miR-17-92 functions as an oncogene and modulates NF-κB signaling by targeting TRAF3 in MGC-803 human gastric cancer cells

Liu,Fei; Cheng,Li; Xu,Jingjing; Guo,Feng; Chen,Weichang

doi:10.3892/ijo.2018.4543

miR-17-92 functions as an oncogene and modulates NF-κB signaling by targeting TRAF3 in MGC-803 human gastric cancer cells

Authors:
- Fei Liu
- Li Cheng
- Jingjing Xu
- Feng Guo
- Weichang Chen
View Affiliations

Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
Published online on: August 28, 2018 https://doi.org/10.3892/ijo.2018.4543
Pages: 2241-2257

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 miR-17-92 cluster plays either an oncogenic or anti-oncogenic role in cancer progression in diverse human cancers. However, the underlying mechanisms of the miR-17-92 cluster in gastric cancer have not yet been fully elucidated. In this study, the function of the miR-17-92 cluster in diverse aspects of MGC-803 gastric cancer cells was systematically elucidated. The enforced introduction of the miR-17-92 cluster into the MGC-803 cells significantly promoted cell growth due to the increased cellular proliferation and decreased cellular apoptosis, which were detected by CCK-8, cell viability and TUNEL assays. Moreover, the results of western blot analyses revealed that the activated protein kinase B (AKT), extracellular-signal-regulated kinase (ERK) and nuclear factor (NF-κB) signaling pathways were activated in these processes. Moreover, the overexpression of the miR-17-92 cluster markedly enhanced the migratory and invasive abilities of the MGC-803 cells, which was associated with the occurrence of epithelial-mesenchymal transition (EMT). Tumor necrosis factor receptor associated factor 3 (TRAF3), which negatively regulates the NF-κB signaling pathway, was identified as a direct target of miR-17-92. Furthermore, TRAF3 silencing enhanced the oncogenic functions of the miR-17-92 cluster in the MGC-803 cells, including the increased cellular proliferation, migration and invasion. Moreover, immunohistochemical staining and survival analyses of a gastric cancer tissue microarray revealed that TRAF3 functioned as a tumor suppressor in gastric cancer. Taken together, the findings of this study provide new insight into the specific biological functions of the miR-17-92 cluster in gastric cancer progression by directly targeting TRAF3.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
3	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
4	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
5	Zhang C: Novel functions for small RNA molecules. Curr Opin Mol Ther. 11:641–651. 2009.
6	Lujambio A and Lowe SW: The microcosmos of cancer. Nature. 482:347–355. 2012. View Article : Google Scholar : PubMed/NCBI
7	Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
8	Tsai MM, Wang CS, Tsai CY, Huang HW, Chi HC, Lin YH, Lu PH and Lin KH: Potential diagnostic, prognostic and therapeutic targets of MicroRNAs in human gastric cancer. Int J Mol Sci. 17:172016. View Article : Google Scholar
9	He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, et al: A microRNA polycistron as a potential human oncogene. Nature. 435:828–833. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ota A, Tagawa H, Karnan S, Tsuzuki S, Karpas A, Kira S, Yoshida Y and Seto M: Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res. 64:3087–3095. 2004. View Article : Google Scholar : PubMed/NCBI
