MicroRNA-362 induces cell proliferation and apoptosis resistance in gastric cancer by activation of NF-κB signaling

Journal of Translational Medicine

Wen Li⁴  De Chen¹  Yu-long He²  Wei-ling He²  Yong-zhen Yang³  Ke-Bing Wang⁴  Wei-hua Jian³  Lian-zhou Chen⁴  Jin-tang Xia³ 

[1] Department of General Surgery, The third Affiliated Hospital, Guangzhou Medical University, #63 Duobao Road, Guangzhou, Guangdong 510150, China;Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China;Department of General Surgery, Guangzhou First Municipal People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, China;Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, #58 Zhongshan er Road, Guangzhou, Guangdong 510080, China

关键词: Apoptosis;    Proliferation;    Gastric cancer;    CYLD;    NF-κB;    miR-362;   

Others  :  821678
DOI  :  10.1186/1479-5876-12-33

 received in 2013-12-09, accepted in 2014-01-30,  发布年份 2014

【 摘 要 】

Background

According to cancer-related microRNA (miRNA) expression microarray research available in public databases, miR-362 expression is elevated in gastric cancer. However, the expression and biological role of miR-362 in gastric progression remain unclear.

Methods

miR-362 expression levels in gastric cancer tissues and cell lines were determined using real-time PCR. The roles of miR-362, in promoting gastric cancer cell proliferation and apoptosis resistance, were assessed by different biological assays, such as colony assay, flow cytometry and TUNEL assay. The effect of miR-362 on NF-κB activation was investigated using the luciferase reporter assay, fluorescent immunostaining.

Results

MiR-362 overexpression induced cell proliferation, colony formation, and resistance to cisplatin-induced apoptosis in BGC-823 and SGC-7901 gastric cancer cells. MiR-362 increased NF-κB activity and relative mRNA expression of NF-κB–regulated genes, and induced nuclear translocation of p65. Expression of the tumor suppressor CYLD was inhibited by miR-362 in gastric cancer cells; miR-362 levels were inversely correlated with CYLD expression in gastric cancer tissue. MiR-362 downregulated CYLD expression by binding its 3′ untranslated region. NF-κB activation was mechanistically associated with siRNA-mediated downregulation of CYLD. MiR-362 inhibitor reversed all the effects of miR-362.

Conclusion

The results suggest that miR-362 plays an important role in repressing the tumor suppressor CYLD and present a novel mechanism of miRNA-mediated NF-κB activation in gastric cancer.

