LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

Abstract

Background Pancreatic cancer is one of the most lethal malignancies and has an extremely poor diagnosis and prognosis. The development of resistance to gemcitabine is still a major challenge. The long noncoding RNA PVT1 was reported to be involved in carcinogenesis and chemoresistance; however, the mechanism by which PVT1 regulates the sensitivity of pancreatic cancer to gemcitabine remains poorly understood. Methods The viability of pancreatic cancer cells was assessed by MTT assay in vitro and xenograft tumor formation assay in vivo. The expression levels of PVT1 and miR-619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting analysis and qRT-PCR were performed to assess the protein and mRNA levels of Pygo2 and ATG14, respectively. Autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of PVT1 were further investigated by gain- and loss-of-function assays in vitro. Results In the present study, we demonstrated that PVT1 was up-regulated in gemcitabine-resistant pancreatic cancer cell lines. Gain- and loss-of-function assays revealed that PVT1 impaired sensitivity to gemcitabine in vitro and in vivo. We further found that PVT1 up-regulated the expression of both Pygo2 and ATG14 and thus regulated Wnt/β-catenin signaling and autophagic activity to overcome gemcitabine resistance through sponging miR-619-5p. Moreover, we discovered three TCF/LEF binding elements (TBEs) in the promoter region of PVT1, and activation of Wnt/β-catenin signaling mediated by the up-regulation of Pygo2 increased PVT1 expression by direct binding to the TBE region. Furthermore, PVT1 was discovered to interact with ATG14, thus promoting assembly of the autophagy specific complex I (PtdIns3K-C1) and ATG14-dependent class III PtdIns3K activity. Conclusions These data indicate that PVT1 plays a critical role in the sensitivity of pancreatic cancer to gemcitabine and highlight its potential as a valuable target for pancreatic cancer therapy.

LncRNA-Associated ceRNA Network Reveals Novel Potential Biomarkers of Laryngeal Squamous Cell Carcinoma

“…Previous evidences have demonstrated that non-coding RNAs, such as miRNAs and lncRNAs, play crucial and complex roles in tumor occurrence and progression. 22 - 24 LncRNAs can regulate mRNA expression by competitively binding to share miRNAs. 25 Increasing studies suggest that the lncRNA-miRNA-mRNA axis is involved in the carcinogenesis of LSCC.…”

Targeting autophagy to overcome drug resistance: further developments

“…In breast cancer, activated autophagy by lncRNA H19, an imprinting lncRNA, contributes to tamoxifen resistance via upregulating Beclin1 expression [ 107 ]. One additional study indicated that lncRNA human plasmacytoma variant translocation 1 (PVT1) induces autophagy through increasing the protein and mRNA levels of Pygo2 and ATG14 and enhances cell resistance to gemcitabine in pancreatic cancer [ 108 ].…”

Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma

“…A relevant study reported that miR-619-5p suppresses proliferative and invasive capacities of colorectal carcinoma cells [42]. A latest report demonstrated that miR-619-5p enhances sensitivity of pancreatic cancer cells to gemcitabine via activating the Wnt/β-catenin signaling pathway [26]. It is concluded that miR-619-5p not only serves as a tumor biomarker, but also a potential therapeutic target for preventing tumor growth and drug resistance.…”

“…We demonstrated that miR-619-5p served an anti-cancer role in OSCC cell lines. An earlier study reported that miR-619-5p enhanced the sensitivity of pancreatic cancer to gemcitabine [26]. MiR-619-5p shows a potential influence in chemotherapy resistance.…”