Adiponectin Suppresses Human Pancreatic Cancer Growth through Attenuating the β-Catenin Signaling Pathway
Adiponectin Suppresses Human Pancreatic Cancer Growth through Attenuating the β-Catenin Signaling Pathway
复制标题
脂联素通过减弱 β-连环蛋白信号通路抑制人胰腺癌的生长
DOI：
10.7150/ijbs.27420
复制
发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Gan, Yu
中科院分区：
文献类型：
--
作者：
Jiang, Jinghui;Fan, Yingchao;Gan, Yu
脂肪因子正在成为肥胖和肥胖相关癌症(包括胰腺癌)之间的联系。脂联素是一种丰富的脂肪因子，在代谢紊乱中具有多种有益作用。在前瞻性流行病学研究中，低脂联素水平在人类肥胖中被普遍观察到，并与胰腺癌风险增加有关。在此，我们研究了脂联素在体外和体内对人胰腺癌的直接作用。结果表明，脂联素对人胰腺癌细胞的增殖有明显的抑制作用。阻断脂联素受体可完全消除脂联素的抗增殖作用，显著促进人胰腺癌裸鼠移植瘤的生长。进一步的分析表明，脂联素阻断了GSK-3β的磷酸化/失活，抑制了β-连环蛋白在细胞内的积聚，降低了细胞周期蛋白D1的表达，从而导致胰腺癌细胞周期在G(0)-G(1)期的积聚。脂联素介导的细胞增殖抑制作用可被GSK-3β抑制剂阻断。此外，微阵列分析显示，脂联素还在转录水平下调了β-连环蛋白的共激活因子TCF7L2的表达。这些结果表明，脂联素对人胰腺癌的保护作用可能与其对β-连环蛋白信号通路的减弱作用有关。综上所述，我们的发现支持低脂联素血症和胰腺癌风险增加之间的因果联系，并表明激活脂联素信号可能是肥胖相关胰腺癌的一种新的治疗策略。
Adipokines are emerging as a link between obesity and obesity-related cancers, including pancreatic cancer. Adiponectin is an abundant adipokine with pleiotropic beneficial roles in metabolic disorders. Low adiponectin levels are commonly observed in human obesity and have been associated with increased pancreatic cancer risk in prospective epidemiologic studies. Here, we investigated the direct effect of adiponectin on human pancreatic cancer in vitro and in vivo. Our results showed that adiponectin treatment significantly inhibited the proliferation of human pancreatic cancer cells. Knockdown of adiponectin receptors completely eliminated the antiproliferation effect of adiponectin and markedly promoted the growth of human pancreatic cancer xenografts in nude mice. Further analysis revealed that adiponectin blocked the phosphorylation/inactivation of GSK-3 beta, suppressed the intracellular accumulation of beta-catenin, reduced the expression of cyclin D1, and consequently caused cell cycle accumulation at the G(0)-G(1) phase in pancreatic cancer cells. Adiponectin-mediated attenuation of cell proliferation was abrogated by the GSK-3 beta inhibitor. In addition, a microarray analysis revealed that adiponectin also downregulated the expression of TCF7L2, a coactivator of beta-catenin, at the transcriptional level in pancreatic cancer cells. These results indicated that the protective role of adiponectin against human pancreatic cancer might be attributed to its attenuating effect on the beta-catenin signaling pathway. Taken together, our findings support a causal link between hypoadiponectinemia and increased pancreatic cancer risk, and suggest that activating adiponectin signaling could be a novel therapeutic strategy for obesity-related pancreatic cancer.