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Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin.[2][3] Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas.
Structure
[edit]EMP3 is a protein composed of a 163-amino acid sequence, which is expressed from its gene located on the band of the 19q13.3 in the Homo sapiens chromosome.[4] EMP3 has the highest expression in the peripheral blood leukocytes compared to the expression in other body tissues.[5] The protein is characterized by 4 transmembrane domains and two N-linked glycosylation sites in the first extracellular loop.[2]
Function
[edit]EMP3 is a transmembrane protein which participates in cell to cell interaction and cell proliferation.[6] Overexpression and silencing of EMP3 both interrupt the normal expression of the EMP3 gene, which induces the progression(and formation) of cancers. Based on these properties of EMP3 and the prognostic analyses on several types of tumors and cancers, EMP3 has a tumor-suppressor-like role in regulating differentiation, apoptosis and development of cancer cells. However, the detailed mechanism still needs to be investigated.[2][3][7]
Tumorgenesis and carcinogenesis
[edit]Primary Breast Carcinomas
[edit]The detailed functions as well as the mechanism of EMP3 in the development of various carcinomas have remained unclear.[2][3] However, it was found that the levels of expression of EMP3 mRNA have a positive correlation in primary breast carcinoma. According to the study, EMP3 mRNA has a higher level of expression in the carcinoma compared to normal breast tissues. The overexpression of EMP3 has a significant correlation with histological grade III, lymph node metastasis, and strong Her-2 expression. Additionally, the hypermethylation on the promoter region of EMP3 has appeared in about 35% of the studies breast carcinoma cases. However, higher EMP3 expression levels occur in patients with both types of breast carcinomas, regardless of the promoter regions of EMP3 being hypermethylated or unmethylated.[7]
HCC, which is mainly caused by the chronic infections of hepatitis B virus and hepatitis C virus, become one of the major causes of cancer mortality worldwide in the recent years.[8][9] EMP3 expression in HCC tumor cells has a higher expression level than that it does in normal tissues at similar regions of the liver. It was also found that the HCC patients who have a relatively lower historlogical grade inversely possess a higher level of expression in EMP3. Then, the researchers found that knockdown (gene silencing) of EMP3 resulted in reduction of cell proliferation and arrest of cell cycle, which suggests a potential role of EMP3 in tumor-suppressing.[10]
Brain cancer
[edit]EMP3 is found to play a large role in the progression of neuroblastomas and glioblastomas, which are two of the most common types of brain cancers. Both have fast carinogenesis result in a high rate of mortality.[2][6] EMP3 is proposed as an oncogene whose overexpression in the progression correlated with glioblastoma (GBM).[6] Reduction in EMP3 expression in CD44-high GBM cell lines promotes apoptosis of the cancer cell lines and disables potential tumorigenesis.[6]
One of the signaling activation pathway involving EMP3 in the progression of glioblastoma was identified in 2016. The pathway was identified as TGF-β/Smad2/3 signaling, in which the unregulated TGF-β signaling promotes tumorigenesis in various human cells, especially CD44-high glioma cells.[6] The interaction between EMP3 and the receptor of TGF-β regulate the TGF-β/Smad2/3 signaling activation, which eventually suppresses cell proliferation and weakens tumorigenesis in glioblastoma.[6]
Clinical Significance
[edit]Due to the controversial effects of EMP3 on tumor suppression, the applicable treatments for certain carcinomas related to EMP3 are still risky and unapproachable.[10][11] However, some animal experiments have showed a positive result on suppressing the tumorous tissues by modifying the EMP3 gene.[10]
References
[edit]- ^ Strausberg, Robert L.; Feingold, Elise A.; Grouse, Lynette H.; Derge, Jeffery G.; Klausner, Richard D.; Collins, Francis S.; Wagner, Lukas; Shenmen, Carolyn M.; Schuler, Gregory D. (2002-12-24). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. ISSN 0027-8424. PMC 139241. PMID 12477932.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c d e Alaminos, Miguel; Dávalos, Verónica; Ropero, Santiago; Setién, Fernando; Paz, Maria F.; Herranz, Michel; Fraga, Mario F.; Mora, Jaume; Cheung, Nai-Kong V. (2005-04-01). "EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma". Cancer Research. 65 (7): 2565–2571. doi:10.1158/0008-5472.CAN-04-4283. ISSN 0008-5472. PMID 15805250.
- ^ a b c Mellai, Marta; Piazzi, Angela; Caldera, Valentina; Annovazzi, Laura; Monzeglio, Oriana; Senetta, Rebecca; Cassoni, Paola; Schiffer, Davide (2013). "Promoter hypermethylation of the EMP3 gene in a series of 229 human gliomas". BioMed Research International. 2013: 756302. doi:10.1155/2013/756302. ISSN 2314-6141. PMC 3776370. PMID 24083241.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–16903. 2002-12-24. doi:10.1073/pnas.242603899. ISSN 0027-8424. PMC 139241. PMID 12477932.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Taylor, V.; Suter, U. (1996-10-10). "Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family". Gene. 175 (1–2): 115–120. ISSN 0378-1119. PMID 8917086.
- ^ a b c d e f Jun, Fu; Hong, Jidong; Liu, Qin; Guo, Yong; Liao, Yiwei; Huang, Jianghai; Wen, Sailan; Shen, Liangfang (2017-02-28). "Epithelial membrane protein 3 regulates TGF-β signaling activation in CD44-high glioblastoma". Oncotarget. 8 (9): 14343–14358. doi:10.18632/oncotarget.11102. ISSN 1949-2553. PMC 5362410. PMID 27527869.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b Zhou, Wei; Jiang, Zheng; Li, Xingang; Xu, Fenghua; Liu, Yanbing; Wen, Peie; Kong, Li; Hou, Ming; Yu, Jinming (2009). "EMP3 Overexpression in Primary Breast Carcinomas is not Associated with Epigenetic Aberrations". Journal of Korean Medical Science. 24 (1): 97–103. doi:10.3346/jkms.2009.24.1.97. ISSN 1011-8934. PMC 2650972. PMID 19270820.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Torre, Lindsey A.; Bray, Freddie; Siegel, Rebecca L.; Ferlay, Jacques; Lortet-Tieulent, Joannie; Jemal, Ahmedin (2015). "Global cancer statistics, 2012". CA: a cancer journal for clinicians. 65 (2): 87–108. doi:10.3322/caac.21262. ISSN 1542-4863. PMID 25651787.
- ^ Degasperi, Elisabetta; Colombo, Massimo (2016). "Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease". The Lancet. Gastroenterology & Hepatology. 1 (2): 156–164. doi:10.1016/S2468-1253(16)30018-8. ISSN 2468-1253. PMID 28404072.
- ^ a b c Hsieh, Yi-Hsien; Hsieh, Shu-Ching; Lee, Chien-Hsing; Yang, Shun-Fa; Cheng, Chun-Wen; Tang, Meng-Ju; Lin, Chia-Liang; Lin, Chu-Liang; Chou, Ruey-Hwang (2015-10-12). "Targeting EMP3 suppresses proliferation and invasion of hepatocellular carcinoma cells through inactivation of PI3K/Akt pathway". Oncotarget. 6 (33): 34859–34874. doi:10.18632/oncotarget.5414. ISSN 1949-2553. PMC 4741495. PMID 26472188.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Morris, Luc G. T.; Chan, Timothy A. (2015-05-01). "Therapeutic targeting of tumor suppressor genes". Cancer. 121 (9): 1357–1368. doi:10.1002/cncr.29140. ISSN 1097-0142. PMC 4526158. PMID 25557041.
{{cite journal}}: CS1 maint: PMC format (link)