Integration analysis of PLAUR as a sunitinib resistance and macrophage related biomarker in ccRCC, an in silicon and experimental study

Abstract

Sunitinib remains the preferred systemic treatment option for specific patients with advanced RCC who are ineligible for immune therapy. However, it’s essential to recognize that Sunitinib fails to elicit a favourable response in all patients. Moreover, most patients eventually develop resistance to Sunitinib. Therefore, identifying new targets associated with Sunitinib resistance is crucial. Utilizing multiple datasets from public cohorts, we conducted an exhaustive analysis and identified a total of 8 microRNAs and 112 mRNAs displaying significant expression differences between Sunitinib responsive and resistant groups. A particular set of six genes, specifically NIPSNAP1, STK40, SDC4, NEU1, TBC1D9, and PLAUR, were identified as highly significant via WGCNA. To delve deeper into the resistance mechanisms, we performed additional investigations using cell, molecular, and flow cytometry tests. These studies confirmed PLAUR's pivotal role in fostering Sunitinib resistance, both in vitro and in vivo. Our findings suggest that PLAUR could be a promising therapeutic target across various cancer types. In conclusion, this investigation not only uncovers vital genes and microRNAs associated with Sunitinib resistance in RCC but also introduces PLAUR as a prospective therapeutic target for diverse cancers. The outcomes contribute to advancing personalized healthcare and developing superior therapeutic strategies.

Communicated by Ramaswamy H. Sarma

Keywords:

• Renal cancer
• drug resistance
• tumor immunity
• single cell
• multiomics

Acknowledgements

We thank Jianming Zeng (University of Macau) and all the members of his bioinformatics team, Biotrainee, for generously sharing their experience and codes. The use of the biorstudio high performance computing cluster (https://biorstudio.cloud (accessed on 12 July 2022)) at Biotrainee and The Shanghai HS Biotech Co., Ltd. was used to conduct the research reported in this paper.

Consent for publication

All authors agreed on the manuscript.

Disclosure statement

All authors declare no competing financial interest.

Ethics statement

This article does not contain any studies with human participants performed by any of the authors.

Author contributions

QY, FY, LL and JC contributed equally to this work. AJ, SG and JC conceptualized and designed this study. YT and AJ wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version. All authors read and approved the final manuscript.

Data availability statement

The datasets presented in the study are included in the Methods and Materials section. Further inquiries can be directed to the corresponding authors.

Additional information

Funding

Sponsored by National Natural Science Foundation of China for Youths (No. 82002664), Shanghai jiading district health commission scientific research project youth fund (No. 2020-QN-02), Meng Chao Talent Training Plan – Youth Research Talent Training Program of Eastern Hepatobiliary Surgery Hospital.