Yu J, Wu W K K, Liang Q, Zhang N, He J, Li X, Zhang X, Xu L, Chan M T V, Ng S S M, Sung J J Y
Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.
Oncogene. 2016 Jan 14;35(2):187-95. doi: 10.1038/onc.2015.72. Epub 2015 Mar 30.
Whole-genome and transcriptome sequencing were used to discover novel gene fusions in a case of colon cancer. A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 was identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/β-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/β-catenin pathway. Collectively, our data supports that NCOA2 is a novel negative growth regulatory gene repressing the Wnt/β-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption.
采用全基因组和转录组测序在一例结肠癌中发现新的基因融合。在DNA和RNA水平均鉴定出一种源自8号染色体内染色体重排的肿瘤特异性LACTB2-NCOA2融合。与传统致癌嵌合蛋白不同，该融合产物缺乏各基因的功能域，提示为无效重排。在99例结直肠癌（CRC）病例中的6例（6.1%）检测到这种嵌合LACTB2-NCOA2转录本，其中NCOA2显著下调。野生型NCOA2而非LACTB2-NCOA2融合蛋白的强制表达损害了CRC细胞的促肿瘤表型，而在正常结肠细胞中敲低内源性NCOA2则产生相反效果。机制上，NCOA2通过同时上调Wnt/β-连环蛋白途径的抑制剂和下调其刺激因子来抑制Wnt/β-连环蛋白信号传导。总体而言，我们的数据支持NCOA2是一种新的负性生长调节基因，在CRC中抑制Wnt/β-连环蛋白途径，其与LACTB2的反复融合导致该途径的破坏。
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