Torgoman AEAE, et al. Gene expression of epithelial membrane protein 2 gene and β1-Integrin gene in patients with breast cancer. Biochem Biophys Rep, 2019, 22: 100708.
37. Fu M, Maresh EL, Soslow RA, et al. Epithelial membrane protein-2 is a novel therapeutic target in ovarian cancer. Clin Cancer Res, 2010, 16(15): 3954-3963.
38. Fu M, Rao R, Sudhakar D, et al. Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src. PLoS One, 2011, 6(5): e19945.
39. Gordon LK, Kiyohara M, Fu M, et al. EMP2 regulates angiogenesis in endometrial cancer cells through induction of VEGF. Oncogene, 2013, 32(46): 5369-5376.
40. Kiyohara MH, Dillard C, Tsui J, et al. EMP2 is a novel therapeutic target for endometrial cancer stem cells. Oncogene, 2017, 36(42): 5793-5807.
41. Habeeb O, Goodglick L, Soslow RA, et al. Epithelial membrane protein-2 expression is an early predictor of endometrial cancer development. Cancer, 2010, 116(20): 4718-4726.
42. Tang M, Liu RY, Zhou C, et al. EMP2re-expressioninhibits growth and enhances radiosensitivity in nasopharyngeal carcinoma. Tumour Biol, 2017, 39(3): 1010428317695972.
43. Wang M, Li S, Zhang P, et al. EMP2 acts as a suppressor of melanoma and is negatively regulated by mTOR-mediated autophagy. J Cancer, 2019, 10(16): 3582-3592.
44. Wang YW, Li WM, Wu WJ, et al. Epithelial membrane protein 2 is a prognostic indictor for patients with urothelial carcinoma of the upper urinary tract. Am J Pathol, 2013, 183(3): 709-719.
45. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature, 2019, 575(7782): 299-309.
46. Shimazaki K, Lepin EJ, Wei B, et al. Diabodies targeting epithelial membrane protein 2 reduce tumorigenicity of human endometrial cancer cell lines. Clin Cancer Res, 2008, 14(22): 7367-7377.

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