Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma

Antonio Mazzocca, Francesco Dituri, Flavia De Santis, Addolorata Filannino, Chiara Lopane, Regina C. Betz, Ying Yi Li, Naofumi Mukaida, Peter Winter, Cosimo Tortorella, Gianluigi Giannelli, Carlo Sabbà

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)532-543
Number of pages12
JournalCancer Research
Volume75
Issue number3
DOIs
Publication statusPublished - Feb 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Mazzocca, A., Dituri, F., De Santis, F., Filannino, A., Lopane, C., Betz, R. C., Li, Y. Y., Mukaida, N., Winter, P., Tortorella, C., Giannelli, G., & Sabbà, C. (2015). Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma. Cancer Research, 75(3), 532-543. https://doi.org/10.1158/0008-5472.CAN-14-1607