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CKLF-like MARVEL transmembrane domain-containing 5

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CKLF-like MARVEL transmembrane domain-containing 5 (CMTM5), previously termed chemokine-like factor superfamily 5 (i.e. CKLFSF5), designates any one of the six protein isoforms (termed CMTM5-v1 to CMTM5-v6) encoded by six different alternative splices of its gene, CMTM5; CMTM5-v1 is the most studied of these isoforms.[1] The CMTM5 gene is located in band 11.2 on the long (i.e. "q") arm of chromosome 14.[2]

The CMTM5 isoforms are members of the CKLF-like MARVEL transmembrane domain-containing family (CMTM). This family consists of 9 proteins although most of them are known to have one or more isoforms. These proteins are: chemokine-like factor (i.e. CLF, the founding member of the family) and CEF-like marvel transmembrane domain-containing 1 through 8 (i.e. CMTM1 through CMTM8).[3] All of these proteins as well as the genes responsible for their production (i.e. CKLF and CMTM1 to CMTM8, respectively) have similar structures[3] but vary in their apparent physiological and pathological functions.[2][4][5][6] Preliminary studies suggest that CMTM5-v1 (which cells commonly secrete to the extracellular spaces such as the blood[7]) or an unspecified CMTM5 isoform has various functions including involvements in regulating the autoimmune system, the development of numerous types of cancers, and the cardiovascular system.

Autoimmune system

The methylation of certain CpG clusters (i.e. DNA areas high in cytosine and guanine) regulate the transcriptional activity of nearby genes. That is, the methylation of a cluster(s) regulates its nearby gene by blocking it from making mRNAs and thereby the proteins encoded by these mRNAs. Studies find that the CMTM5 gene in the DNA isolated from the blood of individuals with the autoimmune diseases of systemic lupus erythematosus and primary Sjögren's syndrome (i.e. Sjorgen's syndrome not associated with other health problems or connective tissue diseases) is hyper-methylated at its CpG cluster(s) and thereby less active or inactive. On the other hand, the CpG cluster(s) controlling the CMTM5 gene in the blood of individuals with the autoimmune disease of rheumatoid arthritis are hypo-methylated and therefore highly active. These methylation changes, the studies suggest, regulate the function of immunologically active blood cells[5] (and, perhaps, blood platelets[8]) and thereby the development, maintenance, and/or worsening of the cited autoimmune diseases.[2][5][8] Further studies are required to prove that these methylations contribute to the immunologic dysregulations occurring in these (and perhaps other) autoimmune diseases and can serve as clinical markers of disease severity and/or as therapeutic targets for controlling the diseases.[2]

Cancers

Studies have reported that: 1) the levels of CMTM5-v1 in the malignant tissues of patients with prostate cancer are lower than the levels in their nearby normal prostate gland tissues[9] as well as in the tissues of patients with benign prostate hyperplasia;[10] 2) patients with lower prostate cancer tissue levels of CMTM5-v1 have higher prostate cancer Gleason scores and therefore poorer prognoses than patients with higher prostate cancer tissue levels of CMTM5-v1;[9] and 3) the forced overexpression of CMTM5-v1 in cultured DU145 cells (a human prostate cancer cell line) reduces, while the forced higher expression of the CMTM5-v1 levels increases, their proliferation and migration.[4][9][10] Similar findings for an unspecified CMTM5 isoform are reported in ovarian cancer,[4][11] hepatocellular carcinoma,[4][12] pancreatic cancer,[4][13] non-small-cell lung carcinoma,[4][14] renal cell carcinoma,[4][15] and breast cancer.[16] The forced over expression of CMTM5-v1 in Huh7 human hepatic cells also inhibited the ability of these cells to grow in a mouse model of cancer.[12] Finally, various cancer human cell lines including those of the liver, breast, prostate, colon, stomach, nasopharynx, laryngopharynx, esophagus, lung, and cervix express low levels of, or no, CMTM5-v1 and concurrently have highly methylated CpG sites near to the CMTM5 gene.[17] These findings suggest that the CMTM5 gene may act as a tumor suppressor gene, i.e. a normal gene whose product(s) inhibit the development and/or progression of various cancers. The findings also support further studies to confirm and expand these relationships and determine if the expression of CMTM5 isoforms can be used as tumor markers for these cancers severities/prognoses and/or targets as for treating them.[4]

Cardiovascular system

A case–control study of hospitalized patients found that the blood plasma levels of CMTM5 protein and CMTM5 messenger RNA (i.e. mRNA) in 350 patients with coronary artery disease were significantly higher than a matched group of 350 patients without this disease.[18] The same research group similarly studied 124 hospitalized patients who had in place a coronary artery stent. They found that high blood plasma levels of CMTM5 mRNA were associated with a higher rate of subsequently developing stenosis (i.e. narrowing) in their stents than patients with lower levels of this mRNA.[19] Furthermore, the forced overexpression of the CMTM5 gene inhibited the proliferation and migration of cultured human endothelial cells,[19][20] while the forced suppression of the CMTM5 gene promote the proliferation of these cells.[20] These studies suggest that the CMTM5 gene, one of its mRNAs, and/or one of its CMTM5 proteins may promote atherosclerosis-based coronary artery disease and the stenosis of coronary artery stents and do so by inhibiting vascular endothelial cells from functioning to inhibit atherosclerosis and stent occlusion. More studies are necessary to confirm and further define these relationships; to determine if expression of the CMTM5 gene's or its products can be used as makers for patient susceptibilities to coronary artery/stent occlusions; and to determine if this gene or its products can used clinically as targets for preventing or decreasing the frequency of these occlusions.[19][20]

References

  1. ^ Li M, Luo F, Tian X, Yin S, Zhou L, Zheng S (2020). "Chemokine-Like Factor-Like MARVEL Transmembrane Domain-Containing Family in Hepatocellular Carcinoma: Latest Advances". Frontiers in Oncology. 10: 595973. doi:10.3389/fonc.2020.595973. PMC 7691587. PMID 33282744.
  2. ^ a b c d Duan HJ, Li XY, Liu C, Deng XL (April 2020). "Chemokine-like factor-like MARVEL transmembrane domain-containing family in autoimmune diseases". Chinese Medical Journal. 133 (8): 951–958. doi:10.1097/CM9.0000000000000747. PMC 7176445. PMID 32195671.
  3. ^ a b Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T, Ma D (June 2003). "Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation". Genomics. 81 (6): 609–17. doi:10.1016/s0888-7543(03)00095-8. PMID 12782130.
  4. ^ a b c d e f g h Wu J, Li L, Wu S, Xu B (August 2020). "CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value". Cancer Biology & Medicine. 17 (3): 528–542. doi:10.20892/j.issn.2095-3941.2020.0032. PMC 7476098. PMID 32944388.
  5. ^ a b c Wang X, Lei D, Ding J, Liu S, Tao L, Zhang F, Peng J, Xu J (2018). "A DNA-Methylated Sight on Autoimmune Inflammation Network across RA, pSS, and SLE". Journal of Immunology Research. 2018: 4390789. doi:10.1155/2018/4390789. PMC 6109517. PMID 30159339.
  6. ^ Zhang JW, Liu TF, Chen XH, Liang WY, Feng XR, Wang L, Fu SW, McCaffrey TA, Liu ML (August 2017). "Validation of aspirin response-related transcripts in patients with coronary artery disease and preliminary investigation on CMTM5 function". Gene. 624: 56–65. doi:10.1016/j.gene.2017.04.041. PMID 28457985.
  7. ^ Li H, Guo X, Shao L, Plate M, Mo X, Wang Y, Han W (March 2010). "CMTM5-v1, a four-transmembrane protein, presents a secreted form released via a vesicle-mediated secretory pathway" (PDF). BMB Reports. 43 (3): 182–7. doi:10.5483/bmbrep.2010.43.3.182. PMID 20356458. S2CID 32280803.
  8. ^ a b Ge YY, Duan HJ, Deng XL (April 2021). "Possible effects of chemokine-like factor-like MARVEL transmembrane domain-containing family on antiphospholipid syndrome". Chinese Medical Journal. 134 (14): 1661–1668. doi:10.1097/CM9.0000000000001449. PMC 8318642. PMID 33813507.
  9. ^ a b c Li L, Hu Y, Chen D, Zhu J, Bao W, Xu X, Chen H, Chen W, Feng R (January 2022). "CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway". Molecular Medicine Reports. 25 (1). doi:10.3892/mmr.2021.12533. PMC 8628290. PMID 34791506.
  10. ^ a b Xiao Y, Yuan Y, Zhang Y, Li J, Liu Z, Zhang X, Sheng Z, Xu T, Wang X (June 2015). "CMTM5 is reduced in prostate cancer and inhibits cancer cell growth in vitro and in vivo". Clinical & Translational Oncology. 17 (6): 431–7. doi:10.1007/s12094-014-1253-z. PMID 25387568. S2CID 22433235.
  11. ^ Li P, Liu K, Li L, Yang M, Gao W, Feng J, Lv Y, Qu X, Kong B (October 2011). "Reduced CMTM5 expression correlates with carcinogenesis in human epithelial ovarian cancer". International Journal of Gynecological Cancer. 21 (7): 1248–55. doi:10.1097/IGC.0b013e3182259c31. PMID 21841490. S2CID 23134052.
  12. ^ a b Xu G, Dang C (2017). "CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling". Cancer Cell International. 17: 113. doi:10.1186/s12935-017-0485-8. PMC 5707824. PMID 29213215.
  13. ^ Guo X, Li T, Wang Y, Shao L, Zhang Y, Ma D, Han W (September 2009). "CMTM5 induces apoptosis of pancreatic cancer cells and has synergistic effects with TNF-alpha". Biochemical and Biophysical Research Communications. 387 (1): 139–42. doi:10.1016/j.bbrc.2009.06.148. PMID 19577543.
  14. ^ Wu K, Li X, Gu H, Yang Q, Liu Y, Wang L (2019). "Research Advances in CKLF-like MARVEL Transmembrane Domain-containing Family in Non-small Cell Lung Cancer". International Journal of Biological Sciences. 15 (12): 2576–2583. doi:10.7150/ijbs.33733. PMC 6854381. PMID 31754330.
  15. ^ Cai B, Xiao Y, Li Y, Zheng S (August 2017). "CMTM5 inhibits renal cancer cell growth through inducing cell-cycle arrest and apoptosis". Oncology Letters. 14 (2): 1536–1542. doi:10.3892/ol.2017.6350. PMC 5529942. PMID 28789377.
  16. ^ Chen Z, Cui N, Zhao JS, Wu JF, Ma F, Li C, Liu XY (January 2021). "Expressions of ZNF436, β-catenin, EGFR, and CMTM5 in breast cancer and their clinical significances". European Journal of Histochemistry. 65 (1). doi:10.4081/ejh.2021.3173. PMC 7856825. PMID 33478201.
  17. ^ Shao L, Cui Y, Li H, Liu Y, Zhao H, Wang Y, Zhang Y, Ng KM, Han W, Ma D, Tao Q (October 2007). "CMTM5 exhibits tumor suppressor activities and is frequently silenced by methylation in carcinoma cell lines". Clinical Cancer Research. 13 (19): 5756–62. doi:10.1158/1078-0432.CCR-06-3082. PMID 17908965. S2CID 23423586.
  18. ^ Liu TF, Lin T, Ren LH, Li GP, Peng JJ (December 2020). "[Association between CMTM5 gene and coronary artery disease and the relative mechanism]". Beijing da Xue Xue Bao. Yi Xue Ban = Journal of Peking University. Health Sciences (in Chinese). 52 (6): 1082–1087. PMC 7745279. PMID 33331317.
  19. ^ a b c Liu TF, Lin T, Ren LH, Li GP, Peng JJ (October 2020). "[Association of CMTM5 gene expression with the risk of in-stent restenosis in patients with coronary artery disease after drug-eluting stent implantation and the effects and mechanisms of CMTM5 on human vascular endothelial cells]". Beijing da Xue Xue Bao. Yi Xue Ban = Journal of Peking University. Health Sciences (in Chinese). 52 (5): 856–862. PMC 7653433. PMID 33047719.
  20. ^ a b c Bress AP, Colantonio LD, Cooper RS, Kramer H, Booth JN, Odden MC, Bibbins-Domingo K, Shimbo D, Whelton PK, Levitan EB, Howard G, Bellows BK, Kleindorfer D, Safford MM, Muntner P, Moran AE (January 2019). "Potential Cardiovascular Disease Events Prevented with Adoption of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline". Circulation. 139 (1): 24–36. doi:10.1161/CIRCULATIONAHA.118.035640. PMC 6311714. PMID 30586736.
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