BACKGROUND & AIMS Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. RESULTS Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

中文翻译：

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致癌性 KRAS 降低 FGF21 在腺泡细胞中的表达，以促进高脂肪饮食小鼠的胰腺肿瘤发生。

背景与目的 肥胖是胰腺癌的危险因素。在小鼠中，高脂肪饮食 (HFD) 和致癌 KRAS 的表达通过未知机制导致侵袭性胰腺导管腺癌 (PDAC) 的发展。我们调查了致癌性 KRAS 如何调节成纤维细胞生长因子 21、FGF21 的表达，FGF21 是一种防止肥胖的代谢调节因子，以及重组人 FGF21 (rhFGF21) 对胰腺肿瘤发生的影响。方法 我们对人胰腺组织阵列中的 FGF21 水平进行了免疫组织化学分析，包括 59 个 PDAC 标本和 45 个非肿瘤组织。我们还研究了在腺泡细胞（KrasG12D/+ 小鼠）和 fElasCreERT 小鼠（对照）中具有他莫昔芬诱导型致癌 KRAS 表达的小鼠。将 KrasG12D/+ 小鼠置于 HFD 或常规食物（对照）中并注射 rhFGF21 或载体；收集胰腺并通过组织学、免疫印迹、定量聚合酶链反应和免疫组织化学进行分析。我们测量了胰腺、肝脏和脂肪组织中的炎症标志物。RAS 的活性是根据结合的三磷酸鸟苷的量来测量的。结果 与肝组织相比，小鼠胰腺组织表达高水平的 FGF21。FGF21 及其受体蛋白由腺泡细胞表达。与来自对照小鼠的腺泡细胞相比，表达 KrasG12D/+ 的腺泡细胞具有显着较低的 Fgf21 信使 RNA 表达，部分原因是 PPARG 表达下调——一种激活 Fgf21 转录的转录因子。与注射载体的小鼠相比，接受对照饮食并注射 rhFGF21 的 KrasG12D/+ 小鼠的胰腺减少了胰腺炎症、免疫细胞浸润和腺泡-导管化生。HFD 喂养的 KrasG12D/+ 小鼠注射赋形剂后腹部脂肪堆积，出现广泛炎症、胰腺囊肿和高级别胰腺上皮内瘤变 (PanINs)；一半的小鼠发展为伴有肝转移的 PDAC。注射 rhFGF21 的 HFD 喂养的 KrasG12D/+ 小鼠腹部脂肪和胰腺甘油三酯的积累减少，胰腺囊肿减少，炎症的全身和胰腺标志物减少，PanIN 减少，存活时间延长——仅约 12% 的小鼠发展为 PDAC，并且没有一只小鼠发生转移。注射 rhFGF21 的 HFD 喂养 KrasG12D/+ 小鼠的胰腺活性 RAS 水平低于给予载体的小鼠。结论 小鼠和人类的正常腺泡细胞表达高水平的 FGF21。在小鼠中，致癌 KRAS 的腺泡表达显着降低 FGF21 表达。当这些小鼠被置于 HFD 上时，它们会出现广泛的炎症、胰腺囊肿、PanIN 和 PDAC，这些都可以通过注射 FGF21 来减少。FGF21 还降低 RAS 的三磷酸鸟苷结合能力。FGF21 可能用于预防或治疗胰腺癌。当这些小鼠被置于 HFD 上时，它们会出现广泛的炎症、胰腺囊肿、PanIN 和 PDAC，这些都可以通过注射 FGF21 来减少。FGF21 还降低 RAS 的三磷酸鸟苷结合能力。FGF21 可能用于预防或治疗胰腺癌。当这些小鼠被置于 HFD 上时，它们会出现广泛的炎症、胰腺囊肿、PanIN 和 PDAC，这些都可以通过注射 FGF21 来减少。FGF21 还降低 RAS 的三磷酸鸟苷结合能力。FGF21 可能用于预防或治疗胰腺癌。