11	Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y and Takahashi T: A polycistronic microRNA cluster, miR-17-92 is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 65:9628–9632. 2005. View Article : Google Scholar : PubMed/NCBI
12	Farazi TA, Horlings HM, Ten Hoeve JJ, Mihailovic A, Halfwerk H, Morozov P, Brown M, Hafner M, Reyal F, van Kouwenhove M, et al: MicroRNA sequence and expression analysis in breast tumors by deep sequencing. Cancer Res. 71:4443–4453. 2011. View Article : Google Scholar : PubMed/NCBI
13	Chow TF, Mankaruos M, Scorilas A, Youssef Y, Girgis A, Mossad S, Metias S, Rofael Y, Honey RJ, Stewart R, et al: The miR-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol. 183:743–751. 2010. View Article : Google Scholar
14	Zhu H, Han C and Wu T: MiR-17-92 cluster promotes hepatocarcinogenesis. Carcinogenesis. 36:1213–1222. 2015. View Article : Google Scholar : PubMed/NCBI
15	Yu G, Tang JQ, Tian ML, Li H, Wang X, Wu T, Zhu J, Huang SJ and Wan YL: Prognostic values of the miR-17-92 cluster and its paralogs in colon cancer. J Surg Oncol. 106:232–237. 2012. View Article : Google Scholar
16	Li H, Wu Q, Li T, Liu C, Xue L, Ding J, Shi Y and Fan D: The miR-17-92 cluster as a potential biomarker for the early diagnosis of gastric cancer: Evidence and literature review. Oncotarget. 8:45060–45071. 2017.PubMed/NCBI
17	Mogilyansky E and Rigoutsos I: The miR-17/92 cluster: A comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 20:1603–1614. 2013. View Article : Google Scholar : PubMed/NCBI
18	Valladares-Ayerbes M, Blanco M, Haz M, Medina V, Iglesias-Díaz P, Lorenzo-Patiño MJ, Reboredo M, Santamarina I, Figueroa A, Antón-Aparicio LM, et al: Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer. Int J Oncol. 39:1253–1264. 2011.PubMed/NCBI
19	Ren C, Wang W, Han C, Chen H, Fu D, Luo Y, Yao H, Wang D, Ma L, Zhou L, et al: Expression and prognostic value of miR-92a in patients with gastric cancer. Tumour Biol. 37:9483–9491. 2016. View Article : Google Scholar : PubMed/NCBI
20	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
21	Wu Q, Luo G, Yang Z, Zhu F, An Y, Shi Y and Fan D: miR-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells. FEBS Lett. 588:2055–2062. 2014. View Article : Google Scholar : PubMed/NCBI
22	Park D, Lee SC, Park JW, Cho SY and Kim HK: Overexpression of miR-17 in gastric cancer is correlated with proliferation-associated oncogene amplification. Pathol Int. 64:309–314. 2014. View Article : Google Scholar : PubMed/NCBI
23	Wu W, Takanashi M, Borjigin N, Ohno SI, Fujita K, Hoshino S, Osaka Y, Tsuchida A and Kuroda M: MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis. Br J Cancer. 108:653–661. 2013. View Article : Google Scholar : PubMed/NCBI
24	Wu Q, Yang Z, An Y, Hu H, Yin J, Zhang P, Nie Y, Wu K, Shi Y and Fan D: MiR-19a/b modulate the metastasis of gastric cancer cells by targeting the tumour suppressor MXD1. Cell Death Dis. 5:e11442014. View Article : Google Scholar : PubMed/NCBI
25	Wang F, Li T, Zhang B, Li H, Wu Q, Yang L, Nie Y, Wu K, Shi Y and Fan D: MicroRNA-19a/b regulates multidrug resistance in human gastric cancer cells by targeting PTEN. Biochem Biophys Res Commun. 434:688–694. 2013. View Article : Google Scholar : PubMed/NCBI
26	Wu Q, Yang Z, Wang F, Hu S, Yang L, Shi Y and Fan D: MiR-19b/20a/92a regulates the self-renewal and proliferation of gastric cancer stem cells. J Cell Sci. 126:4220–4229. 2013. View Article : Google Scholar : PubMed/NCBI
