Abstract
Lung adenocarcinoma (LUAD), as the most common subtype of non‐small cell lung cancer, is responsible for more than 500 000 deaths worldwide annually. In this study, we identify a novel microRNA‐26b‐5p (miR‐26b‐5p) and elucidated its function on LUAD. The survival rate of parent LUAD cells and radiation‐resistant LUAD cells were determined using clonogenic survival assay. We overexpressed or inhibited miR‐26b‐5p in LUAD, and the correlation between activating transcription factor 2 (ATF2) and miR‐26b‐5p was determined using integrated bioinformatics analysis and dual‐luciferase reporter gene assay. Exosomes derived from A549 cell lines were then detected using Western blot assay, followed by co‐transfection with radiation‐resistant A549R cells. LUAD tissues and serum were collected, followed by miR‐26b‐5p relative expression quantification using RT‐qPCR. miR‐26b‐5p was identified as the most differentially expressed miRNA and was down‐regulated in LUAD. Radiation‐resistant cells were more resistant to X‐radiation compared with parent cells. miR‐26b‐5p overexpression and X‐irradiation led to enhanced radiosensitivity of LUAD cells. ATF2 was negatively targeted by miR‐26b‐5p. Exosomal miR‐26b‐5p derived from A549 cells could be transported to irradiation‐resistant LUAD cells and inhibit ATF2 expression to promote DNA damage, apoptosis and radiosensitivity of LUAD cells, which was verified using serum‐based miR‐26b‐5p. Our results show a regulatory network of miR‐26b‐5p on radiosensitivity of LUAD cells, which may serve as a non‐invasive biomarker for LUAD.
Highlights
Lung cancer contributed to high incidence and mortality rate and lung adenocarcinoma (LUAD) is the most common histological subtype.[1,2] Patients with LUAD were found to be subject to greater mortality and the risk of distant metastasis exceeds that of local recurrence at every disease stage, pinpointing the systemic threat of the disease.[3]
A previous study noted that exosomal miR-26b-5p was down-regulated in LUAD and its tumour-suppressive role was investigated in bladder cancer by inhibiting cell aggressiveness.[11,12] miR-26b-5p was found to be involved in proliferation, angiogenesis and apoptosis in hepatocellular carcinoma.[13]
The results indicated that miR-26b-5p overexpression restored radiosensitivity of A549 cells, and knockdown of miR-26b-5p resulted in radioresistance
Summary
Lung cancer contributed to high incidence and mortality rate and lung adenocarcinoma (LUAD) is the most common histological subtype.[1,2] Patients with LUAD were found to be subject to greater mortality and the risk of distant metastasis exceeds that of local recurrence at every disease stage, pinpointing the systemic threat of the disease.[3]. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, and miRNA-based anticancer therapies are achievable with the goal to improve treatment response and cure rate.[8] Critical role of miRNAs in cancer pathogenesis and response to therapy have been previously demonstrated in different cancers.[9,10] A previous study noted that exosomal miR-26b-5p was down-regulated in LUAD and its tumour-suppressive role was investigated in bladder cancer by inhibiting cell aggressiveness.[11,12] miR-26b-5p was found to be involved in proliferation, angiogenesis and apoptosis in hepatocellular carcinoma.[13] A prior study has demonstrated that exosomes can be derived from LUAD cells[14] and exosomal miRNAs were found to be a potential biomarker in cancers.[15] For example, exosomal miR-451a was identified as a non-invasive biomarker for early prediction of recurrence and prognosis of nonsmall cell lung cancer.[16] Interestingly, activating transcription factor 2 (ATF2) was predicted to be one of the target genes of miR-26b-5p by TargetScan. Radiation is known to result in DNA double-strand breaks, which lead to the formation of phosphorylated H2AX (γH2AX) foci, and γH2AX is required for DNA damage signalling and DNA repair.[20,21,22] poly ADP-ribose polymerase (PARP) enzymes are implicated in cellular response to DNA damage.[23,24] Accumulating evidence shed light on Cleaved-Caspase 3 as a biomarker of tumour cell apoptosis.[25,26] experiments were designed to explore the regulatory mechanism of miR26b-5p/ATF2 in LUAD by using γH2AX, PARP and Cleaved-Caspase 3 as detection indicators
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