Modulation of IGF2BP1 by long non-coding RNA HCG11 suppresses apoptosis of hepatocellular carcinoma cells via MAPK signaling transduction

Xu,Yantian; Zheng,Yuanwen; Liu,Hongyan; Li,Tao

doi:10.3892/ijo.2017.4066

Modulation of IGF2BP1 by long non-coding RNA HCG11 suppresses apoptosis of hepatocellular carcinoma cells via MAPK signaling transduction

Authors:
- Yantian Xu
- Yuanwen Zheng
- Hongyan Liu
- Tao Li
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Affiliations: Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
Published online on: July 5, 2017 https://doi.org/10.3892/ijo.2017.4066
Pages: 791-800
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatocellular carcinoma (HCC) is a common malignancy of the liver. HCG11 is a member of long non‑coding family, upregulation of which in HCC was proved by our previous study. In the present study, the role of HCG11 in the development of HCC was detected by focusing on the interaction between HCG11 and its target protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). The expression status of HCG11 and IGF2BP1 was first investigated with clinical HCC samples. Then the expressions of HCG11 and IGF2BP1 were both inhibited in the human HCC cell line HepG2 and the cell viability, proliferation, apoptosis and metastasis potential of HepG2 cells were assessed. At molecular level, the expression levels of p-ERK, p-JNK, p-p38, p21 and cleaved caspase-3 were also determined to explain the pathways involved in the function of HCG11 in the progression of HCC. Expression of HCG11 and IGF2BP1 were significantly higher in HCC tissues than those in para-tumor tissues. Knockdown of both indicators led to decreased cell viability, proliferation, and migration ability in HepG2 cells while the cell apoptosis and G1 cell cycle arrest were induced after knockdown of HCG11 and IGF2BP1. In addition, suppressed activity of HCG11 and IGF2BP1 blocked the phosphorylation of anti-apoptosis factors, including ERK, JNK and p38 while the mitochondrial apoptosis in HCC cells was initiated by activation of p21 and cleaved caspase-3. HCG11 exerted its effect on HCC via interaction with IGF2BP1, leading to activation of MAPK signaling, which eventually promoted the progression of HCC.

