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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis

Authors: Yuhang Zhou, Tingting Huang, Ho Lam Siu, Chi Chun Wong, Yujuan Dong, Feng Wu, Bin Zhang, William K. K. Wu, Alfred S. L. Cheng, Jun Yu, Ka Fai To, Wei Kang

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

Gastric cancer (GC) is one of the frequent causes of cancer-related death in eastern Asian population. IGF2BP2 lists in the top rank up-regulated genes in GC, but its functional role is unclear.

Method

The expression of IGF2BP3 in GC cell lines and primary samples was examined by qRT-PCR and Western blot. The biological role of IGF2BP3 was revealed by a series of functional in vitro studies. Its regulation by microRNAs (miRNAs) was predicted by TargetScan and confirmed by luciferase assays and rescue experiments.

Results

IGF2BP3 ranked the No.1 of the up-regulated genes by expression microarray analysis in GC cell lines. The expression level of IGF2BP3 was observed in GC tissues comparing with non-tumorous gastric epitheliums. The up-regulated IGF2BP3 expression was associated with poor disease specific survival. IGF2BP3 knockdown significantly inhibited cell proliferation and invasion. Apart from copy number gain, IGF2BP3 has been confirmed to be negatively regulated by tumor-suppressive miRNA, namely miR-34a. The expression of miR-34a showed negative correlation with IGF2BP3 mRNA expression in primary GC samples and more importantly, re-overexpression of IGF2BP3 rescued the inhibitory effect of miR-34a.

