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Published in: Journal of Experimental & Clinical Cancer Research 1/2015

Open Access 01-12-2015 | Research article

Hypoxia-inducible MiR-182 promotes angiogenesis by targeting RASA1 in hepatocellular carcinoma

Authors: Chengli Du, Xiaoyu Weng, Wendi Hu, Zhen Lv, Heng Xiao, Chaofeng Ding, Owusu-anash K. Gyabaah, Haiyang Xie, Lin Zhou, Jian Wu, Shusen Zheng

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2015

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Abstract

Background

Hypoxia is a common feature of solid tumors, including HCC. And hypoxia has been reported to play an important role in HCC progression. However, the potential mechanism of miRNAs in hypoxia mediating HCC progression still remains unclear.

Methods

The HCC cells were cultured in the atmosphere of 1 % oxygen to induce hypoxia. The microRNA microarray was employed to search for the hypoxia-inducible miRNAs. RT-PCR, western blot and immunohistochemistry were used to detect the RNA and protein levels. HUVEC were applied to explore the angiogenesis level.

Results

We found that miR-182 was upregulated in the hypoxia-based microarray. We then revealed that miR-182 was also significantly increased in the HCC tissues compared to the corresponding normal tissues. In vitro capilliary tube formation assays showed that the miR-182 promoted angiogenesis. RASA1 was demonstrated as the direct target of miR-182. In addition, the suppression of RASA1 phenocopied the pro-angiogenesis effects of miR-182. Besides, RASA1 was also decreased in the hypoxia HCC cells while the inhibition of miR-182 partially restored the level of RASA1.

Conclusions

Our data showed that hypoxia regulated the expression of miR-182 and RASA1 to promote HCC angiogenesis.
Appendix
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Literature
1.
go back to reference Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed
2.
go back to reference Nguyen MP, Lee S, Lee YM. Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics. Arch Pharm Res. 2013;36:252–63.CrossRefPubMed Nguyen MP, Lee S, Lee YM. Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics. Arch Pharm Res. 2013;36:252–63.CrossRefPubMed
3.
go back to reference Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–47.CrossRefPubMed Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–47.CrossRefPubMed
4.
go back to reference Myung SJ, Yoon JH. Hypoxia in hepatocellular carcinoma. Korean J Hepatol. 2007;13:9–19.PubMed Myung SJ, Yoon JH. Hypoxia in hepatocellular carcinoma. Korean J Hepatol. 2007;13:9–19.PubMed
5.
go back to reference He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.CrossRefPubMed He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.CrossRefPubMed
7.
go back to reference Du C, Lv Z, Cao L, Ding C, Gyabaah OA, Xie H, et al. MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2. J Transl Med. 2014;12:259.CrossRefPubMedCentralPubMed Du C, Lv Z, Cao L, Ding C, Gyabaah OA, Xie H, et al. MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2. J Transl Med. 2014;12:259.CrossRefPubMedCentralPubMed
8.
go back to reference Yu G, Yao W, Xiao W, Li H, Xu H, Lang B. MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. J Exp Clin Cancer Res. 2014;33(1):779.CrossRefPubMedCentralPubMed Yu G, Yao W, Xiao W, Li H, Xu H, Lang B. MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. J Exp Clin Cancer Res. 2014;33(1):779.CrossRefPubMedCentralPubMed
9.
go back to reference Li Y, Choi PS, Casey SC, Dill DL, Felsher DW. MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell. 2014;26:262–72.CrossRefPubMed Li Y, Choi PS, Casey SC, Dill DL, Felsher DW. MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell. 2014;26:262–72.CrossRefPubMed
10.
go back to reference Ying Q, Liang L, Guo W, Zha R, Tian Q, Huang S, et al. Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma. Hepatology. 2011;54:2064–75.CrossRefPubMed Ying Q, Liang L, Guo W, Zha R, Tian Q, Huang S, et al. Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma. Hepatology. 2011;54:2064–75.CrossRefPubMed
11.
go back to reference Lan J, Xue Y, Chen H, Zhao S, Wu Z, Fang J, et al. Hypoxia-induced miR-497 decreases glioma cell sensitivity to TMZ by inhibiting apoptosis. FEBS Lett. 2014;588:3333–9.CrossRefPubMed Lan J, Xue Y, Chen H, Zhao S, Wu Z, Fang J, et al. Hypoxia-induced miR-497 decreases glioma cell sensitivity to TMZ by inhibiting apoptosis. FEBS Lett. 2014;588:3333–9.CrossRefPubMed
12.
go back to reference Qiu Y, Luo X, Kan T, Zhang Y, Yu W, Wei Y, et al. TGF-beta upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1. Mol Biosyst. 2014;10:679–85.CrossRefPubMed Qiu Y, Luo X, Kan T, Zhang Y, Yu W, Wei Y, et al. TGF-beta upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1. Mol Biosyst. 2014;10:679–85.CrossRefPubMed
13.
go back to reference Sachdeva M, Mito JK, Lee CL, Zhang M, Li Z, Dodd RD, et al. MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest. 2014;124:4305–19.CrossRefPubMedCentralPubMed Sachdeva M, Mito JK, Lee CL, Zhang M, Li Z, Dodd RD, et al. MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest. 2014;124:4305–19.CrossRefPubMedCentralPubMed
14.
go back to reference Wang J, Li J, Shen J, Wang C, Yang L, Zhang X. MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer. 2012;12:227.CrossRefPubMedCentralPubMed Wang J, Li J, Shen J, Wang C, Yang L, Zhang X. MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer. 2012;12:227.CrossRefPubMedCentralPubMed
15.
go back to reference Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, et al. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 2010;120:4141–54.CrossRefPubMedCentralPubMed Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, et al. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 2010;120:4141–54.CrossRefPubMedCentralPubMed
16.
17.
go back to reference Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med. 2010;16:909–14.CrossRefPubMedCentralPubMed Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med. 2010;16:909–14.CrossRefPubMedCentralPubMed
18.
go back to reference Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 2003;29:297–307.CrossRefPubMed Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 2003;29:297–307.CrossRefPubMed
20.
go back to reference Wong CC, Kai AK, Ng IO. The impact of hypoxia in hepatocellular carcinoma metastasis. Front Med. 2014;8:33–41.CrossRefPubMed Wong CC, Kai AK, Ng IO. The impact of hypoxia in hepatocellular carcinoma metastasis. Front Med. 2014;8:33–41.CrossRefPubMed
21.
go back to reference Luo D, Wang Z, Wu J, Jiang C. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int. 2014;2014:409272.PubMedCentralPubMed Luo D, Wang Z, Wu J, Jiang C. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int. 2014;2014:409272.PubMedCentralPubMed
22.
go back to reference Liu R, Li J, Teng Z, Zhang Z, Xu Y. Overexpressed microRNA-182 promotes proliferation and invasion in prostate cancer PC-3 cells by down-regulating N-myc downstream regulated gene 1 (NDRG1). PLoS One. 2013;8:e68982.CrossRefPubMedCentralPubMed Liu R, Li J, Teng Z, Zhang Z, Xu Y. Overexpressed microRNA-182 promotes proliferation and invasion in prostate cancer PC-3 cells by down-regulating N-myc downstream regulated gene 1 (NDRG1). PLoS One. 2013;8:e68982.CrossRefPubMedCentralPubMed
23.
go back to reference Yang MH, Yu J, Jiang DM, Li WL, Wang S, Ding YQ. microRNA-182 targets special AT-rich sequence-binding protein 2 to promote colorectal cancer proliferation and metastasis. J Transl Med. 2014;12:109.CrossRefPubMedCentralPubMed Yang MH, Yu J, Jiang DM, Li WL, Wang S, Ding YQ. microRNA-182 targets special AT-rich sequence-binding protein 2 to promote colorectal cancer proliferation and metastasis. J Transl Med. 2014;12:109.CrossRefPubMedCentralPubMed
25.
go back to reference Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50:604–20.CrossRefPubMed Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50:604–20.CrossRefPubMed
26.
go back to reference Wang R, Zhao N, Li S, Fang JH, Chen MX, Yang J, et al. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology. 2013;58:642–53.CrossRefPubMed Wang R, Zhao N, Li S, Fang JH, Chen MX, Yang J, et al. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology. 2013;58:642–53.CrossRefPubMed
27.
go back to reference Fang JH, Zhou HC, Zeng C, Yang J, Liu Y, Huang X, et al. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology. 2011;54:1729–40.CrossRefPubMed Fang JH, Zhou HC, Zeng C, Yang J, Liu Y, Huang X, et al. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology. 2011;54:1729–40.CrossRefPubMed
28.
go back to reference Chen H, Li L, Wang S, Lei Y, Ge Q, Lv N, et al. Reduced miR-126 expression facilitates angiogenesis of gastric cancer through its regulation on VEGF-A. Oncotarget. 2014;5:11873–85.PubMedCentralPubMed Chen H, Li L, Wang S, Lei Y, Ge Q, Lv N, et al. Reduced miR-126 expression facilitates angiogenesis of gastric cancer through its regulation on VEGF-A. Oncotarget. 2014;5:11873–85.PubMedCentralPubMed
29.
go back to reference Ahluwalia A, Tarnawski AS. Critical role of hypoxia sensor–HIF-1alpha in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem. 2012;19:90–7.CrossRefPubMed Ahluwalia A, Tarnawski AS. Critical role of hypoxia sensor–HIF-1alpha in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem. 2012;19:90–7.CrossRefPubMed
31.
go back to reference Sun D, Yu F, Ma Y, Zhao R, Chen X, Zhu J, et al. MicroRNA-31 activates the RAS pathway and functions as an oncogenic MicroRNA in human colorectal cancer by repressing RAS p21 GTPase activating protein 1 (RASA1). J Biol Chem. 2013;288:9508–18.CrossRefPubMedCentralPubMed Sun D, Yu F, Ma Y, Zhao R, Chen X, Zhu J, et al. MicroRNA-31 activates the RAS pathway and functions as an oncogenic MicroRNA in human colorectal cancer by repressing RAS p21 GTPase activating protein 1 (RASA1). J Biol Chem. 2013;288:9508–18.CrossRefPubMedCentralPubMed
32.
go back to reference Li Z, Li D, Zhang G, Xiong J, Jie Z, Cheng H, et al. Methylation-associated silencing of MicroRNA-335 contributes tumor cell invasion and migration by interacting with RASA1 in gastric cancer. Am J Cancer Res. 2014;4:648–62.PubMedCentralPubMed Li Z, Li D, Zhang G, Xiong J, Jie Z, Cheng H, et al. Methylation-associated silencing of MicroRNA-335 contributes tumor cell invasion and migration by interacting with RASA1 in gastric cancer. Am J Cancer Res. 2014;4:648–62.PubMedCentralPubMed
Metadata
Title
Hypoxia-inducible MiR-182 promotes angiogenesis by targeting RASA1 in hepatocellular carcinoma
Authors
Chengli Du
Xiaoyu Weng
Wendi Hu
Zhen Lv
Heng Xiao
Chaofeng Ding
Owusu-anash K. Gyabaah
Haiyang Xie
Lin Zhou
Jian Wu
Shusen Zheng
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2015
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-015-0182-1

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