Diabetes mellitus is a well-known risk factor for pancreatic cancer. We focused on hyperglycemia, a main feature of diabetes mellitus, and uncovered its effect on precancerous pancreatic intraepithelial neoplasia (PanIN) progression. In vivo induction of hyperglycemia with 100 mg/kg streptozotocin in Kras^{LSL G12D} Pdx1Cre (KP) mice promoted the PanIN formation and progression. Preconditioning with a high- or low-glucose medium for 28 days showed that a high-glucose environment increased cell viability and sphere formation in PANC-1, a Kras-mutant human pancreatic ductal adenocarcinoma cell line, and mPKC1, a Kras-mutant murine pancreatic cancer cell line. In contrast, no changes were observed in BxPC3, a Kras-wild-type human pancreatic cancer cell line. Orthotopic injection of mPKC1 into the pancreatic tails of BL6/J mice showed that cells maintained in high-glucose medium grew into larger tumors than did those maintained in low-glucose medium. Hyperglycemia strengthened the STAT3 phosphorylation, which was accompanied by elevated MYC expression in Kras-mutant cells. Immunohistochemistry showed stronger phosphorylated STAT3 (pSTAT3) and MYC staining in PanINs from diabetic KP mice than in those from euglycemic counterparts. STAT3 inhibition with 1 μM STAT3 inhibitor STATTIC in Kras-mutant pancreatic cell lines blocked the cell viability- and sphere formation-enhancing effects of the hyperglycemic environment and reversed the elevated pSTAT3 and MYC expression. MYC knockdown did not affect cell viability but did reduce sphere formation. No decrease in pSTAT3 expression was observed upon siMYC treatment. In conclusion, hyperglycemia, on a Kras-mutant background, aggravates the PanIN progression, which is accompanied by elevated pSTAT3 and MYC expression.

糖尿病是胰腺癌的众所周知的危险因素。我们集中于高血糖症（糖尿病的主要特征），并揭示了其对癌前胰腺上皮内瘤变（PanIN）进展的影响。用100 mg / kg链脲佐菌素在Kras ^{LSL G12D} Pdx1Cre中体内诱导高血糖（KP）小鼠促进PanIN的形成和发展。用高糖或低糖培养基预处理28天表明，高糖环境增加了PANC-1（一种Kras突变型人胰腺导管腺癌细胞系）和mPKC1（一种Kras突变型鼠）的细胞活力和球形成。胰腺癌细胞系。相反，在Kras-野生型人胰腺癌细胞系BxPC3中未观察到变化。将mPKC1原位注射到BL6 / J小鼠的胰腺尾巴中显示，与低葡萄糖培养基相比，高葡萄糖培养基中维持的细胞长成更大的肿瘤。高血糖会增强STAT3磷酸化，并伴随着Kras突变细胞中MYC表达的升高。免疫组化显示，与正常血糖对照组相比，糖尿病KP小鼠的PanINs的磷酸化STAT3（pSTAT3）和MYC染色更强。在Kras突变型胰腺细胞系中用1μMSTAT3抑制剂STATTIC抑制STAT3可以阻止高血糖环境对细胞活力和球形成的增强作用，并逆转升高的pSTAT3和MYC表达。MYC敲低并不影响细胞生存力，但确实减少了球的形成。siMYC处理后未观察到pSTAT3表达降低。总之，在Kras突变背景下，高血糖会加剧PanIN进展，并伴随pSTAT3和MYC表达升高。在Kras突变型胰腺细胞系中用1μMSTAT3抑制剂STATTIC抑制STAT3可以阻止高血糖环境对细胞活力和球形成的增强作用，并逆转升高的pSTAT3和MYC表达。MYC敲低并不影响细胞生存力，但确实减少了球的形成。siMYC处理后未观察到pSTAT3表达降低。总之，在Kras突变背景下，高血糖会加剧PanIN进展，并伴随pSTAT3和MYC表达升高。在Kras突变型胰腺细胞系中用1μMSTAT3抑制剂STATTIC抑制STAT3可以阻止高血糖环境对细胞活力和球形成的增强作用，并逆转升高的pSTAT3和MYC表达。MYC敲低并不影响细胞活力，但确实减少了球的形成。siMYC处理后未观察到pSTAT3表达降低。总之，在Kras突变背景下，高血糖会加剧PanIN进展，并伴随pSTAT3和MYC表达升高。