Increased m6A modification of lncRNA DBH-AS1 suppresses pancreatic cancer growth and gemcitabine resistance via the miR-3163/USP44 axis

Abstract

Background: Gemcitabine is among the most commonly utilized chemotherapeutic agents for treating pancreatic cancer (PC), yet patients ultimately develop chemoresistance and thus exhibit a poor prognosis.Long noncoding RNAs (lncRNAs) can function as key regulators of PC progression and may serve as prognostic biomarkers in individuals with gemcitabine-resistant PC. This study sought to explore the role of the lncRNA DBH-AS1 in this oncogenic setting.Methods: Based on public databases and qRT-PCR analyses the expression of lncRNA DBH-AS1 in PC tissues and cell lines. The effects of lncRNA DBH-AS1 on proliferation and gemcitabine resistance were determined by in vitro and in vivo experiments. Luciferase reporter assay and RNA immunoprecipitation (RIP) were carried out to reveal the interaction between lncRNA DBH-AS1, miR-3163 and USP44.Results: We found that PC tissues exhibited DBH-AS1 downregulation that was particularly pronounced in gemcitabine-resistant PC tissues and cells. This DBH-AS1 downregulation was negatively correlated with the malignancy of PC tumors and with patient survival outcomes. Additionally, decreased DBH-AS1 expression in PC was found to be linked to the METTL3-dependent m 6 A methylation of the lncRNA, with functional analyses revealing that DBH-AS1 was able to suppress the growth of PC cells. Mechanistically, DBH-AS1 was able to increase PC cell sensitivity to gemcitabine by sequestering miR-3163 and thus upregulating USP44 in these tumor cells. Clinically, patient-derived PC tumor xenografts exhibiting high levels of DBH-AS1 expression were found to be responsive to gemcitabine treatment.Conclusions: Overall, these data underscore a key role for DBH-AS1 as a regulator of PC tumor growth and a promising therapeutic target capable of predicting PC patient responsiveness to gemcitabine treatment.

Emerging roles of m6A RNA modification in cancer therapeutic resistance

“…m6A methylation sustain RNA stability of DBH-AS1 in PC cells, which sensitizes PC cell to GEM by sequestering miR-3163 and thus upregulating USP44. Particularly, downregulation of DBH-AS1 was observed in GEM-resistant PC tissues and cells, and closely related with low expression of METTL3 [ 58 ]. Opposite to METTL3, the METTL14 was upregulated in GEM-resistant PC cells, induced by transcriptional factor p65 and downstream enhanced the expression of cytidine deaminase (CDA) to inactivate GEM.…”

Regulation of temozolomide resistance via lncRNAs: Clinical and biological properties of lncRNAs in gliomas (Review)

“…Apart from the aforementioned reports, lncRNAs that are associated with cancer have been previously detected in the body fluids of patients with cancer, which suggests the potential of using lncRNAs as biomarkers and therapeutic targets for cancer applications (25). Of note, lncRNAs have been reported to participate in the development of resistance to chemotherapy in various human malignancies, such as head and neck squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, bladder cancer, including glioma (26)(27)(28)(29)(30)(31)(32).…”

The role of N6-methyladenosine-modified non-coding RNAs in the pathological process of human cancer

“…It has been reported that increased m6A levels in adipocyte exosomal LncRNAs can mediate myeloma drug resistance [ 123 ]. In contrast, increased m6A levels of lncRNA DBH-AS1 can inhibit gemcitabine resistance in pancreatic cancer [ 124 ]. In a word, these findings suggest that m6A-modified ncRNAs may be a potential direction for addressing cancer chemoradiotherapy resistance in the future.…”