title: Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma.
abstract: The aberrant processes driving hepatocellular carcinoma (HCC) are not fully understood. Lysophosphatidic acid receptors (LPAR) are commonly overexpressed in HCC, but their contributions to malignant development are not well established. In this report, we show that aberrant expression of LPAR6 sustains tumorigenesis and growth of HCC. Overexpression of LPAR6 in HCC specimens associated with poor survival in a cohort of 128 patients with HCC. We took a genetic approach to elucidate how LPAR6 sustains the HCC tumorigenic process, including through an expression profiling analysis to identify genes under the control of LPAR6. RNAi-mediated attenuation of LPAR6 impaired HCC tumorigenicity in tumor xenograft assays. Expression profiling and mechanistic analyses identified Pim-3 as a pathophysiologically relevant LPAR6 target gene. In nonmalignant cells where LPAR6 overexpression was sufficient to drive malignant character, Pim-3 was upregulated at the level of transcription initiation through a STAT3-dependent mechanism. A further analysis of HCC clinical specimens validated the connection between overexpression of LPAR6 and Pim-3, high proliferation rates, and poorer survival outcomes. Together, our findings establish LPAR6 as an important theranostic target in HCC tumorigenesis.
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy. IRCCS "S. de Bellis", National Institute for Digestive Diseases, Bari, Italy. a.mazzocca@intmed.uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mazzocca
authors.affiliation: Department of Emergency and Organ Transplantation, Section of Internal Medicine, Allergology and Clinical Immunology, University of Bari School of Medicine, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dituri
authors.affiliation: Institut Curie, Centre de Recherche, Pole de Biologie du Développement et Cancer, Paris, France.
authors.forename: Flavia
authors.initials: F
authors.lastname: De Santis
authors.affiliation: Department of Emergency and Organ Transplantation, Section of Internal Medicine, Allergology and Clinical Immunology, University of Bari School of Medicine, Bari, Italy.
authors.forename: Addolorata
authors.initials: A
authors.lastname: Filannino
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lopane
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.affiliation: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Li
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.affiliation: GenXPro GmbH, Altenhöferallee 3, Frankfurt Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Winter
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Tortorella
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari School of Medicine, Bari, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Giannelli
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sabbà
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D018076:DNA, Complementary; C545560:LPAR6 protein, human; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid