Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels
Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels
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DOI：
10.1371/journal.pone.0235573
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发表时间：
2020-07-01
期刊：
影响因子：
3.7
通讯作者：
Takehara, Tetsuo
中科院分区：
文献类型：
--
作者：
Sato, Katsuhiko;Hikita, Hayato;Takehara, Tetsuo
糖尿病是众所周知的胰腺癌的危险因素。我们聚焦于高血糖，这是糖尿病的一个主要特征，并揭示了它在癌前胰腺上皮内瘤变(Panin)进展中的作用。在体内用100 mg/kg链脲佐菌素诱导Kras(LSL G12D)Pdx1Cre(KP)小鼠高血糖可促进Panin的形成和进展。高糖或低糖处理28天后，发现高糖环境可增加Kras突变的人胰腺癌细胞株PANC-1和突变的小鼠胰腺癌细胞株mPKC1的细胞存活率和球体形成。相比之下，Kras野生型人胰腺癌细胞株BxPC3没有观察到变化。在BL6/J小鼠的胰腺尾部原位注射mPKC_1，结果表明，维持在高糖培养液中的细胞比在低糖培养液中维持的细胞生长出更大的肿瘤。高血糖增强了Kras突变细胞中STAT3的磷酸化，并伴随着MYC表达的升高。免疫组织化学显示糖尿病KP小鼠Panins的磷酸化STAT3(PSTAT3)和MYC染色比正常血糖小鼠更强。在Kras突变的胰腺细胞系中，用1MU M STAT3抑制剂STATTIC抑制STAT3，可阻断高血糖环境对细胞活力和球体形成的促进作用，并逆转pSTAT3和MYC表达的升高。MYC基因敲除不影响细胞活力，但减少了球体的形成。经siMYC处理后，pSTAT3的表达未见下降。总而言之，高血糖，在Kras突变的背景下，加重了Panin进展，伴随着pSTAT3和MYC表达的升高。
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 inKras(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 mu M 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.