Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice.
Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice.
复制标题
结肠上皮中瘦素受体的条件性敲除揭示了瘦素受体信号传导在小鼠结肠肿瘤进展中的局部效应。
DOI：
10.1093/carcin/bgu135
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Nakagama H.
中科院分区：
文献类型：
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作者：
Higurashi T;Endo H;Uchiyama T;Uchiyama S;Yamada E;Ohkubo H;Sakai E;Takahashi H;Maeda S;Wada K;Natsumeda Y;Hippo Y;Nakajima A;Nakagama H.
瘦素由脂肪组织分泌，已知与肥胖有关，被认为与结直肠癌的发病和进展有关。然而，瘦素在结直肠癌发生中的确切作用仍不清楚，因为已经发表了一些关于瘦素各种系统效应的有争议的报告。本研究的目的是使用肠上皮特异性 LEPRb 条件性敲除 (cKO) 小鼠来阐明瘦素受体 (LEPR) 介导的信号在结肠癌发生中的局部和精确作用。我们制备并使用结肠上皮特异性 LEPRb cKO 小鼠来研究致癌物诱导的结肠中异常隐窝病灶 (ACF) 和肿瘤的形成，并使用其同窝小鼠作为对照。对照小鼠和cKO小鼠之间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的数量显着较低。另一方面，对照组和cKO小鼠之间正常结肠上皮细胞的增殖活性或ACF形成没有显着差异。在对照小鼠中，与正常上皮细胞相比，在结肠肿瘤中观察到LEPRb表达水平显着增加；此外，肿瘤细胞中的信号转导子和转录激活子（STAT3）被激活。这些发现表明STAT3是LEPRb下游的重要分子之一，LEPRb/STAT3信号传导控制肿瘤细胞增殖。我们证明了局部/区域 LEPR 介导的信号在结直肠癌发生中的重要性。
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.