Abstract
BackgroundLong non-coding RNA LINC00346 has been recently suggested as a prognostic marker in pancreatic cancer. However, its biological function in pancreatic cancer has not yet been determined. In this study, we attempted to ascertain the role of LINC00346 in regulating the aggressiveness of pancreatic cancer.MethodsThe effects of overexpression and knockdown of LINC00346 on the proliferation, cell cycle progression, apoptosis, and gemcitabine resistance were investigated. Bioinformatic analysis, luciferase reporter assay, and RNA immunoprecipitation assay were performed to search for potential microRNAs (miRs) that can interact with LINC00346.ResultsOverexpression of LINC00346 significantly enhanced the proliferation, colony formation, and tumorigenesis of pancreatic cancer cells. Conversely, knockdown of LINC00346 suppressed pancreatic cancer cell proliferation and caused a cell-cycle arrest at the G2/M-phase. Depletion of LINC00346 also enhanced gemcitabine sensitivity in pancreatic cancer cells both in vitro and in vivo. Mechanistic investigation revealed that LINC00346 acted as a sponge for miR-188-3p and blocked the repression of BRD4 by miR-188-3p in pancreatic cancer cells. Clinical evidence indicated a negative correlation between LINC00346 and miR-188-3p in pancreatic cancer specimens. Rescue experiments showed that LINC00346 attenuated the growth-suppressing and chemosensitizing effects of miR-188-3p on pancreatic cancer cells. In addition, silencing of BRD4 significantly inhibited LINC00346-induced pancreatic cancer cell proliferation and colony formation.ConclusionsLINC00346 shows the ability to promote pancreatic cancer growth and gemcitabine resistance, which is in part mediated by antagonization of miR-188-3p and induction of BRD4. Targeting LINC00346 may improve gemcitabine-based therapeutic efficacy.
Highlights
Pancreatic cancer is one of the most lethal malignancies, with a median overall survival of 6 months and 5-year survival rate of less than 5% [1, 2]
Pearson correlation analysis was conducted to determine the relationship between LINC00346 and miR-188-3p levels in Overexpression of LINC00346 facilitates the growth of pancreatic cancer To investigate the biological relevance of LINC00346 in pancreatic cancer, we performed gain- and loss-of-function studies
Real-time PCR analysis revealed that LINC00346 was expressed at higher levels in pancreatic cancer cells than in HPDE6c7 pancreatic epithelial cells (Fig. 1a)
Summary
Pancreatic cancer is one of the most lethal malignancies, with a median overall survival of 6 months and 5-year survival rate of less than 5% [1, 2]. LncRNAs play an important role in tumor progression and drug resistance [7, 8]. They can function as competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRs), derepressing multiple target genes [9]. Linc-ROR was found to induce gemcitabine resistance in pancreatic cancer cells through regulation of the miR-124/ PTBP1/PKM2 axis [11]. A recent study has showed that LINC00346 is overexpressed and serves as a prognostic marker in pancreatic cancer [14]. Long non-coding RNA LINC00346 has been recently suggested as a prognostic marker in pancreatic cancer. We attempted to ascertain the role of LINC00346 in regulating the aggressiveness of pancreatic cancer
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