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Cancer Res. 2015 Feb 1;75(3):532-43. doi: 10.1158/0008-5472.CAN-14-1607. Epub 2015 Jan 14.

Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma.

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Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy. IRCCS "S. de Bellis", National Institute for Digestive Diseases, Bari, Italy.
Department of Emergency and Organ Transplantation, Section of Internal Medicine, Allergology and Clinical Immunology, University of Bari School of Medicine, Bari, Italy.
Institut Curie, Centre de Recherche, Pole de Biologie du Développement et Cancer, Paris, France.
Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
GenXPro GmbH, Altenhöferallee 3, Frankfurt Main, Germany.
Department of Biomedical Sciences and Human Oncology, University of Bari School of Medicine, Bari, Italy.


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.

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