Abstract
Closely located at the tumor suppressor locus 16q22.1, CKLF-like MARVEL transmembrane domain-containing member 3 and 4 (CMTM3 and CMTM4) encode two CMTM family proteins, which link chemokines and the transmembrane-4 superfamily. In contrast to the broad expression of both CMTM3 and CMTM4 in normal human adult tissues, only CMTM3 is silenced or down-regulated in common carcinoma (gastric, breast, nasopharyngeal, esophageal, and colon) cell lines and primary tumors. CMTM3 methylation was not detected in normal epithelial cell lines and tissues, with weak methylation present in only 5 of 35 (14%) gastric cancer adjacent normal tissues. Furthermore, immunohistochemistry showed that CMTM3 protein was absent in 12 of 35 (34%) gastric and 1 of 2 colorectal tumors, which was well correlated with its methylation status. The silencing of CMTM3 is due to aberrant promoter CpG methylation that could be reversed by pharmacologic demethylation. Ectopic expression of CMTM3 strongly suppressed the colony formation of carcinoma cell lines. In addition, CMTM3 inhibited tumor cell growth and induced apoptosis with caspase-3 activation. Thus, CMTM3 exerts tumor-suppressive functions in tumor cells, with frequent epigenetic inactivation by promoter CpG methylation in common carcinomas.
Highlights
CKLF-like MARVEL transmembrane domain-containing family (CMTM) is a novel family of proteins linking chemokines and the transmembrane-4 superfamily, consisting of 9 genes, CKLF and CMTM1 to CMTM8
CMTM3 is frequently silenced by methylation in carcinoma cell lines
In consistence, cleaved poly(ADP-ribose) polymerase, which is associated with caspase-3 activation [30], was present in CMTM3- or Bax-transfected cells but rarely detected in control cells (Fig. 5D). We found that both CMTM3 and CMTM4 were widely expressed in normal adult tissues
Summary
CKLF-like MARVEL transmembrane domain-containing family (CMTM) is a novel family of proteins linking chemokines and the transmembrane-4 superfamily, consisting of 9 genes, CKLF and CMTM1 to CMTM8. CMTMs play important roles in immune and male reproductive systems as well as tumorigenesis [1,2,3,4,5,6,7]. Our previous study showed that CMTM5 has tumor-suppressive functions [6]. CMTM5 has at least six RNA splicing forms CMTM5-v1 is evolutionarily conserved and broadly expressed in normal adult and fetal tissues but frequently down-regulated or silenced in tumor cell lines due to promoter methylation. Restoration of CMTM5-v1 in PC-3 and HeLa cells suppresses tumor cell growth and migration [6]
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