Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance.
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ABSTRACT:
SUBMITTER: Rampioni Vinciguerra GL
PROVIDER: S-EPMC9879967 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Publications
Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance.
Rampioni Vinciguerra Gian Luca GL Capece Marina M Distefano Rosario R Nigita Giovanni G Vecchione Andrea A Lovat Francesca F Croce Carlo M CM
Signal transduction and targeted therapy 20230127 1
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Project description:Background and objectiveChemotherapy drugs, such as cisplatin (DDP), improve the survival of patients with lung cancer by inducing apoptosis in cancer cells, which quickly develop resistance to DDP through uncharacterized mechanisms. Glioma Pathogenesis-Related Protein 1 (GLIPR1) plays an important role in cell proliferation, migration and apoptosis. However, the expression and function of GLIPR1 in mediating DDP resistance in human lung adenocarcinoma A549/DDP and human large cell lung cancer H460/DDP cells has not yet been reported.MethodsIn this study, real-time PCR (RT-PCR) and western blot were used to examine the mRNA and protein expression of GLIPR1, respectively. Bright-field microscopy, the cell counting kit-8 (CCK-8) assay, flow cytometry analysis and JC-1 dye were used to measure the cellular morphology, proliferation, apoptosis and mitochondrial membrane potential, respectively.ResultsCompared to human lung adenocarcinoma A549 cells, the mRNA and protein expression of GLIPR1 were significantly increased in DDP-resistant A549/DDP cells (p < 0.05). Similarly, the mRNA level of GLIPR1 in DDP-resistant H460/DDP cells was also significantly higher than that in DDP-sensitive H460 cells (p < 0.05). Silencing of GLIPR1 in A549/DDP and H460/DDP cells led to increased apoptosis via a mitochondrial signaling pathway following incubation with various concentrations of DDP. Furthermore, GLIPR1 downregulation markedly reduced the protein expression of Bcl-2, and increased the cleaved Poly (ADP-Ribose) Polymerase (PARP) and cleaved caspase-3 in DDP-resistant A549/DDP cells.ConclusionIn this study, we demonstrated for the first time that GLIPR1 could modulate the response of DDP-resistant A549/DDP and H460/DDP cells to cisplatin. Therefore, GLIPR1 deserves further investigation in the context of none-small lung cancer (NSCLC).
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Project description:BackgroundCircular RNAs (circRNAs) play vital roles in non-small cell lung cancer (NSCLC) progression. Our research analyzed the role of circ_0110498 on the cisplatin (DDP) resistance of NSCLC.MethodsCell glycolysis was analyzed by measuring glucose consumption and lactate production. Protein expression was determined by western blot analysis. The expression of circ_0110498, microRNA (miR)-1287-5p and RBBP4 was detected by RT-qPCR assay. Cell counting kit-8, colony formation and transwell assays, together with flow cytometry were conducted to analyze cell DDP resistance, proliferation, metastasis and apoptosis.ResultsCirc_0110498 expression was elevated in DDP-resistant NSCLC tissues and cells. Circ_0110498 silencing not only suppressed the DDP resistance of NSCLC cells by inhibiting cell growth, metastasis and glycolysis, but also enhanced the DDP sensitivity of NSCLC tumors. MiR-1287-5p was sponged by circ_0110498, and its inhibitor also reversed the effect of circ_0110498 silencing on the DDP resistance of NSCLC cells. MiR-1287-5p interacted with RBBP4, and RBBP4 overexpression partly reversed the inhibitory effect of miR-1287-5p on the DDP resistance of NSCLC cells.ConclusionCirc_0110498 facilitated DDP resistance partly through mediating the miR-1287-5p/RBBP4 signaling in NSCLC.
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Project description:Resistance to chemotherapeutic drugs limits the efficacy of chemotherapy in non-small cell lung cancer (NSCLC). Autophagy is an essential mechanism which involves in drug resistance. Our previous research has revealed that miR-152-3p represses NSCLC progression. However, the mechanism of miR-152-3p in autophagy-mediated chemoresistance in NSCLC remains unclear. Cisplatin-resistant cell lines (A549/DDP and H446/DDP) were transfected with related vectors and subjected to cisplatin, autophagy inhibitor, activator, or extracellular signal-regulated kinase (ERK) activator. Flow cytometry, CCK8 and colony formation assays were performed for testing apoptosis and cell viability. The related RNAs or proteins were detected by qRT-PCR or Western blot. Chromatin immunoprecipitation, luciferase reporter assay or RNA immunoprecipitation were used for validating the interaction between miR-152-3p and ELF1 or NCAM1. Co-IP verified the binding between NCAM1 and ERK. The role of miR-152-3p in cisplatin resistance of NSCLC was also validated in vivo. The results showed that miR-152-3p and ELF1 were decreased in NSCLC tissues. miR-152-3p reversed cisplatin resistance by inhibiting autophagy through NCAM1. NCAM1 promoted autophagy through the ERK pathway and facilitated cisplatin resistance. ELF1 positively regulated miR-152-3p level by directly interacting with miR-152-3p promoter. miR-152-3p targeted NCAM1 to regulate NCAM1 level and then affected the binding of NCAM1 to ERK1/2. ELF1 inhibited autophagy and reversed cisplatin resistance through miR-152-3p/NCAM1. miR-152-3p inhibited autophagy and cisplatin resistance of xenograft tumor in mice. In conclusion, our study revealed that ELF1 inhibited autophagy to attenuate cisplatin resistance through the miR-152-3p/NCAM1/ERK pathway in H446/DDP and A549/DDP cells, suggesting a potential novel treatment strategy for NSCLC.
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Project description:The long non-coding RNA HLA complex P5 (HCP5) is extensively related to cancer chemoresistance, while its function in gastric cancer (GC) has not been well elucidated yet. Here, the role and mechanism of HCP5 in regulating the chemoresistance of GC to cisplatin (DDP) was investigated. Our results revealed that HCP5 was increased in GC patients and indicated a poor prognosis. HCP5 knockdown weakens DDP resistance and reduced apoptosis of GC cells. miR-128 was decreased in GC patients and sponged by HCP5. HMGA2 was targeted by miR-128 and was increased in GC patients. HCP5 aggravated the resistance of GC cells to DDP in vitro by elevating HMGA2 expression via sponging miR-128. HCP5 silencing inhibited GC cells growth, resistance to DDP, and Ki-67 expression in vivo. In summary, HCP5 contributed to DDP resistance in GC cells through miR-128/HMGA2 axis, providing a promising therapeutic target for GC chemoresistance.
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Project description:Purpose:Lung cancer is one of the most prevailing human cancers worldwide. Emerging evidence implies that long non-coding RNA nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) is implicated in the tumorigenesis of lung cancer. Herein, we aimed to expose the impact of NNT-AS1 on the drug resistance of lung cancer. Methods:Levels of NNT-AS1, microRNA (miR)-1236-3p and autophagy-related gene 7 (ATG7) were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was implemented to detect cell proliferation and the half maximal inhibitory concentration (IC50) of cisplatin (DDP) in vitro. Moreover, flow cytometry was performed to assess cell apoptosis. Cell migration and invasion were examined utilizing transwell assay in lung cancer cells. Besides, levels of ATG7 and cell behavior-related proteins were determined via Western blot. Dual-luciferase reporter assay was administrated to identify the interaction between miR-1236-3p and NNT-AS1 or ATG7. The biological role of NNT-AS1 in DDP ?resistance of lung cancer was examined by xenograft tumor model in vivo. Results:NNT-AS1 and ATG7 were upregulated, whereas miR-1236-3p was curbed in lung cancer tissues and in with or without DDP-resistant cell lines. NNT-AS1 detection significantly constrained cell growth, metastasis, and the IC50 of DDP in A549/DDP and H522/DDP cells. Interestingly, the influence of miR-1236-3p mimic on DDP resistance was overturned via NNT-AS1 upregulation in vitro. Reintroduction of miR-1236-3p inhibitor relieved the effect of ATG7 silencing on DDP sensitivity in A549/DDP and H522/DDP cells. Importantly, NNT-AS1 was a sponge of miR-1236-3p to separate ATG7. Besides, NNT-AS1 silencing enhanced DDP sensitivity of lung cancer in vivo. Conclusion:NNT-AS1/miR-1236-3p/ATG7 axis regulated DDP resistance in lung cancer cells and might supply a probable target and prognostic marker in lung cancer treatment.
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Project description:BackgroundOur previous report demonstrated that genetic ablation of miR-301a reduces Kras-driven lung tumorigenesis in mice. However, the impact of miR-301a on host anti-tumor immunity remains unexplored. Here we assessed the underlying molecular mechanisms of miR-301a in the tumor microenvironment.MethodsThe differentially expressed genes were identified by using deep sequencing. The immune cell counts, and cytokines expression were analyzed by realtime PCR, immunohistochemistry and flow cytometry. The role of miR-301a/Runx3 in lung tumor was evaluated on cell growth, migration and invasion. The function of miR-301a/Runx3 in regulating tumor microenvironment and tumor metastasis were evaluated in Kras transgenic mice and B16/LLC1 syngeneic xenografts tumor models.ResultsIn this work, we identified 1166 up-regulated and 475 down-regulated differentially expressed genes in lung tumor tissues between KrasLA2 and miR-301a-/-; KrasLA2 mice. Immune response and cell cycle were major pathways involved in the protective role of miR-301a deletion in lung tumorigenesis. Overexpression of the miR-301a target, Runx3, was an early event identified in miR-301a-/-; KrasLA2 mice compared to WT-KrasLA2 mice. We found that miR-301a deletion enhanced CD8+ T cell accumulation and IFN-γ production in the tumor microenvironment and mediated antitumor immunity. Further studies revealed that miR-301a deficiency in the tumor microenvironment effectively reduced tumor metastasis by elevating Runx3 and recruiting CD8+ T cells, whereas miR-301a knockdown in tumor cells themselves restrained cell migration by elevating Runx3 expression.ConclusionsOur findings further underscore that miR-301a facilitates tumor microenvironment antitumor immunity by Runx3 suppression in lung tumorigenesis.
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