CMTM6在肺腺癌组织中的表达及其临床意义
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摘要
目的:检测人类趋化因子CMTM6在肺腺癌组织中的表达水平,探索其与患者临床病理特征和预后间的联系。方法:选取苏州大学附属第三医院于2004年9月至2009年6月期间经病理学方法确诊为肺腺癌患者的癌组织和癌旁组织各86例,应用免疫组织化学法检测其中CMTM6的表达水平。收集52例肺腺癌确诊患者手术前后的血清及32例健康体检者的血清,采用ELISA检测手术前后外周血中CMTM6和PD-L1的水平。采用卡方检验分析CMTM6表达情况与临床病理特征的关系,Kaplan-Meier法及Log-rank检验分析患者生存数据。结果:CMTM6在肺腺癌组织中广泛表达,与相应癌旁组织比较,30%上调、70%无差异。CMTM6表达水平与临床分期、远处转移有关(均P<0.05),与患者的年龄、性别、肿瘤大小、T分期无显著相关(均P>0.05)。Kaplan-Meier生存分析显示CMTM6表达上调患者的生存率显著低于表达不变者(P=0.014),‐期患者中CMTM6上调者生存率显著低于CMTM6表达不变者(P=0.001)。Cox回归模型多因素分析显示,CMTM6的表达状态是肺腺癌患者预后的独立危险因素。CMTM6在肺腺癌术前术后及健康体检者3组间血清表达水平差异有统计学意义(P<0.05),与患者肿瘤大小和年龄有关。Spearman相关性分析显示血清CMTM6和PD-L1表达水平显著相关(r=0.623,P<0.01)。结论:CMTM6是肺腺癌患者预后的独立危险因素,在肺腺癌发生发展中发挥重要作用,是潜在的抑癌基因。
Objective: To evaluate the expression of CKLF-like MARVEL transmembrane domain containing member 6(CMTM6) in lung adenocarcinoma tissues, and to explore its correlation with the clinicopathologic features and prognosis of patients. Methods:Eighty-six pairs of cancer tissues and para-cancer tissues from patients that pathologically confirmed with lung adenocarcinoma were collected during September 2004 and June 2009 at the Third Affiliated Hospital of Soochow University. The expression levels of CMTM6 in above mentioned tissues were detected by immunohistochemistry. Serum of 52 patients with confirmed lung adenocarcinoma was collected before and after surgery, and serum of 32 healthy subjects was also collected. The levels of CMTM6 and PD-L1 in peripheral blood before and after surgery were measured and analyzed by ELISA. Chi-square test was used to analyze the relationship between CMTM6 expression and clinicopathological features; Kaplan-Meier method and Log-Rank test were used to analyze the survival data of patients. Results: CMTM6 was widely expressed in lung adenocarcinoma tissues; 30% of the tumor tissues showed an up-regulation as compared with para-cancer tissues, and 70% showed no difference. CMTM6 expression was associated with clinical stage and distant metastasis(all P<0.05), but not significantly associated with age, gender, tumor size, and T stage(P>0.05). Kaplan-Meier survival analysis showed the survival rate of patients with high CMTM6 expression was significantly lower than those with stable expression(P=0.014), and among patients at stage ‐, the survival rate of patients with high CMTM6 expression was significantly lower than those with stable CMTM6 expression(P=0.001). Cox regression model analysis of multiple factors showed CMTM6 expression was an independent risk factor for the prognosis of patients with lung adenocarcinoma. CMTM6 expression in pre-surgery serum, post-surgery serum and healthy donors' serum showed statistically significant differences(P<0.05), which was significantly correlated with tumor size and age of the patients. Spearman correlation analysis showed a significant correlation between serum CMTM6 and PD-L1 expression level(r=0.623, P<0.01). Conclusion: CMTM6 is an independent risk factor for the prognosis of lung adenocarcinoma patients. It plays an important role in the occurrence and development of lung adenocarcinoma and it is a potential tumor suppressor gene.
Objective: To evaluate the expression of CKLF-like MARVEL transmembrane domain containing member 6(CMTM6) in lung adenocarcinoma tissues, and to explore its correlation with the clinicopathologic features and prognosis of patients. Methods:Eighty-six pairs of cancer tissues and para-cancer tissues from patients that pathologically confirmed with lung adenocarcinoma were collected during September 2004 and June 2009 at the Third Affiliated Hospital of Soochow University. The expression levels of CMTM6 in above mentioned tissues were detected by immunohistochemistry. Serum of 52 patients with confirmed lung adenocarcinoma was collected before and after surgery, and serum of 32 healthy subjects was also collected. The levels of CMTM6 and PD-L1 in peripheral blood before and after surgery were measured and analyzed by ELISA. Chi-square test was used to analyze the relationship between CMTM6 expression and clinicopathological features; Kaplan-Meier method and Log-Rank test were used to analyze the survival data of patients. Results: CMTM6 was widely expressed in lung adenocarcinoma tissues; 30% of the tumor tissues showed an up-regulation as compared with para-cancer tissues, and 70% showed no difference. CMTM6 expression was associated with clinical stage and distant metastasis(all P<0.05), but not significantly associated with age, gender, tumor size, and T stage(P>0.05). Kaplan-Meier survival analysis showed the survival rate of patients with high CMTM6 expression was significantly lower than those with stable expression(P=0.014), and among patients at stage ‐, the survival rate of patients with high CMTM6 expression was significantly lower than those with stable CMTM6 expression(P=0.001). Cox regression model analysis of multiple factors showed CMTM6 expression was an independent risk factor for the prognosis of patients with lung adenocarcinoma. CMTM6 expression in pre-surgery serum, post-surgery serum and healthy donors' serum showed statistically significant differences(P<0.05), which was significantly correlated with tumor size and age of the patients. Spearman correlation analysis showed a significant correlation between serum CMTM6 and PD-L1 expression level(r=0.623, P<0.01). Conclusion: CMTM6 is an independent risk factor for the prognosis of lung adenocarcinoma patients. It plays an important role in the occurrence and development of lung adenocarcinoma and it is a potential tumor suppressor gene.
