Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Hepatocellular Carcinoma | Research

MiR-144-3p-mediated dysregulation of EIF4G2 contributes to the development of hepatocellular carcinoma through the ERK pathway

Authors: Shuangshuang Li, Jiajia Shao, Guohua Lou, Chao Wu, Yanning Liu, Min Zheng

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Login to get access

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most common cancers with high incidence and mortality. However, the underlying mechanisms of HCC still remain unclear. Eukaryotic translation initiation factors (eIFs) have a substantial effect on tumor development. In this study, we were aimed to investigate the role of eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) in HCC.

Methods

Western blot (WB) of 30 paired HCC tissues and tissue microarrays (TMAs) conducted by immunohistochemistry (IHC) in 89 paired HCC samples were performed to assess EIF4G2 expression. Clone formation, real-time cell analysis (RTCA), wound healing and transwell assays were adopted to evaluate the role of EIF4G2 on HCC cell proliferation, migration and invasion abilities. The function of EIF4G2 in HCC tumor growth was assessed in a xenograft nude mouse model in vivo. The regulation of EIF4G2 by miR-144-3p was performed by luciferase reporter assay and WB.

Results

The EIF4G2 protein was clearly upregulated in HCC tissues, and high EIF4G2 expression was closely related to HCC prognosis. EIF4G2 silencing could inhibit HCC cell growth and metastasis in vitro, and suppress tumorigenesis in vivo by repressing the ERK signaling pathway. The results of luciferase reporter assays, WB and IHC staining verified that EIF4G2 was negatively regulated by miR-144. And re-expression of EIF4G2 could partially reverse the inhibiting effect of miR-144 in HCC.

