title: PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation.
abstract: Aberrant activation of the Wnt/β-catenin pathway is frequent in hepatocellular carcinoma (HCC) and contributes to HCC initiation and progression. This abnormal activation may result from somatic mutations in the genes of the Wnt/β-catenin pathway and/or dysregulation of the Wnt/β-catenin pathway. The mechanism for the latter remains poorly understood. Prospero-related homeobox 1 (PROX1) is a downstream target of the Wnt/β-catenin pathway in human colorectal cancer and elevated PROX1 expression promotes malignant progression. However, the Wnt/β-catenin pathway does not regulate PROX1 expression in the liver and HCC cells. Here we report that PROX1 promotes HCC cell proliferation in vitro and tumor growth in HCC xenograft mice. PROX1 and β-catenin levels are positively correlated in tumor tissues as well as in cultured HCC cells. PROX1 can upregulate β-catenin transcription by stimulating the β-catenin promoter and enhance the nuclear translocation of β-catenin in HCC cells, which leads to the activation of the Wnt/β-catenin pathway. Moreover, we show that increase in PROX1 expression renders HCC cells more resistant to sorafenib treatment, which is the standard therapy for advanced HCC. Overall, we have pinpointed PROX1 as a critical factor activating the Wnt/β-catenin pathway in HCC, which promotes HCC proliferation and sorafenib resistance.
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China.
authors: Y
authors: Y
authors: Liu
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: X
authors: X
authors: Ye
authors: Liver Cancer Institute, Zhongshan Hospital; Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China.
authors: J-B
authors: JB
authors: Zhang
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: H
authors: H
authors: Ouyang
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Z
authors: Z
authors: Shen
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Y
authors: Y
authors: Wu
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: W
authors: W
authors: Wang
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: J
authors: J
authors: Wu
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: S
authors: S
authors: Tao
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: X
authors: X
authors: Yang
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: K
authors: K
authors: Qiao
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: J
authors: J
authors: Zhang
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: J
authors: J
authors: Liu
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Immunology, Binzhou Medical University, Yantai, China.
authors: Q
authors: http://orcid.org/0000-0002-6932-7103
authors: Q
authors: Fu
authors: Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Y
authors: Y
authors: Xie
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D000077157:Sorafenib; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D010671:Phenylurea Compounds; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000098551:Prospero-Related Homeobox 1 Protein; D009536:Niacinamide; D000077157:Sorafenib