Abstract
MicroRNAs (miRNAs) are critical for cancer development and progression. Elucidating the underlying mechanism of miRNAs in carcinogenesis may lead to novel diagnostic and therapeutic strategies for malignancy. In this study, we found that miR-511 expression was markedly downregulated in hepatocellular carcinoma (HCC) cell lines and tissues. Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was identified as a direct target of miR-511 and miR-511 expression inversely correlated with PIK3R3 mRNA expression in clinical HCC tissues. We further demonstrated that miR-511 suppressed HCC cell proliferation, migration, and invasion by repressing PIK3R3 expression. Investigations of possible mechanisms underlying these results revealed that miR-511 inhibited the phosphorylation of AKT and mTOR, which are key participants in the AKT/mTOR pathway. Taken together, our findings provide new insights into tumor suppression by miR-511 by negatively regulating the PIK3R3/AKT/mTOR signaling pathway.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Yang LY, Fang F, Ou DP, Wu W, Zeng ZJ, Wu F. Solitary large hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma with good outcome after hepatic resection. Ann Surg. 2009;249:118–23.
Bartel DP. Micrornas: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009;10:126–39.
Thomson DW, Bracken CP, Goodall GJ. Experimental strategies for microRNA target identification. Nucleic Acids Res. 2011;39:6845–53.
Wiemer EA. The role of microRNAs in cancer: no small matter. Eur J Cancer. 2007;43:1529–44.
Shen G, Rong X, Zhao J, Yang X, Li H, Jiang H, Zhou Q, Ji T, Huang S, Zhang J, Jia H. MicroRNA-105 suppresses cell proliferation and inhibits PI3K/AKT signaling in human hepatocellular carcinoma. Carcinogenesis 2014.
Li L, Liu Y, Guo Y, Liu B, Zhao Y, Li P, Song F, Zheng H, Yu J, Song T, Niu R, Li Q, Wang XW, Zhang W, Chen K. Regulatory mir-148a-acvr1/bmp circuit defines a cancer stem cell-like aggressive subtype of hepatocellular carcinoma. Hepatology 2014.
Xiao Z, Li CH, Chan SL, Xu F, Feng L, Wang Y, Jiang JD, Sung JJ, Cheng CH, Chen Y. A small molecule modulator of the tumor suppressor miRNA-34a inhibits the growth of hepatocellular carcinoma. Cancer Res 2014.
Li CH, Xu F, Chow S, Feng L, Yin D, Ng TB, et al. Hepatitis b virus × protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression. Eur J Cancer. 2014;50:2560–9.
Ge YY, Shi Q, Zheng ZY, Gong J, Zeng C, Yang J, et al. MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mtor and igf-1r. Oncotarget. 2014;5:6218–28.
Liu Z, Tu K, Liu Q. Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma. FEBS Lett. 2014;588:3089–97.
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.
Yuan Q, Loya K, Rani B, Mobus S, Balakrishnan A, Lamle J, et al. MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration. Hepatology. 2013;57:299–310.
Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122:2884–97.
Zhang C, Chi YL, Wang PY, Wang YQ, Zhang YX, Deng J, et al. Mir-511 and mir-1297 inhibit human lung adenocarcinoma cell proliferation by targeting oncogene trib2. PLoS ONE. 2012;7:e46090.
Kim TH, Kim YK, Kwon Y, Heo JH, Kang H, Kim G, et al. Deregulation of mir-519a, 153, and 485-5p and its clinicopathological relevance in ovarian epithelial tumours. Histopathology. 2010;57:734–43.
Tombol Z, Szabo PM, Molnar V, Wiener Z, Tolgyesi G, Horanyi J, et al. Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. Endocr Relat Cancer. 2009;16:895–906.
Wang W, Zhao LJ, Tan YX, Ren H, Qi ZT. Mir-138 induces cell cycle arrest by targeting cyclin d3 in hepatocellular carcinoma. Carcinogenesis. 2012;33:1113–20.
Wang H, An H, Wang B, Liao Q, Li W, Jin X, et al. Mir-133a represses tumour growth and metastasis in colorectal cancer by targeting lim and sh3 protein 1 and inhibiting the mapk pathway. Eur J Cancer. 2013;49:3924–35.
Chang RM, Yang H, Fang F, Xu JF, Yang LY. Microrna-331-3p promotes proliferation and metastasis of hepatocellular carcinoma by targeting ph domain and leucine-rich repeat protein phosphatase. Hepatology. 2014;60:1251–63.
Xu L, Wen Z, Zhou Y, Liu Z, Li Q, Fei G, et al. Microrna-7-regulated tlr9 signaling-enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/akt pathway. Mol Biol Cell. 2013;24:42–55.
Augello C, Gianelli U, Savi F, Moro A, Bonoldi E, Gambacorta M, et al. Microrna as potential biomarker in hcv-associated diffuse large B-cell lymphoma. J Clin Pathol. 2014;67:697–701.
Tserel L, Runnel T, Kisand K, Pihlap M, Bakhoff L, Kolde R, et al. MicroRNA expression profiles of human blood monocyte-derived dendritic cells and macrophages reveal mir-511 as putative positive regulator of toll-like receptor 4. J Biol Chem. 2011;286:26487–95.
Zhang L, Huang J, Yang N, Greshock J, Liang S, Hasegawa K, et al. Integrative genomic analysis of phosphatidylinositol 3′-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer. Clin Cancer Res. 2007;13:5314–21.
Soroceanu L, Kharbanda S, Chen R, Soriano RH, Aldape K, Misra A, et al. Identification of igf2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma. Proc Natl Acad Sci U S A. 2007;104:3466–71.
Zhou J, Chen GB, Tang YC, Sinha RA, Wu Y, Yap CS, et al. Genetic and bioinformatic analyses of the expression and function of PI3K regulatory subunit PIK3R3 in an Asian patient gastric cancer library. BMC Med Genom. 2012;5:34.
Wang G, Yang X, Li C, Cao X, Luo X, Hu J. PIK3R3 induces epithelial-to-mesenchymal transition and promotes metastasis in colorectal cancer. Mol Cancer Ther. 2014;13:1837–47.
Klahan S, Wu MS, Hsi E, Huang CC, Hou MF, Chang WC. Computational analysis of mRNA expression profiles identifies the ITG family and PIK3R3 as crucial genes for regulating triple negative breast cancer cell migration. Biomed Res Int. 2014;2014:536591.
Wu DM, Zhang P, Liu RY, Sang YX, Zhou C, Xu GC, et al. Phosphorylation and changes in the distribution of nucleolin promote tumor metastasis via the PI3K/AKT pathway in colorectal carcinoma. FEBS Lett. 2014;588:1921–9.
Yu T, Li J, Yan M, Liu L, Lin H, Zhao F, Sun L, Zhang Y, Cui Y, Zhang F, He X, Yao M. MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway. Oncogene 2014.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cao, G., Dong, W., Meng, X. et al. MiR-511 inhibits growth and metastasis of human hepatocellular carcinoma cells by targeting PIK3R3. Tumor Biol. 36, 4453–4459 (2015). https://doi.org/10.1007/s13277-015-3085-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-3085-z