Gprc5a, a member of the G protein-coupled receptor (GPCR) superfamily, is preferentially expressed in lung tissues and is regulated at multiple levels [2]. It has been implicated in various cellular events like cytoskeleton reorganization, cell proliferation, cycle regulation, migration, and survival, playing a role in tumorigenesis, inflammation, immune response, and tissue damage [3]. It is associated with multiple signaling pathways, such as cAMP, NF-κB, STAT3, and FAK/Src [2].

In triple-negative breast cancer (TNBC), knockdown of Gprc5a alleviated metastasis and docetaxel resistance, while overexpression had the opposite effects. Gprc5a activates mTORC1/p70s6k signaling pathway by inhibiting the ubiquitination-dependent degradation of LAMTOR1, promoting liver metastasis and docetaxel resistance [1]. In gallbladder cancer (GBC), knocking down Gprc5A inhibited cell metastasis in vitro and in vivo, and it upregulated TNS4 via the JAK2-STAT3 pathway to promote GBC metastasis [4]. In esophageal squamous cell carcinoma (ESCC), Gprc5a overexpression enhanced lung colonization, and it potentially interacted with WWP1 to activate YAP1 signaling pathways for metastasis [5]. In hepatocellular carcinoma (HCC), overexpression of Gprc5a suppressed cell proliferation and EMT, induced oxidative stress and apoptosis, by inhibiting the STAT3/Socs3/c-MYC pathway [6].

In conclusion, Gprc5a is involved in multiple biological processes related to cancer progression, including metastasis, drug resistance, and cell proliferation. Loss-of-function experiments in these cancer types have revealed its pro-tumorigenic role in TNBC, GBC, and ESCC, while it shows an anti-tumor effect in HCC. These findings contribute to understanding the mechanisms of cancer development and may provide potential therapeutic targets.

References:

1. Ou, Xueqi, Tan, Yeru, Xie, Jindong, Li, Yuehua, Tang, Hailin. 2024. Methylation of GPRC5A promotes liver metastasis and docetaxel resistance through activating mTOR signaling pathway in triple negative breast cancer. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 73, 101063. doi:10.1016/j.drup.2024.101063. https://pubmed.ncbi.nlm.nih.gov/38335844/

2. Jiang, Xiaoxia, Xu, Xin, Wu, Mengjie, Wang, Haiyong, Teng, Lisong. 2018. GPRC5A: An Emerging Biomarker in Human Cancer. In BioMed research international, 2018, 1823726. doi:10.1155/2018/1823726. https://pubmed.ncbi.nlm.nih.gov/30417009/

3. Iglesias González, Pablo A, Valdivieso, Ángel G, Santa-Coloma, Tomás A. 2023. The G protein-coupled receptor GPRC5A-a phorbol ester and retinoic acid-induced orphan receptor with roles in cancer, inflammation, and immunity. In Biochemistry and cell biology = Biochimie et biologie cellulaire, 101, 465-480. doi:10.1139/bcb-2022-0352. https://pubmed.ncbi.nlm.nih.gov/37467514/

4. Yang, Jiahua, Li, Xuechuan, Chen, Shili, Geng, Yajun, Liu, Yingbin. 2024. GPRC5A promotes gallbladder cancer metastasis by upregulating TNS4 via the JAK2-STAT3 pathway. In Cancer letters, 598, 217067. doi:10.1016/j.canlet.2024.217067. https://pubmed.ncbi.nlm.nih.gov/38942137/

5. Zhou, Hongyu, Tan, Licheng, Zhang, Baifeng, Liu, Beilei, Guan, Xin-Yuan. 2024. GPRC5A promotes lung colonization of esophageal squamous cell carcinoma. In Nature communications, 15, 9950. doi:10.1038/s41467-024-54251-9. https://pubmed.ncbi.nlm.nih.gov/39550386/

6. Zhang, Lixia, Yang, Weibing, Yang, Jin, Sun, Fu. 2023. GPRC5A regulates proliferation and oxidative stress by inhibiting the STAT3/Socs3/c-MYC pathway in hepatocellular carcinoma. In Journal of clinical biochemistry and nutrition, 73, 43-51. doi:10.3164/jcbn.22-125. https://pubmed.ncbi.nlm.nih.gov/37534091/