Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan.
Int J Cancer. 2012 Dec 15;131(12):2939-50. doi: 10.1002/ijc.27589. Epub 2012 Apr 30.
Autophagy is known to have a cytoprotective role under various cellular stresses; however, it also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Autophagy is regulated by cell signalling including microRNA (miRNA), a post-transcriptional regulator of gene expression. Here, we show that genetically engineered telomerase-specific oncolytic adenovirus induced miR-7 expression, which is significantly associated with its cytopathic activity in human cancer cells. Virus-mediated miR-7 upregulation depended on enhanced expression of the E2F1 protein. Ectopic expression of miR-7 suppressed cell viability and induced autophagy by inhibiting epidermal growth factor receptor (EGFR) expression. Our results suggest that oncolytic adenovirus induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy.
自噬在各种细胞应激下具有细胞保护作用; 然而，它也会导致强烈的细胞死亡，作为一种重要的保护机制，防止机体受到入侵病原体和不需要的癌细胞的侵害。自噬受细胞信号的调节，包括 microRNA（miRNA），这是一种基因表达的转录后调节因子。在这里，我们表明，基因工程端粒酶特异性溶瘤腺病毒诱导 miR-7 的表达，这与它在人类癌细胞中的细胞病变活性显著相关。病毒介导的 miR-7 上调依赖于 E2F1 蛋白的表达增强。miR-7 的异位表达通过抑制表皮生长因子受体（EGFR）的表达抑制细胞活力并诱导自噬。我们的结果表明，溶瘤腺病毒通过 E2F1-miR-7-EGFR 途径诱导人类癌细胞中的自噬性细胞死亡，为抗癌病毒治疗的分子机制提供了新的见解。