27	Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e452001. View Article : Google Scholar : PubMed/NCBI
28	Liu F, Zhou J, Zhou P, Chen W and Guo F: The ubiquitin ligase CHIP inactivates NF-κB signaling and impairs the ability of migration and invasion in gastric cancer cells. Int J Oncol. 46:2096–2106. 2015. View Article : Google Scholar : PubMed/NCBI
29	Zhou P, Ma L, Zhou J, Jiang M, Rao E, Zhao Y and Guo F: miR-17-92 plays an oncogenic role and conveys chemo-resistance to cisplatin in human prostate cancer cells. Int J Oncol. 48:1737–1748. 2016. View Article : Google Scholar : PubMed/NCBI
30	Xu J, Zhou P, Wang W, Sun A and Guo F: RelB, together with RelA, sustains cell survival and confers proteasome inhibitor sensitivity of chronic lymphocytic leukemia cells from bone marrow. J Mol Med (Berl). 92:77–92. 2014. View Article : Google Scholar
31	Li L, Shi B, Chen J, Li C, Wang S, Wang Z and Zhu G: An E2F1/MiR-17-92 Negative Feedback Loop mediates proliferation of Mouse Palatal Mesenchymal Cells. Sci Rep. 7:51482017. View Article : Google Scholar : PubMed/NCBI
32	Li L, Song W, Yan X, Li A, Zhang X, Li W, Wen X, Zhou L, Yu D, Hu JF, et al: Friend leukemia virus integration 1 promotes tumorigenesis of small cell lung cancer cells by activating the miR-17-92 pathway. Oncotarget. 8:41975–41987. 2017.PubMed/NCBI
33	Chen Y, Tian L, Wan S, Xie Y, Chen X, Ji X, Zhao Q, Wang C, Zhang K, Hock JM, et al: MicroRNA-17-92 cluster regulates pancreatic beta-cell proliferation and adaptation. Mol Cell Endocrinol. 437:213–223. 2016. View Article : Google Scholar : PubMed/NCBI
34	Zhou J, Jiang J, Wang S and Xia X: Oncogenic role of microRNA 20a in human uveal melanoma. Mol Med Rep. 14:1560–1566. 2016. View Article : Google Scholar : PubMed/NCBI
35	Zhang W, Lei C, Fan J and Wang J: miR-18a promotes cell proliferation of esophageal squamous cell carcinoma cells by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis. Biochem Biophys Res Commun. 477:144–149. 2016. View Article : Google Scholar : PubMed/NCBI
36	Li Y, Deutzmann A, Choi PS, Fan AC and Felsher DW: BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia. Oncotarget. 7:26926–26934. 2016.PubMed/NCBI
37	Gupta S, Read DE, Deepti A, Cawley K, Gupta A, Oommen D, Verfaillie T, Matus S, Smith MA, Mott JL, et al: Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. Cell Death Dis. 3:e3332012. View Article : Google Scholar : PubMed/NCBI
38	Zhang X, Chen Y, Zhao P, Zang L, Zhang Z and Wang X: MicroRNA-19a functions as an oncogene by regulating PTEN/ AKT/pAKT pathway in myeloma. Leuk Lymphoma. 58:932–940. 2017. View Article : Google Scholar
39	Jia Q, Sun H, Xiao F, Sai Y, Li Q, Zhang X, Yang S, Wang H, Wang H, Yang Y, et al: miR-17-92 promotes leukemogenesis in chronic myeloid leukemia via targeting A20 and activation of NF-κB signaling. Biochem Biophys Res Commun. 487:868–874. 2017. View Article : Google Scholar : PubMed/NCBI
40	Trenkmann M, Brock M, Gay RE, Michel BA, Gay S and Huber LC: Tumor necrosis factor α-induced microRNA-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling. Arthritis Rheum. 65:916–927. 2013. View Article : Google Scholar : PubMed/NCBI
41	Jin HY, Oda H, Lai M, Skalsky RL, Bethel K, Shepherd J, Kang SG, Liu WH, Sabouri-Ghomi M, Cullen BR, et al: MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways. EMBO J. 32:2377–2391. 2013. View Article : Google Scholar : PubMed/NCBI
