Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet

Luo, Yongde; Yang, Yunfeng; Liu, Muyun; Wang, Dan; Wang, Feng; Bi, Yang; Ji, Jun-Tao; Li, Suyun; Liu, Yan; Chen, Rong; Huang, Haojie; Wang, Xiaojie; Świdnicka-Siergiejko, Agnieszka Katarzyna; Janowitz, Tobias; Beyaz, Semir; Wang, Guoqiang; Xu, Suheng; Bialkowska, Agnieszka B.; Luo, Catherine K.; Pin, Christoph L.; Liang, Guang; Lu, Xiongbin; Wu, Maoxin; Shroyer, Kenneth R.; Wolff, Robert A.; Plunkett, William; Ji, Baoan; Li, Zhao‐Shen; Li, Ellen; Li, Xiaokun; Yang, Vincent W.; Logsdon, Craig D.; Abbruzzese, James L.; Lu, Weiqin

doi:10.1053/j.gastro.2019.07.030

Cited by 58 publications

(59 citation statements)

References 43 publications

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“…The injection of recombinant FGF21 can significantly reduce pancreatic inflammation and tumorigenesis, and its specific mechanism is that FGF21 can decease the ability of RAS to bind guanosine triphosphate. Therefore, it is speculated that FGF21 can be used for the prevention and treatment of pancreatic cancer [51]. The above results indicate that NUPR1, FGF21, and FLI1 promote tumor growth in certain tumors.…”

Section: Discussionmentioning

confidence: 91%

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

Bao

Feng

Zhao

et al. 2021

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Fanconi anemia complementation group D2 (FANCD2) has been associated with the sensitivity of tumor cells to DNA crosslinking damaging agents in certain solid tumors. However, its role in nasopharyngeal carcinoma (NPC) is still unclear. In the present study, the role of FANCD2 in the response of NPC CNE-2 cells to radiation was investigated. A CNE-2 cell model with stable FANCD2 silencing was constructed by lentiviral transfection. Fluorescence quantitative PCR and western blotting were used to evaluate FANCD2 expression in CNE-2 cells. The biological impact of FANCD2 silencing on the response of CNE-2 cells to radiation was investigated in vitro and in vivo. The microarray technology, western blotting, and immunohistochemistry were used to analyze the proteins involved in related pathways after irradiation to investigate the underlying mechanism. Lentivirus-mediated shRNA interference stably silenced the FANCD2 gene in CNE-2 cells. In vitro, in the FANCD2-silenced group, cell proliferation was significantly inhibited, apoptosis was increased, and the cell cycle was arrested at the G2/M phase after irradiation. In vivo, FANCD2 s ilencing slowed tumor growth, as the volume and weight of the xenograft tumors were significantly decreased. Both in vitro and in vivo, the differentially expressed genes NUPR1, FLI1, and FGF21 were downregulated in the FANCD2-silenced group. Our results show that FANCD2 silencing affected the sensitivity of CNE-2 cells to ionizing radiation by regulating cell proliferation, apoptosis, and cell cycle distribution. The mechanism might be associated with changes in NUPR1, FLI1, and FGF21 protein expression due to the FANCD2 silencing. This study provides a promising target for NPC radiotherapy.

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Section: Discussionmentioning

confidence: 91%

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

Bao

Feng

Zhao

et al. 2021

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“…High body mass index in individuals with no previously diagnosed tumor has been shown as being associated with high cancer risk [155]. In mice, high-fat diet stimulates oncogenic KRAS via cyclooxygenase 2 (COX2) activation, leading to pancreatic inflammation, fibrosis, and development of invasive PDAC [156], whereas fibroblast growth factor 21, a metabolic regulator preventing obesity, causes reduction in tumor growth [157].…”

Section: Lipid Biosynthesismentioning

confidence: 99%

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Moldogazieva

Mokhosoev

Terentiev

2020

Cancers

102

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It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

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“…High-fat diets have been associated with increased risk for human PDAC [4][5][6] . In preclinical animal models, high-fat diets promote both chemically-induced and oncogenic KRAS-initiated pancreatic carcinogenesis [7][8][9][10][11][12][13][14] . Fatty acids in high-fat diets act as activating ligands of PPARD, a transcriptional factor that exerts a wide spectrum of effects on important molecular events 15 .…”

Section: Introductionmentioning

confidence: 99%

Ppard Is Essential in Acceleration of Pancreatic Ductal Adenocarcinoma Development by High-Fat Diet in Mutant Kras Mice

Liu

Deguchi

Wei

et al. 2020

Preprint

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Pro-obesity high-fat diet is linked with an increased incidence of pancreatic cancers, but the molecular underpinnings of this association remain poorly understood. Here, we report that PPARD is upregulated in pancreatic intraepithelial neoplasia lesions (PanINs) at early stages of pancreatic tumorigenesis in humans and mutant Kras mice. Transgenic overexpression of Ppard in pancreatic epithelial cells drastically accelerates the development and progression of pancreatic ductal adenocarcinoma in mutant Kras mice when activated by feeding the mice with a high-fat diet or a diet containing GW501516 (50 mg/kg), a selective PPARD agonist. In contrast, pancreatic Ppard genetic deletion significantly suppressed the promotion of pancreatic tumorigenesis by these diets. Mechanistically, we found that this Ppard hyperactivation in pancreatic epithelial cells of mutant Kras mice increased production of chemokines and cytokines (e.g., CcI2, CcI4-5, CxcI5 and II6), leading to the robustly increased recruitment of myeloid-derived suppressor cells and macrophages into pancreata, which fostered an immune suppressive microenvironment and subsequently accelerated pancreatic ductal adenocarcinoma development and progression. Our findings demonstrate that PPARD plays an essential role in the promotion of pancreatic tumorigenesis by a high-fat diet. Targeted inhibition of PPARD activation is a potential interventive strategy for pancreatic cancer prevention and therapy.

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Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet

Cited by 58 publications

References 43 publications

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Ppard Is Essential in Acceleration of Pancreatic Ductal Adenocarcinoma Development by High-Fat Diet in Mutant Kras Mice

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