A pleiotropic effect of the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p on insulin-like growth factor II, insulin-like growth factor-1 receptor and insulin-like growth factor-binding protein-3 in hepatocellular carcinoma

Assal,Reem  Amr; El Tayebi,Hend   Mohamed; Hosny,Karim  Adel; Esmat,Gamal; Abdelaziz,Ahmed  Ihab

doi:10.3892/mmr.2015.3382

July-2015 Volume 12 Issue 1

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

July-2015 Volume 12 Issue 1

Full Size Image

Article

A pleiotropic effect of the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p on insulin-like growth factor II, insulin-like growth factor-1 receptor and insulin-like growth factor-binding protein-3 in hepatocellular carcinoma

Authors:
- Reem Amr Assal
- Hend Mohamed El Tayebi
- Karim Adel Hosny
- Gamal Esmat
- Ahmed Ihab Abdelaziz
View Affiliations / Copyright

Affiliations: The Molecular Pathology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt, Department of General Surgery, Faculty of Medicine, Cairo University, Cairo 11559, Egypt, Department of Endemic Medicine and Hepatology, Cairo University, Cairo 11559, Egypt
Pages: 645-650
|
Published online on: February 24, 2015

https://doi.org/10.3892/mmr.2015.3382
Expand metrics +

Abstract

MicroRNAs (miRs) have a major role in the pathogenesis of hepatocellular carcinoma (HCC). As the insulin‑like growth factor (IGF) axis is a highly tumorigenic pathway in HCC, the present study attempted to target it with miRs. Potential targeting of crucial members of the IGF axis by miRNAs at the 3'-untranslated region (3'-UTR) was predicted using bioinformatic tools, such as microrna.org, Diana lab and Targetscan, while 5'-UTR targeting was predicted using bibiserv software. Expression profiling of obtained miRNAs was performed using quantitative polymerase chain reaction (qPCR) in 22 non‑metastatic HCC biopsy samples and 10 healthy tissues. To investigate the impact of miRNAs on their potential downstream targets, transfection of miRNAs was performed in HuH‑7 cells and the targets' expression was quantified using qPCR. Transcripts of insulin‑like growth factor‑1 receptor (IGF‑1R), insulin‑like growth factor binding protein‑3 (IGFBP‑3) and IGF‑II were found to be potentially targeted at the 5'-UTR and 3'-UTR regions by the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p. The two miRNAs showed a similar expression pattern in HCC tissues compared to those in healthy tissues. Forced expression of miR‑96‑5p and miR‑182‑5p in the HCC cell line HuH‑7 had inducing effects on IGFBP‑3 and IGF‑II transcripts. Of note, the two miRs had differential effects on IGF‑1R, where miR‑96‑5p induced IGF‑1R mRNA expression and miR‑182‑5p inhibited its expression. The present study revealed the pleiotropic impact of the single clustered hepatic metastamiRs miR‑96‑5p and miR‑182‑5p on IGF‑1R, and an inducing effect on IGF‑II and IGFBP‑3 in hepatocellular carcinoma.

