Abstract
Many studies have indicated that the aberrant expression of long noncoding RNAs (lncRNAs) is responsible for drug resistance, which represents a substantial obstacle for cancer therapy. In the present study, we aimed to investigate the role of the lncRNA HOXA-AS3 in drug resistance and elucidate its underlying mechanisms in non-small-cell lung carcinoma (NSCLC) cells. The role of HOXA-AS3 in drug resistance was demonstrated by the cell counting kit-8 assay (CCK-8), ethynyldeoxyuridine (EDU) assay, and flow cytometry analysis. Tumor xenografts in nude mice were established to evaluate the antitumor effects of HOXA-AS3 knockdown in vivo. Western blotting and quantitative real-time PCR were used to evaluate protein and RNA expression. RNA pull-down assays, mass spectrometry, and RNA immunoprecipitation were performed to confirm the molecular mechanism of HOXA-AS3 in the cisplatin resistance of NSCLC cells. We found that HOXA-AS3 levels increased with cisplatin treatment and knockdown of HOXA-AS3 enhance the efficacy of cisplatin in vitro and in vivo. Mechanistic investigations showed that HOXA-AS3 conferred cisplatin resistance by down-regulating homeobox A3 (HOXA3) expression. Moreover, HOXA-AS3 was demonstrated to interact with both the mRNA and protein forms of HOXA3. In addition, HOXA3 knockdown increased cisplatin resistance and induced epithelial-mesenchymal transition (EMT). Taken together, our findings suggested that additional research into HOXA-AS3 might provide a better understanding of the mechanisms of drug resistance and promote the development of a novel and efficient strategy to treat NSCLC.
Highlights
Lung cancer is one of the most common cancers and is the predominant cause of cancer-related mortality worldwide[1]
Despite recent studies showing that long noncoding RNAs (lncRNAs) could confer chemoresistance in cancer cells by improving DNA repair, cellular apoptosis, epithelial-mesenchymal transition (EMT), and altering drug metabolism and membrane efflux[8], the molecular mechanisms underlying the action of lncRNAs in these cancer cell functions remain largely elusive
Responses of Non-small-cell lung carcinoma (NSCLC) cell lines and HOXA-AS3 levels to cisplatin treatment To investigate the potential role of HOXA-AS3 in NSCLC, we first used the StarBasev.[3] project to analyze the level of HOXA-AS3 in LUSC
Summary
Lung cancer is one of the most common cancers and is the predominant cause of cancer-related mortality worldwide[1]. The prognosis of lung cancer has improved because of early diagnosis, radical surgery, and the emergence of new adjuvant chemotherapy regimens and targeted biological agents, the prognosis of NSCLC. Abnormal lncRNA expression has been found in many types of tumors, Lin et al Oncogenesis (2019)8:60 playing roles in regulating cancer cell proliferation, differentiation, invasion, and metastasis[4,5]. LncRNAs are considered key regulators in drug resistance, and may act as promising prognostic and therapeutic targets. Despite recent studies showing that lncRNAs could confer chemoresistance in cancer cells by improving DNA repair, cellular apoptosis, epithelial-mesenchymal transition (EMT), and altering drug metabolism and membrane efflux[8], the molecular mechanisms underlying the action of lncRNAs in these cancer cell functions remain largely elusive. A better understanding of the molecular mechanisms of lncRNAs in drug resistance may lead to the development of more effective cancer treatments
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