國家衛生研究院 NHRI:Item 3990099045/13806
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    题名: Obesity-associated leptin promotes chemoresistance in colorectal cancer through YAP-dependent AXL upregulation
    作者: Chen, YC;Chien, CY;Hsu, CC;Lee, CH;Chou, YT;Shiah, SG;Liu, SY;Yen, CY;Hsieh, AC;Wabitsch, M;Shieh, YS
    贡献者: National Institute of Cancer Research
    摘要: Obesity results from an imbalance between caloric intake and energy expenditure, and it is highly associated with colorectal carcinogenesis and therapeutic resistance in patients with colorectal cancer (CRC). Dysregulation of adipokine production in obesity has been reported to cause malignant behaviors in CRC. Leptin, which is the principal hormone secreted by adipocytes and an obesity-associated adipokine, is significantly overexpressed in CRC tissues. However, the effect of leptin on chemoresistance in CRC is unclear. Therefore, the aim of this study was to clarify the role of leptin and the underlying mechanisms in mediating 5-fluorouracil (5-FU) resistance in CRC. We used palmitate to artificially generate obese adipocytes. As expected, lipid accumulation was significantly increased in obese adipocytes. We demonstrated that CRC cells incubated with conditioned media (CM) harvested from obese adipocytes were associated with increased resistance to 5-FU. Notably, this increase in resistance to 5-FU was through the elevated production and secretion of leptin. Leptin could further stimulate the expression of AXL and activate its downstream signaling molecule, PLCγ, thereby resulting in an increased expression of p-glycoprotein (P-gp) in CRC cells. Mechanistically, leptin induced AXL expression via the inhibition of AMPK and subsequent increase in YAP activation and nuclear translocation. In addition, nuclear YAP interacted with TEAD and promoted the occupancy of TEAD on the AXL promoter, thereby stimulating AXL promoter activity after leptin treatment. Furthermore, leptin neutralization rescued the sensitivity of CRC tumors to 5-FU in mice fed on a high-fat diet (HFD). These results indicated that leptin mediated 5-FU resistance through YAP-dependent AXL overexpression in CRC.
    日期: 2021-09-15
    關聯: American Journal of Cancer Research. 2021 Sep 15;11(9):4220-4240.
    Link to: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493400/
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2156-6976&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000707716300010
    显示于类别:[夏興國] 期刊論文

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