引文
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[15]BEI C H,ZHANG Y,WEI R M,et al.Clinical significance of CMTM4 expression in hepatocellular carcinoma[J/OL].Onco Targets Ther,2017,10:5439-5443[2018-11-30].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694205/.DOI:10.2147/OTT.S149786.
[16]ZHANG H Y,NAN X,LI X F,et al.CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamous cell carcinoma[J].Biochem Biophys Res Commun,2014,447(2):304-310.DOI:10.1016/j.bbrc.2014.03.158.
[17]LIU Q,SU Y,JIANG G C,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,2013,126(16):3006-3012.
[18]高等会,胡浩,方志伟,等.趋化素样因子超家族8研究进展[J].中国医学科学院学报,2016,38(6):746-749.DOI:10.3881/j.issn.1000-503X.2016.06.021.
[2]WOODARD G A,JONES K D,JABLONS D M.Lung cancer staging and prognosis[J].Cancer Treat Res,2016,170(8):47-75.DOI:10.1007/978-3-319-40389-2_3.
[3]孙婷,金晨宇.肺腺癌术后早期复发的影响因素分析[J].实用肿瘤杂志,2017,32(4):359-362.DOI:10.13267/j.cnki.syzlzz.2017.04.017.
[4]KRIS M G,HELLMANN M D,CHAFT J E.Chemotherapy for lung cancers:here to stay[J/OL].Am Soc Clin Oncol Educ Book,2014:e375-e380[2018-11-29].https://meetinglibrary.asco.org/record/89241/edbook.DOI:10.14694/EdBook_AM.2014.34.e375.
[5]WAKELEE H,KELLY K,EDELMAN M J.50 Years of progress in the systemic therapy of non-small cell lung cancer[J/OL].Am Soc Clin Oncol Educ Book,2014:177-189[2018-11-29].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600272/.DOI:10.14694/EdBook_AM.2014.34.177.
[6]AMGARTEN D,BRAGA L P P,DA SILVA A M,et al.MARVEL,a tool for prediction of bacteriophage sequences in metagenomic Bins[J/OL].Front Genet,2018,9:304[2018-11-29].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090037/.DOI:10.3389/fgene.2018.00304.
[7]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.
[8]BURR M L,SPARBIER C E,CHAN Y C,et al.CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity[J/OL].Nature,2017,549(7670):101-105[2018-11-29].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706633/.DOI:10.1038/nature23643.
[9]MEZZADRA R,SUN C,JAE L T,et al.Identification of CMTM6and CMTM4 as PD-L1 protein regulators[J/OL].Nature,2017,549(7670):106-110[2018-11-29].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333292/.DOI:10.1038/nature23669.
[10]MAMESSIER E,BIRNBAUM D J,FINETTI P,et al.CMTM6 stabilizes PD-L1 expression and refines its prognostic value in tumors[J/OL].Ann Transl Med,2018,6(3):54[2018-11-30].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879522/.DOI:10.21037/atm.2017.11.26.
[11]SI J H,ZHANG P 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[2018-11-29].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5273821/.DOI:10.1186/s12957-016-1094-z.
[12]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,2010,123(17):2440-2445.DOI:10.3760/cma.j.issn.0366-6999.2010.17.027.
[13]张晓威,顿耀军,唐旭,等.人类趋化素样因子超家族2在精索静脉曲张大鼠模型中的表达[J].北京大学学报(医学版),2016,48(1):579-583.DOI:10.3969/j.issn.1671-167X.2016.04.002.
[14]SU Y,LIN Y,ZHANG L H,et al.CMTM3 inhibits cell migration and invasion and correlates with favorable prognosis in gastric cancer[J/OL].Cancer Sci,2014,105(1):26-34.DOI:10.1111/cas.12304.
[15]BEI C H,ZHANG Y,WEI R M,et al.Clinical significance of CMTM4 expression in hepatocellular carcinoma[J/OL].Onco Targets Ther,2017,10:5439-5443[2018-11-30].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694205/.DOI:10.2147/OTT.S149786.
[16]ZHANG H Y,NAN X,LI X F,et al.CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamous cell carcinoma[J].Biochem Biophys Res Commun,2014,447(2):304-310.DOI:10.1016/j.bbrc.2014.03.158.
[17]LIU Q,SU Y,JIANG G C,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,2013,126(16):3006-3012.
[18]高等会,胡浩,方志伟,等.趋化素样因子超家族8研究进展[J].中国医学科学院学报,2016,38(6):746-749.DOI:10.3881/j.issn.1000-503X.2016.06.021.