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Int J Cancer. 2019 Jan 15;144(2):251-262. doi: 10.1002/ijc.31656. Epub 2018 Oct 30.

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients.

Cheng L1,2, Qiu L1,2,3, Zhang R1,2, Qian D1,2,4,5, Wang M1,2, Sun M1,2,6, Zhu X1,2,3, Wang Y1,2,7, Guo W2,3, Wei Q1,2,4,5.

Author information

1
Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
2
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
3
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
4
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
5
Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.
6
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
7
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Abstract

We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.

KEYWORDS:

MTORC1; gastric cancer; gene expression; genetic variants; survival

PMID:
29978580
DOI:
10.1002/ijc.31656

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