title: 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.
abstract: 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.
authors: 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.
authors: Takuma
authors: T
authors: Higurashi
authors: 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.
authors: Hiroki
authors: H
authors: Endo
authors: 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.
authors: Takashi
authors: T
authors: Uchiyama
authors: 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.
authors: Shiori
authors: S
authors: Uchiyama
authors: 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.
authors: Eiji
authors: E
authors: Yamada
authors: 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.
authors: Hidenori
authors: H
authors: Ohkubo
authors: 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.
authors: Eiji
authors: E
authors: Sakai
authors: 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.
authors: Hirokazu
authors: H
authors: Takahashi
authors: 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.
authors: Shin
authors: S
authors: Maeda
authors: Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
authors: Koichiro
authors: K
authors: Wada
authors: Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan and.
authors: Yutaka
authors: Y
authors: Natsumeda
authors: Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Yoshitaka
authors: Y
authors: Hippo
authors: 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 nakajima-tky@umin.ac.jp.
authors: Atsushi
authors: A
authors: Nakajima
authors: Biochemistry Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Hitoshi
authors: H
authors: Nakagama
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C515447:leptin receptor, mouse