Biomolecules & Therapeutics

  • 제32권6호
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  • Pages.697-707
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  • 2024
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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The Multifaceted Role of Epithelial Membrane Protein 2 in Cancer: from Biomarker to Therapeutic Target

  • Ji Yun Jang (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Mi Kyung Park (Department of Biomedical Science, Hwasung Medi-Science University) ;
  • Chang Hoon Lee (Pharmaceutical Biochemistry, College of Pharmacy, Dongguk University) ;
  • Ho Lee (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center)
  • 투고 : 2024.09.09
  • 심사 : 2024.10.07
  • 발행 : 2024.11.01
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초록

Tetraspanin superfamily proteins not only facilitate the trafficking of specific proteins to distinct plasma membrane domains but also influence cell-to-cell and cell-extracellular matrix interactions. Among these proteins, Epithelial Membrane Protein 2 (EMP2), a member of the growth arrest-specific gene 3/peripheral myelin protein 22 (GAS3/PMP22) family, is known to affect key cellular processes. Recent studies have revealed that EMP2 modulates critical signaling pathways and interacts with adhesion molecules and growth factor receptors, underscoring its potential as a biomarker for cancer diagnosis and prognosis. These findings suggest that EMP2 expression patterns could provide valuable insights into tumorigenesis and metastasis. Moreover, EMP2 has emerged as a promising therapeutic target, with approaches aimed at inhibiting or modulating its activity showing potential to disrupt tumor growth and metastasis. This review provides a comprehensive overview of recent advances in understanding the multifaceted roles of EMP2 in cancer, with a focus on its underlying mechanisms and clinical significance.

키워드

과제정보

This research was supported by a grant from the National Research Foundation (NRF) funded by the Ministry of Science and ICT (RS-2023-00261905 and RS-2024-00441068) and a grant from the National Cancer Center (2010271 and 2410770) of Korean government.

참고문헌

  1. Aguirre, B., Lin, M. C., Araujo, E., Lu, C. H., Casero, D., Sun, M., Nusinowitz, S., Hanson, J., Calkins, K., Gordon, L., Wadehra, M. and Chu, A. (2024) Epithelial membrane protein 2 (EMP2) blockade attenuates pathological neovascularization in murine oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 65, 10.
  2. Ahmat Amin, M. K. B., Shimizu, A. and Ogita, H. (2019) The pivotal roles of the epithelial membrane protein family in cancer invasiveness and metastasis. Cancers (Basel) 11, 1620.
  3. Ashki, N., Gordon, L. and Wadehra, M. (2015) Review of the GAS3 family of proteins and their relevance to cancer. Crit. Rev. Oncog. 20, 435-447.
  4. Bartha, A. and Gyorffy, B. (2021) TNMplot.com: a web tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int. J. Mol. Sci. 22, 2622.
  5. Berditchevski, F. (2001) Complexes of tetraspanins with integrins: more than meets the eye. J. Cell Sci. 114, 4143-4151.
  6. Cha, Y. J. and Koo, J. S. (2020) Expression and role of epithelial membrane proteins in tumorigenesis of hormone receptor-positive breast cancer. J. Breast Cancer 23, 385-397.
  7. Chan, A. M., Aguirre, B., Liu, L., Mah, V., Balko, J. M., Tsui, J., Wadehra, N. P., Moatamed, N. A., Khoshchehreh, M., Dillard, C. M., Kiyohara, M., Elshimali, Y., Chang, H. R., Marquez-Garban, D., Hamilton, N., Pietras, R. J., Gordon, L. K. and Wadehra, M. (2024) EMP2 serves as a functional biomarker for chemotherapy-resistant triple-negative breast cancer. Cancers (Basel) 16, 1481.
  8. Chen, Y. H., Wu, L. C., Wu, W. R., Lin, H. J., Lee, S. W., Lin, C. Y., Chang, S. L., Chow, N. H., Huang, H. Y., Li, C. F., Hsu, H. P. and Shiue, Y. L. (2012) Loss of epithelial membrane protein-2 expression confers an independent prognosticator in nasopharyngeal carcinoma: a cohort study. BMJ Open 2, e000900.
  9. Chung, L. K., Pelargos, P. E., Chan, A. M., Demos, J. V., Lagman, C., Sheppard, J. P., Nguyen, T., Chang, Y. L., Hojat, S. A., Prins, R. M., Liau, L. M., Nghiemphu, L., Lai, A., Cloughesy, T. F., Yong, W. H., Gordon, L. K., Wadehra, M. and Yang, I. (2018) Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas. Brain Tumor Pathol. 35, 1-9.
