Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2016 | Research

Heregulin-1ß and HER3 in hepatocellular carcinoma: status and regulation by insulin

Authors: Corina Buta, Eva Benabou, Marie Lequoy, Hélène Régnault, Dominique Wendum, Fatiha Merabtene, Hamza Chettouh, Lynda Aoudjehane, Filomena Conti, Yves Chrétien, Olivier Scatton, Olivier Rosmorduc, Françoise Praz, Laetitia Fartoux, Christèle Desbois-Mouthon

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

Abstract

Background

The heregulin-1ß/HER3-driven pathway is implicated in several epithelial malignancies and its blockade is currently undergoing clinical investigation. Paradoxically, the status and the regulation of this pathway is poorly known in hepatocellular carcinoma (HCC).

Methods

Using 85 HCC obtained after tumour resection, heregulin-1ß and HER3 expression was evaluated by real-time RT-PCR, ELISA and/or immunohistochemistry. Statistics were performed to analyze associations between gene expression and clinicopathological parameters. The effects of insulin on the heregulin-1ß/HER3 pathway was investigated in four HCC cell lines.

Results

HER3 mRNA was upregulated in 52 % of tumours, while heregulin-1ß mRNA was downregulated in 82 %. Hepatitis B and C viral infections were respectively associated with high and low HER3 mRNA expression. No association was seen between neither HER3 or heregulin-1ß mRNA and prognostic factors, survival or recurrence. Immunohistochemistry showed predominant cytoplasmic staining of HER3 in tumours but the staining was nonreproducible. HER3 mRNA and protein levels were not correlated in liver tissues. In HCC cells, insulin promoted HER3 proteasomal degradation and inhibited heregulin-1ß stimulation of cell migration. HER3 and insulin receptor co-immunoprecipitated in these cells. The loss of insulin receptor expression by RNA interference sensitized cells to heregulin-1ß-induced AKT phosphorylation.

Conclusions

Autocrine heregulin-1ß loop is uncommon in HCC and HER3 mRNA expression is differentially influenced by hepatitis viruses. Insulin is a negative regulator of HER3 protein expression and function in HCC cells. Altogether these data may explain why HER3 and heregulin-1ß expression have no prognostic value and suggest that HCC patients are unlikely to derive benefit from HER3-targeted monotherapies.

Available only for authorised users

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.CrossRefPubMed

Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63:844–55.CrossRefPubMedPubMedCentral

Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12:408–24.CrossRefPubMed

Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463–75.CrossRefPubMed

Desbois-Mouthon C. The HER3/ErbB3 receptor: a promising target in cancer drug therapy. Gastroenterol Clin Biol. 2010;34:255–9.CrossRefPubMed

Amin DN, Campbell MR, Moasser MM. The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol. 2010;21:944–50.CrossRefPubMedPubMedCentral

Tanner B, Hasenclever D, Stern K, Schormann W, Bezler M, Hermes M, et al. ErbB-3 predicts survival in ovarian cancer. J Clin Oncol. 2006;24:4317–23.CrossRefPubMed

Giltnane JM, Moeder CB, Camp RL, Rimm DL. Quantitative multiplexed analysis of ErbB family coexpression for primary breast cancer prognosis in a large retrospective cohort. Cancer. 2009;115:2400–9.CrossRefPubMedPubMedCentral

Berghoff AS, Bartsch R, Preusser M, Ricken G, Steger GG, Bago-Horvath Z, et al. Co-overexpression of HER2/HER3 is a predictor of impaired survival in breast cancer patients. Breast. 2014;23:637–43.CrossRefPubMed

10.

Reschke M, Mihic-Probst D, Van Der Horst EH, Knyazev P, Wild PJ, Hutterer M, et al. HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res. 2008;14:5188–97.CrossRefPubMed

11.

Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, Da Costa Jr WL, et al. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011;29:3030–6.CrossRefPubMed

12.

Hayashi M, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J, et al. High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res. 2008;14:7843–9.CrossRefPubMed

13.

Wilson TR, Lee DY, Berry L, Shames DS, Settleman J. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell. 2011;20:158–72.CrossRefPubMed

14.

Shames DS, Carbon J, Walter K, Jubb AM, Kozlowski C, Januario T, et al. High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck. PLoS One. 2013;8, e56765.CrossRefPubMedPubMedCentral

15.

Memon AA, Sorensen BS, Melgard P, Fokdal L, Thykjaer T, Nexo E. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer. 2004;91:2034–41.CrossRefPubMedPubMedCentral

16.

Trocme E, Mougiakakos D, Johansson CC, All-Eriksson C, Economou MA, Larsson O, et al. Nuclear HER3 is associated with favorable overall survival in uveal melanoma. Int J Cancer. 2012;130:1120–7.CrossRefPubMed

17.

Pan B, Wang R, Huang Y, Garfield D, Zhang J, Chen H. HGF and NRG1 protein expression are not poor prognostic markers in surgically resected lung adenocarcinoma. Onco Targets Ther. 2015;8:1185–91.CrossRefPubMedPubMedCentral

18.

