Identification of a novel oncogene, MMS22L, involved in lung and esophageal carcinogenesis.
Genome-wide gene expression profile analyses using a cDNA microarray containing 27,648 genes or expressed sequence tags identified MMS22L (methyl methanesulfonate-sensitivity protein 22-like) to be overexpressed in the majority of clinical lung and esophageal cancers, but not expressed in normal organs except testis. Transfection of siRNAs against MMS22L into cancer cells suppressed its expression and inhibited cell growth, while exogenous expression of MMS22L enhanced the growth of mammalian cells. MMS22L protein was translocated to the nucleus and stabilized by binding to C-terminal portion of NFKBIL2 [nuclear factor of kappa (NFKB) light polypeptide gene enhancer in B-cells inhibitor-like 2]. Expression of a C-terminal portion of NFKBIL2 protein including the MMS22L-interacting site in cancer cells could reduce the levels of MMS22L in nucleus and suppressed cancer cell growth. Interestingly, reduction of MMS22L by siRNAs in cancer cells inhibited the TNF-α-dependent activation of RelA/p65 in the NFKB pathway and expression of its downstream anti-apoptotic molecules such as Bcl-XL and TRAF1. In addition, knockdown of MMS22L expression also enhanced the apoptosis of cancer cells that were exposed to DNA-damaging agents including 5-FU and CDDP. Our data strongly suggest that targeting MMS22L as well as its interaction with NFKBIL2 could be a promising strategy for novel cancer treatments, and also improve the efficacy of DNA damaging anticancer drugs.
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Minh-Hue
MH
Nguyen
Koji
K
Ueda
Yusuke
Y
Nakamura
Yataro
Y
Daigo
D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; C554517:MMS22L protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C093394:TONSL protein, human; D014409:Tumor Necrosis Factor-alpha