title: Heregulin-1ß and HER3 in hepatocellular carcinoma: status and regulation by insulin.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.
authors: Corina
authors: C
authors: Buta
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.
authors: Eva
authors: E
authors: Benabou
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Department of Hepatology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France.
authors: Marie
authors: M
authors: Lequoy
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Department of Hepatology, AP-HP, Pitié-Salpétrière Hospital, F-75013, Paris, France.
authors: Hélène
authors: H
authors: Régnault
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Department of Pathology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France.
authors: Dominique
authors: D
authors: Wendum
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Histomorphology Platform, UMS 30 Lumic, F-75012, Paris, France.
authors: Fatiha
authors: F
authors: Meratbene
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.
authors: Hamza
authors: H
authors: Chettouh
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Human HepCell, Saint-Antoine Hospital, F-75012, Paris, France.
authors: Lynda
authors: L
authors: Aoudjehane
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Human HepCell, Saint-Antoine Hospital, F-75012, Paris, France.|Department of Hepatobiliary Surgery and Liver Transplantation, AP-HP, Pitié-Salpétrière Hospital, F-75013, Paris, France.
authors: Filomena
authors: F
authors: Conti
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.
authors: Yves
authors: Y
authors: Chrétien
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Department of Hepatobiliary Surgery and Liver Transplantation, AP-HP, Pitié-Salpétrière Hospital, F-75013, Paris, France.
authors: Olivier
authors: O
authors: Scatton
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Department of Hepatology, AP-HP, Pitié-Salpétrière Hospital, F-75013, Paris, France.
authors: Olivier
authors: O
authors: Rosmorduc
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.
authors: Françoise
authors: F
authors: Praz
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France.|Department of Hepatology, AP-HP, Pitié-Salpétrière Hospital, F-75013, Paris, France.
authors: Laetitia
authors: L
authors: Fartoux
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Saint-Antoine Research Center, 34 rue Crozatier, F-75012, Paris, France. christele.desbois-mouthon@inserm.fr.
authors: Christèle
authors: C
authors: Desbois-Mouthon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019898:Autocrine Communication; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D007328:Insulin; C094131:NRG1 protein, human; D020890:Neuregulin-1; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: HER3/ERBB3; Hepatitis virus; Insulin receptor; Liver cancer