42	Quattrochi B, Gulvady A, Driscoll DR, Sano M, Klimstra DS, Turner CE and Lewis BC: MicroRNAs of the mir-17~92 cluster regulate multiple aspects of pancreatic tumor development and progression. Oncotarget. 8:35902–35918. 2017. View Article : Google Scholar : PubMed/NCBI
43	Cohen R, Greenberg E, Nemlich Y, Schachter J and Markel G: miR-17 regulates melanoma cell motility by inhibiting the translation of ETV1. Oncotarget. 6:19006–19016. 2015. View Article : Google Scholar : PubMed/NCBI
44	Li J, Yang S, Yan W, Yang J, Qin YJ, Lin XL, Xie RY, Wang SC, Jin W, Gao F, et al: MicroRNA-19 triggers epithelial-mesenchymal transition of lung cancer cells accompanied by growth inhibition. Lab Invest. 95:1056–1070. 2015. View Article : Google Scholar : PubMed/NCBI
45	Bahari F, Emadi-Baygi M and Nikpour P: miR-17-92 host gene, uderexpressed in gastric cancer and its expression was negatively correlated with the metastasis. Indian J Cancer. 52:22–25. 2015. View Article : Google Scholar
46	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
47	Gilmore TD: Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene. 25:6680–6684. 2006. View Article : Google Scholar : PubMed/NCBI
48	He JQ, Oganesyan G, Saha SK, Zarnegar B and Cheng G: TRAF3 and its biological function. Adv Exp Med Biol. 597:48–59. 2007. View Article : Google Scholar : PubMed/NCBI
49	Arch RH, Gedrich RW and Thompson CB: Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death. Genes Dev. 12:2821–2830. 1998. View Article : Google Scholar : PubMed/NCBI
50	Liao G, Zhang M, Harhaj EW and Sun SC: Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem. 279:26243–26250. 2004. View Article : Google Scholar : PubMed/NCBI
51	Asano N, Imatani A, Watanabe T, Fushiya J, Kondo Y, Jin X, Ara N, Uno K, Iijima K, Koike T, et al: Cdx2 expression and intestinal metaplasia induced by H. pylori infection of gastric cells is regulated by NOD1-mediatedinnate immune responses. Cancer Res. 76:1135–1145. 2016. View Article : Google Scholar : PubMed/NCBI
52	Malcomson FC, Willis ND, McCallum I, Xie L, Lagerwaard B, Kelly S, Bradburn DM, Belshaw NJ, Johnson IT and Mathers JC: Non-digestible carbohydrates supplementation increases miR-32 expression in the healthy human colorectal epithelium: A randomized controlled trial. Mol Carcinog. 56:2104–2111. 2017. View Article : Google Scholar : PubMed/NCBI
53	Liu J, Li D, Dang L, Liang C, Guo B, Lu C, He X, Cheung HY, He B, Liu B, et al: Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer. Sci Rep. 7:404872017. View Article : Google Scholar : PubMed/NCBI
54	Fang Y, Chen H, Hu Y, Li Q, Hu Z, Ma T and Mao X: Burkholderia pseudomallei-derived miR-3473 enhances NF-κB via targeting TRAF3 and is associated with different inflammatory responses compared to Burkholderia thailandensis in murine macrophages. BMC Microbiol. 16:2832016. View Article : Google Scholar
55	Zou M, Wang F, Jiang A, Xia A, Kong S, Gong C, Zhu M, Zhou X, Zhu J, Zhu W, et al: MicroRNA-3178 ameliorates inflammation and gastric carcinogenesis promoted by Helicobacter pylori new toxin, Tip-α, by targeting TRAF3. Helicobacter. 22:222017. View Article : Google Scholar
56	Gu H, Yu J, Dong D, Zhou Q, Wang JY and Yang P: The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells. Toxicol Sci. 144:186–196. 2015. View Article : Google Scholar :
57	Yarbrough ML, Zhang K, Sakthivel R, Forst CV, Posner BA, Barber GN, White MA and Fontoura BM: Primate-specific miR-576-3p sets host defense signalling threshold. Nat Commun. 5:49632014. View Article : Google Scholar : PubMed/NCBI