Xiao Wenjing, Chen Xin, Li Xia, Deng Kaiwen, Liu Huawei, Ma Jie, Wang Zhanhao, Hu Yonghe, Hou Jun
School of Materials Science and Engineering, Southwest Jiaotong University Chengdu 611756, China.
Department of Pharmacy, The General Hospital of Western Theater Command of PLA Chengdu 610083, China.
Am J Cancer Res. 2021 Jan 1;11(1):157-170. eCollection 2021.
Dysregulation of alternative splicing of hTERT gene to generate full-length Htert (hTERT-FL) that reactivate telomerase has been recognized as a major pathological alteration in pancreatic cancer (PrCa). Mechanism about the factors that regulate hTERT-FL splicing is lacking. Through bioinformatics approach, we focus on a candidate splicing factor RBM10, which leads to a switch in hTERT transcripts to generate a function-less isoform hTERT-s in PrCa, suppressed both telomerase activity and subsequent telomere shortening. RBM10 expression is negatively associated with PrCa progression. Gain or loss of RBM10 also significantly changed PrCa cell proliferation in vitro and in xenografts. RNA-IP and RNA pull-down assays reveal that RBM10 promotes the exclusion of exons7 and 8 which results in the production of TERT-s transcripts. This study may increase knowledge about potentially targetable cancer associated splicing factors and provide novel insights into therapeutic approach in PrCa.
人端粒酶逆转录酶（hTERT）基因可变剪接失调，产生重新激活端粒酶的全长Htert（hTERT-FL），这已被认为是胰腺癌（PrCa）的主要病理改变。目前缺乏关于调节hTERT-FL剪接的因素的机制。通过生物信息学方法，我们聚焦于一个候选剪接因子RBM10，它导致PrCa中hTERT转录本发生转换，产生无功能的异构体hTERT-s，抑制端粒酶活性及随后的端粒缩短。RBM10表达与PrCa进展呈负相关。RBM10的增减也显著改变了PrCa细胞在体外和异种移植中的增殖。RNA免疫沉淀（RNA-IP）和RNA下拉实验表明，RBM10促进外显子7和8的排除，从而产生TERT-s转录本。本研究可能会增加对潜在可靶向的癌症相关剪接因子的认识，并为PrCa的治疗方法提供新的见解。
