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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2016

Open Access 01-12-2016 | Research

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Authors: Yang Liu, Yumei Li, Rui Wang, Shukui Qin, Jing Liu, Fang Su, Yan Yang, Fuyou Zhao, Zishu Wang, Qiong Wu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

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Abstract

Background

Emerging evidence demonstrates that microRNAs (miRNAs) play an important role in regulation of cell growth, invasion and metastasis through inhibiting the expression of their targets. It has been reported that miR-130a-3p controls cell growth, migration and invasion in a variety of cancer cells. However, it is unclear whether miR-130a-3p regulates epithelial-mesenchymal transition (EMT) in drug resistant cancer cells. Therefore, in the current study, we explore the role and molecular mechanisms of miR-130a-3p in gemcitabine resistant (GR) hepatocellular carcinoma (HCC) cells.

Methods

The real-time RT-PCR was used to measure the miR-130a-3p expression in GR HCC cells compared with their parental cells. The wound healing assay was conducted to determine the cell migratory activity in GR HCC cells treated with miR-130a-3p mimics. The migration and invasion assays were also performed to explore the role of miR-130a-3p in GR HCC cells. Western blotting analysis was used to measure the expression of Smad4, E-cadherin, Vimentin, and MMP-2 in GR HCC cells after depletion of Smad4. The luciferase assay was conducted to validate whether Smad4 is a target of miR-130a-3p. The student t-test was used to analyze our data.

Results

We found the down-regulation of miR-130a-3p in GR HCC cells. Moreover, we validate the Smad4 as a potential target of miR-130a-3p. Furthermore, overexpression of miR-130a-3p suppressed Smad4 expression, whereas inhibition of miR-130a-3p increased Smad4 expression. Consistently, overexpression of miR-130a-3p or down-regulation of Smad4 suppressed the cell detachment, attachment, migration, and invasion in GR HCC cells.

