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Published on: February 8, 2020
The tumor-suppressive function of UNC5D and its repressed expression in renal cell carcinoma
1Department of Immunology, Key Laboratory of Medical Immunology (Ministry of Health), Peking University Health Science Center, Beijing, China.
Purpose:
As a newly added member of the UNC5H receptors, the function of UNC5D/H4 in tumorigenesis remains poorly defined. The aim of this study was to examine the expression of UNC5D in primary renal cell carcinomas (RCC), analyze the mechanisms responsible for its downregulation in RCC, and assess its functional relevance to tumor growth and migration.
Experimental Design:
Forty-four paired primary RCCs and corresponding adjacent noncancerous tissues were collected. The mRNA and protein expression level of UNC5D was assessed by reverse transcriptase-PCR, real-time PCR, or immunohistochemistry. Epigenetic alterations in UNC5D promoter and LOH in the UNC5D locus were also analyzed. Ectopic expression of UNC5D in renal cancer cells with silenced expression of UNC5D was used for analysis of the biologic functions of UNC5D.
Results:
UNC5D expression was attenuated in multiple carcinoma cell lines including renal cancer cells. Similar reduction was also observed in primary RCC tissues as compared with paired adjacent noncancerous tissues. Methylation-specific PCR showed hypermethylation in UNC5D promoter in a significant proportion (18 of 44) of tumor tissue (40.9%). LOH of UNC5D was observed in 13 of 44 patients with RCCs (29.5%). Restoration of UNC5D expression in renal cancer cells significantly inhibited cell proliferation, anchorage-dependent and -independent growth, as well as migration and invasion, whereas knockdown of UNC5D promoted cell growth. Furthermore, ectopic expression of UNC5D induced G2-M cell-cycle arrest.
Conclusions:
UNC5D is a functional tumor suppressor that is frequently downregulated in RCCs due to promoter hypermethylation and LOH.
Insights
UNC5D is frequently downregulated in renal cell carcinoma (RCC) due to epigenetic changes and loss of heterozygosity. Restoring UNC5D suppresses tumor growth and migration, identifying it as a key tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The UNC5H receptor family plays a role in cell growth and development.
- The specific function of UNC5D/H4 in tumorigenesis, particularly in renal cell carcinoma (RCC), is not well understood.
- Understanding UNC5D's role is crucial for developing targeted therapies for RCC.
Purpose of the Study:
- To investigate the expression of UNC5D in primary RCC tissues.
- To elucidate the mechanisms causing UNC5D downregulation in RCC, including epigenetic alterations and loss of heterozygosity (LOH).
- To evaluate the functional impact of UNC5D on tumor growth, migration, and cell-cycle progression in RCC.
Main Methods:
- Analysis of paired primary RCC and adjacent noncancerous tissues (n=44) for UNC5D mRNA and protein expression using RT-PCR, real-time PCR, and immunohistochemistry.
- Assessment of UNC5D promoter hypermethylation using methylation-specific PCR.
- Evaluation of LOH at the UNC5D locus.
- Functional studies involving ectopic UNC5D expression and UNC5D knockdown in renal cancer cell lines.
Main Results:
- UNC5D expression was significantly reduced in both RCC cell lines and primary RCC tissues compared to normal tissues.
- Promoter hypermethylation of UNC5D was detected in 40.9% (18/44) of tumors, and LOH was observed in 29.5% (13/44) of RCCs.
- Restoration of UNC5D expression inhibited proliferation, anchorage-dependent/independent growth, migration, and invasion, while inducing G2-M cell-cycle arrest.
- Knockdown of UNC5D promoted cell growth.
Conclusions:
- UNC5D functions as a tumor suppressor in renal cell carcinoma.
- Frequent downregulation of UNC5D in RCC is attributed to promoter hypermethylation and LOH.
- UNC5D represents a potential therapeutic target for managing RCC progression.
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