  10. Dahlin, K., Mager, E. M., Allen, L., Tigue, Z., Goodglick, L., Wadehra, M. and Dobbs, L. (2004) Identification of genes differentially expressed in rat alveolar type I cells. Am. J. Respir. Cell Mol. Biol. 31, 309-316.
  11. Desgrosellier, J. S. and Cheresh, D. A. (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 10, 9-22.
  12. Dickson, K. M., Bergeron, J. J., Shames, I., Colby, J., Nguyen, D. T., Chevet, E., Thomas, D. Y. and Snipes, G. J. (2002) Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases. Proc. Natl. Acad. Sci. U. S. A. 99, 9852-9857.
  13. Dillard, C., Kiyohara, M., Mah, V., McDermott, S. P., Bazzoun, D., Tsui, J., Chan, A. M., Haddad, G., Pellegrini, M., Chang, Y. L., Elshimali, Y., Wu, Y., Vadgama, J. V., Kim, S. R., Goodglick, L., Law, S. M., Patel, D. D., Dhawan, P., O'Brien, N. A., Gordon, L. K., Braun, J., Lazar, G., Wicha, M. S. and Wadehra, M. (2020) EMP2 is a novel regulator of stemness in breast cancer cells. Mol. Cancer Ther. 19, 1682-1695.
  14. El-Ghlban, S., AbouElnour, E. S., El-Torgoman, A. and Abu Elabas, S. M. S. (2020) Gene expression of Epithelial Membrane Protein 2 gene and beta1-Integrin gene in patients with breast cancer. Biochem. Biophys. Rep. 22, 100708.
  15. Enkhtaivan, E., Kim, H. J., Kim, B., Byun, H. J., Yu, L., Nguyen, T. M., Nguyen, T. H., Do, P. A., Kim, E. J., Kim, K. S., Huy, H. P., Rahman, M., Jang, J. Y., Rho, S. B., Lee, H., Kang, G. J., Park, M. K., Kim, N. H., Choi, C. I., Lee, K., Han, H. K., Cho, J., Lee, A. Y. and Lee, C. H. (2022) Loss of EMP2 inhibits melanogenesis of MNT1 melanoma cells via regulation of TRP-2. Biomol. Ther. (Seoul) 30, 203-211.
  16. Evans, W. H. and Martin, P. E. (2002) Gap junctions: structure and function (review). Mol. Membr. Biol. 19, 121-136.
  17. Fessler, M. B. and Parks, J. S. (2011) Intracellular lipid flux and membrane microdomains as organizing principles in inflammatory cell signaling. J. Immunol. 187, 1529-1535.
  18. Fu, M., Maresh, E. L., Helguera, G. F., Kiyohara, M., Qin, Y., Ashki, N., Daniels-Wells, T. R., Aziz, N., Gordon, L. K., Braun, J., Elshimali, Y., Soslow, R. A., Penichet, M. L., Goodglick, L. and Wadehra, M. (2014) Rationale and preclinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer. Mol. Cancer Ther. 13, 902-915.
  19. Fu, M., Maresh, E. L., Soslow, R. A., Alavi, M., Mah, V., Zhou, Q., Iasonos, A., Goodglick, L., Gordon, L. K., Braun, J. and Wadehra, M. (2010) Epithelial membrane protein-2 is a novel therapeutic target in ovarian cancer. Clin. Cancer Res. 16, 3954-3963.
  20. Fu, M., Rao, R., Sudhakar, D., Hogue, C. P., Rutta, Z., Morales, S., Gordon, L. K., Braun, J., Goodglick, L. and Wadehra, M. (2011) Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src. PLoS One 6, e19945.
  21. Gordon, L. K., Kiyohara, M., Fu, M., Braun, J., Dhawan, P., Chan, A., Goodglick, L. and Wadehra, M. (2013) EMP2 regulates angiogenesis in endometrial cancer cells through induction of VEGF. Oncogene 32, 5369-5376.
  22. Habeeb, O., Goodglick, L., Soslow, R. A., Rao, R. G., Gordon, L. K., Schirripa, O., Horvath, S., Braun, J., Seligson, D. B. and Wadehra, M. (2010) Epithelial membrane protein-2 expression is an early predictor of endometrial cancer development. Cancer 116, 4718-4726.