Conclusions

Our findings provide a molecular insight on understanding drug resistance in HCC cells. Therefore, activation of miR-130a-3p or inactivation of Smad4 could be a novel approach for the treatment of HCC.
Literature
1.
2.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed
3.
4.
Mileo AM, Mattarocci S, Matarrese P, Anticoli S, Abbruzzese C, Catone S, et al. Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation. J Exp Clin Cancer Res. 2015;34:140.PubMedCentralCrossRefPubMed
5.
Kawano M, Tanaka K, Itonaga I, Ikeda S, Iwasaki T, Tsumura H. microRNA-93 promotes cell proliferation via targeting of PTEN in Osteosarcoma cells. J Exp Clin Cancer Res. 2015;34:76.PubMedCentralCrossRefPubMed
6.
Zhang GJ, Li JS, Zhou H, Xiao HX, Li Y, Zhou T. MicroRNA-106b promotes colorectal cancer cell migration and invasion by directly targeting DLC1. J Exp Clin Cancer Res. 2015;34:73.PubMedCentralCrossRefPubMed
7.
Wang H, Guan X, Tu Y, Zheng S, Long J, Li S, et al. MicroRNA-29b attenuates non-small cell lung cancer metastasis by targeting matrix metalloproteinase 2 and PTEN. J Exp Clin Cancer Res. 2015;34:59.PubMedCentralCrossRefPubMed
8.
Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, et al. Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist Updat. 2010;13:109–18.PubMedCentralCrossRefPubMed
9.
Zhou Y, Huang Z, Wu S, Zang X, Liu M, Shi J. miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST. J Exp Clin Cancer Res. 2014;33:12.PubMedCentralCrossRefPubMed
10.
Qin J, Luo M, Qian H, Chen W. Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1. Gene. 2014;538:342–7.CrossRefPubMed
11.
Shi L, Chen ZG, Wu LL, Zheng JJ, Yang JR, Chen XF, et al. miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. Asian Pac J Cancer Prev. 2014;15:10439–44.CrossRefPubMed
12.
Liu K, Liu S, Zhang W, Ji B, Wang Y, Liu Y. miR222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma. Int J Oncol. 2014;45:1537–46.PubMed
13.
Mao K, Zhang J, He C, Xu K, Liu J, Sun J, et al. Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib. Cancer Lett. 2014;352:245–52.CrossRefPubMed
14.
Koga C, Kobayashi S, Nagano H, Tomimaru Y, Hama N, Wada H, et al. Reprogramming using microRNA-302 improves drug sensitivity in hepatocellular carcinoma cells. Ann Surg Oncol. 2014;21 Suppl 4:S591–600.CrossRefPubMed
15.
Yang T, Zheng ZM, Li XN, Li ZF, Wang Y, Geng YF, et al. MiR-223 modulates multidrug resistance via downregulation of ABCB1 in hepatocellular carcinoma cells. Exp Biol Med (Maywood). 2013;238:1024–32.CrossRef
16.
Xu H, Zhao L, Fang Q, Sun J, Zhang S, Zhan C, et al. MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1alpha. PLoS One. 2014;9:e115565.PubMedCentralCrossRefPubMed
17.
Ma J, Guo R, Wang T, Pan X, Lei X. Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3′UTR is associated with fluorouracil resistance of hepatocellular carcinoma. Mol Med Rep. 2015;11:677–81.PubMed
18.
Liu N, Zuo C, Wang X, Chen T, Yang D, Wang J, et al. miR-942 decreases TRAIL-induced apoptosis through ISG12a downregulation and is regulated by AKT. Oncotarget. 2014;5:4959–71.PubMedCentralCrossRefPubMed
19.
Tang J, Tao ZH, Wen D, Wan JL, Liu DL, Zhang S, et al. MiR-612 suppresses the stemness of liver cancer via Wnt/beta-catenin signaling. Biochem Biophys Res Commun. 2014;447:210–5.CrossRefPubMed
20.
Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A, Kobayashi S, et al. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 2010;103:1617–26.PubMedCentralCrossRefPubMed
21.
Zhao N, Wang R, Zhou L, Zhu Y, Gong J, Zhuang SM. MicroRNA-26b suppresses the NF-kappaB signaling and enhances the chemosensitivity of hepatocellular carcinoma cells by targeting TAK1 and TAB3. Mol Cancer. 2014;13:35.PubMedCentralCrossRefPubMed
22.
Yang F, Li QJ, Gong ZB, Zhou L, You N, Wang S, et al. MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technol Cancer Res Treat. 2014;13:77–86.PubMed
23.
Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013;58:629–41.CrossRefPubMed
24.
Ma K, He Y, Zhang H, Fei Q, Niu D, Wang D, et al. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. J Biol Chem. 2012;287:5639–49.PubMedCentralCrossRefPubMed
25.
Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL, et al. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2010;70:5184–93.CrossRefPubMed
26.
Xu Y, Xia F, Ma L, Shan J, Shen J, Yang Z, et al. MicroRNA-122 sensitizes HCC cancer cells to adriamycin and vincristine through modulating expression of MDR and inducing cell cycle arrest. Cancer Lett. 2011;310:160–9.PubMed
27.
Yang F, Zhang L, Wang F, Wang Y, Huo XS, Yin YX, et al. Modulation of the unfolded protein response is the core of microRNA-122-involved sensitivity to chemotherapy in hepatocellular carcinoma. Neoplasia. 2011;13:590–600.PubMedCentralCrossRefPubMed
28.
Sorrentino A, Liu CG, Addario A, Peschle C, Scambia G, Ferlini C. Role of microRNAs in drug-resistant ovarian cancer cells. Gynecol Oncol. 2008;111:478–86.CrossRefPubMed
29.
Dai Y, Xie CH, Neis JP, Fan CY, Vural E, Spring PM. MicroRNA expression profiles of head and neck squamous cell carcinoma with docetaxel-induced multidrug resistance. Head Neck. 2011;33:786–91.CrossRefPubMed
30.
Acunzo M, Visone R, Romano G, Veronese A, Lovat F, Palmieri D, et al. miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene. 2012;31:634–42.PubMedCentralPubMed
31.
Zhang X, Huang L, Zhao Y, Tan W. Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly. Acta Biochim Biophys Sin (Shanghai). 2013;45:995–1001.CrossRef
32.
