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Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
Long non-coding RNA GAS5 sensitizes renal cell carcinoma to sorafenib via miR-21/SOX5 pathway
Lei Liu1, Xinlu Pang1, Wenjin Shang1
1a Department of kidney transplantation , the First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan Province , P. R. China.
Abstract:
Although the use of sorafenib appears to increase the survival rate of renal cell carcinoma (RCC) patients, there is also a proportion of patients who exhibit a poor primary response to sorafenib treatment. Therefore, it is critical to elucidate the mechanisms underlying sorafenib resistance and find representative biomarkers for sorafenib treatment in RCC patients. Herein, we identified that a long noncoding RNA GAS5 was downregulated in sorafenib nonresponsive RCCs. GAS5 overexpression conferred sorafenib sensitive to nonresponsive RCC cells, whereas knockdown of GAS5 promoted responsive RCC cells resistant to sorafenib treatment in vitro and in vivo. Mechanistically, GAS5 functioned as competing endogenous RNA to repress miR-21, which controlled its down-stream target SOX5. We proposed that GAS5 was responsible for sorafenib resistance in RCC cells and GAS5 exerted its function through the miR-21/ SOX5 axis. Our findings suggested that GAS5 downregulation may be a new marker of poor response to sorafenib and GAS5 could be a potential therapeutic target for sorafenib treatment in RCC.
Insights
A long noncoding RNA, GAS5, is downregulated in sorafenib-resistant renal cell carcinoma (RCC). Restoring GAS5 may overcome resistance, suggesting GAS5 as a potential therapeutic target and biomarker for RCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Sorafenib improves survival in renal cell carcinoma (RCC) but resistance occurs.
- Understanding sorafenib resistance mechanisms and identifying biomarkers are crucial for effective RCC treatment.
Purpose of the Study:
- To investigate the role of long noncoding RNA GAS5 in sorafenib resistance in RCC.
- To identify GAS5 as a potential biomarker and therapeutic target for sorafenib treatment in RCC.
Main Methods:
- Quantitative analysis of GAS5 expression in sorafenib-responsive and nonresponsive RCC.
- In vitro and in vivo experiments involving GAS5 overexpression and knockdown in RCC cells.
- Investigation of the molecular mechanism involving GAS5, miR-21, and SOX5.
Main Results:
- GAS5 was significantly downregulated in sorafenib-nonresponsive RCC.
- GAS5 overexpression sensitized nonresponsive RCC cells to sorafenib.
- GAS5 knockdown induced sorafenib resistance in responsive RCC cells.
- GAS5 acts as a competing endogenous RNA, repressing miR-21 and subsequently SOX5.
Conclusions:
- GAS5 downregulation is associated with poor response to sorafenib in RCC.
- The GAS5/miR-21/SOX5 axis plays a critical role in regulating sorafenib resistance in RCC.
- GAS5 represents a potential predictive biomarker and therapeutic target for sorafenib treatment in RCC.
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