Conclusion

We compressively revealed the oncogenic role of IGF2BP3 in gastric tumorigenesis and confirmed its activation is partly due to the silence of miR-34a. Our findings identified useful prognostic biomarker and provided clinical translational potential.
Appendix
Available only for authorised users
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed
2.
Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol. 2003;56:1–9.CrossRefPubMed
3.
Lauren P. The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification. Acta Pathol Microbiol Scand. 1965;64:31–49.PubMed
4.
Flejou JF. WHO Classification of digestive tumors: the fourth edition. Ann Pathol. 2011;31:S27–31.CrossRefPubMed
5.
The Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRef
6.
Müeller-Pillasch F, Lacher U, Wallrapp C, Micha A, Zimmerhackl F, Hameister H, Varga G, Friess H, Büchler M, Beger HG, et al. Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein. Oncogene. 1997;14:2729–33.CrossRefPubMed
7.
Clauditz TS, Wang CJ, Gontarewicz A, Blessmann M, Tennstedt P, Borgmann K, Tribius S, Sauter G, Dalchow C, Knecht R, et al. Expression of insulin-like growth factor II mRNA-binding protein 3 in squamous cell carcinomas of the head and neck. J Oral Pathol Med. 2013;42:125–32.CrossRefPubMed
8.
Wang T, Fan L, Watanabe Y, Mcneill PD, Moulton GG, Bangur C, Fanger GR, Okada M, Inoue Y, Persing DH, Reed SG. L523S, an RNA-binding protein as a potential therapeutic target for lung cancer. Br J Cancer. 2003;88:887–94.CrossRefPubMedPubMedCentral
9.
Pryor JG, Bourne PA, Yang Q, Spaulding BO, Scott GA, Xu H. IMP-3 is a novel progression marker in malignant melanoma. Mod Pathol. 2008;21:431–7.CrossRefPubMed
10.
Li D, Yan D, Tang H, Zhou C, Fan J, Li S, Wang X, Xia J, Huang F, Qiu G, Peng Z. IMP3 is a novel prognostic marker that correlates with colon cancer progression and pathogenesis. Ann Surg Oncol. 2009;16:3499–506.CrossRefPubMed
11.
Jeng YM, Chang CC, Hu FC, Chou HY, Kao HL, Wang TH, Hsu HC. RNA-binding protein insulin-like growth factor II mRNA-binding protein 3 expression promotes tumor invasion and predicts early recurrence and poor prognosis in hepatocellular carcinoma. Hepatology. 2008;48:1118–27.CrossRefPubMed
12.
Lochhead P, Imamura Y, Morikawa T, Kuchiba A, Yamauchi M, Liao X, Qian ZR, Nishihara R, Wu K, Meyerhardt JA, et al. IGF2BP3 (IMP3) expression is a marker of unfavourable prognosis in colorectal cancer. Eur J Cancer. 2012;48:3405–13.CrossRefPubMedPubMedCentral
13.
Kim HJ, Kim GE, Lee JS, Lee JH, Nam JH, Choi C. Insulin-like growth factor-II mRNA-binding protein 3 expression in effusion cytology: a marker for metastatic adenocarcinoma cells and a potential prognostic indicator in gastric adenocarcinoma. Acta Cytol. 2014;58:167–73.CrossRefPubMed
14.
He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.CrossRefPubMed
15.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMed
16.
17.
18.
Huang T, Kang W, Zhang B, Wu F, Dong Y, Tong JH, Yang W, Zhou Y, Zhang L, Cheng AS, et al. miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-kappaB signaling in gastric carcinogenesis. Mol Cancer. 2016;15:9.CrossRefPubMedPubMedCentral
19.
Kang W, Tong JH, Lung RW, Dong Y, Yang W, Pan Y, Lau KM, Yu J, Cheng AS, To KF. let-7b/g silencing activates AKT signaling to promote gastric carcinogenesis. J Transl Med. 2014;12:281.CrossRefPubMedPubMedCentral
20.
Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, So KK, Wu K, Fan D, Yu J, et al. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011;17:2130–9.CrossRefPubMed
21.
Kang W, Tong JH, Chan AW, Zhao J, Dong Y, Wang S, Yang W, Sin FM, Ng SS, Yu J, et al. Yin Yang 1 contributes to gastric carcinogenesis and its nuclear expression correlates with shorter survival in patients with early stage gastric adenocarcinoma. J Transl Med. 2014;12:80.CrossRefPubMedPubMedCentral
22.
Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008;135:257–69.CrossRefPubMed
23.
Zehentmayr F, Hauser-Kronberger C, Zellinger B, Hlubek F, Schuster C, Bodenhofer U, Fastner G, Deutschmann H, Steininger P, Reitsamer R, et al. Hsa-miR-375 is a predictor of local control in early stage breast cancer. Clin Epigenetics. 2016;8:28.CrossRefPubMedPubMedCentral
24.
Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, Zhang L, Pan Y, Yang W, Pang JC, et al. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer. 2015;14:52.CrossRefPubMedPubMedCentral
25.
Shin G, Kang TW, Yang S, Baek SJ, Jeong YS, Kim SY. GENT: gene expression database of normal and tumor tissues. Cancer Inform. 2011;10:149–57.PubMedPubMedCentral
26.
Zhang X, Ni Z, Duan Z, Xin Z, Wang H, Tan J, Wang G, Li F. Overexpression of E2F mRNAs associated with gastric cancer progression identified by the transcription factor and miRNA co-regulatory network analysis. Plos One. 2015;10:e0116979.CrossRefPubMedPubMedCentral
27.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:1.CrossRef
28.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.CrossRefPubMed
29.
Gyorffy B, Surowiak P, Budczies J, Lanczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. Plos One. 2013;8:e82241.CrossRefPubMedPubMedCentral
30.
Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.CrossRefPubMed
31.
Liu BH, Goh CH, Ooi LL, Hui KM. Identification of unique and common low abundance tumour-specific transcripts by suppression subtractive hybridization and oligonucleotide probe array analysis. Oncogene. 2008;27:4128–36.CrossRefPubMed
32.
Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, Leblanc AC, Donovan DJ, Thung SN, Sole M, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68:6779–88.CrossRefPubMedPubMedCentral
33.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9.CrossRefPubMedPubMedCentral
34.
