Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma

Background: LINC00173 had been reported as a cisplatin (cis-diamminedichloroplatinum, DDP) chemotherapy-resistant inducer in small cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). Here, reversed data was displayed for LINC00173 as a DDP chemosensitivity-inducing factor in lung adenocarcinoma (LUAD). Methods LINC00173 was screened from GEO databases (GSE43493), then In situ hybridization and qRT-PCR were used to detect the expression level of LINC00173 in tissue samples and LUAD cell lines. Moreover, colony formation assay, cell viability and IC50 assays, flow cytometry, nude mouse tumor xenograft model were individually performed to certificate the effect of LINC00173 on LUAD in vitro and in vivo. The relationships between miR-1275 and LINC00173 or PROCA1 were identified by dual-luciferase reporter assay, as well as c-Myc binding with LINC00173 promoter. The direct binding of miR-1275 with LINC00173 was investigated c by RAP. ZFP36L2 protein bind to the 3’UTR of BCL2 was confirmed by RIP. The apoptosis related proteins (including c-CASP3, c-PARP and BCL2) and related signal proteins were analysed by Western blot. Results LINC00173 down-regulation in DDP-resistant LUAD patients was correlated with poor prognosis. Further, LINC00173 expression was significantly reduced in DDP-resistant LUAD cells and DDP-treated human LUAD tissues. Suppressed LINC00173 in LUAD cells enhanced DDP chemoresistance in vivo and in vitro , while restored LINC00173 in DDP-resistant LUAD cells markedly regained chemosensitivity to DDP. Mechanistically, DDP-resistant LUAD cells activated PI3K/AKT signal and further elevated c-Myc expression. C-Myc binds to the promoter of LINC00173 to suppress its expression. Reduced LINC00173 attenuated the adsorption of oncogenic miR-1275 and thus down-regulated the expression of miR-1275-target gene PROCA1. PROCA1 played a potential tumor-suppressive role inducing cell apoptosis and DDP chemosensitivity via recruiting ZFP36L2 to bind to the 3’UTR of BCL2, reducing the stability of BCL2 mRNA and thus activating apoptotic signal. Conclusion Our study demonstrated a novel and critical role of LINC00173 which was transcriptionally repressed by DDP activated PI3K/AKT/c-Myc signal in LUAD and thus promoted DDP-acquired chemotherapeutic resistance via regulating miR-1275 to suppress PROCA1/ZFP36L2-induced BCL2 degradation, leading to apoptotic signal reduction.