CMTM家族的生物学功能及其作用机制
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摘要
CMTM家族作为一个新的基因家族,在免疫、生殖等系统以及多种肿瘤的发病机制中起到重要作用。CMTM家族中,CMTM1可影响细胞增殖,导致肿瘤发生;与非小细胞肺癌(NSCLC)患者的化疗耐药和预后有关。CMTM2通过AP-1、CREB通路一定程度上影响HIV-1转录,同时在男性生殖系统中起重要作用。CMTM3等位基因失活或甲基化使其丧失对细胞增殖的负性调控能力,是胃癌独立的预后指标。CMTM4调控细胞周期影响肿瘤细胞增殖,通过对PD-L1的协同保护参与免疫逃逸。CMTM5在许多肿瘤中沉默表达,参与肿瘤发生发展相关的信号通路。CMTM6协同PD-L1参与免疫逃逸,是潜在的免疫治疗靶点。CMTM7在NSCLC中通过Rab5控制EGFR-AKT信号影响肿瘤发展,且与胃癌发展相关。CMTM8通过MARVEL区域影响EGFR和相关信号通路,调控细胞增殖、分化和凋亡等。上述重要发现,为研究肿瘤的发生发展及肿瘤基因治疗提供了新思路。
引文
[1]YUAN W,LIU B,WANG X,et al.CMTM3 decreases EGFR expression and EGF-mediated tumorigenicity by promoting Rab5 activity in gastric cancer[J/OL].Cancer Lett,2017,386:77-86[2018-12-12].http://sciencedirect.com/science/journal/03043835.DOI:10.1016/j.canlet.2016.11.015.
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[19]PLATE M,LI T,WANG Y,et al.Identification and characterization of CMTM4,a novel gene with inhibitory effects on HeLa cell growth through inducing G2/M phase accumulation[J].Mol Cells,2010,29(4):355-361.DOI:10.1007/s10059-010-0038-7.
[20]MEZZADRA R,SUN C,JAE L T,et al.Identification of CMTM6and CMTM4 as PD-L1 protein regulators[J].Nature,2017,549(7670):106-110.DOI:10.1038/nature23669.
[21]GUAN L,JI D,LIANG N,et al.Up-regulation of miR-10b-3p promotes the progression of hepatocellular carcinoma cells via targeting CMTM5[J].J Cell Mol Med,2018,22(7):3434-3441.DOI:10.1111/jcmm.13620.
[22]CAI B,XIAO Y,LI Y,et al.CMTM5 inhibits renal cancer cell growth through inducing cell-cycle arrest and apoptosis[J].Oncol Lett,2017,14(2):1536-1542.DOI:10.3892/ol.2017.6350.
[23]XIAO Y,YUAN Y,ZHANG Y,et al.CMTM5 is reduced in prostate cancer and inhibits cancer cell growth in vitro and in vivo[J].Clin Transl Oncol,2015,17(6):431-437.DOI:10.1007/s12094-014-1253-z.
[24]ZHANG J W,LIU T F,CHEN X H,et al.Validation of aspirin response-related transcripts in patients withcoronary artery disease and preliminary investigation on CMTM5 function[J/OL].Gene,2017,624:56-65[2018-12-12].http://sciencedirect.com/science/journal/03781119.DOI:10.1016/j.gene.2017.04.041.
[25]ZHANG H,NAN X,LI X,et al.CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamouscell carcinoma[J].Biochem Biophys Res Commun,2014,447(2):304-310.DOI:10.1016/j.bbrc.2014.03.158.
[26]YUAN Y Q,XIAO Y B,LIU Z H,et al.Research advances in CKLF-like MARVEL transmembrane domain containing member 5[J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao,2012,34(6):625-628.DOI:10.3881/j.issn.1000-503X.2012.06.018.
[27]BURR M L,SPARBIER C E,CHAN Y C,et al.CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity[J].Nature,2017,549(7670):101-105.DOI:10.1038/nature23643.
[28]赵宇飞,陈晓,李薇,等.PD1/PD-L1抑制剂治疗肿瘤[J].中国肿瘤生物治疗杂志,2017,24(8):904-911.DOI:10.3872/j.issn.1007-385X.2017.08.016.
[29]ZHU X,QI G,LI C,et al.Expression and clinical significance of CMTM6 in hepatocellular carcinoma[J].DNA Cell Biol,2018,38(2):193-197.DOI:10.1089/dna.2018.4513.
[30]LIU B,SU Y,LI T,et al.CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKTsignaling by reducing Rab5 activation[J/OL].Oncotarget,2015,6(38):41092-41107[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747392/.DOI:10.18632/oncotarget.5732.
[31]LIU Q,SU Y,JIANG GC,et al.Change of CMTM7 expression,a potential tumor suppressor,is associated with poor clinical outcome in human non-small cell lung cancer[J].Chin Med J(Engl),2013,126(16):3006-3012.
[32]JIN Y,QIN X,JIA G.SOX10-dependent CMTM7 expression inhibits cell proliferation and tumor growth in gastric carcinoma[J].Biochem Biophys Res Commun,2018,507(1/4):91-99.DOI:10.1016/j.bbrc.2018.10.172.