  23. Holliger, P., Prospero, T. and Winter, G. (1993) "Diabodies": small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. U. S. A. 90, 6444-6448.
  24. Hou, J., Wang, L., Zhao, J., Zhuo, H., Cheng, J., Chen, X., Zheng, W., Hong, Z. and Cai, J. (2021) Inhibition of protein PMP22 enhances etoposide-induced cell apoptosis by p53 signaling pathway in Gastric Cancer. Int. J. Biol. Sci. 17, 3145-3157.
  25. Jetten, A. M. and Suter, U. (2000) The peripheral myelin protein 22 and epithelial membrane protein family. Prog. Nucleic Acid Res. Mol. Biol. 64, 97-129.
  26. Kim, E. K. and Koo, J. S. (2022) Expression of epithelial membrane protein (EMP) 1, EMP 2, and EMP 3 in thyroid cancer. Histol. Histopathol. 37, 51-61.
  27. Lee, E. J., Park, M. K., Kim, H. J., Kim, E. J., Kang, G. J., Byun, H. J. and Lee, C. H. (2016) Epithelial membrane protein 2 regulates sphingosylphosphorylcholine-induced keratin 8 phosphorylation and reorganization: changes of PP2A expression by interaction with alpha4 and caveolin-1 in lung cancer cells. Biochim. Biophys. Acta 1863, 1157-1169.
  28. Li, C.-F., Chen, L.-T., Lin, C.-Y., Wang, Y.-H., Huang, H.-Y., Hsing, C.-H., Tsai, C.-J. and Shiue, Y.-L. (2013) Loss of epithelial membrane protein-2 expression confers an independent prognosticator in gallbladder carcinoma. Biomarkers and Genomic Medicine 5, 31-38.
  29. Li, C. F., Wu, W. J., Wu, W. R., Liao, Y. J., Chen, L. R., Huang, C. N., Li, C. C., Li, W. M., Huang, H. Y., Chen, Y. L., Liang, S. S., Chow, N. H. and Shiue, Y. L. (2015) The cAMP responsive element binding protein 1 transactivates epithelial membrane protein 2, a potential tumor suppressor in the urinary bladder urothelial carcinoma. Oncotarget 6, 9220-9239.
  30. Lin, W. C., Gowdy, K. M., Madenspacher, J. H., Zemans, R. L., Yamamoto, K., Lyons-Cohen, M., Nakano, H., Janardhan, K., Williams, C. J., Cook, D. N., Mizgerd, J. P. and Fessler, M. B. (2020) Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace. J. Clin. Invest. 130, 157-170.
  31. Ma, Y., Schroder, D. C., Nenkov, M., Rizwan, M. N., Abubrig, M., Sonnemann, J., Murrieta-Coxca, J. M., Morales-Prieto, D. M., Westermann, M., Gassler, N. and Chen, Y. (2021) Epithelial membrane protein 2 suppresses non-small cell lung cancer cell growth by inhibition of MAPK pathway. Int. J. Mol. Sci. 22, 2944.
  32. Maecker, H. T., Todd, S. C. and Levy, S. (1997) The tetraspanin superfamily: molecular facilitators. FASEB J. 11, 428-442.
  33. Morales, S. A., Mareninov, S., Wadehra, M., Zhang, L., Goodglick, L., Braun, J. and Gordon, L. K. (2009) FAK activation and the role of epithelial membrane protein 2 (EMP2) in collagen gel contraction. Invest. Ophthalmol. Vis. Sci. 50, 462-469.
  34. Mozaffari, K., Mekonnen, M., Harary, M., Lum, M., Aguirre, B., Chandla, A., Wadehra, M. and Yang, I. (2023) Epithelial membrane protein 2 (EMP2): a systematic review of its implications in pathogenesis. Acta Histochem. 125, 151976.
  35. Oh, K., Moon, H. G., Lee, D. S. and Yoo, Y. B. (2015) Tissue transglutaminase-interleukin-6 axis facilitates peritoneal tumor spreading and metastasis of human ovarian cancer cells. Lab. Anim. Res. 31, 188-197.
  36. Pan, J., Luo, X., Zhao, S., Li, J. and Jiang, Z. (2022) miR-340-5p mediates the therapeutic effect of mesenchymal stem cells on corneal neovascularization. Graefes Arch. Clin. Exp. Ophthalmol. 260, 497-507.
