Xie Kaipeng, Ma Hongxia, Liang Cheng, Wang Cheng, Qin Na, Shen Wei, Gu Yayun, Yan Caiwang, Zhang Kai, Dai Ningbin, Zhu Meng, Wu Shuangshuang, Wang Hui, Dai Juncheng, Jin Guangfu, Shen Hongbing, Hu Zhibin
Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Oncotarget. 2015 Dec 15;6(40):42781-92. doi: 10.18632/oncotarget.5840.
Emerging evidence suggested that upregulation of miR-155 could serve as a promising marker for the diagnosis and prognosis of non-small cell lung cancer (NSCLC). In the present study, we genotyped rs767649 (A > T) located in miR-155 regulation region in 1341 cases and 1982 controls, and analyzed the associations of rs767649 with NSCLC risk and survival. Consequently, rs767649 exhibited the significant associations with the risk (adjusted OR = 1.12, 95% CI = 1.01-1.24, P = 0.031) and prognosis of NSCLC (adjusted HR = 1.17, 95% CI = 1.03-1.32, P = 0.014). Meanwhile, rs767649 specifically interacted with radio-chemotherapy (P(int) = 0.013), and patients with both the rs767649-TT genotype and radio-chemotherapy had the highest hazard ratio (adjusted HR = 1.65, 95% CI = 1.26-2.16, P < 0.001). Furthermore, using functional assays and The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma (LUAD) dataset, we found that rs767649 variant allele could increase the transcriptional activity of miR-155, which in turn facilitated tumor growth and metastasis by inhibiting HBP1, TJP1, SMAD5 and PRKAR1A expression. Our findings suggested that rs767649 A > T might contribute to the increased risk and poor prognosis of NSCLC, highlighting the importance of rs767649 in the prevention and therapy of NSCLC.
新出现的证据表明，miR-155的上调可能成为非小细胞肺癌（NSCLC）诊断和预后的一个有前景的标志物。在本研究中，我们对1341例病例和1982例对照中位于miR-155调控区域的rs767649（A>T）进行基因分型，并分析rs767649与NSCLC风险和生存的关联。结果显示，rs767649与NSCLC的风险（校正OR=1.12，95%CI=1.01-1.24，P=0.031）和预后（校正HR=1.17，95%CI=1.03-1.32，P=0.014）存在显著关联。同时，rs767649与放化疗存在特异性相互作用（P(int)=0.013），rs767649-TT基因型且接受放化疗的患者具有最高的风险比（校正HR=1.65，95%CI=1.26-2.16，P<(0.001)）。此外，通过功能试验和癌症基因组图谱（TCGA）肺腺癌（LUAD）数据集，我们发现rs767649变异等位基因可增加miR-155的转录活性，进而通过抑制HBP1、TJP1、SMAD5和PRKAR1A的表达促进肿瘤生长和转移。我们的研究结果表明，rs767649 A>T可能导致NSCLC风险增加和预后不良，凸显了rs767649在NSCLC预防和治疗中的重要性。