Gene Ontology C. Gene Ontology Consortium: going forward. Nucleic Acids Res. 2015;43:D1049–56.CrossRef
35.
Kolesnikov N, Hastings E, Keays M, Melnichuk O, Tang YA, Williams E, Dylag M, Kurbatova N, Brandizi M, Burdett T, et al. ArrayExpress update--simplifying data submissions. Nucleic Acids Res. 2015;43:D1113–6.CrossRefPubMed
36.
Anaya J. OncoLnc: Linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. Peer J Pre Prints. 2016;4:e1780v–1v.CrossRef
37.
Bell JL, Wächter K, Mühleck B, Pazaitis N, Köhn M, Lederer M, Hüttelmaier S. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression? Cell Mol Life Sci. 2012;70:2657–75.CrossRefPubMedPubMedCentral
38.
Wachter K, Kohn M, Stohr N, Huttelmaier S. Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains. Biol Chem. 2013;394:1077–90.CrossRefPubMed
39.
Ueki A, Shimizu T, Masuda K, Yamaguchi SI, Ishikawa T, Sugihara E, Onishi N, Kuninaka S, Miyoshi K, Muto A, et al. Up-regulation of Imp3 confers in vivo tumorigenicity on murine osteosarcoma cells. Plos One. 2012;7:e50621.CrossRefPubMedPubMedCentral
40.
Findeis-Hosey JJ, Xu H. The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology. Hum Pathol. 2011;42:303–14.CrossRefPubMed
41.
Suvasini R, Shruti B, Thota B, Shinde SV, Friedmann-Morvinski D, Nawaz Z, Prasanna KV, Thennarasu K, Hegde AS, Arivazhagan A, et al. Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2. J Biol Chem. 2011;286:25882–90.CrossRefPubMedPubMedCentral
42.
Rivera Vargas T, Boudoukha S, Simon A, Souidi M, Cuvellier S, Pinna G, Polesskaya A. Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization. Oncogene. 2014;33:2866–75.CrossRefPubMed
43.
Jonson L, Christiansen J, Hansen TV, Vikesa J, Yamamoto Y, Nielsen FC. IMP3 RNP safe houses prevent miRNA-directed HMGA2 mRNA decay in cancer and development. Cell Rep. 2014;7:539–51.CrossRefPubMed
44.
Samanta S, Sharma VM, Khan A, Mercurio AM. Regulation of IMP3 by EGFR signaling and repression by ERbeta: implications for triple-negative breast cancer. Oncogene. 2012;31:4689–97.CrossRefPubMedPubMedCentral
45.
Samanta S, Pursell B, Mercurio AM. IMP3 protein promotes chemoresistance in breast cancer cells by regulating breast cancer resistance protein (ABCG2) expression. J Biol Chem. 2013;288:12569–73.CrossRefPubMedPubMedCentral
46.
Okada K, Fujiwara Y, Nakamura Y, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Takahashi T, Mori M, Doki Y. Oncofetal protein, IMP-3, a potential marker for prediction of postoperative peritoneal dissemination in gastric adenocarcinoma. J Surg Oncol. 2012;105:780–5.CrossRefPubMed
47.
Damasceno EA, Carneiro FP, Magalhaes AV, Carneiro Mde V, Takano GH, Vianna LM, Seidler HB, Castro TM, Muniz-Junqueira MI, Amorim RF, et al. IMP3 expression in gastric cancer: association with clinicopathological features and HER2 status. J Cancer Res Clin Oncol. 2014;140:2163–8.CrossRefPubMed
48.
49.
50.
Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, Zarone MR, Gulla A, Tagliaferri P, Tassone P, Caraglia M. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids. 2014;3:e194.CrossRefPubMed
51.
Han Y, Meng F, Venter J, Wu N, Wan Y, Standeford H, Francis H, Meininger C, Greene Jr J, Trzeciakowski JP, et al. miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth. J Hepatol. 2016;64:1295–304.CrossRefPubMed
52.
Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, Goerger JP, Sun J, Witherspoon M, Rakhilin N, et al. A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell. 2013;12:602–15.CrossRefPubMedPubMedCentral
53.
Gougelet A, Sartor C, Bachelot L, Godard C, Marchiol C, Renault G, Tores F, Nitschke P, Cavard C, Terris B, et al. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut. 2016;65:1024–34.CrossRefPubMed
54.
Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang TC, Xie XJ, He L, Mangala LS, Lopez-Berestein G, et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature. 2014;512:431–5.CrossRefPubMed
55.
Cao W, Yang W, Fan R, Li H, Jiang J, Geng M, Jin Y, Wu Y. miR-34a regulates cisplatin-induce gastric cancer cell death by modulating PI3K/AKT/survivin pathway. Tumour Biol. 2014;35:1287–95.CrossRefPubMed
56.
Di Martino MT, Leone E, Amodio N, Foresta U, Lionetti M, Pitari MR, Cantafio ME, Gulla A, Conforti F, Morelli E, et al. Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res. 2012;18:6260–70.CrossRefPubMedPubMedCentral
57.
Scognamiglio I, Di Martino MT, Campani V, Virgilio A, Galeone A, Gulla A, Gallo Cantafio ME, Misso G, Tagliaferri P, Tassone P, et al. Transferrin-conjugated SNALPs encapsulating 2'-O-methylated miR-34a for the treatment of multiple myeloma. Biomed Res Int. 2014;2014:217365.CrossRefPubMedPubMedCentral
58.
Di Martino MT, Campani V, Misso G, Gallo Cantafio ME, Gulla A, Foresta U, Guzzi PH, Castellano M, Grimaldi A, Gigantino V, et al. In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma. Plos One. 2014;9:e90005.CrossRefPubMedPubMedCentral
Metadata
Title
IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis
Authors
Yuhang Zhou
Tingting Huang
Ho Lam Siu
Chi Chun Wong
Yujuan Dong
Feng Wu
Bin Zhang
William K. K. Wu
Alfred S. L. Cheng
Jun Yu
Ka Fai To
Wei Kang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0647-2

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

Antagonizing miR-455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma

Research

HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity

Review

Intra-tumor heterogeneity from a cancer stem cell perspective

Review

11q deletion in neuroblastoma: a review of biological and clinical implications

Research

Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway

Research

Over-expressed long noncoding RNA HOXA11-AS promotes cell cycle progression and metastasis in gastric cancer
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