title: Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma.
abstract: Klotho, an anti-aging gene, has recently been shown to contribute to human hepatic tumorigenesis. In addition, it is known that Wnt signaling is antagonized by the protein klotho. Because augmented Wnt signaling has an important role in tumorigenesis of human hepatocellular carcinoma (HCC), we studied the relationship of klotho expression and activity to the Wnt pathway in this malignancy. Immunohistochemical analysis performed on tissue arrays revealed that klotho expression levels were significantly lower in HCC than in adjacent noncancerous tissues, while klotho staining was inversely correlated with clinical stage and histologic grade. Patients with klotho-expressing tumors had longer survival periods than did those with klotho-negative tumors. Overexpression of klotho as well as treatment with soluble klotho protein reduced hepatoma cell growth in vitro and in vivo, whereas klotho silencing enhanced cellular proliferation. Moreover, forced expression of klotho inhibited Wnt/β-catenin signaling, as confirmed by reduced expression of β-catenin, inhibition of translocation of β-catenin from the cytoplasm to the nucleus, and reduced expression of c-myc and cyclin D1, two known target genes of the Wnt/β-catenin pathway. In contrast, activation of the Wnt/β-catenin pathway was enhanced when klotho was silenced by inhibitory RNAs. Furthermore, serum levels of soluble klotho in patients with malignant tumors were studied, and results suggested a significant increase in these levels in HCC patients. These data suggest that klotho acts as a tumor suppressor and an inhibitor of the Wnt/β-catenin pathway in HCC, and moreover, that soluble klotho is a potential serum biomarker for HCC.
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.|Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Tang
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Zhining
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Ji
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.affiliation: Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Huang
authors.affiliation: Departments of Medicine (Gastroenterology Division) and Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology
chemical_list: D025521:Tumor Suppressor Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins