MicroRNA-146a affects the chemotherapeutic sensitivity and prognosis of advanced gastric cancer through the regulation of LIN52

Luo,Zhifen; Li,Xiqing; Zhao,Zunlan; Yang,Xinglong; Xiao,Shengjun; Zhou,Yun

doi:10.3892/ol.2016.5536

MicroRNA-146a affects the chemotherapeutic sensitivity and prognosis of advanced gastric cancer through the regulation of LIN52

Authors:
- Zhifen Luo
- Xiqing Li
- Zunlan Zhao
- Xinglong Yang
- Shengjun Xiao
- Yun Zhou
View Affiliations

Affiliations: Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China, Cancer Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Pathology, Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
Published online on: December 27, 2016 https://doi.org/10.3892/ol.2016.5536
Pages: 1386-1392
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to evaluate the correlation between the expression of microRNA-146a (miR-146a) and its target gene, LIN52, in advanced gastric cancer, and determine their potential effects on chemotherapeutic sensitivity and prognosis. Total RNA was extracted from 93 tissue samples of advanced gastric cancer and corresponding adjacent non‑tumor tissues to quantify the relative expression levels of miR‑146a using reverse transcription‑quantitative polymerase chain reaction analysis. The expression of LIN52 was detected in tumors and normal tissues using immunohistochemical analysis. Correlation analysis was performed to assess the correlation between the expression of miR‑146a and LIN52 and clinicopathological parameters of gastric cancer, including clinical diagnostic specificity, clinical tumor‑necrosis‑metastasis staging, lymph node metastasis, differentiation grade, chemotherapeutic sensitivity and prognosis. The expression of miR‑146a in advanced gastric cancer tissues was lower, compared with that in the adjacent non‑tumor tissues, and was negatively correlated with lymph node metastasis (P<0.05). Gastric cancer tissues with a low expression level of miR146a exhibited an increased expression level of LIN52 (P<0.05). Receiver operating characteristic curve regression analysis showed that miR‑146a had 98% sensitivity in distinguishing gastric cancer tissues and adjacent non‑tumor tissues. A high expression of miR‑146a in gastric cancer was associated with improved treatment efficacy in patients. The chemotherapeutic sensitivity of patients with tumors expressing high levels of miR‑146a was significantly higher, compared with that of patients with tumors expressing low levels of miR‑146a (P<0.05). The expression of miR‑146a was low in advanced gastric cancer tissues. As a tumor suppressor gene in advanced gastric cancer, miR‑146a had a significant negative correlation with LIN52. High expression levels of miR‑146a in advanced gastric cancer tissue may be associated with improved treatment efficacy of chemotherapy, suggesting that miR‑146a may be a molecular marker for the diagnosis, prediction of treatment efficacy and prognosis of advanced gastric cancer.

View Figures

View References

1	Yang T, Zeng H, Chen W, Zheng R, Zhang Y, Li Z, Qi J, Wang M, Chen T, Lou J, et al: Helicobacter pylori infection, H19 and LINC00152 expression in serum and risk of gastric cancer in a Chinese population. Cancer Epidemiol. 44:147–153. 2016. View Article : Google Scholar : PubMed/NCBI
2	Colquhoun A, Arnold M, Ferlay J, Goodman KJ, Forman D and Soerjomataram I: Global patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut. 64:1881–1882. 2015. View Article : Google Scholar : PubMed/NCBI
3	Sempere LF: Integrating contextual miRNA and protein signatures for diagnostic and treatment decisions in cancer. Expert Rev Mol Diagn. 11:813–827. 2011. View Article : Google Scholar : PubMed/NCBI
4	Imam JS, Buddavarapu K, LeeChang JS, Ganapathy S, Camosy C, Chen Y and Rao MK: MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers. Oncogene. 29:4971–4979. 2010. View Article : Google Scholar : PubMed/NCBI
5	Jin ZW, Jiang W and Wang L: Biomarkers for gastric cancer: Progression in early diagnosis and prognosis (Review). Oncol Lett. 9:1502–1508. 2015.PubMed/NCBI
6	Yao Q, Cao Z, Tu C, Zhao Y, Liu H and Zhang S: MicroRNA-146a acts as a metastasis suppressor in gastric cancer by targeting WASF2. Cancer Lett. 335:219–224. 2013. View Article : Google Scholar : PubMed/NCBI
7	Hou Z, Xie L, Yu L, Qian X and Liu B: MicroRNA-146a is down-regulated in gastric cancer and regulates cell proliferation and apoptosis. Med Oncol. 29:886–892. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kogo R, Mimori K, Tanaka F, Komune S and Mori M: Clinical significance of miR-146a in gastric cancer cases. Clin Cancer Res. 17:4277–4284. 2011. View Article : Google Scholar : PubMed/NCBI
9	Boichuk S, Parry JA, Makielski KR, Litovchick L, Baron JL, Zewe JP, Wozniak A, Mehalek KR, Korzeniewski N, Seneviratne DS, et al: The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res. 73:5120–5129. 2013. View Article : Google Scholar : PubMed/NCBI
10	Grimson A, Farh KK, Johnston WK, GarrettEngele P, Lim LP and Bartel DP: MicroRNA targeting specificity in mammals: Determinants beyond seed pairing. Mol Cell. 27:91–105. 2007. View Article : Google Scholar : PubMed/NCBI
11	Jensen EH and Tuttle TM: Preoperative staging and postoperative surveillance for gastric cancer. Surg Oncol Clin N Am. 16:329–342. 2007. View Article : Google Scholar : PubMed/NCBI
12	Duan X, Cao W, Wang L, Liu S, Liu Z, Zhang B, Yang H, Feng T, Zhang J, Zhang X, et al: Genetic variants in TERT are associated with risk of gastric cancer in a Chinese Han population. Oncotarget. Nov 4–2016.(Epub ahead of print). View Article : Google Scholar
13	Takahashi TY, Saikawa Y and Kitagawa Y: Gastric cancer: Current status of diagnosis and treatment. Cancers (Basel). 5:48–63. 2013. View Article : Google Scholar : PubMed/NCBI
14	Matsumoto K, Ueyama H, Matsumoto K, Akazawa Y, Komori H, Takeda T, Murakami T, Asaoka D, Hojo M, Tomita N, et al: Clinicopathological features of alpha-fetoprotein producing early gastric cancer with enteroblastic differentiation. World J Gastroenterol. 22:8203–8210. 2016. View Article : Google Scholar : PubMed/NCBI
15	He CZ, Zhang KH, Li Q, Liu XH, Hong Y and Lv NH: Combined use of AFP, CEA, CA125 and CAl9-9 improves the sensitivity for the diagnosis of gastric cancer. BMC Gastroenterol. 13:872013. View Article : Google Scholar : PubMed/NCBI
16	Wu WY, Xue XY, Chen ZJ, Han SL, Huang YP, Zhang LF, Zhu GB and Shen X: Potentially predictive microRNAs of gastric cancer with metastasis to lymph node. World J Gastroenterol. 17:3645–3651. 2011. View Article : Google Scholar : PubMed/NCBI
17	Liu HS and Xiao HS: MicroRNAs as potential biomarkers for gastric cancer. World J Gastroenterol. 20:12007–12017. 2014. View Article : Google Scholar : PubMed/NCBI
18	Cui L, Zhang X, Ye G, Zheng T, Song H, Deng H, Xiao B, Xia T, Yu X, Le Y and Guo J: Gastric juice MicroRNAs as potential biomarkers for the screening of gastric cancer. Cancer. 119:1618–1626. 2013. View Article : Google Scholar : PubMed/NCBI