[33]GAO D H,HU H,FANG Z W,et al.Research advances in chemokine-like factor super family member 8[J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao,2016,38(6):746-749.DOI:10.3881/j.issn.1000-503X.2016.06.021.
[34]ZHANG W,MENDOZA M C,PEI X,et al.Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase(ERK)signaling[J].J Biol Chem,2012,287(15):11850-11858.DOI:10.1074/jbc.m111.258236.
[35]BOTH J,KRIJGSMAN O,BRAS J,et al.Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma[J/OL].PLoS One,2014,9(12):e115835[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281204/.DOI:10.1371/journal.pone.0115835.
[36]GAO D,HU H,WANG Y,et al.CMTM8 inhibits the carcinogenesis and progression of bladder cancer[J].Oncol Rep,2015,34(6):2853-2863.DOI:10.3892/or.2015.4310.
[37]胡浩,陈京文,许克新,等.CMTM8与E-cadherin在原发性和转移性肾透明细胞癌中的表达[J].北京大学学报(医学版),2013,45(4):537-541.DOI:10.3969/j.issn.1671-167X.2013.04.007.
[2]DELIC S,THUY A,SCHULZE M,et al.Systematic investigation of CMTM family genes suggests relevance to glioblastoma pathogenesis and CMTM1 and CMTM3 as priority targets[J].Genes Chromosomes Cancer,2015,54(7):433-443.DOI:10.1002/gcc.22255.
[3]SANCHEZ-PULIDO L,MARTIN-BELMONTE F,VALENCIA A,et al.MARVEL:a conserved domain involved in membrane apposition events[J].Trends Biochem Sci,2002,27(12):599-601.DOI:10.1016/s0968-0004(02)-02229-6.
[4]LU J,WU Q Q,ZHOU Y B,et al.Cancer research advance in CKLF-like MARVEL transmembrane domain containing member family(review)[J].Asian Pac J Cancer Prev,2016,17(6):2741-2744.
[5]WANG J,ZHANG G,ZHANG Y,et al.CMTM1_v17 is a novel potential therapeutic target in breast cancer[J].Oncol Rep,2014,32(5):1829-1836.DOI:10.3892/or.2014.3429.
[6]SI J,ZHANG P,TIAN D,et al.CMTM1_v17 is associated with chemotherapy resistance and poor prognosis in non-small cell lung cancer[J/OL].World J Surg Oncol,2017,15(1):34[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5273821/.DOI:10.1016/j.jtho.2016.11.1261.
[7]SONG H S,SHI S,LU X Z,et al.Intracellular CMTM2 negatively regulates human immunodeficiency virus type-1 transcription through targeting the transcription factors AP-1 and CREB[J].Chin Med J(Engl),2010,123(17):2440-2445.DOI:10.3760/cma.j.issn.0366-6999.2010.17.027.
[8]ZHANG X W,DUN Y J,TANG X,et al.Expression of chemokine like factor-like myelin and lymphocyte and related proteins for vesicle trafficking and membrane link transmembrane domain-containing protein 2 in rats with varicocele[J].Beijing Da Xue Xue Bao Yi Xue Ban,2016,48(1):579-583.
[9]ZHANG X W,LAN K,YANG W B,et al.Expression and localization of transmembrane protein CMTM2 in human testis and sperm[J].Beijing Da Xue Xue Bao Yi Xue Ban,2017,49(4):575-579.
[10]HU F Z,SHENG Z Z,QIN C P,et al.Research advances in CKLFSF-like MARVEL transmembrane domain containing member 3[J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao,2016,38(3):360-363.DOI:10.3881/j.issn.1000-503X.2016.03.022.
[11]LI H,LI J,SU Y,et al.A novel 3p22.3 gene CMTM7 represses oncogenic EGFR signaling and inhibits cancer cell growth[J].Oncogene,2014,33(24):3109-3118.DOI:10.1038/onc.2013.282.
[12]ZHANG Y,WANG R,SONG H,et al.Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer[J].Cancer Lett,2011,303(1):21-28.DOI:10.1016/j.canlet.2010.12.011.
[13]OGAWA T,LIGGETT T E,MELNIKOV A A,et al.Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance[J].Cell Cycle,2012,11(8):1656-1663.DOI:10.4161/cc.20120.
[14]SU Y,LIN Y,ZHANG L,et al.CMTM3 inhibits cell migration and invasion and correlates with favorable prognosis in gastric cancer[J].Cancer Sci,2014,105(1):26-34.DOI:10.3389/conf.fimmu.2013.02.00484.
[15]YUAN W,LI T,MO X,et al.Knockdown of CMTM3 promotes metastasis of gastric cancer via the STAT3/Twist1/EMT signaling pathway[J].Oncotarget,2016,7(20):29507-29519.DOI:10.18632/oncotarge.8789.
[16]LU M,HUANG Y,SUN W,et al.miR-135b-5p promotes gastric cancer progression by targeting CMTM3[J].Int J Oncol,2018,52(2):589-598.DOI:10.3892/ijo.2017.4222.
