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MRNA profiling after knockdown of Circular RNA-INSR

ABSTRACT: The recent advances in anti-cancer treatments have led to a steady increase in the number of cancer survivors, paradoxically also enhancing the number of HF patients who suffer from the undesired cardiotoxic side effects of these anti-tumor treatments. Therapeutic options to reduce or reverse chemotherapy-induced HF are not available. Circular RNAs exhibit high druggability due to the high stability of their special closed loop structure. Circ-INSR overexpression prevents doxorubicin-induced cardiac dysfunction in preclinical murine and human models. Circ-INSR mimics produced in vitro also reduced cardiomyocyte death under doxorubicin stress, highlighting the potential of Circ-INSR-based RNA therapy for future clinical applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE199081 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.

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MRNA profiling after knockdown of Circular RNA-INSR

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