  37. Pang, X., He, X., Qiu, Z., Zhang, H., Xie, R., Liu, Z., Gu, Y., Zhao, N., Xiang, Q. and Cui, Y. (2023) Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct. Target. Ther. 8, 1.
  38. Patel, K. S., Kejriwal, S., Sun, M. M., Thammachantha, S., Duong, C., Chan, A., Cherian, N., Romiyo, P., Gordon, L. K., Yong, W., Wadehra, M. and Yang, I. (2020a) Identification of epithelial membrane protein 2 (EMP2) as a molecular marker and correlate for angiogenesis in meningioma. J. Neurooncol. 147, 15-24.
  39. Patel, K. S., Kejriwal, S., Thammachantha, S., Duong, C., Murillo, A., Gordon, L. K., Cloughesy, T. F., Liau, L., Yong, W., Yang, I. and Wadehra, M. (2020b) Increased epithelial membrane protein 2 expression in glioblastoma after treatment with bevacizumab. Neurooncol. Adv. 2, vdaa112.
  40. Powell, C. A., Spira, A., Derti, A., DeLisi, C., Liu, G., Borczuk, A., Busch, S., Sahasrabudhe, S., Chen, Y., Sugarbaker, D., Bueno, R., Richards, W. G. and Brody, J. S. (2003) Gene expression in lung adenocarcinomas of smokers and nonsmokers. Am. J. Respir. Cell Mol. Biol. 29, 157-162.
  41. Qin, Y., Fu, M., Takahashi, M., Iwanami, A., Kuga, D., Rao, R. G., Sudhakar, D., Huang, T., Kiyohara, M., Torres, K., Dillard, C., Inagaki, A., Kasahara, N., Goodglick, L., Braun, J., Mischel, P. S., Gordon, L. K. and Wadehra, M. (2014) Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma. J. Biol. Chem. 289, 13974-13985.
  42. Qin, Y., Takahashi, M., Sheets, K., Soto, H., Tsui, J., Pelargos, P., Antonios, J. P., Kasahara, N., Yang, I., Prins, R. M., Braun, J., Gordon, L. K. and Wadehra, M. (2017) Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme. J. Neurooncol. 134, 29-40.
  43. Shimazaki, K., Lepin, E. J., Wei, B., Nagy, A. K., Coulam, C. P., Mareninov, S., Fu, M., Wu, A. M., Marks, J. D., Braun, J., Gordon, L. K. and Wadehra, M. (2008) Diabodies targeting epithelial membrane protein 2 reduce tumorigenicity of human endometrial cancer cell lines. Clin. Cancer Res. 14, 7367-7377.
  44. Siegel, R. L., Giaquinto, A. N. and Jemal, A. (2024) Cancer statistics, 2024. CA Cancer J. Clin. 74, 12-49.
  45. Street, V. A., Goldy, J. D., Golden, A. S., Tempel, B. L., Bird, T. D. and Chance, P. F. (2002) Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am. J. Hum. Genet. 70, 244-250.
  46. Sun, M., Cherian, N., Liu, L., Chan, A. M., Aguirre, B., Chu, A., Strawbridge, J., Kim, E. S., Lin, M. C., Tsui, I., Gordon, L. K. and Wadehra, M. (2022) Epithelial membrane protein 2 (EMP2) regulates hypoxia-induced angiogenesis in the adult retinal pigment epithelial cell lines. Sci. Rep. 12, 19432.
  47. Sun, M., Wadehra, M., Casero, D., Lin, M. C., Aguirre, B., Parikh, S., Matynia, A., Gordon, L. and Chu, A. (2020) Epithelial membrane protein 2 (EMP2) promotes VEGF-induced pathological neovascularization in murine oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 61, 3.
  48. Taylor, V. and Suter, U. (1996) Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family. Gene 175, 115-120.
  49. Todorovska, A., Roovers, R. C., Dolezal, O., Kortt, A. A., Hoogenboom, H. R. and Hudson, P. J. (2001) Design and application of diabodies, triabodies and tetrabodies for cancer targeting. J. Immunol. Methods 248, 47-66.
  50. Wadehra, M., Forbes, A., Pushkarna, N., Goodglick, L., Gordon, L. K., Williams, C. J. and Braun, J. (2005) Epithelial membrane protein-2 regulates surface expression of alphavbeta3 integrin in the endometrium. Dev. Biol. 287, 336-345.
