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PAQR5 inhibits the growth and metastasis of clear cell renal cell carcinoma by suppressing the JAK/STAT3 signaling pathway

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Abstract

Background

Clear cell renal cell carcinoma (ccRCC) has a high degree of malignancy and poor overall prognosis in advanced and metastatic patients. Therefore, it is of great significance to find new prognostic biomarkers and therapeutic targets for ccRCC. The expression of progestin and adipoQ receptor family member 5 (PAQR5) is significantly downregulated in ccRCC compared with normal tissues, but its specific mechanism and potential biological function in ccRCC remain unclear.

Methods

The expression pattern of PAQR5 and the correlation between the PAQR5 expression and clinicopathological parameters and various survival periods in ccRCC patients were analyzed by using multiple public databases and ccRCC tissues chip. Its prognostic value was analyzed by univariate/multivariate Cox regression. In addition, MTT assay, EdU staining assay, flow cytometry, wound healing assay, transwell migration and invasion assay, colony formation assay, immunofluorescence assay, and a xenograft tumor model were conducted to assess the biological function of PAQR5 in ccRCC in vitro and in vivo.

Results

Our results indicated that the downregulation of PAQR5 was demonstrated in ccRCC tumor tissues and associated with poorer OS, DSS, and PFI. Meanwhile, the univariate/multivariate Cox regression analysis confirmed that PAQR5 might serve as an independent prognostic factor for ccRCC, and its low expression was tightly correlated with tumor progression and distant metastasis. Mechanistically, a series of gain- and loss-of-function assay revealed that PAQR5 could suppress the ccRCC proliferation, invasion, metastasis, and tumorigenicity in vitro and in vivo by inhibiting the JAK/STAT3 signaling pathway.

Conclusion

Our study revealed the tumor suppressor role of PAQR5 in ccRCC. PAQR5 is a valuable prognostic biomarker for ccRCC and may provide new strategies for clinical targeted therapy.

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Data Availability

The datasets generated/analyzed during the current study are available.

Abbreviations

ccRCC:

clear cell renal cell carcinoma

PAQR5:

progestin and adipoQ receptor family member 5

TKI:

tyrosine kinase inhibitor

ICI:

immune checkpoint inhibitor

JAK2:

Janus kinase 2

STAT3:

signal transducer and activator of transcription 3

NF-κB:

nuclear factor-kappa B

EMT:

epithelial-mesenchymal transition

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

5-Aza:

5-Aza-2’-deoxycytidine

GSEA:

gene set enrichment analysis

FBS:

fetal bovine serum

HR:

hazard ratio

CI:

confidence interval

KIRC:

kidney renal clear cell carcinoma

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

Funding

This work was supported by the National Natural Science Foundation of China (No: 81572520, 82103563). Key research and development plan in Shaanxi province (No. 2020SF-123 and 2020SF-195). Medical research program of department of science and technology of Xi’an, Shaanxi Province (No.2019115713 YX012SF048 (4)).

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Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, No.277 Yanta West Road, Xi’an, 710061, Shaanxi, China

    Lu Wang, Lu Zhang, Minxuan Jing, Minghai Ma, Shan Xu, Ke Wang, Xinyang Wang & Jinhai Fan

  2. Department of Vascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, No.277 Yanta West Road, Xi’an, 710061, Shaanxi, China

    Yangyang Yue, Chao Liu, Yan Li & Mengzhao Zhang

  3. Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of education, Xi’an, China

    Jinhai Fan

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  1. Lu Wang
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Contributions

L. W, and Y.Y. Y performed the experiments. L. Z, M.X. J, and Y.Y. Y analyzed and interpreted the data. L. W and M.Z. Z wrote the manuscript. M.H. M, Y. L, and C. L provided critical suggestions. S. X, K. W, and X.Y. W revised the manuscript critically for important intellectual content. J.H. F and M.Z. Z designed and supervised the project. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Jinhai Fan or Mengzhao Zhang.

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This study was approved and supervised by the Ethical Committee of the First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China. The study was conducted following the Declaration of Helsinki principles.

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Wang, L., Yue, Y., Zhang, L. et al. PAQR5 inhibits the growth and metastasis of clear cell renal cell carcinoma by suppressing the JAK/STAT3 signaling pathway. Cell Oncol. 46, 1317–1332 (2023). https://doi.org/10.1007/s13402-023-00813-w

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