Recent studies show p85α up-regulates epidermal growth factor (EGF) receptor, thereby promoting malignant cell transformation and migration in normal mouse embryonic fibroblasts (MEFs). However, the potential role of p85α in human bladder cancer (BC) remains unknown. Here, we show that p85α is down-regulated in BC tumor tissues. Ectopic expression of p85α inhibited cell invasion, but not migration, whereas p85α knockdown promoted invasion in BC cells, revealing that p85α inhibits BC invasion. Overexpression of kinase-deficient p110 in T24 T(p85α) cells inhibited BC cell migration, but not invasion, suggesting that the inhibition of p85α on invasion is independent of PI3K activity. The effect of p85α on inhibiting BC invasion was mediated by the inactivation of MMP-2 concomitant with the up-regulation of TIMP-2 and down-regulation of MMP-14. Mechanistic studies revealed c-Jun inactivation was associated with p85α knockdown-induced MMP-14 expression, and down-regulated miR-190, leading to ATG7 mRNA degradation. This suppressed the autophagy-dependent removal of TIMP-2 in human BC cells. The present results identify a novel function of p85α and clarify the mechanisms underlying its inhibition of BC invasion, providing insight into the role of p85α in normal and cancer cells.

最近的研究表明p85α上调表皮生长因子（EGF）受体，从而促进正常小鼠胚胎成纤维细胞（MEF）的恶性细胞转化和迁移。然而，p85α 在人类膀胱癌 (BC) 中的潜在作用仍不清楚。在这里，我们发现 p85α 在 BC 肿瘤组织中下调。p85α的异位表达抑制细胞侵袭，但不抑制细胞迁移，而p85α敲低则促进BC细胞的侵袭，表明p85α抑制BC细胞侵袭。T24 T(p85α) 细胞中激酶缺陷型 p110 的过度表达抑制 BC 细胞迁移，但不抑制侵袭，表明 p85α 对侵袭的抑制与 PI3K 活性无关。p85α抑制BC侵袭的作用是通过MMP-2失活以及TIMP-2上调和MMP-14下调介导的。机制研究表明，c-Jun 失活与 p85α 敲低诱导的 MMP-14 表达和下调 miR-190 相关，从而导致ATG7 mRNA 降解。这抑制了人 BC 细胞中 TIMP-2 的自噬依赖性去除。目前的结果鉴定了 p85α 的新功能，并阐明了其抑制 BC 侵袭的机制，从而深入了解 p85α 在正常细胞和癌细胞中的作用。