  51. Wadehra, M., Goodglick, L. and Braun, J. (2004) The tetraspan protein EMP2 modulates the surface expression of caveolins and glycosylphosphatidyl inositol-linked proteins. Mol. Biol. Cell 15, 2073-2083.
  52. Wadehra, M., Iyer, R., Goodglick, L. and Braun, J. (2002) The tetraspan protein epithelial membrane protein-2 interacts with beta1 integrins and regulates adhesion. J. Biol. Chem. 277, 41094-41100.
  53. Wadehra, M., Mainigi, M., Morales, S. A., Rao, R. G., Gordon, L. K., Williams, C. J. and Braun, J. (2008) Steroid hormone regulation of EMP2 expression and localization in the endometrium. Reprod. Biol. Endocrinol. 6, 15.
  54. Wadehra, M., Natarajan, S., Seligson, D. B., Williams, C. J., Hummer, A. J., Hedvat, C., Braun, J. and Soslow, R. A. (2006) Expression of epithelial membrane protein-2 is associated with endometrial adenocarcinoma of unfavorable outcome. Cancer 107, 90-98.
  55. Wadehra, M., Su, H., Gordon, L. K., Goodglick, L. and Braun, J. (2003a) The tetraspan protein EMP2 increases surface expression of class I major histocompatibility complex proteins and susceptibility to CTL-mediated cell death. Clin. Immunol. 107, 129-136.
  56. Wadehra, M., Sulur, G. G., Braun, J., Gordon, L. K. and Goodglick, L. (2003b) Epithelial membrane protein-2 is expressed in discrete anatomical regions of the eye. Exp. Mol. Pathol. 74, 106-112.
  57. Waks, A. G. and Winer, E. P. (2019) Breast cancer treatment: a review. JAMA 321, 288-300.
  58. Wang, C. X., Wadehra, M., Fisk, B. C., Goodglick, L. and Braun, J. (2001) Epithelial membrane protein 2, a 4-transmembrane protein that suppresses B-cell lymphoma tumorigenicity. Blood 97, 3890-3895.
  59. Wang, M., Li, S., Zhang, P., Wang, Y., Wang, C., Bai, D. and Jiang, X. (2019) EMP2 acts as a suppressor of melanoma and is negatively regulated by mTOR-mediated autophagy. J. Cancer 10, 3582-3592.
  60. Wang, Y., Wang, C., Chen, C., Wu, F., Shen, P., Zhang, P., He, G. and Li, X. (2017a) Long non-coding RNA NEAT1 regulates epithelial membrane protein 2 expression to repress nasopharyngeal carcinoma migration and irradiation-resistance through miR-101-3p as a competing endogenous RNA mechanism. Oncotarget 8, 70156-70171.
  61. Wang, Y. W., Cheng, H. L., Ding, Y. R., Chou, L. H. and Chow, N. H. (2017b) EMP1, EMP 2, and EMP3 as novel therapeutic targets in human cancer. Biochim. Biophys. Acta Rev. Cancer 1868, 199-211.
  62. Wang, Y. W., Li, W. M., Wu, W. J., Chai, C. Y., Chang, T. Y., Sun, Y., Cheng, C. J., Shiue, Y. L., Su, S. J., Cheng, H. L., Liu, H. S. and Chow, N. H. (2013) Epithelial membrane protein 2 is a prognostic indictor for patients with urothelial carcinoma of the upper urinary tract. Am. J. Pathol. 183, 709-719.
  63. Wilson, H. L., Wilson, S. A., Surprenant, A. and North, R. A. (2002) Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus. J. Biol. Chem. 277, 34017-34023.
  64. Xia, H., Liu, B., Shen, N., Xue, J., Chen, S., Guo, H. and Zhou, X. (2022) circRNA-0002109 promotes glioma malignant progression via modulating the miR-129-5P/EMP2 axis. Mol. Ther. Nucleic Acids 27, 1-15.
  65. Zhang, N., Zhu, H. P., Huang, W., Wen, X., Xie, X., Jiang, X., Peng, C., Han, B. and He, G. (2022) Unraveling the structures, functions and mechanisms of epithelial membrane protein family in human cancers. Exp. Hematol. Oncol. 11, 69.
  66. Zhang, Q., Fan, X., Xu, B., Pang, Q. and Teng, L. (2018) miR-133b acts as a tumor suppressor and negatively regulates EMP2 in glioma. Neoplasma 65, 494-504.