Zhou YM, Liu J, Sun W. MiR-130a overcomes gefitinib resistance by targeting met in non-small cell lung cancer cell lines. Asian Pac J Cancer Prev. 2014;15:1391–6.CrossRefPubMed
33.
Fujita Y, Kojima T, Kawakami K, Mizutani K, Kato T, Deguchi T, et al. miR-130a activates apoptotic signaling through activation of caspase-8 in taxane-resistant prostate cancer cells. Prostate. 2015;75:1568–78.CrossRefPubMed
34.
Ouyang M, Li Y, Ye S, Ma J, Lu L, Lv W, et al. MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer. PLoS One. 2014;9:e96228.PubMedCentralCrossRefPubMed
35.
Yang L, Li N, Wang H, Jia X, Wang X, Luo J. Altered microRNA expression in cisplatin-resistant ovarian cancer cells and upregulation of miR-130a associated with MDR1/P-glycoprotein-mediated drug resistance. Oncol Rep. 2012;28:592–600.PubMed
36.
Li N, Yang L, Wang H, Yi T, Jia X, Chen C, et al. MiR-130a and MiR-374a Function as Novel Regulators of Cisplatin Resistance in Human Ovarian Cancer A2780 Cells. PLoS One. 2015;10:e0128886.PubMedCentralCrossRefPubMed
37.
Wang R, Li Y, Hou Y, Yang Q, Chen S, Wang X, et al. The PDGF-D/miR-106a/Twist1 pathway orchestrates epithelial-mesenchymal transition in gemcitabine resistance hepatoma cells. Oncotarget. 2015;6:7000–10.PubMedCentralCrossRefPubMed
38.
Kong D, Wang Z, Sarkar SH, Li Y, Banerjee S, Saliganan A, et al. Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells. 2008;26:1425–35.PubMedCentralCrossRefPubMed
39.
Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69:2400–7.PubMedCentralCrossRefPubMed
40.
Wu Q, Wang R, Yang Q, Hou X, Chen S, Hou Y, et al. Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. Oncotarget. 2013;4:1999–2009.PubMedCentralCrossRefPubMed
41.
Yang Q, Huang J, Wu Q, Cai Y, Zhu L, Lu X, et al. Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. Br J Cancer. 2014;110:1958–67.PubMedCentralCrossRefPubMed
42.
Pan Y, Wang R, Zhang F, Chen Y, Lv Q, Long G, et al. MicroRNA-130a inhibits cell proliferation, invasion and migration in human breast cancer by targeting the RAB5A. Int J Clin Exp Pathol. 2015;8:384–93.PubMedCentralPubMed
43.
Hager M, Pedersen CC, Larsen MT, Andersen MK, Hother C, Gronbaek K, et al. MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-beta1 stimulation in granulocytic precursors. Blood. 2011;118:6649–59.CrossRefPubMed
44.
Zumbrennen-Bullough KB, Wu Q, Core AB, Canali S, Chen W, Theurl I, et al. MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription. J Biol Chem. 2014;289:23796–808.PubMedCentralCrossRefPubMed
45.
Li B, Huang P, Qiu J, Liao Y, Hong J, Yuan Y. MicroRNA-130a is down-regulated in hepatocellular carcinoma and associates with poor prognosis. Med Oncol. 2014;31:230.CrossRefPubMed
46.
Motawi TK, Shaker OG, El-Maraghy SA, Senousy MA. Serum MicroRNAs as Potential Biomarkers for Early Diagnosis of Hepatitis C Virus-Related Hepatocellular Carcinoma in Egyptian Patients. PLoS One. 2015;10:e0137706.PubMedCentralCrossRefPubMed
47.
Xu N, Shen C, Luo Y, Xia L, Xue F, Xia Q, et al. Upregulated miR-130a increases drug resistance by regulating RUNX3 and Wnt signaling in cisplatin-treated HCC cell. Biochem Biophys Res Commun. 2012;425:468–72.CrossRefPubMed
48.
Tang L, Pu Y, Wong DK, Liu T, Tang H, Xiang T, et al. The hepatitis B virus-associated estrogen receptor alpha (ERalpha) was regulated by microRNA-130a in HepG2.2.15 human hepatocellular carcinoma cells. Acta Biochim Biophys Sin (Shanghai). 2011;43:640–6.CrossRef
49.
Shi KQ, Lin Z, Chen XJ, Song M, Wang YQ, Cai YJ, et al. Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance. Oncotarget. 2015;6:25093–108.PubMedCentralCrossRefPubMed
50.
Lan X, Lu G, Yuan C, Mao S, Jiang W, Chen Y, et al. Valproic acid (VPA) inhibits the epithelial-mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4. J Cancer Res Clin Oncol. 2015;142:177–85.CrossRefPubMed
51.
Qiao P, Li G, Bi W, Yang L, Yao L, Wu D. microRNA-34a inhibits epithelial mesenchymal transition in human cholangiocarcinoma by targeting Smad4 through transforming growth factor-beta/Smad pathway. BMC Cancer. 2015;15:469.PubMedCentralCrossRefPubMed
52.
Xia X, Wu W, Huang C, Cen G, Jiang T, Cao J, et al. SMAD4 and its role in pancreatic cancer. Tumour Biol. 2015;36:111–9.CrossRefPubMed
53.
54.
Hernanda PY, Chen K, Das AM, Sideras K, Wang W, Li J, et al. SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma. Oncogene. 2015;34:5055–68.CrossRefPubMed
55.
Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, et al. Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res (Phila). 2011;4:1698–709.PubMedCentralCrossRef
56.
Vo DD, Staedel C, Zehnacker L, Benhida R, Darfeuille F, Duca M. Targeting the production of oncogenic microRNAs with multimodal synthetic small molecules. ACS Chem Biol. 2014;9:711–21.CrossRefPubMed
57.
Chen S, Zhu L, Huang J, Cai Y, Lu X, Yang Q, et al. Arsenic trioxide targets miR-125b in glioma cells. Curr Pharm Des. 2014;20:5354–61.CrossRefPubMed
58.
Xia J, Cheng L, Mei C, Ma J, Shi Y, Zeng F, et al. Genistein inhibits cell growth and invasion through regulation of miR-27a in pancreatic cancer cells. Curr Pharm Des. 2014;20:5348–53.CrossRefPubMed
59.
Xia J, Duan Q, Ahmad A, Bao B, Banerjee S, Shi Y, et al. Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. Curr Drug Targets. 2012;13:1750–6.CrossRefPubMed
Metadata
Title
MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells
Authors
Yang Liu
Yumei Li
Rui Wang
Shukui Qin
Jing Liu
Fang Su
Yan Yang
Fuyou Zhao
Zishu Wang
Qiong Wu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-016-0296-0

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