LncRNA MBNL1‐AS1 represses cell proliferation and enhances cell apoptosis via targeting miR‐135a‐5p/PHLPP2/FOXO1 axis in bladder cancer

摘要

LncRNAs have been shown to play essential roles in bladder cancer (BC) progress. Our microarrays of clinical samples firstly screened that lncRNA muscleblind‐like 1 antisense RNA 1 (MBNL1‐AS1) was poorly expressed in BC tissues. However, its biological function in BC remains not well understood. Here we examined the clinical correlations with MBNL1‐AS1 in BC patients. Then, 5673 and T24 cell lines were employed to investigate the role of MBNL1‐AS1 in the proliferation and apoptosis of BC cells in vitro and in vivo. Furthermore, miR‐135a‐5p (miR‐135a)/PHLPP2/FOXO1 axis was focused to explore its regulatory mechanism in BC. The results showed that MBNL1‐AS1 was significantly downregulated in bladder tumor tissues, and associated with BC progression. In vitro, MBNL1‐AS1 knockdown increased the number of viable cells and bromodeoxyuridine‐positive cells, accelerated cell cycle, and dysregulated proliferative regulators (Ki67, p21, p27, and Cyclin D1) in BC cells. The apoptotic cells and the cleavages of caspase‐3/9 were reduced in MBNL1‐AS1‐silenced BC cells. Overexpression of MBNL1‐AS1 had opposite effects on BC cell proliferation and apoptosis. Moreover miR‐135a was demonstrated to interact with MBNL1‐AS1, and inhibiting miR‐135a reversed the effects of shMBNL1‐AS1 on BC cells. The downstream effectors (PHLPP2 and FOXO1) were positively regulated by MBNL1‐AS1, but negatively regulated by miR‐135a. Similar results were also observed in xenograft tumors. In conclusion, this study firstly suggests that MBNL1‐AS1 acts as a tumor suppressor of BC by targeting miR‐135a/PHLPP2/FOXO1 axis, providing a novel insight for BC diagnosis and treatment.