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2015 ; 34
(ä): 122
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CMTM4 is frequently downregulated and functions as a tumour suppressor in clear
cell renal cell carcinoma
#MMPMID26474560
Li T
; Cheng Y
; Wang P
; Wang W
; Hu F
; Mo X
; Lv H
; Xu T
; Han W
J Exp Clin Cancer Res
2015[Oct]; 34
(ä): 122
PMID26474560
show ga
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.