Luo, Y., Yang, Y., Liu, M., Wang, D., Wang, F., Bi, Y., Ji, J., Li, S., Liu, Y., Chen, R., Huang, H., Wang, X., Swidnicka-Siergiejko, A. K., Janowitz, T., Beyaz, S., Wang, G., Xu, S., Bialkowska, A. B., Luo, C. K., Pin, C. L., Liang, G., Lu, X., Wu, M., Shroyer, K. R., Wolff, R. A., Plunkett, W., Ji, B., Li, Z., Li, E., Li, X., Yang, V. W., Logsdon, C. D., Abbruzzese, J. L., Lu, W. (July 2019) Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet. Gastroenterology, 157 (5). ISSN 0016-5085
Abstract
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 non-tumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (Kras(G12D/+) mice) and fElas(CreERT) mice (controls). Kras(G12D/+) mice were placed on a HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative PCR, 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 GTP. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed Kras(G12D/+) had significantly lower expression of Fgf21 mRNA, compared with acinar cells from control mice, partly due to downregulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from Kras(G12D/+) 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 Kras(G12D/+) 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 Kras(G12D/+) 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 about 12% of mice developed PDACs and none of the mice had metastases. Pancreata from HFD-fed Kras(G12D/+) 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 a HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the GTP binding capacity of RAS. FGF21 might be used in prevention or treatment of pancreatic cancer.
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