Integration analysis of PLAUR as a sunitinib resistance and macrophage related biomarker in ccRCC, an in silicon and experimental study
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Updated: Jul 6, 2025
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
Qiwei Yang1,2, Fangdie Ye3, Lin Li2
1Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
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.
Insights
Researchers identified key genes and microRNAs linked to Sunitinib resistance in advanced renal cell carcinoma (RCC). PLAUR was confirmed as a significant factor in resistance, suggesting its potential as a therapeutic target for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Sunitinib is a primary treatment for advanced renal cell carcinoma (RCC) in patients ineligible for immunotherapy.
- Treatment response to Sunitinib varies, and most patients develop resistance over time.
- Identifying mechanisms and targets of Sunitinib resistance is critical for improving patient outcomes.
Purpose of the Study:
- To identify molecular markers associated with Sunitinib resistance in advanced RCC.
- To investigate the role of specific genes, including PLAUR, in Sunitinib resistance.
- To explore PLAUR as a potential therapeutic target for Sunitinib-resistant cancers.
Main Methods:
- Analysis of public gene expression datasets from Sunitinib-treated RCC patients.
- Weighted Gene Co-expression Network Analysis (WGCNA) to identify key genes.
- In vitro and in vivo experiments, including cell, molecular, and flow cytometry assays, to validate findings.
Main Results:
- Identified 8 microRNAs and 112 mRNAs with differential expression between Sunitinib-responsive and resistant groups.
- Six genes (NIPSNAP1, STK40, SDC4, NEU1, TBC1D9, PLAUR) were highlighted by WGCNA.
- Confirmed PLAUR's significant role in promoting Sunitinib resistance both in vitro and in vivo.
Conclusions:
- Discovered novel microRNAs and mRNAs implicated in Sunitinib resistance in RCC.
- Established PLAUR as a critical mediator of Sunitinib resistance.
- Proposed PLAUR as a promising therapeutic target for overcoming Sunitinib resistance in RCC and potentially other cancer types.
