Hepatocyte expression of fetal insulin receptor isoform contributes to the promotion of liver cancer through non-cell autonomous mechanisms
Abstract
The insulin receptor (INSR) exists in two isoforms, INSR-A and INSR-B, resulting from alternative splicing of theINSRpre-mRNA. INSR-B mediates the metabolic and mitogenic effects of insulin in the adult liver, while INSR-A is expressed during development. Recently, INSR-A has been detected in pathological murine and human livers. Here, we develop anin vivoCRISPR/Cas9 strategy to assess the impact of INSR-A on mouse liver homeostasis and susceptibility to carcinogenesis. We find that INSR-A expression in hepatocytes leads to the spontaneous development of liver tumours and also increases tumour initiation in a context of β-catenin-driven liver carcinogenesis. Mechanistically, this is attributed to the higher intrinsic capacity of INSR-A expressing hepatocytes to enter apoptosis, rendering the microenvironment more inflammatory, thus making way for the proliferation of preneoplastic cells. Collectively, our data highlight a novel function for INSR-A in promoting liver cancervianon-cell autonomous mechanisms.
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