Conclusion

In summary, our study revealed the role of EIF4G2 in HCC development via the activation of the ERK pathway. We also found that EIF4G2 could be negatively regulated by the tumor suppressor miR-144. Our investigations indicated that EIF4G2 might be a promising therapeutic target in HCC.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.CrossRef
2.
Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53.CrossRef
3.
Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015;14(4):261–78.CrossRef
4.
Gantenbein N, Bernhart E, Anders I, Golob-Schwarzl N, Krassnig S, Wodlej C, et al. Influence of eukaryotic translation initiation factor 6 on non-small cell lung cancer development and progression. Eur J Cancer. 2018;101:165–80.CrossRef
5.
Golob-Schwarzl N, Krassnig S, Toeglhofer AM, Park YN, Gogg-Kamerer M, Vierlinger K, et al. New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur J Cancer. 2017;83:56–70.CrossRef
6.
Lewis SM, Cerquozzi S, Graber TE, Ungureanu NH, Andrews M, Holcik M. The eIF4G homolog DAP5/p97 supports the translation of select mRNAs during endoplasmic reticulum stress. Nucleic Acids Res. 2007;36(1):168–78.CrossRef
7.
Warnakulasuriyarachchi D, Cerquozzi S, Cheung HH, Holcik M. Translational induction of the inhibitor of apoptosis protein HIAP2 during endoplasmic reticulum stress attenuates cell death and is mediated via an inducible internal ribosome entry site element. J Biol Chem. 2004;279(17):17148–57.CrossRef
8.
Nousch M, Reed V, Bryson-Richardson RJ, Currie PD, Preiss T. The eIF4G-homolog p97 can activate translation independent of caspase cleavage. RNA. 2007;13(3):374–84.CrossRef
9.
Emmrich S, Engeland F, El-Khatib M, Henke K, Obulkasim A, Schoning J, et al. miR-139-5p controls translation in myeloid leukemia through EIF4G2. Oncogene. 2016;35(14):1822–31.CrossRef
10.
Mazan-Mamczarz K, Zhao XF, Dai B, Steinhardt JJ, Peroutka RJ, Berk KL, et al. Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development. PLoS Genet. 2014;10(1):e1004105.CrossRef
11.
Xie X, Li YS, Xiao WF, Deng ZH, He HB, Liu Q, et al. MicroRNA-379 inhibits the proliferation, migration and invasion of human osteosarcoma cells by targetting EIF4G2. Biosci Rep. 2017;37:3.
12.
13.
14.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.CrossRef
15.
Lou G, Chen L, Xia C, Wang W, Qi J, Li A, et al. MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. J Exp Clin Cancer Res. 2020;39(1):4.
16.
Liu Y, Lou G, Norton JT, Wang C, Kandela I, Tang S, et al. 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib. FASEB J. 2017;31(12):5453–65.CrossRef
17.
Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY. The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem. 2002;277(35):31818–25.CrossRef
18.
Gavino C, Hamel N, Zeng JB, Legault C, Guiot MC, Chankowsky J, et al. Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. J Allergy Clin Immunol 2016;137(4):1178–1188 e7.
19.
Lan F, Yu H, Hu M, Xia T, Yue X. miR-144-3p exerts anti-tumor effects in glioblastoma by targeting c-met. J Neurochem. 2015;135(2):274–86.CrossRef
20.
Jahanbani I, Al-Abdallah A, Ali RH, Al-Brahim N, Mojiminiyi O. Discriminatory miRNAs for the Management of Papillary Thyroid Carcinoma and Noninvasive Follicular Thyroid Neoplasms with papillary-like nuclear features. Thyroid. 2018;28(3):319–27.CrossRef
21.
Wang H, Wang A, Hu Z, Xu X, Liu Z, Wang Z. A critical role of miR-144 in diffuse large B-cell lymphoma proliferation and invasion. Cancer Immunol Res. 2016;4(4):337–44.CrossRef
22.
Nakagawa S, Wei L, Song WM, Higashi T, Ghoshal S, Kim RS, et al. Molecular liver Cancer prevention in cirrhosis by organ Transcriptome analysis and Lysophosphatidic acid pathway inhibition. Cancer Cell. 2016;30(6):879–90.CrossRef
23.
Goossens N, Sun X, Hoshida Y. Molecular classification of hepatocellular carcinoma: potential therapeutic implications. Hepat Oncol. 2015;2(4):371–9.CrossRef
24.
Weingarten-Gabbay S, Khan D, Liberman N, Yoffe Y, Bialik S, Das S, et al. The translation initiation factor DAP5 promotes IRES-driven translation of p53 mRNA. Oncogene. 2014;33(5):611–8.CrossRef
25.
de la Parra C, Ernlund A, Alard A, Ruggles K, Ueberheide B, Schneider RJ. A widespread alternate form of cap-dependent mRNA translation initiation. Nat Commun. 2018;9(1):3068.CrossRef
26.
Bellsolell L, Cho-Park PF, Poulin F, Sonenberg N, Burley SK. Two structurally atypical HEAT domains in the C-terminal portion of human eIF4G support binding to eIF4A and Mnk1. Structure. 2006;14(5):913–23.CrossRef
27.
Marash L, Liberman N, Henis-Korenblit S, Sivan G, Reem E, Elroy-Stein O, et al. DAP5 promotes cap-independent translation of Bcl-2 and CDK1 to facilitate cell survival during mitosis. Mol Cell. 2008;30(4):447–59.CrossRef
28.
Hundsdoerfer P, Thoma C, Hentze MW. Eukaryotic translation initiation factor 4GI and p97 promote cellular internal ribosome entry sequence-driven translation. Proc Natl Acad Sci U S A. 2005;102(38):13421–6.CrossRef
29.
Zhao H, Wang A, Zhang Z. LncRNA SDHAP1 confers paclitaxel resistance of ovarian cancer by regulating EIF4G2 expression via miR-4465. J Biochem. 2020.
30.
Hao GJ, Hao HJ, Ding YH, Wen H, Li XF, Wang QR, et al. Suppression of EIF4G2 by miR-379 potentiates the cisplatin chemosensitivity in nonsmall cell lung cancer cells. FEBS Lett. 2017;591(4):636–45.CrossRef
31.
Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55–72.CrossRef
32.
Hommes DW, Peppelenbosch MP, van Deventer SJ. Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets. Gut. 2003;52(1):144–51.CrossRef
33.
Liu Y, Zhang X, Yang B, Zhuang H, Guo H, Wei W, et al. Demethylation-induced overexpression of Shc3 drives c-Raf-independent activation of MEK/ERK in HCC. Cancer Res. 2018;78(9):2219–32.CrossRef
34.
Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A, et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology. 1998;27(4):951–8.CrossRef
35.
Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013;13(9):679–92.CrossRef
36.
Sabio G, Davis RJ. TNF and MAP kinase signalling pathways. Semin Immunol. 2014;26(3):237–45.CrossRef
37.
Sugiyama H, Takahashi K, Yamamoto T, Iwasaki M, Narita M, Nakamura M, et al. Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2017;114(2):340–5.CrossRef
38.
Craig EA, Stevens MV, Vaillancourt RR, Camenisch TD. MAP 3Ks as central regulators of cell fate during development. Dev Dyn. 2008;237(11):3102–14.CrossRef
39.
Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–91.CrossRef
40.
Frost JA, Xu S, Hutchison MR, Marcus S, Cobb MH. Actions of rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members. Mol Cell Biol. 1996;16(7):3707–13.CrossRef
41.
Alonso A, Saxena M, Williams S, Mustelin T. Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem. 2001;276(7):4766–71.CrossRef
42.
Liang HW, Ye ZH, Yin SY, Mo WJ, Wang HL, Zhao JC, et al. A comprehensive insight into the clinicopathologic significance of miR-144-3p in hepatocellular carcinoma. Onco Targets Ther. 2017;10:3405–19.CrossRef
43.
Gu J, Liu X, Li J, He Y. MicroRNA-144 inhibits cell proliferation, migration and invasion in human hepatocellular carcinoma by targeting CCNB1. Cancer Cell Int. 2019;19:15.CrossRef
44.
Wu M, Huang C, Huang X, Liang R, Feng Y, Luo X. MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma. Oncol Rep. 2017;38(4):2173–81.CrossRef
45.
Zhou S, Ye W, Zhang Y, Yu D, Shao Q, Liang J, et al. miR-144 reverses chemoresistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. Am J Transl Res. 2016;8(7):2992–3002.PubMedPubMedCentral
Metadata
Title
MiR-144-3p-mediated dysregulation of EIF4G2 contributes to the development of hepatocellular carcinoma through the ERK pathway
Authors
Shuangshuang Li
Jiajia Shao
Guohua Lou
Chao Wu
Yanning Liu
Min Zheng
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01853-6

Other articles of this Issue 1/2021

Journal of Experimental & Clinical Cancer Research 1/2021 Go to the issue

Review

Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer

Meeting Report

A vision of immuno-oncology: the Siena think tank of the Italian network for tumor biotherapy (NIBIT) foundation

Research

ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling

Correction

Correction to: Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

Research

Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression

Research

Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits