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Molecular Diagnostics

Clinical significance and functional role of adhesion G-protein-coupled receptors in human pancreatic ductal adenocarcinoma

Abstract

Background

The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear.

Methods

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.

Results

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.

Conclusion

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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Fig. 1: Overall survival (OS) and Relapse-free survival (RFS) in patients in the training and validation cohorts.
Fig. 2: Expression of GPR115 alone or when combined with CA19-9 levels, T and N status, tumour status, or all of these factors in combination were a superior predictor for 5-year OS in PDAC patients in the training and validation cohorts.
Fig. 3: Inhibition of GPR115 expression by gene silencing decreases cell proliferation in pancreatic cancer cell lines.

Data availability

All data are available within the article.

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Acknowledgements

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.

Funding

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.

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Contributions

Study concept and design: SN, MS, AG; Specimen providers: SN, KN, MN, TT, SY, TF, YK, MS; Acquisition of clinical data: SN, KN, MN, TT, SY, TF, YK, MS; Analysis and interpretation of data and statistical analysis: SN, TS, KY, AG; Drafting of the manuscript: SN, MS and AG.

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Correspondence to Ajay Goel.

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All study-related procedures were performed as per the Declarations of Helsinki, wherein a written informed consent was obtained from each patient, and the institutional review boards of all participating institutions involved approved the study.

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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

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