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Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Metastasis | Research article

miR-196a-5p promotes metastasis of colorectal cancer via targeting IκBα

Authors: He Xin, Chuanzhuo Wang, Zhaoyu Liu

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

MicroRNA-196a-5p (miR-196a-5p) has been reported to be involved in the metastatic process of several cancers. In present work, we aimed to investigate the effects of miR-196a-5p and its potential target IκBα on migration, invasion and epithelial-mesenchymal transition (EMT) of colorectal cancer (CRC) cells.

Methods

CCK-8 assay, wound healing assay and cell invasion assay were performed to evaluate the cell proliferation, migration and invasion. In vivo metastasis models were used to investigate the tumor metastasis ability. Real-time PCR, immunofluorescence staining or western blot were utilized to detect the expression of miR-196a-5p, IκBα, p-IκBα, nuclear p65 and EMT markers including E-cadherin, N-cadherin and fibronectin. Dual luciferase reporter assay was carried out to determine whether there is a direct interaction between miR-196a-5p and IκBα mRNA.

Results

Using SW480 cell with miR-196-5p over-expressed plus SW620 and HCT116 cells with miR-196a-5p knockdown, we found that miR-196a-5p promoted cell proliferation, migration and invasion in vitro and facilitated liver metastasis in vivo. We also observed that miR-196a-5p knockdown or NF-κB pathway inhibition up-regulated E-cadherin while down-regulated N-cadherin and fibronectin. By contrast, miR-196a-5p over-expression promoted EMT process of CRC. Data of dual luciferase reporter assay indicated that miR-196a-5p targeted the IκBα. Moreover, miR-196a-5p down-regulated IκBα expression while up-regulated nuclear p65 expression. Additionally, over-expression of IκBα in CRC cells attenuated the effects of miR-196a-5p on cell migration, invasion and EMT.

Conclusions

miR-196a-5p may play a key role in EMT, invasion and metastasis of CRC cells via targeting the IκBα.
Appendix
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Literature
1.
go back to reference Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383(9927):1490–502.CrossRef Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383(9927):1490–502.CrossRef
2.
go back to reference Kekelidze M, D'Errico L, Pansini M, Tyndall A, Hohmann J. Colorectal cancer: current imaging methods and future perspectives for the diagnosis, staging and therapeutic response evaluation. World J Gastroenterol. 2013;19(46):8502–14.CrossRef Kekelidze M, D'Errico L, Pansini M, Tyndall A, Hohmann J. Colorectal cancer: current imaging methods and future perspectives for the diagnosis, staging and therapeutic response evaluation. World J Gastroenterol. 2013;19(46):8502–14.CrossRef
3.
go back to reference Worni M, Shah KN, Clary BM. Colorectal cancer with potentially resectable hepatic metastases: optimizing treatment. Curr Oncol Rep. 2014;16(10):407.CrossRef Worni M, Shah KN, Clary BM. Colorectal cancer with potentially resectable hepatic metastases: optimizing treatment. Curr Oncol Rep. 2014;16(10):407.CrossRef
4.
go back to reference Van Cutsem E, Oliveira J. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):61–3.PubMed Van Cutsem E, Oliveira J. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):61–3.PubMed
5.
go back to reference Li S, Wang J, Lu Y, Fan D. Screening and early diagnosis of colorectal cancer in China: a 12 year retrospect (1994-2006). J Cancer Res Clin Oncol. 2007;133(10):679–86.CrossRef Li S, Wang J, Lu Y, Fan D. Screening and early diagnosis of colorectal cancer in China: a 12 year retrospect (1994-2006). J Cancer Res Clin Oncol. 2007;133(10):679–86.CrossRef
6.
go back to reference Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9(10):775–89.CrossRef Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9(10):775–89.CrossRef
7.
go back to reference Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3’UTR evolution. Cell. 2005;123(6):1133–46.CrossRef Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3’UTR evolution. Cell. 2005;123(6):1133–46.CrossRef
8.
go back to reference Zhao S, Sun H, Jiang W, Mi Y, Zhang D, Wen Y, et al. miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFbeta-mediated epithelial to mesenchymal transition. Mol Cancer. 2017;16(1):12.CrossRef Zhao S, Sun H, Jiang W, Mi Y, Zhang D, Wen Y, et al. miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFbeta-mediated epithelial to mesenchymal transition. Mol Cancer. 2017;16(1):12.CrossRef
9.
go back to reference Ge J, Chen Z, Li R, Lu T, Xiao G. Upregulation of microRNA-196a and microRNA-196b cooperatively correlate with aggressive progression and unfavorable prognosis in patients with colorectal cancer. Cancer Cell Int. 2014;14(1):128.CrossRef Ge J, Chen Z, Li R, Lu T, Xiao G. Upregulation of microRNA-196a and microRNA-196b cooperatively correlate with aggressive progression and unfavorable prognosis in patients with colorectal cancer. Cancer Cell Int. 2014;14(1):128.CrossRef
10.
go back to reference Ye Y, Yang S, Han Y, Sun J, Xv L, Wu L, et al. Linc00472 suppresses proliferation and promotes apoptosis through elevating PDCD4 expression by sponging miR-196a in colorectal cancer. Aging (Albany NY). 2018;10(6):1523–33.CrossRef Ye Y, Yang S, Han Y, Sun J, Xv L, Wu L, et al. Linc00472 suppresses proliferation and promotes apoptosis through elevating PDCD4 expression by sponging miR-196a in colorectal cancer. Aging (Albany NY). 2018;10(6):1523–33.CrossRef
11.
go back to reference Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–59.CrossRef Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–59.CrossRef
12.
go back to reference Wang Y, Xu H, Jiao H, Wang S, Xiao Z, Zhao Y, et al. STX2 promotes colorectal cancer metastasis through a positive feedback loop that activates the NF-kappaB pathway. Cell Death Dis. 2018;9(6):664.CrossRef Wang Y, Xu H, Jiao H, Wang S, Xiao Z, Zhao Y, et al. STX2 promotes colorectal cancer metastasis through a positive feedback loop that activates the NF-kappaB pathway. Cell Death Dis. 2018;9(6):664.CrossRef
13.
go back to reference Feng M, Feng J, Chen W, Wang W, Wu X, Zhang J, et al. Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-kappaB-dependent activation of snail and epithelial mesenchymal transition. Mol Cancer. 2016;15(1):77.CrossRef Feng M, Feng J, Chen W, Wang W, Wu X, Zhang J, et al. Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-kappaB-dependent activation of snail and epithelial mesenchymal transition. Mol Cancer. 2016;15(1):77.CrossRef
14.
go back to reference Liang F, Liang J, Wang WQ, Sun JP, Udho E, Zhang ZY. PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. J Biol Chem. 2007;282(8):5413–9.CrossRef Liang F, Liang J, Wang WQ, Sun JP, Udho E, Zhang ZY. PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. J Biol Chem. 2007;282(8):5413–9.CrossRef
15.
go back to reference Kubens BS, Zanker KS. Differences in the migration capacity of primary human colon carcinoma cells (SW480) and their lymph node metastatic derivatives (SW620). Cancer Lett. 1998;131(1):55–64.CrossRef Kubens BS, Zanker KS. Differences in the migration capacity of primary human colon carcinoma cells (SW480) and their lymph node metastatic derivatives (SW620). Cancer Lett. 1998;131(1):55–64.CrossRef
16.
go back to reference Muhammad S, Kaur K, Huang R, Zhang Q, Kaur P, Yazdani HO, et al. MicroRNAs in colorectal cancer: role in metastasis and clinical perspectives. World J Gastroenterol. 2014;20(45):17011–9.CrossRef Muhammad S, Kaur K, Huang R, Zhang Q, Kaur P, Yazdani HO, et al. MicroRNAs in colorectal cancer: role in metastasis and clinical perspectives. World J Gastroenterol. 2014;20(45):17011–9.CrossRef
17.
go back to reference Luthra R, Singh RR, Luthra MG, Li YX, Hannah C, Romans AM, et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene. 2008;27(52):6667–78.CrossRef Luthra R, Singh RR, Luthra MG, Li YX, Hannah C, Romans AM, et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene. 2008;27(52):6667–78.CrossRef
18.
go back to reference Liu XH, Lu KH, Wang KM, Sun M, Zhang EB, Yang JS, et al. MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer. 2012;12:348.CrossRef Liu XH, Lu KH, Wang KM, Sun M, Zhang EB, Yang JS, et al. MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer. 2012;12:348.CrossRef
19.
go back to reference Zhang J, Zheng F, Yu G, Yin Y, Lu Q. miR-196a targets netrin 4 and regulates cell proliferation and migration of cervical cancer cells. Biochem Biophys Res Commun. 2013;440(4):582–8.CrossRef Zhang J, Zheng F, Yu G, Yin Y, Lu Q. miR-196a targets netrin 4 and regulates cell proliferation and migration of cervical cancer cells. Biochem Biophys Res Commun. 2013;440(4):582–8.CrossRef
20.
go back to reference Lu YC, Chang JT, Liao CT, Kang CJ, Huang SF, Chen IH, et al. OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway. Mol Cancer. 2014;13:218.CrossRef Lu YC, Chang JT, Liao CT, Kang CJ, Huang SF, Chen IH, et al. OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway. Mol Cancer. 2014;13:218.CrossRef
21.
go back to reference Schimanski CC, Frerichs K, Rahman F, Berger M, Lang H, Galle PR, et al. High miR-196a levels promote the oncogenic phenotype of colorectal cancer cells. World J Gastroenterol. 2009;15(17):2089–96.CrossRef Schimanski CC, Frerichs K, Rahman F, Berger M, Lang H, Galle PR, et al. High miR-196a levels promote the oncogenic phenotype of colorectal cancer cells. World J Gastroenterol. 2009;15(17):2089–96.CrossRef
22.
go back to reference Loboda A, Nebozhyn MV, Watters JW, Buser CA, Shaw PM, Huang PS, et al. EMT is the dominant program in human colon cancer. BMC Med Genet. 2011;4:9. Loboda A, Nebozhyn MV, Watters JW, Buser CA, Shaw PM, Huang PS, et al. EMT is the dominant program in human colon cancer. BMC Med Genet. 2011;4:9.
23.
go back to reference Li L, Li W. Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation. Pharmacol Ther. 2015;150:33–46.CrossRef Li L, Li W. Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation. Pharmacol Ther. 2015;150:33–46.CrossRef
24.
go back to reference Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.CrossRef Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.CrossRef
25.
go back to reference Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. 2008;121(Pt 6):727–35.CrossRef Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. 2008;121(Pt 6):727–35.CrossRef
26.
go back to reference Yang G, Han D, Chen X, Zhang D, Wang L, Shi C, et al. MiR-196a exerts its oncogenic effect in glioblastoma multiforme by inhibition of IkappaBalpha both in vitro and in vivo. Neuro-Oncology. 2014;16(5):652–61.CrossRef Yang G, Han D, Chen X, Zhang D, Wang L, Shi C, et al. MiR-196a exerts its oncogenic effect in glioblastoma multiforme by inhibition of IkappaBalpha both in vitro and in vivo. Neuro-Oncology. 2014;16(5):652–61.CrossRef
27.
go back to reference Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci. 2005;30(1):43–52.CrossRef Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci. 2005;30(1):43–52.CrossRef
28.
go back to reference Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2(4):301–10.CrossRef Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2(4):301–10.CrossRef
29.
go back to reference Ji L, Zhang B, Zhao G. Liver X receptor alpha (LXRalpha) promoted invasion and EMT of gastric cancer cells by regulation of NF-kappaB activity. Hum Cell. 2017;30(2):124–32.CrossRef Ji L, Zhang B, Zhao G. Liver X receptor alpha (LXRalpha) promoted invasion and EMT of gastric cancer cells by regulation of NF-kappaB activity. Hum Cell. 2017;30(2):124–32.CrossRef
30.
go back to reference Lu Z, Li Y, Wang J, Che Y, Sun S, Huang J, et al. Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-kappaB/snail pathway. J Exp Clin Cancer Res. 2017;36(1):54.CrossRef Lu Z, Li Y, Wang J, Che Y, Sun S, Huang J, et al. Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-kappaB/snail pathway. J Exp Clin Cancer Res. 2017;36(1):54.CrossRef
Metadata
Title
miR-196a-5p promotes metastasis of colorectal cancer via targeting IκBα
Authors
He Xin
Chuanzhuo Wang
Zhaoyu Liu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5245-1

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