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

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

Edité par CCSD ; BioMed Central -

International audience. Background: The heregulin-1ß/HER3-driven pathway is implicated in several epithelial malignancies and itsblockade is currently undergoing clinical investigation. Paradoxically, the status and the regulation of this pathwayis poorly known in hepatocellular carcinoma (HCC).Methods: Using 85 HCC obtained after tumour resection, heregulin-1ß and HER3 expression was evaluated byreal-time RT-PCR, ELISA and/or immunohistochemistry. Statistics were performed to analyze associations betweengene expression and clinicopathological parameters. The effects of insulin on the heregulin-1ß/HER3 pathway wasinvestigated in four HCC cell lines.Results: HER3 mRNA was upregulated in 52 % of tumours, while heregulin-1ß mRNA was downregulated in82 %. Hepatitis B and C viral infections were respectively associated with high and low HER3 mRNAexpression. 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 tumoursbut the staining was nonreproducible. HER3 mRNA and protein levels were not correlated in liver tissues. InHCC cells, insulin promoted HER3 proteasomal degradation and inhibited heregulin-1ß stimulation of cellmigration. HER3 and insulin receptor co-immunoprecipitated in these cells. The loss of insulin receptorexpression 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 differentiallyinfluenced by hepatitis viruses. Insulin is a negative regulator of HER3 protein expression and function in HCCcells. Altogether these data may explain why HER3 and heregulin-1ß expression have no prognostic value andsuggest that HCC patients are unlikely to derive benefit from HER3-targeted monotherapies

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