View Figures

View References

1	Baskerville S and Bartel DP: Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA. 11:241–247. 2005. View Article : Google Scholar : PubMed/NCBI
2	Guo H, Ingolia NT, Weissman JS and Bartel DP: Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 466:835–840. 2010. View Article : Google Scholar : PubMed/NCBI
3	Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R and Rajewsky N: Widespread changes in protein synthesis induced by microRNAs. Nature. 455:58–63. 2008. View Article : Google Scholar : PubMed/NCBI
4	Gottwein E and Cullen BR: Viral and cellular microRNAs as determinants of viral pathogenesis and immunity. Cell Host Microbe. 3:375–387. 2008. View Article : Google Scholar : PubMed/NCBI
5	Segura MF, Hanniford D, Menendez S, et al: Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci USA. 106:1814–1819. 2009. View Article : Google Scholar : PubMed/NCBI
6	Wang Y, Lee AT, Ma JZ, et al: Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target. J Biol Chem. 283:13205–13215. 2008. View Article : Google Scholar : PubMed/NCBI
7	Sato F, Hatano E, Kitamura K, et al: MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the milan criteria. PLoS One. 6:e164352011. View Article : Google Scholar : PubMed/NCBI
8	Ladeiro Y, Couchy G, Balabaud C, et al: MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 47:1955–1963. 2008. View Article : Google Scholar : PubMed/NCBI
9	Pineau P, Volinia S, McJunkin K, et al: miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA. 107:264–269. 2010. View Article : Google Scholar :
10	Chen RX, Xia YH, Xue TC and Ye SL: Suppression of microRNA-96 expression inhibits the invasion of hepatocellular carcinoma cells. Mol Med Rep. 5:800–804. 2012.
11	Wang J, Li J, Shen J, Wang C, Yang L and Zhang X: MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer. 12:2272012. View Article : Google Scholar : PubMed/NCBI
12	Dong ZZ, Yao DF, Wu W, et al: Correlation between epigenetic alterations in the insulin growth factor-II gene and hepatocellular carcinoma. Chin J Hepatol. 20:593–597. 2012.In Chinese.
13	Scharf JG, Schmidt-Sandte W, Pahernik SA, Ramadori G, Braulke T and Hartmann H: Characterization of the insulin-like growth factor axis in a human hepatoma cell line (PLC). Carcinogenesis. 19:2121–2128. 1998. View Article : Google Scholar
14	Gong Y, Cui L and Minuk GY: The expression of insulin-like growth factor binding proteins in human hepatocellular carcinoma. Mol Cell Biochem. 207:101–104. 2000. View Article : Google Scholar : PubMed/NCBI
15	Gray SG, Eriksson T, Ekstrom C, et al: Altered expression of members of the IGF-axis in hepatoblastomas. Br J Cancer. 82:1561–1567. 2000. View Article : Google Scholar : PubMed/NCBI
16	Xu D, He X, Chang Y, et al: Inhibition of miR-96 expression reduces cell proliferation and clonogenicity of HepG2 hepatoma cells. Oncol Rep. 29:653–661. 2013.
17	Yin Y, Li M, Li H, et al: Expressions of 6 microRNAs in prostate cancer. Natl J Androl. 16:599–605. 2010.In Chinese.
18	Nussbaum T, Samarin J, Ehemann V, et al: Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis. Hepatology. 48:146–156. 2008. View Article : Google Scholar : PubMed/NCBI
19	Aleem E, Nehrbass D, Klimek F, Mayer D and Bannasch P: Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol Pathol. 39:524–543. 2011. View Article : Google Scholar : PubMed/NCBI
20	Jalvy-Delvaille S, Maurel M, Majo V, et al: Molecular basis of differential target regulation by miR-96 and miR-182: the Glypican-3 as a model. Nucleic Acids Res. 40:1356–1365. 2012. View Article : Google Scholar :
21	Gu C, Li X, Tan Q, Wang Z, Chen L and Liu Y: MiR-183 family regulates chloride intracellular channel 5 expression in inner ear hair cells. Toxicol In Vitro. 27:486–491. 2013. View Article : Google Scholar
22	Henke JI, Goergen D, Zheng J, et al: microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J. 27:3300–3310. 2008. View Article : Google Scholar : PubMed/NCBI
23	Villanueva RA, Jangra RK, Yi M, Pyles R, Bourne N and Lemon SM: miR-122 does not modulate the elongation phase of hepatitis C virus RNA synthesis in isolated replicase complexes. Antiviral Res. 88:119–123. 2010. View Article : Google Scholar : PubMed/NCBI
24	Norman KL and Sarnow P: Modulation of hepatitis C virus RNA abundance and the isoprenoid biosynthesis pathway by microRNA miR-122 involves distinct mechanisms. J Virol. 84:666–670. 2010. View Article : Google Scholar :
25	Jopling CL: Regulation of hepatitis C virus by microRNA-122. Biochem Soc Trans. 36:1220–1223. 2008. View Article : Google Scholar : PubMed/NCBI
26	Tsai NP, Lin YL and Wei LN: MicroRNA mir-346 targets the 5′-untranslated region of receptor-interacting protein 140 (RIP140) mRNA and up-regulates its protein expression. Biochem J. 424:411–418. 2009. View Article : Google Scholar : PubMed/NCBI