Augmented leptin-induced trefoil factor 3 expression and epidermal growth factor receptor transactivation differentially influences neoplasia progression in the stomach and colorectum of dietary fat-induced obese mice
Augmented leptin-induced trefoil factor 3 expression and epidermal growth factor receptor transactivation differentially influences neoplasia progression in the stomach and colorectum of dietary fat-induced obese mice
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瘦素诱导的三叶因子 3 表达和表皮生长因子受体反式激活的增强对膳食脂肪诱导的肥胖小鼠的胃和结直肠肿瘤进展有不同影响
DOI：
10.1016/j.abb.2022.109379
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发表时间：
2022
影响因子：
3.9
通讯作者：
Inagaki-Ohara K
中科院分区：
文献类型：
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作者：
Kinoshita Y;Arita S;Ogawa T;Takenouchi A;Inagaki-Ohara K
肥胖是胃肠道恶性肿瘤和肿瘤的危险因素。然而，哪些因素保护或使胃肠道器官易于发生高脂饮食（HFD）诱导的肿瘤仍不清楚。在这里，我们表明，HFD影响胃在更大程度上相比，结直肠，导致瘦素受体（LepR）信号介导的肿瘤组织。HFD激活瘦素信号传导，这反过来又加速胃粘膜中的发病率高于沿着异位TFF 3表达的结肠直肠中的发病率。此外，在胃中，除了STAT 3和Akt的活化之外，还观察到与结肠直肠相比更高水平的磷酸化表皮生长因子受体（EGFR）。在胃肠道上皮中LepR缺失的小鼠在胃中表现出对瘦素、TFF 3和磷酸化EGFR的抑制诱导，而在结肠直肠中的水平不显著。在用LepR和EGFR质粒DNA共转染的COS-7细胞中，瘦素反式激活EGFR以加速TFF 3诱导，并沿着激活STAT 3、ERK 1/2、Akt和PI 3 K p85/p55。此外，TFF 3可以结合EGFR，但不反式激活LepR。瘦素诱导的TFF 3诱导被PI 3 K（LY 294002）和EGFR（厄洛替尼）的抑制剂显著抑制。总之，这些结果表明LepR介导的信号转导在EGFR反式激活中的新作用，其通过PI 3 K-Akt途径导致TFF 3表达。因此，这项研究揭示了潜在的新的治疗目标，用于治疗胃癌和结直肠癌前症状的识别。
Obesity is a risk factor for gastrointestinal malignancies and tumors. However, which factors either protect or predispose the gastrointestinal organs to high-fat diet (HFD)-induced neoplasia remains unclear. Here, we demonstrate that HFD impacts the stomach to a greater extent as compared to the colorectum, resulting in leptin receptor (LepR) signaling-mediated neoplasia in the tissues. HFD activated leptin signaling, which in turn, accelerates the pathogenesis in the gastric mucosa more than that in the colorectum along with ectopic TFF3 expression. Moreover, in the stomach, higher levels of phosphorylated epidermal growth factor receptor (EGFR) in addition to the activation of STAT3 and Akt were observed as compared to the colorectum. The mice with LepR deletion in the gastrointestinal epithelium exhibited a suppressed induction of leptin, TFF3, and phosphorylated EGFR in the stomach, whereas the levels in the colorectum were insignificant. In co-transfected COS-7 cells with LepR and EGFR plasmid DNA, leptin transactivated EGFR to accelerate TFF3 induction along with activation of STAT3, ERK1/2, Akt, and PI3K p85/p55. Furthermore, TFF3 could bind to EGFR but did not transactivate LepR. Leptin-induced TFF3 induction was markedly suppressed by inhibitors of PI3K (LY294002) and EGFR (Erlotinib). Together, these results suggest a novel role of LepR-mediated signaling in transactivating EGFR that leads to TFF3 expression via the PI3K-Akt pathway. Therefore, this study sheds light on the identification of potentially new therapeutic targets for the treatment of pre-cancerous symptoms in stomach and colorectum.