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

Hepatocyte autotaxin expression promotes liver fibrosis and cancer

“…To interrogate human patients liver mRNA expression of ATX, as well as of LPA receptors ( LPAR1‐6 ) and phospholipid phosphatases ( PPAP2A‐C/LPP1‐3 ), we performed data mining in all CLD patient microarray data sets publically available at http://www.ncbi.nlm.nih.gov/geo/ (http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo). Statistically significant increased ATX mRNA expression was found in the majority of data sets/patient cohorts; the same is true for LPAR6 , previously suggested to support the tumorigenicity of HCC . Similarly, increased ATX mRNA levels were also detected in HCC data sets (http://onlinelibrary.wiley.com/doi/10.1002/hep.28973/suppinfo), accompanied by decreased expression of PPA2PB suggested to mediate LPA turnover …”

“…Statistically significant increased ATX mRNA expression was found in the majority of data sets/patient cohorts; the same is true for LPAR6, previously suggested to support the tumorigenicity of HCC. (12) Similarly, increased ATX mRNA levels were also detected in HCC data sets ( Supporting Table S1B), accompanied by decreased expression of PPA2PB suggested to mediate LPA turnover. (13) Increased ATX sera levels were identified in patients with CVH (including HCV and hepatitis B virus), as well as in ALD and NASH patients ( Fig.…”

Long Noncoding RNA HOST2 Promotes Epithelial-Mesenchymal Transition, Proliferation, Invasion and Migration of Hepatocellular Carcinoma Cells by Activating the JAK2-STAT3 Signaling Pathway

“…Each experiment was repeated 3 times. Forty-eight hours after transfection, the cells were collected to detect the mRNA expression according to the experimental method described above [25].…”

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

“…Mazzocca et al confirmed in vitro experiments that LPAR6 promoted the proliferation and tumorigenic phenotype of HCC cells, and established a relevant model to prove that LPAR6 promotes tumor growth, and the higher the expression level of LPAR6 in tumor tissues of liver cancer patients, the worse the prognosis of patients. Abnormally expressed LPAR6 can activate the protooncogene pim-3 via the signal transducers and activators of transcription 3 (STAT3) binding site, thereby maintaining the tumor proliferative capacity and tumorigenic capacity of HCC [76]. LPAR1/3/6 mRNA expression was more elevated than non-tumor liver tissue, and LPA6 mRNA expression was highest.…”