[17]LI T,CHENG Y,WANG P,et al.CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma[J/OL].J Exp Clin Cancer Res,2015,34:122[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609138/.DOI:10.1186/s13046-015-0236-4.
[18]BEI C,ZHANG Y,WEI R,et al.Clinical significance of CMTM4expression in hepatocellular carcinoma[J/OL].Onco Targets Ther,2017,10:5439-5443[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694205/.DOI:10.2147/ott.s149786.
[19]PLATE M,LI T,WANG Y,et al.Identification and characterization of CMTM4,a novel gene with inhibitory effects on HeLa cell growth through inducing G2/M phase accumulation[J].Mol Cells,2010,29(4):355-361.DOI:10.1007/s10059-010-0038-7.
[20]MEZZADRA R,SUN C,JAE L T,et al.Identification of CMTM6and CMTM4 as PD-L1 protein regulators[J].Nature,2017,549(7670):106-110.DOI:10.1038/nature23669.
[21]GUAN L,JI D,LIANG N,et al.Up-regulation of miR-10b-3p promotes the progression of hepatocellular carcinoma cells via targeting CMTM5[J].J Cell Mol Med,2018,22(7):3434-3441.DOI:10.1111/jcmm.13620.
[22]CAI B,XIAO Y,LI Y,et al.CMTM5 inhibits renal cancer cell growth through inducing cell-cycle arrest and apoptosis[J].Oncol Lett,2017,14(2):1536-1542.DOI:10.3892/ol.2017.6350.
[23]XIAO Y,YUAN Y,ZHANG Y,et al.CMTM5 is reduced in prostate cancer and inhibits cancer cell growth in vitro and in vivo[J].Clin Transl Oncol,2015,17(6):431-437.DOI:10.1007/s12094-014-1253-z.
[24]ZHANG J W,LIU T F,CHEN X H,et al.Validation of aspirin response-related transcripts in patients withcoronary artery disease and preliminary investigation on CMTM5 function[J/OL].Gene,2017,624:56-65[2018-12-12].http://sciencedirect.com/science/journal/03781119.DOI:10.1016/j.gene.2017.04.041.
[25]ZHANG H,NAN X,LI X,et al.CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamouscell carcinoma[J].Biochem Biophys Res Commun,2014,447(2):304-310.DOI:10.1016/j.bbrc.2014.03.158.
[26]YUAN Y Q,XIAO Y B,LIU Z H,et al.Research advances in CKLF-like MARVEL transmembrane domain containing member 5[J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao,2012,34(6):625-628.DOI:10.3881/j.issn.1000-503X.2012.06.018.
[27]BURR M L,SPARBIER C E,CHAN Y C,et al.CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity[J].Nature,2017,549(7670):101-105.DOI:10.1038/nature23643.
[28]赵宇飞,陈晓,李薇,等.PD1/PD-L1抑制剂治疗肿瘤[J].中国肿瘤生物治疗杂志,2017,24(8):904-911.DOI:10.3872/j.issn.1007-385X.2017.08.016.
[29]ZHU X,QI G,LI C,et al.Expression and clinical significance of CMTM6 in hepatocellular carcinoma[J].DNA Cell Biol,2018,38(2):193-197.DOI:10.1089/dna.2018.4513.
[30]LIU B,SU Y,LI T,et al.CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKTsignaling by reducing Rab5 activation[J/OL].Oncotarget,2015,6(38):41092-41107[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747392/.DOI:10.18632/oncotarget.5732.
[31]LIU Q,SU Y,JIANG GC,et al.Change of CMTM7 expression,a potential tumor suppressor,is associated with poor clinical outcome in human non-small cell lung cancer[J].Chin Med J(Engl),2013,126(16):3006-3012.
[32]JIN Y,QIN X,JIA G.SOX10-dependent CMTM7 expression inhibits cell proliferation and tumor growth in gastric carcinoma[J].Biochem Biophys Res Commun,2018,507(1/4):91-99.DOI:10.1016/j.bbrc.2018.10.172.
[33]GAO D H,HU H,FANG Z W,et al.Research advances in chemokine-like factor super family member 8[J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao,2016,38(6):746-749.DOI:10.3881/j.issn.1000-503X.2016.06.021.
[34]ZHANG W,MENDOZA M C,PEI X,et al.Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase(ERK)signaling[J].J Biol Chem,2012,287(15):11850-11858.DOI:10.1074/jbc.m111.258236.
[35]BOTH J,KRIJGSMAN O,BRAS J,et al.Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma[J/OL].PLoS One,2014,9(12):e115835[2018-12-12].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281204/.DOI:10.1371/journal.pone.0115835.
[36]GAO D,HU H,WANG Y,et al.CMTM8 inhibits the carcinogenesis and progression of bladder cancer[J].Oncol Rep,2015,34(6):2853-2863.DOI:10.3892/or.2015.4310.
[37]胡浩,陈京文,许克新,等.CMTM8与E-cadherin在原发性和转移性肾透明细胞癌中的表达[J].北京大学学报(医学版),2013,45(4):537-541.DOI:10.3969/j.issn.1671-167X.2013.04.007.