GPR176 May Be Potential Gene Therapy Target in Ovarian Cancer

Building on previous research in other cancer types, researchers of a new study in ovarian cancer cells have found potential in targeting a certain protein.

The biomarker, G-protein-coupled receptor 176 (GPR176), may be a driver in the progression of ovarian cancer and potential target for gene therapy, suggested researchers of the study, who published their findings in Journal of Obstetrics and Gynaecology.¹

“GPR176 is likely involved in the progression of ovarian cancer by promoting proliferation, anti-apoptosis, anti-pyroptosis, migration and invasion, [epithelial-mesenchymal transition], and weakening the cellular adhesion of ovarian cancer cells,” wrote the researchers. “GPR176 could potentially be used as a biomarker to indicate the aggressive behaviour and poor prognosis of ovarian cancer and a target of genetic therapy.”

Prior research has suggested that atypical GPR176 expression may help drive tumorigenesis and progression in certain cancer types, although its role in ovarian cancer has not been explored. For example, a paper published in 2023 showed that aberrant GPR176 expression was correlated with poor prognosis in colorectal cancer due to its key role in modulating proliferation of the cancer through high affinity for G protein GNAS.² In gastric cancer, research has shown that GPR176 can indicate prognosis and immune infiltration, suggesting it may be a potential target for immunotherapy.³

In their analysis, the researchers compared GPR176 with various ovarian cancer characteristics in cancer cells from a cell bank in China. Tissue samples were obtained from 91 patients with ovarian cancer.

In line with previous findings, GPR176 showed indications of promoting proliferation, anti-apoptosis, migration, and invasion of ovarian cancer cells. The expression of GPR176 mRNA did not differ between cancer and normal tissue, suggesting that the gene may not be a driver in the formation of ovarian cancer.

Bioinformatics analysis findings also show that GPR176 expression was positively correlated with clinicopathological staging, tumor residual status, and worse survival. Aberrant expression of the gene was also associated with older age.

The group also observed that GPR176 expression was negatively associated with purity loss, infiltration of B cells, and CD8+ T cells.

“The top 5 positively-correlated genes were less expressed in ovarian cancer than in normal tissues; however, the opposite was observed for the top 5 negatively correlated genes,” detailed the researchers. “NUAK1 mRNA expression was negatively associated with the long overall survival times and disease-specific survival times in ovarian cancer patients; however, the opposite was observed for MT-CO2 mRNA expression.”

Western blotting revealed that overexpression of GPR176 increased expression of Pi3K, p-Akt, m-TOR, P-mTOR, BCL-2, n-cadherin, zeb1, Snail, and twist1. Meanwhile, expression levels were reduced for Bax, e-cadherin, gasdermin D, caspase 1, vascular cell adhesion molecule 1, and col4a3.

References

1. Yang N, Yun WJ, Cui ZG, Zheng HC. The oncogenic role of GPR176 in ovarian cancer: a molecular target for aggressiveness and gene therapy. Obstet Gynaecol. Published online June 4, 2024. doi:10.1080/01443615.2024.2347430

2. Tang J, Peng W, Ji J, et al. GPR176 promotes cancer progression by interacting with G protein GNAS to restrain cell mitophagy in colorectal cancer. Adv Sci (Weinh). Published online March 11, 2023. doi:10.1002/advs.202205627

3. Ni L, Chen S, Liu J, et al. GPR176 if a biomarker for predicting prognosis and immune infiltration in stomach adenocarcinoma. Mediators Inflamm. Published online April 19, 2023. doi:10.1155/2023/7123568