Lysophosphatidic acid receptor expression and function in human hepatocellular carcinoma

Sokolov, Eugene P.; Eheim, Ashley; Ahrens, William A.; Walling, Tracy L.; Swet, Jacob H.; McMillan, Matthew T.; Simo, Kerri A.; Thompson, Kyle J.; Sindram, David; McKillop, Iain H.

doi:10.1016/j.jss.2012.10.054

Cited by 32 publications

(44 citation statements)

References 41 publications

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“…Lastly, we show that data obtained in patients on the involvement of LPAR6 in HCC progression, as well as on the existing cross-talk between LPAR6 and Pim-3, are consistent with the experimental data. A descriptive study by Sokolov and colleagues (20) recently reported increased expression levels of LPAR6 in HCC. Our findings have extended these observations, disclosing a disease mechanism and attributing to LPAR6 a potential role as a biomarker predicting clinical outcome in patients with HCC.…”

Section: Discussionmentioning

confidence: 98%

Lysophosphatidic Acid Receptor LPAR6 Supports the Tumorigenicity of Hepatocellular Carcinoma

et al. 2015

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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. Cancer Res; 75(3); 532-43. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 98%

Lysophosphatidic Acid Receptor LPAR6 Supports the Tumorigenicity of Hepatocellular Carcinoma

et al. 2015

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“…LPAR6 was previously shown to be highly expressed in tumour tissue and metastases of human hepatocellular carcinoma compared to normal liver, 21 but the function of LPAR6 was not investigated. Our data show that overexpression of LPAR6 leads to increased migration and metastasis of PC-3M-luc and DU145 cells.…”

Section: Discussionmentioning

confidence: 99%

LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

et al. 2014

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Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.

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“…Many lines of evidence strongly suggest that LPA can have a role in cancer [4,[8][9][10][11][12][13][14][15][16][17][18][19][20]. There are several signaling pathways that conceivably could mediate the effects of LPA in malignant cells.…”

Section: Discussionmentioning

confidence: 99%

“…The biological actions of LPA are mediated via at least six different receptors (LPA [1][2][3][4][5][6] belonging to the Gprotein-coupled receptor (GPCR) family [1,3,6,7]. Strong evidence implicates LPA in malignancy [1,4,[8][9][10][11] and indicates a role in the development, progression, and invasiveness of various cancers, such as carcinomas of the ovary, prostate, breast, thyroid, liver, head and neck, and gastrointestinal tract [4,9,[11][12][13][14][15][16][17][18][19][20]. Both autotaxin and LPA receptors have been proposed as potential targets for anticancer therapy [1,21,22].…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid induces both EGFR-dependent and EGFR-independent effects on DNA synthesis and migration in pancreatic and colorectal carcinoma cells

et al. 2015

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Lysophosphatidic acid (LPA) is a small glycerophospholipid ubiquitously present in tissues and plasma. It acts through receptors belonging to the G-protein-coupled receptor (GPCR) family, is involved in several biological processes, and is strongly implicated in different cancers. In this paper, we have investigated the effects of LPA on DNA synthesis and migration in a panel of pancreatic and colon cancer cells, with particular focus on the involvement of the epidermal growth factor (EGF) receptor (EGFR) in LPA-induced signaling. LPA stimulated DNA synthesis and/or migration in all the cell lines included in this study. In five of the six cell lines, LPA induced phosphorylation of the EGFR, and the effects on EGFR and Akt, and in some of the cells also ERK, were sensitive to the EGFR tyrosine kinase inhibitor gefitinib, strongly suggesting LPA-induced EGFR transactivation in these cells. In contrast, in one of the pancreatic carcinoma cell lines (Panc-1), we found no evidence of transactivation of the EGFR. In the pancreatic carcinoma cell lines where transactivation took place (BxPC3, AsPC1, HPAFII), gefitinib reduced LPA-induced DNA synthesis and/or migration. However, we also found evidence of transactivation in the two colon carcinoma cell lines (HT29, HCT116) although gefitinib did not inhibit LPA-induced DNA synthesis or migration in these cells. Taken together, the data indicate that in many gastrointestinal carcinoma cells, LPA uses EGFR transactivation as a mechanism when exerting such effects as stimulation of cell proliferation and migration, but EGFR-independent pathways may be involved instead of, or in concerted action with, the EGFR transactivation.

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Lysophosphatidic acid receptor expression and function in human hepatocellular carcinoma

Cited by 32 publications

References 41 publications

Lysophosphatidic Acid Receptor LPAR6 Supports the Tumorigenicity of Hepatocellular Carcinoma

Lysophosphatidic Acid Receptor LPAR6 Supports the Tumorigenicity of Hepatocellular Carcinoma

LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

Lysophosphatidic acid induces both EGFR-dependent and EGFR-independent effects on DNA synthesis and migration in pancreatic and colorectal carcinoma cells

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