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Updated: Mar 31, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma
Ting Li1, Yingying Cheng2, Pingzhang Wang3
1Peking University Center for Human Disease Genomics, Department of Immunology, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Center for Human Disease Genomics, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China. tingfanta@163.com.
Background:
Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is a gene family involved in multiple malignancies. CMTM4 is a member of this family and is located at chromosome 16q22.1, a locus that harbours a number of tumour suppressor genes. It has been defined as a regulator of cell cycle and division in HeLa cells; however, its roles in tumourigenesis remain poorly studied.
Methods:
An integrated bioinformatics analysis based on the array data from the GEO database was conducted to view the differential expression of CMTM4 across multiple cancers and their corresponding control tissues. Primary clear cell renal cell carcinoma (ccRCC) and the paired adjacent non-tumour tissues were then collected to examine the expression of CMTM4 by western blotting, immunohistochemistry, and quantitative RT-PCR. The ccRCC cell lines A498 and 786-O and the normal renal tubular epithelial cell line HK-2 were also tested for CMTM4 expression by western blotting. Cell Counting Kit-8 (CCK-8) and viable cell counting assays were used to delineate the growth curves of 786-O cells after CMTM4 overexpression or knockdown. Wound healing and transwell assays were performed to assess the cells' ability to migrate. The effects of CMTM4 on cellular apoptosis and cell cycle progression were analysed by flow cytometry, and cell cycle hallmarks were detected by western blotting and RT-PCR. The xenograft model in nude mice was used to elucidate the function of CMTM4 in tumourigenesis ex vivo.
Results:
By omic data analysis, we found a substantial downregulation of CMTM4 in ccRCC. Western blotting then confirmed that CMTM4 was dramatically reduced in 86.9 % (53/61) of ccRCC tissues compared with the paired adjacent non-tumour tissues, as well as in the 786-O and A498 ccRCC cell lines. Restoration of CMTM4 significantly suppressed 786-O cell growth by inducing G2/M cell cycle arrest and p21 upregulation, and cell migration was also inhibited. However, knockdown of CMTM4 led to a completely opposite effect on these cell behaviours. Overexpression of CMTM4 also markedly inhibited the tumour xenograft growth in nude mice.
Conclusions:
CMTM4 is downregulated and exhibits tumour-suppressor activities in ccRCC, and could be exploited as a target for ccRCC treatment.
Insights
Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 4 (CMTM4) is downregulated in clear cell renal cell carcinoma (ccRCC). CMTM4 exhibits tumor-suppressor activities, making it a potential therapeutic target for ccRCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM) is implicated in various cancers.
- CMTM4, a member of this family, is located at a chromosomal locus associated with tumor suppressor genes.
- Its specific role in tumorigenesis, particularly in renal cell carcinoma, remains largely uninvestigated.
Purpose of the Study:
- To investigate the expression profile of CMTM4 in clear cell renal cell carcinoma (ccRCC).
- To elucidate the functional role of CMTM4 in ccRCC progression and tumorigenesis.
- To assess the potential of CMTM4 as a therapeutic target for ccRCC.
Main Methods:
- Integrated bioinformatics analysis of GEO database array data for differential gene expression.
- Experimental validation of CMTM4 expression in ccRCC tissues and cell lines using western blotting, immunohistochemistry, and RT-PCR.
- Functional assays including cell proliferation (CCK-8, viable cell counting), migration (wound healing, transwell), apoptosis, and cell cycle analysis via flow cytometry.
- In vivo studies using a xenograft model in nude mice to evaluate CMTM4's effect on tumor growth.
Main Results:
- Bioinformatic analysis revealed significant downregulation of CMTM4 in ccRCC.
- Experimental validation confirmed reduced CMTM4 expression in 86.9% of ccRCC tissues and ccRCC cell lines (786-O, A498).
- Overexpression of CMTM4 suppressed ccRCC cell growth, induced G2/M cell cycle arrest, inhibited migration, and reduced tumor xenograft growth in mice. Conversely, CMTM4 knockdown promoted these oncogenic behaviors.
Conclusions:
- CMTM4 is significantly downregulated in clear cell renal cell carcinoma.
- CMTM4 demonstrates tumor-suppressor activities in ccRCC by inhibiting cell proliferation, migration, and promoting cell cycle arrest.
- CMTM4 represents a promising therapeutic target for ccRCC treatment.
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