Mesenchymal splice isoform of CD44 (CD44s) promotes EMT/invasion and imparts stem-like properties to ovarian cancer cells
Mesenchymal splice isoform of CD44 (CD44s) promotes EMT/invasion and imparts stem-like properties to ovarian cancer cells
复制标题
DOI：
10.1002/jcb.26504
复制
发表时间：
2018-04-01
影响因子：
4
通讯作者：
Roy, Sib Sankar
中科院分区：
文献类型：
--
作者：
Bhattacharya, Rahul;Mitra, Tulika;Roy, Sib Sankar
卵巢癌（OC）的转移和复发增加是导致其死亡的原因之一。包括异常剪接在内的一些分子机制与癌症进展的程度密切相关。许多基因转录物在癌细胞中被不同地剪接，CD44就是其中之一。CD44剪接异构体有助于不同类型癌症的侵袭性和干细胞样特性的获得，但它们在卵巢癌中的作用仍有待阐明。我们观察到人类卵巢癌患者样本中CD44水平的增强与间充质剪接变体CD44s（标准）的表达增强以及上皮变体CD44v的同时降低相关。此外，CD44s在tgf1诱导的EMT中上调，这是通过下调剪接因子ESRP1介导的。此外，这种间充质异构体在OC细胞中的过度表达会诱导EMT和侵袭，随后获得茎样特性和化学抗性。由于所有这些现象都对这种疾病类型具有致命性，cd44可归因于在剪接失调介导的卵巢癌进展中发挥主要作用。
Increased metastasis and a precipitous recurrence contribute to the lethality of ovarian cancer (OC). Several molecular mechanisms including aberrant-splicing have been closely associated with the extent of cancer progression. Numerous gene transcripts are differentially spliced in cancer cells, CD44 being one of them. CD44 splice isoforms contribute to the aggressiveness and gain of stem-like properties in different cancer types, but their role in ovarian cancer remains to be elucidated. We observed augmented CD44 levels in human ovarian cancer patient samples correlated with enhanced expression of the mesenchymal spliced variant CD44s (standard) and a concurrent decrease in the epithelial variants (CD44v). Moreover, CD44s was upregulated upon TGF1-induced EMT, which was mediated through the downregulation of the splicing factor, ESRP1. Furthermore, overexpression of this mesenchymal isoform in the OC cells induced EMT and invasion, followed by the gain of stem-like characteristics and chemoresistance. Since all these phenomena render lethality to this disease type, CD44s can be attributed for playing a major role in deregulated-splicing mediated ovarian cancer progression.