Lpar6, also known as Lysophosphatidic acid receptor 6, is a G protein-coupled receptor of lysophosphatidic acid. It is involved in multiple biological processes, such as cellular morphology, hair growth, and energy metabolism regulation. It is associated with pathways like the ROCK2/NF-κB signal pathway and has significance in understanding disease mechanisms [1,3,4]. Genetic models, especially gene knockout models, have been crucial in studying its functions.

In a mouse model of chronic constriction injury (CCI) simulating neuropathic pain (NPP), knocking out Lpar6 increased mechanical and thermal pain thresholds, indicating its role in NPP development. Lpar6 activates the NF-κB pathway through ROCK2, increasing A1-type (neurotoxic) astrocytes and decreasing A2-type (neuroprotective) astrocytes [1]. In hepatocellular carcinoma (HCC), knockdown of Lpar6 in cell lines affected energy metabolism, overcoming sorafenib resistance by switching from glycolysis to oxidative phosphorylation [3]. Loss of Lpar6 in urothelial cells dysregulated the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis [2].

In conclusion, Lpar6 plays essential roles in pain perception, cancer development, and cell differentiation. Gene knockout mouse models have been instrumental in revealing its functions in neuropathic pain, hepatocellular carcinoma, and bladder carcinogenesis, providing potential therapeutic targets for these diseases.

References:

1. Fan, Xiaoyi, Chu, Ruitong, Jiang, Xin, Xiang, Zhenghua, Yuan, Hongbin. 2024. LPAR6 Participates in Neuropathic Pain by Mediating Astrocyte Cells via ROCK2/NF-κB Signal Pathway. In Molecular neurobiology, 61, 8402-8413. doi:10.1007/s12035-024-04108-5. https://pubmed.ncbi.nlm.nih.gov/38509397/

2. Lee, Sangkyou, Bondaruk, Jolanta, Wang, Yishan, Wei, Peng, Czerniak, Bogdan. 2024. Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis. In Cell reports, 43, 114146. doi:10.1016/j.celrep.2024.114146. https://pubmed.ncbi.nlm.nih.gov/38676926/

3. Gnocchi, Davide, Kurzyk, Agata, Mintrone, Antonella, Sabbà, Carlo, Mazzocca, Antonio. 2022. Inhibition of LPAR6 overcomes sorafenib resistance by switching glycolysis into oxidative phosphorylation in hepatocellular carcinoma. In Biochimie, 202, 180-189. doi:10.1016/j.biochi.2022.07.016. https://pubmed.ncbi.nlm.nih.gov/35952946/

4. Zheng, Xuan, Jia, Yinghui, Qiu, Lei, Chen, Liangyi, Han, Junhong. 2019. A potential target for liver cancer management, lysophosphatidic acid receptor 6 (LPAR6), is transcriptionally up-regulated by the NCOA3 coactivator. In The Journal of biological chemistry, 295, 1474-1488. doi:10.1074/jbc.RA119.009899. https://pubmed.ncbi.nlm.nih.gov/31914406/