19	Liu JL, Gao W, Kang QM, Zhang XJ and Yang SG: Prognostic value of survivin in patients with gastric cancer: A systematic review with meta-analysis. PLoS One. 8:e719302013. View Article : Google Scholar : PubMed/NCBI
20	Cerne JZ, Gersak K and Novakovic S: The influence of the genetic variant within miRNA-binding site in estrogen receptor alpha gene on the risk of breast cancer in postmenopausal women on hormone replacement therapy. Cancer Biomark. 8:123–128. 2010. View Article : Google Scholar : PubMed/NCBI
21	Kim BH, Hong SW, Kim A, Choi SH and Yoon SO: Prognostic implications for high expression of oncogenic microRNAs in advanced gastric carcinoma. J Surg Oncol. 107:505–510. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wang J, Song YX and Wang ZN: Non-coding RNAs in gastric cancer. Gene. 560:1–8. 2015. View Article : Google Scholar : PubMed/NCBI
23	Zandberga E, Kozirovskis V, Ābols A, Andrējeva D, Purkalne G and Linē A: Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer. Genes Chromosomes Cancer. 52:356–369. 2013. View Article : Google Scholar : PubMed/NCBI
24	Verma M, Lam TK, Hebert E and Divi RL: Extracellular vesicles: Potential applications in cancer diagnosis prognosis, and epidemiology. BMC Clin Pathol. 15:62015. View Article : Google Scholar : PubMed/NCBI
25	Migliore C and Giordano S: Resistance to targeted therapies: A role for microRNAs? Trends Mol Med. 19:633–642. 2013. View Article : Google Scholar : PubMed/NCBI
26	Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
27	Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M, Benjamin H, Shabes N, Tabak S, Levy A, et al: MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol. 26:462–429. 2008. View Article : Google Scholar : PubMed/NCBI
28	Li C, Li JF, Cai Q, Qiu QQ, Yan M, Liu BY and Zhu ZG: MiRNA-199a-3p: A potential circulating diagnostic biomarker for early gastric cancer. J Surg Oncol. 108:89–92. 2013. View Article : Google Scholar : PubMed/NCBI
29	Cai H, Yuan Y, Hao YF, Guo TK, Wei X and Zhang YM: Plasma microRNAs serve as novel potential biomarkers for early detection of gastric cancer. Med Oncol. 30:4522013. View Article : Google Scholar : PubMed/NCBI
30	Shah MA and Schwartz GK: Cell cycle-mediated drug resistance: An emerging concept in cancer therapy. Clin Cancer Res. 7:2168–2181. 2001.PubMed/NCBI
31	Litovchick L, Florens LA, Swanson SK, Washburn MP and DeCaprio JA: DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 25:801–813. 2011. View Article : Google Scholar : PubMed/NCBI
32	Sadasivam SS, Duan S and DeCaprio JA: The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev. 26:474–489. 2012. View Article : Google Scholar : PubMed/NCBI
33	Xie L, Jing R, Qi J, Lin Z and Ju S: Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies. Blood Rev. 29:33–44. 2015. View Article : Google Scholar : PubMed/NCBI
34	Rotkrua P, Shimada S, Mogushi K, Akiyama Y, Tanaka H and Yuasa Y: Circulating microRNAs as biomarkers for early detection of diffuse-type gastric cancer using a mouse model. Br J Cancer. 108:932–940. 2013. View Article : Google Scholar : PubMed/NCBI
35	Tsujiura M, Komatsu S, Ichikawa D, Shiozaki A, Konishi H, Takeshita H, Moriumura R, Nagata H, Kawaguchi T, Hirajima S, et al: Circulating miR-18a in plasma contributes to cancer detection and monitoring in patients with gastric cancer. Gastric Cancer. 18:271–279. 2015. View Article : Google Scholar : PubMed/NCBI
36	Tiberio P, Callari M, Angeloni V, Daidone MG and Appierto V: Challenges in using circulating miRNAs as cancer biomarkers. Biomed Res Int. 2015:7314792015. View Article : Google Scholar : PubMed/NCBI
37	Song J, Bai Z, Han W, Zhang J, Meng H, Bi J, Ma X, Han S and Zhang Z: Identification of suitable reference genes for qPCR analysis of serum microRNA in gastric cancer patients. Dig Dis Sci. 57:897–904. 2012. View Article : Google Scholar : PubMed/NCBI
38	Kroh EM, Parkin RK, Mitchell PS and Tewari M: Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods. 50:298–301. 2010. View Article : Google Scholar : PubMed/NCBI