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1	Shi L, Peng F, Tao Y, Fan X and Li N: Roles of long noncoding RNAs in hepatocellular carcinoma. Virus Res. 223:131–139. 2016. View Article : Google Scholar : PubMed/NCBI
2	Al Salloom AA: An update of biochemical markers of hepatocellular carcinoma. Int J Health Sci (Qassim). 10:121–136. 2016.
3	Yang JD and Roberts LR: Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol Hepatol. 7:448–458. 2010. View Article : Google Scholar : PubMed/NCBI
4	Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Kammula US, Chen Y, Qin LX, Tang ZY, et al: Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 10:99–111. 2006. View Article : Google Scholar : PubMed/NCBI
5	Tejeda-Maldonado J, García-Juárez I, Aguirre-Valadez J, González-Aguirre A, Vilatobá-Chapa M, Armengol-Alonso A, Escobar-Penagos F, Torre A, Sánchez-Ávila JF and Carrillo-Pérez DL: Diagnosis and treatment of hepatocellular carcinoma: An update. World J Hepatol. 7:362–376. 2015. View Article : Google Scholar : PubMed/NCBI
6	Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009. View Article : Google Scholar : PubMed/NCBI
7	Ma L, Bajic VB and Zhang Z: On the classification of long non- coding RNAs. RNA Biol. 10:925–933. 2013. View Article : Google Scholar : PubMed/NCBI
8	Taft RJ, Pang KC, Mercer TR, Dinger M and Mattick JS: Non-coding RNAs: Regulators of disease. J Pathol. 220:126–139. 2010. View Article : Google Scholar
9	Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 464:1071–1076. 2010. View Article : Google Scholar : PubMed/NCBI
10	Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J and Fang G: Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 279:3159–3165. 2012. View Article : Google Scholar : PubMed/NCBI
11	Huang JL, Zheng L, Hu YW and Wang Q: Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma. Carcinogenesis. 35:507–514. 2014. View Article : Google Scholar
12	Yang X, Xie X, Xiao YF, Xie R, Hu CJ, Tang B, Li BS and Yang SM: The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma. Cancer Lett. 360:119–124. 2015. View Article : Google Scholar : PubMed/NCBI
13	He Y, Meng XM, Huang C, Wu BM, Zhang L, Lv XW and Li J: Long noncoding RNAs: Novel insights into hepatocelluar carcinoma. Cancer Lett. 344:20–27. 2014. View Article : Google Scholar
14	Zhang Y, Zhang P, Wan X, Su X, Kong Z, Zhai Q, Xiang X, Li L and Li Y: Downregulation of long non-coding RNA HCG11 predicts a poor prognosis in prostate cancer. Biomed Pharmacother. 83:936–941. 2016. View Article : Google Scholar : PubMed/NCBI
15	Liu H, Li J, Koirala P, Ding X, Chen B, Wang Y, Wang Z, Wang C, Zhang X and Mo YY: Long non-coding RNAs as prognostic markers in human breast cancer. Oncotarget. 7:20584–20596. 2016. View Article : Google Scholar : PubMed/NCBI
16	Gu Y, Chen T, Li G, Yu X, Lu Y, Wang H and Teng L: LncRNAs: Emerging biomarkers in gastric cancer. Future Oncol. 11:2427–2441. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wu Z, Yang L, Cai L, Zhang M, Cheng X, Yang X and Xu J: Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an α-smooth muscle actin-Cre transgenic mouse. Respir Res. 8:12007. View Article : Google Scholar
18	Gutschner T, Hämmerle M, Pazaitis N, Bley N, Fiskin E, Uckelmann H, Heim A, Groβ M, Hofmann N, Geffers R, et al: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an important protumorigenic factor in hepatocellular carcinoma. Hepatology. 59:1900–1911. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhang J, Cheng J, Zeng Z, Wang Y, Li X, Xie Q, Jia J, Yan Y, Guo Z, Gao J, et al: Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma. Oncotarget. 6:42040–42052. 2015. View Article : Google Scholar : PubMed/NCBI
20	Zhou X, Zhang CZ, Lu SX, Chen GG, Li LZ, Liu LL, Yi C, Fu J, Hu W, Wen JM, et al: miR-625 suppresses tumour migration and invasion by targeting IGF2BP1 in hepatocellular carcinoma. Oncogene. 34:965–977. 2015. View Article : Google Scholar
21	Suzuki A, Tsutomi Y, Yamamoto N, Shibutani T and Akahane K: Mitochondrial regulation of cell death: Mitochondria are essential for procaspase 3-p21 complex formation to resist Fas-mediated cell death. Mol Cell Biol. 19:3842–3847. 1999. View Article : Google Scholar : PubMed/NCBI
22	Shibata C, Otsuka M, Kishikawa T, Ohno M, Yoshikawa T, Takata A and Koike K: Diagnostic and therapeutic application of noncoding RNAs for hepatocellular carcinoma. World J Hepatol. 7:1–6. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang KC and Chang HY: Molecular mechanisms of long noncoding RNAs. Mol Cell. 43:904–914. 2011. View Article : Google Scholar : PubMed/NCBI
24	Deng L, Yang SB, Xu FF and Zhang JH: Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge. J Exp Clin Cancer Res. 34:182015. View Article : Google Scholar : PubMed/NCBI
25	Quagliata L, Matter MS, Piscuoglio S, Arabi L, Ruiz C, Procino A, Kovac M, Moretti F, Makowska Z, Boldanova T, et al: Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 59:911–923. 2014. View Article : Google Scholar :
26	Bell JL, Wächter K, Mühleck B, Pazaitis N, Köhn M, Lederer M and Hüttelmaier S: Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): Post-transcriptional drivers of cancer progression? Cell Mol Life Sci. 70:2657–2675. 2013. View Article : Google Scholar :
27	Farina KL, Hüttelmaier S, Musunuru K, Darnell R and Singer RH: Two ZBP1 KH domains facilitate β-actin mRNA localization, granule formation, and cytoskeletal attachment. J Cell Biol. 160:77–87. 2003. View Article : Google Scholar : PubMed/NCBI
28	Hüttelmaier S, Zenklusen D, Lederer M, Dictenberg J, Lorenz M, Meng X, Bassell GJ, Condeelis J and Singer RH: Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1. Nature. 438:512–515. 2005. View Article : Google Scholar : PubMed/NCBI
29	Bernstein PL, Herrick DJ, Prokipcak RD and Ross J: Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev. 6:642–654. 1992. View Article : Google Scholar : PubMed/NCBI
30	Ioannidis P, Mahaira LG, Perez SA, Gritzapis AD, Sotiropoulou PA, Kavalakis GJ, Antsaklis AI, Baxevanis CN and Papamichail M: CRD-BP/IMP1 expression characterizes cord blood CD34⁺ stem cells and affects c-myc and IGF-II expression in MCF-7 cancer cells. J Biol Chem. 280:20086–20093. 2005. View Article : Google Scholar : PubMed/NCBI
31	Wagner EF and Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009. View Article : Google Scholar : PubMed/NCBI