RESUMO
Leptin is an adipose-tissue specific cytokine described 20 years ago and classically thought to be involved in regulation of food intake and energy homeostasis. More recently, leptin was proven to exert other multiple roles in carbohydrate and lipid metabolism, reproductive system, and inflammatory and immune reactions. Emerging data propose leptin to be a modulator of bone mass. In some particular circumstances leptin synthesis follow specific patterns in inflammation and sepsis, not being proportional with fat mass. Therefore, it may be used as diagnostic or prognostic marker for critical illness.
Assuntos
Metabolismo dos Carboidratos , Ingestão de Alimentos , Inflamação/diagnóstico , Leptina/metabolismo , Metabolismo dos Lipídeos , Sepse/diagnóstico , Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Osso e Ossos/metabolismo , Homeostase/genética , Humanos , Inflamação/metabolismo , Leptina/genética , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Sepse/metabolismoRESUMO
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.
