Department of Genetics, Medical College of Soochow University, Suzhou 215123, China, Department of Obstetrics and Gynecology, Third Hospital, Peking University, Beijing 100191, China, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou 215004, China, Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94304, USA and The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou 510182, China.
Department of Obstetrics and Gynecology, Third Hospital, Peking University, Beijing 100191, China.
Carcinogenesis. 2014 Dec;35(12):2687-97. doi: 10.1093/carcin/bgu201. Epub 2014 Sep 19.
Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development.
基因融合是产生新基因的主要过程之一，作为致癌的有力途径已得到很好的描述。在这里，通过对 9 对人子宫内膜癌 (EC) 和匹配的非癌组织进行高通量 RNA 测序，我们发现嵌合转膜相关因子 X 精神分裂症缺失基因 1 (TSNAX-DISC1) 在多个 EC 样本中显著上调。实验研究表明，TSNAX-DISC1 似乎是通过不涉及染色体重排的剪接形成的。该嵌合体的表达与绝缘子结合的 CCCTC 结合因子 (CTCF) 呈负相关。随后的研究表明，长链非编码 RNA lincRNA-NR_034037 将 TSNAX 与 DISC1 分隔开，通过将 CTCF 从绝缘子中分离出来，调节 TSNAX-DISC1 的产生和 TSNAX/DISC1 的表达水平。TSNAX 的失调影响甾体生成因子 1 刺激 StAR 启动子的转录，改变孕激素的作用，暗示与癌症有关。总之，这些结果增进了我们对 lincRNA-NR_034037 调节 TSNAX-DISC1 形成程序的机制的理解，这些程序紧密调节 EC 的发育。
