The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear.
We analysed 796 PDAC patients, including 331 from public data sets (TCGA, ICGC and GSE57495) and 465 from independent cohorts (training: n = 321, validation: n = 144). Using in-vitro studies, we confirmed the biological function of the candidate GPCRs.
Analysis of all 33 adhesion GPCRs, led to identify GPR115, as the only significant prognostic factor in all public data sets. The patients with high GPR115 expression exhibited significantly poorer prognosis for OS and RFS, in training (P < 0.01, P < 0.01) and validation cohort (P < 0.01, P = 0.04). Multivariate analysis indicated that GPR115 high expression was an independent prognostic factor in both cohorts (HR = 1.43; P = 0.01, HR = 2.55; P < 0.01). A risk-prediction model using Cox regression by incorporating GPR115 and clinicopathological factors accurately predicted 5-year survival following surgery. In addition, GPR115 silencing inhibited cell proliferation and migration in PDAC cells.
We demonstrated that GPR115 has important prognostic significance and functional role in tumour progression; providing a rationale that this may be a potential therapeutic target in patients with PDAC.
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We thank Tatsuhiko Kakisaka, Takeo Toshima, Raju Kandimalla, Goretti Hernandez, Priyanka Sharma, Raju Adduri, and Souvik Ghatak for discussing the how best to set up the experiments and their analyses. We thank Jasjit Banwait for assisting with the analysis. We thank Naoya Ikeda, Takahiro Akahori, and Tadataka Takagi for collecting clinical samples and patient information.
The present work was supported by the CA72851, CA187956, CA202797 and CA214254 grants from the National Cancer Institute, National Institute of Health; In addition, this work was also supported by a pilot research award from the City of Hope Ludwig Cancer Research-Hilton Foundation Partnership award.
The authors declare no competing interests.
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Nishiwada, S., Shimura, T., Yamamura, K. et al. Clinical significance and functional role of adhesion G-protein-coupled receptors in human pancreatic ductal adenocarcinoma. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02057-1