【 授权许可】

   
2014 Xia et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Roder DM: The epidemiology of gastric cancer. Gastric Cancer 2002, 5:5-11.
• [2]Gallo A, Cha C: Updates on esophageal and gastric cancers. World J Gastroenterol 2006, 12:3237-3242.
• [3]Gunderson LL: Gastric cancer–patterns of relapse after surgical resection. Semin Radiat Oncol 2002, 12:150-161.
• [4]Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006, 355:11-20.
• [5]Bang YJ, Kim YW, Yang HK, et al.: Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012, 379:315-321.
• [6]Harewood GC: Treatment of gastric cancer. N Engl J Med 2006, 355:1386. author reply 1387-1388
• [7]Mesner PW Jr, Budihardjo II, Kaufmann SH: Chemotherapy-induced apoptosis. Adv Pharmacol 1997, 41:461-499.
• [8]Kaufmann SH, Earnshaw WC: Induction of apoptosis by cancer chemotherapy. Exp Cell Res 2000, 256:42-49.
• [9]Hannun YA: Apoptosis and the dilemma of cancer chemotherapy. Blood 1997, 89:1845-1853.
• [10]Pacifico F, Leonardi A: NF-kappaB in solid tumors. Biochem Pharmaco 2006, 72:1142-1152.
• [11]Greten FR, Eckmann L, Greten TF, et al.: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004, 118:285-296.
• [12]Baldwin AS: Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 2001, 107:241-246.
• [13]Karin M: Nuclear factor-kappaB in cancer development and progression. Nature 2006, 441:431-436.
• [14]Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR: DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. Mol Cell 1998, 1:543-551.
• [15]Meteoglu I, Erdogdu IH, Meydan N, Erkus M, Barutca S: NF-KappaB expression correlates with apoptosis and angiogenesis in clear cell renal cell carcinoma tissues. J Exp Clin Cancer Res 2008, 27:53. BioMed Central Full Text
• [16]Wertz IE, Dixit VM: Signaling to NF-kappaB: regulation by ubiquitination. Cold Spring Harb Perspect Biol 2010, 2:a003350.
• [17]Liu S, Chen ZJ: Expanding role of ubiquitination in NF-kappaB signaling. Cell Res 2011, 21:6-21.
• [18]Tokunaga F, Sakata S, Saeki Y, et al.: Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 2009, 11:123-132.
• [19]Düwel M, Hadian K, Krappmann D: Ubiquitin conjugation and deconjugation in NF-kappaB Signaling. Subcell Biochem 2010, 54:88-99.
• [20]Song L, Liu L, Wu Z, et al.: TGF-beta induces miR-182 to sustain NF-kappaB activation in glioma subsets. J Clin Invest 2012, 122:3563-3578.
• [21]Kovalenko A, Chable-Bessia C, Cantarella G, Israël A, Wallach D, Courtois G: The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 2003, 424:801-805.
• [22]Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G: CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 2003, 424:793-796.
• [23]Sun SC: CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell Death Differ 2010, 17:25-34.
• [24]Brummelkamp TR, Nijman SM, Dirac AM, Bernards R: Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003, 424:797-801.
• [25]Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fässler R: Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 2006, 125:665-677.
• [26]Urbanik T, Köhler BC, Boger RJ, et al.: Down-regulation of CYLD as a trigger for NF-kappaB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells. Int J Oncol 2001, 38:121-131.
• [27]Lee YS, Dutta A: MicroRNAs in cancer. Annu Rev Pathol 2009, 4:199-227.
• [28]Ueda T, Volinia S, Okumura H, et al.: Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol 2010, 11:136-146.
• [29]Guo J, Miao Y, Xiao B, et al.: Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol 2009, 24:652-657.
• [30]Xia L, Zhang D, Du R, et al.: miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer 2008, 123:372-379.
• [31]Chan E, Patel R, Nallur S, et al.: MicroRNA signatures differentiate melanoma subtypes. Cell Cycle 2011, 10:1845-52.
• [32]Smoot DT, Sewchand J, Young K, Desbordes BC, Allen CR, Naab T: A method for establishing primary cultures of human gastric epithelial cells. Methods Cell Sci 2000, 22:133-136.
• [33]Li J, Zhang N, Song LB, et al.: Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res 2008, 14:3319-3326.
• [34]Li J, Shen L, Lu FR, et al.: Plumbagin inhibits cell growth and potentiates apoptosis in human gastric cancer cells in vitro through the NF-kappaB signaling pathway. Acta Pharmacol Sin 2012, 33:242-249.
• [35]Sasaki N, Morisaki T, Hashizume K, et al.: Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 2001, 7:4136-4142.
• [36]Camp ER, Li J, Minnich DJ, et al.: Inducible nuclear factor-kappaB activation contributes to chemotherapy resistance in gastric cancer. J Am Coll Surg 2004, 199:249-258.
• [37]Nishizawa T, Suzuki H: The Role of microRNA in Gastric Malignancy. Int J Mol Sci 2013, 14:9487-9496.
• [38]Qin S, Ai F, Ji WF, Rao W, Zhang HC, Yao WJ: miR-19a promotes cell growth and tumorigenesis through targeting SOCS1 in gastric cancer. Asian Pac J Cancer Prev 2013, 14:835-840.
• [39]Yang SM, Huang C, Li XF, Yu MZ, He Y, Li J: miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Toxicology 2013, 306:162-168.
• [40]Kuphal S, Shaw-Hallgren G, Eberl M, Karrer S, et al.: GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma. Oncogene 2011, 30:4523-4530.
• [41]Massoumi R, Kuphal S, Hellerbrand C, et al.: Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma. J Exp Med 2009, 206:221-232.
• [42]Espinosa L, Cathelin S, D'Altri T, et al.: The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell 2010, 18:268-281.
• [43]Hellerbrand C, Bumes E, Bataille F, Dietmaier W, Massoumi R, Bosserhoff AK: Reduced expression of CYLD in human colon and hepatocellular carcinomas. Carcinogenesis 2007, 28:21-27.
• [44]Varro A, Noble PJ, Pritchard DM, et al.: Helicobacter pylori induces plasminogen activator inhibitor 2 in gastric epithelial cells through nuclear factor-kappaB and RhoA: implications for invasion and apoptosis. Cancer Res 2004, 64:1695-1702.
• [45]Chiba T, Marusawa H, Matsumoto Y, Takai A: Chronic inflammation and gastric cancer development. Nihon Rinsho 2012, 70:1694-1698.
• [46]Zhou C, Li X, Zhang X, et al.: microRNA-372 maintains oncogene characteristics by targeting TNFAIP1 and affects NFkappaB signaling in human gastric carcinoma cells. Int J Oncol 2013, 42:635-642.
• [47]Jono H, Lim JH, Chen LF, et al.: NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. J Biol Chem 2004, 279:36171-36174.
• [48]Wang CY, Mayo MW, Baldwin AS Jr: TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996, 274:784-787.
• [49]Liu T, Liu D, Liu J, et al.: Effect of NF-kappaB inhibitors on the chemotherapy-induced apoptosis of the colon cancer cell line HT-29. Exp Ther Med 2012, 4:716-722.
• [50]Yamamoto Y, Gaynor RB: Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 2001, 107:135-142.