201. Heregulin-1ß and HER3 in hepatocellular carcinoma: status and regulation by insulin
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Hamza Chettouh, Eva Benabou, Fatiha Meratbene, Yves Chrétien, Laetitia Fartoux, Françoise Praz, Filomena Conti, Olivier Rosmorduc, Marie Lequoy, Lynda Aoudjehane, Dominique Wendum, Christèle Desbois-Mouthon, Hélène Regnault, Olivier Scatton, Corina Buta, BMC, BMC, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatologie [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Histomorphologie Saint-Antoine (HISA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), E. Benabou is a fellow from Ligue Nationale Contre le Cancer, H. Chettouhwas a fellow from Ministère de l’Enseignement Supérieur et de la Rechercheand Fondation ARC pour la Recherche sur le Cancer, H. Régnault was afellow from Fondation pour la Recherche Médicale. This work has beensupported by grants from INSERM, GEFLUC, Ligue Nationale Contre leCancer, Cancéropôle Ile de France and INCa (INCa-DGOS_5790)., Service d'hépatologie [Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service d'Hépatologie [AP-HP Hôpital Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Histomorphologie Saint-Antoine ( HISA ), AP-HP - Hôpital Saint-Antoine -Unité Mixte de Service d'Imagerie et de Cytométrie ( UMS LUMIC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Human HepCell [AP-HP Hôpital Saint-Antoine], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP - Hôpital Saint-Antoine -Paris Biotech santé, and Service de chirurgie digestive hépato-bilio-pancréatique transplantation hépatique [CHU Pitié-Salpêtrière]
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0301 basic medicine ,Cancer Research ,animal structures ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,HER3/ERBB3 ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Gene expression ,medicine ,skin and connective tissue diseases ,Protein kinase B ,[ SDV ] Life Sciences [q-bio] ,biology ,business.industry ,Research ,Insulin ,medicine.disease ,3. Good health ,Hepatitis virus ,[SDV] Life Sciences [q-bio] ,body regions ,Insulin receptor ,030104 developmental biology ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,biology.protein ,Liver cancer ,business - 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. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0402-3) contains supplementary material, which is available to authorized users.
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