Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan, Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Carcinogenesis. 2014 Sep;35(9):2134-41. doi: 10.1093/carcin/bgu135. Epub 2014 Jun 23.
Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis.
瘦素是由脂肪组织分泌的，与肥胖有关，被认为参与了结直肠癌的发生和发展。然而，瘦素在结直肠癌发生中的确切作用尚不清楚，因为已经发表了一些关于瘦素的各种系统作用的有争议的报告。本研究的目的是使用肠上皮细胞特异性瘦素受体（LEPR）介导的信号转导的条件敲除（cKO）小鼠来阐明 LEPR 介导的信号转导在结直肠癌变中的局部和精确作用。我们生产并使用结肠上皮细胞特异性 LEPRb cKO 小鼠，以研究其同窝对照的致突变剂诱导的结肠异常隐窝病灶（ACF）和肿瘤的形成。cKO 小鼠与对照小鼠的体重或全身状况没有差异。与对照小鼠相比，cKO 小鼠的肿瘤大小和大肿瘤数量明显较小。另一方面，cKO 小鼠和对照小鼠之间的正常结肠上皮细胞的增殖活性或 ACF 形成没有显著差异。在对照小鼠中，与正常上皮相比，结肠肿瘤中 LEPRb 的表达水平显著增加；此外，肿瘤细胞中的信号转导和转录激活因子（STAT3）被激活。这些发现表明 STAT3 是 LEPRb 的下游重要分子之一，LEPRb/STAT3 信号转导控制肿瘤细胞增殖。我们证明了局部/区域 LEPR 介导的信号转导在结直肠癌发生中的重要性。