Ito Y, Takeda T, Sakon M, Tsujimoto M, Higashiyama S, Noda K, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer. 2001;84:1377–83.CrossRefPubMedPubMedCentral

19.

Neo SY, Leow CK, Vega VB, Long PM, Islam AF, Lai PB, et al. Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach. Hepatology. 2004;39:944–53.CrossRefPubMed

20.

Hsieh SY, He JR, Hsu CY, Chen WJ, Bera R, Lin KY, et al. Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. Hepatology. 2011;53:504–16.CrossRefPubMed

21.

Chettouh H, Fartoux L, Aoudjehane L, Wendum D, Claperon A, Chretien Y, et al. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. Cancer Res. 2013;73:3974–86.CrossRefPubMed

22.

Blivet-Van Eggelpoel MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, et al. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012;57:108–15.CrossRefPubMed

23.

Podevin P, Carpentier A, Pene V, Aoudjehane L, Carriere M, Zaidi S, et al. Production of infectious hepatitis C virus in primary cultures of human adult hepatocytes. Gastroenterology. 2010;139:1355–64.CrossRefPubMed

24.

Carver RS, Mathew PM, Russell WE. Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors. Endocrinology. 1997;138:5195–201.PubMed

25.

Mujoo K, Choi BK, Huang Z, Zhang N, An Z. Regulation of ERBB3/HER3 signaling in cancer. Oncotarget. 2014;5:10222–36.CrossRefPubMedPubMedCentral

26.

Cao K, Gong H, Qiu Z, Wen Q, Zhang B, Tang T, et al. Hepatitis B virus X protein reduces the stability of Nrdp1 to up-regulate ErbB3 in hepatocellular carcinoma cells. Tumour Biol. 2016. doi:10.1007/s13277-016-4936-y.

27.

Hsieh SY, He JR, Yu MC, Lee WC, Chen TC, Lo SJ, et al. Secreted ERBB3 isoforms are serum markers for early hepatoma in patients with chronic hepatitis and cirrhosis. J Proteome Res. 2011;10:4715–24.CrossRefPubMed

28.

Stindt S, Cebula P, Albrecht U, Keitel V, Schulte Am Esch J, Knoefel WT, et al. Hepatitis C virus activates a neuregulin-driven circuit to modify surface expression of growth factor receptors of the ErbB family. PLoS One. 2016;11, e0148711.CrossRefPubMedPubMedCentral

29.

Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 2008;68:2391–9.CrossRefPubMed

30.

Zhao H, Desai V, Wang J, Epstein DM, Miglarese M, Buck E. Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines. Mol Cancer Ther. 2012;11:503–13.CrossRefPubMed

31.

Meetze K, Vincent S, Tyler S, Mazsa EK, Delpero AR, Bottega S, et al. Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models. Clin Cancer Res. 2015;21:1106–14.CrossRefPubMed

32.

Ocana A, Diez-Gonzalez L, Esparis-Ogando A, Montero JC, Amir E, Pandiella A. Neuregulin expression in solid tumors: Prognostic value and predictive role to anti-HER3 therapies. Oncotarget. 2016. doi:10.18632/oncotarget.8648.

33.

Bianchi S, Palli D, Falchetti M, Saieva C, Masala G, Mancini B, et al. ErbB-receptors expression and survival in breast carcinoma: a 15-year follow-up study. J Cell Physiol. 2006;206:702–8.CrossRefPubMed

34.

Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW, Younes M, et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol. 1997;10:142–8.PubMed

35.

Anagnostou VK, Welsh AW, Giltnane JM, Siddiqui S, Liceaga C, Gustavson M, et al. Analytic variability in immunohistochemistry biomarker studies. Cancer Epidemiol Biomarkers Prev. 2010;19:982–91.CrossRefPubMedPubMedCentral

36.

Zhande R, Mitchell JJ, Wu J, Sun XJ. Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1. Mol Cell Biol. 2002;22:1016–26.CrossRefPubMedPubMedCentral

37.

Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci U S A. 2003;100:11285–90.CrossRefPubMedPubMedCentral

38.

Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35:2203–17.CrossRefPubMed

Title: Heregulin-1ß and HER3 in hepatocellular carcinoma: status and regulation by insulin
Authors: Corina Buta
Eva Benabou
Marie Lequoy
Hélène Régnault
Dominique Wendum
Fatiha Merabtene
Hamza Chettouh
Lynda Aoudjehane
Filomena Conti
Yves Chrétien
Olivier Scatton
Olivier Rosmorduc
Françoise Praz
Laetitia Fartoux
Christèle Desbois-Mouthon
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-016-0402-3

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

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate

MicroRNA-361-3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC

Tripartite motif containing 62 is a novel prognostic marker and suppresses tumor metastasis via c-Jun/Slug signaling-mediated epithelial-mesenchymal transition in cervical cancer

MicroRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis

MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer

MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer