TP53 mitigates cisplatin resistance in non-small cell lung cancer by mediating the effects of resistant cell-derived exosome mir-424-5p
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ABSTRACT:
SUBMITTER: Deng Y
PROVIDER: S-EPMC10909722 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:Laryngeal carcinoma is the predominant kind of tumor seen under the category of head and neck malignancies. LncRNA MIR600HG affects tumor morphology in numerous cancer types. However, the function of MIR600HG in laryngeal cancer remains unclear. Protein and gene expressions were analyzed by using western blot and quantitative real time polymerase chain reaction. Cells proliferation and migration were evaluated by EdU and transwell assays. Flow cytometry was performed to detect cells apoptosis. The interaction between MIR600HG or B-cell translocation gene 2 (BTG2) and miR-424-5p was analyzed by dual luciferase reporter assay and RNA immunoprecipitation. The expression of MIR600HG in laryngeal cancer tissues was lower than that in normal tissues, and low expression of MIR600HG was associated with poor prognosis in laryngeal cancer. Furthermore, overexpression of MIR600HG resulted in a reduction in cellular proliferation and the promotion of apoptosis in both HEp-2 and Tu-212. Mechanically, miR-424-5p was a direct target of MIR600HG, and overexpression of MIR600HG reduced miR-424-5p expression. Furthermore, BTG2 was a target gene of miR-424-5p and miR-424-5p upregulation suppressed the expression of BTG2. In addition, overexpression of BTG2 inhibited laryngeal cancer progression, whereas MIR600HG knockdown or miR-424-5p overexpression reversed the role of BTG2. This work suggested that MIR600HG represses laryngeal tumor development by regulating the miR-424-5p/BTG2 axis, which provides new molecules for early diagnosis of laryngeal cancer in the future.
| S-EPMC11786319 | biostudies-literature
Project description:Chemoresistance is a major obstacle in the treatment of gastric cancer (GC). Notably, aberrant expression of microRNAs (miRs) is closely related to tumor development and progression. In the present study, the role of miR-424-5p in the chemoresistance of GC was investigated. Reverse transcription-quantitative PCR was used to detect the expression levels of miR-424-5p in tissues and different cell lines. Cell viability and apoptosis were detected via a Cell Counting Kit-8 assay, western blotting and flow cytometry. The targeting relationship between miR-424-5p and SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) was verified via dual-luciferase reporter assays and the molecular mechanism was investigated by western blotting. The results revealed that miR-424-5p was expressed at low levels in GC tissues and cell lines, and that low miR-424-5p expression was associated with poor N stage and worse prognosis, especially in patients who received adjuvant chemotherapy. Further experiments revealed that the overexpression of miR-424-5p reduced cisplatin (CDDP) resistance and promoted GC cell apoptosis, whereas inhibiting miR-424-5p had the opposite effect. Mechanistically, it was found that miR-424-5p downregulated the expression of SMURF1 to regulate the expression of ING2 and p53, thereby modulating CDDP resistance in GC. In summary, the present study demonstrated that miR-424-5p may serve an important regulatory role in CDDP resistance in GC, and could be a potential diagnostic biomarker and therapeutic target for GC chemoresistance.
| S-EPMC11755228 | biostudies-literature
Project description:BackgroundChemotherapy including cisplatin is recommended for the treatment of advanced bladder cancer, but its effectiveness is limited due to the acquisition of drug resistance. Although several mechanisms of cisplatin resistance have been reported, there are still many unknowns, and treatment of cisplatin-resistant bladder cancer remains difficult. Accordingly, in this study, we aimed to identify and characterize microRNAs involved in cisplatin resistance.MethodsSmall RNA sequencing analysis was performed to search for microRNAs related to cisplatin resistance. The identified microRNAs were then characterized using gain-of-function studies, sensitivity analysis, target gene analysis, and cellular assays.ResultsWe identified miR-424-5p as a candidate microRNA that was downregulated in cisplatin-resistant strains compared with parental strains. Notably, in gain-of-function studies, miR-424-5p suppressed the proliferative ability of cisplatin-resistant bladder cancer (CDDP-R BC). Furthermore, miR-424-5p restored sensitivity to cisplatin. RNA sequence analysis revealed seven candidate genes targeted by this microRNA. Among them, cyclin E1 (CCNE1) was chosen for subsequent analyses because its expression was upregulated in cisplatin-resistant cells compared with parental cells and because recent studies have shown that CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Therefore, we performed functional analysis using the PKMYT1 inhibitor RP-6306 and demonstrated that RP-6306 inhibited cell growth through suppression of mitotic entry and restored cisplatin sensitivity in CDDP-R BC.ConclusionsOverall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC.
| S-EPMC11523841 | biostudies-literature
Project description:Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100-5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100-5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100-5p. Exosomes confer recipient cells' resistance to DDP in an exosomal miR-100-5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells' sensitivity to DDP in exosomal miR-100-5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.
| S-EPMC5439933 | biostudies-literature
Project description:Cholangiocarcinoma is a highly aggressive malignant tumor disease with the increasing incidence and mortality. It's urgent to identify specific biomarkers for cholangiocarcinoma treatment and diagnosis. Recent studies have noted the importance of lncRNAs in cancer and the following downstream mechanism with miRNAs network has been a hotspot. This work aimed to discover the role of lncRNA HCG18 and its possible downstream mechanism in cholangiocarcinoma tumor progression. Initially, through bioinformatics tools, we observed abnormal expression of lncRNA HCG18 in cholangiocarcinoma. In vitro experiments like (CCK-8, EdU, colony formation, flow cytometry, transwell, wound healing assays) and animal study confirmed that lncRNA HCG18 served as a cancer-promoting gene, promoted cancer proliferation, migration and invasion abilities. Besides, we found cancer cell-secreted exosomes transitted HCG18 to surrounding tumor cells and accelerated tumor growth and metastasis. After that, we confirmed HCG18 directly interacted with miR-424-5p through FISH, RIP and dual luciferase reporter assays with negative modulation. The inhibition of miR-424-5p reversed the HCG18 knockdown induced suppression on cholangiocarcinoma cancer cells. More specific, miR-424-5p targeted to SOX9 contributed to cholangiocarcinoma growth and metastasis through mediating PI3K/AKT pathway. In conclusion, these findings provide solid evidence of lncRNAs/miRNAs regulation in cholangiocarcinoma progression.
| S-EPMC10104778 | biostudies-literature
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.
| S-EPMC9981309 | biostudies-literature
Project description:ObjectiveLncRNAs are non-coding RNAs exerting vital roles in the occurrence and development of various cancer types. This study tended to describe the expression pattern of FENDRR in colorectal cancer (CRC), and further investigate the role of FENDRR in CRC cell biological behaviors.MethodsGene expression profile of colon cancer was accessed from the TCGA database, and then processed for differential analysis for identification of differentially expressed lncRNAs and miRNAs. Some in vitro experiments like qRT-PCR, MTT, colony formation assay, wound healing assay and Transwell assay were performed to assess the effect of FENDRR on cell biological behaviors. Dual-luciferase reporter assay was conducted to further validate the targeting relationship between FENDRR and miR-424-5p, and rescue experiments were carried out for determining the mechanism of FENDRR/miR-424-5p underlying the proliferation, migration and invasion of CRC cells.ResultsBioinformatics analysis suggested that FENDRR was significantly down-regulated in CRC tissue, and low FENDRR was intimately correlated to poor prognosis. FENDRR overexpression could greatly inhibit cell proliferation, migration and invasion. Besides, there was a negative correlation between FENDRR and miR-424-5p. Dual-luciferase reporter assay indicated that miR-424-5p was a direct target of FENDRR. Rescue experiments discovered that FENDRR exerted its role in cell proliferation, migration and invasion in CRC via targeting miR-424-5p.ConclusionFENDRR is poorly expressed in CRC tissue and cells, and low FENDRR is responsible for the inhibition of cell proliferation, migration and invasion of CRC by means of targeting miR-424-5p.
| S-EPMC7768317 | biostudies-literature
Project description:There is increasing evidence that dysregulated long non-coding RNA (lncRNA) is implicated in tumorigenesis and progression. We aim to explore the role of lncRNA MIR600HG in glycometabolism and cisplatin (DDP) resistance of oral squamous cell carcinoma (OSCC) cells via regulating microRNA-125a-5p (miR-125a-5p) and RING finger 44 (RNF44). Expression of MIR600HG, miR-125a-5p, and RNF44 in OSCC clinical samples, cell lines, and DDP-resistant OSCC cells (SCC-9/DDP) was determined. In SCC-9 cells, proliferation, IC50 value of DDP, migration, invasion, and apoptosis were detected; in SCC-9/DDP cells, proliferation, IC50 value of DDP, apoptosis, glucose consumption, and production of lactic acid and ATP were evaluated. The interaction of MR600HG, miR-125a-5p, and RNF44 was verified. MIR600HG and RNF44 were upregulated while miR-125a-5p was downregulated in OSCC tissues and cell lines, and also in SCC-9/DDP cells. In SCC-9 cells, MIR600HG overexpression improved cell growth, metastasis, and inhibited cell susceptibility to DDP; in SCC-9/DDP cells, silencing of MIR600HG promoted apoptosis, improved DDP sensitivity, and inhibited cell glycolysis. Downregulation of miR-125a-5p showed the opposite effect to downregulation of MIR600HG. MIR600HG bound to miR-125a-5p and miR-125a-5p targeted RNF44. Downregulation of miR-125a-5p reversed the improvement of DDP sensitivity and the inhibition of cell glycolysis by downregulated MIR600HG on SCC-9/DDP cells. Downregulating RNF44 reversed the promotion of DDP resistance and cell glycolysis of SCC-9/DDP cells mediated by downregulation of miR-125a-5p. Collectively, our study addresses that MIR600HG downregulation elevates miR-125a-5p and reduces RNF44 expression, thereby improving DDP sensitivity and inhibiting glycolysis in DDP-resistant OSCC cells.
| S-EPMC9021257 | biostudies-literature
Project description:If not detected early, oral squamous cell carcinoma (OSCC) has very poor prognosis, emphasizing the need for reliable early diagnostics. Saliva is considered a promising surrogate biosample for OSCC detection, because it comes into contact with many cells of the tumor mass, providing a comprehensive sampling of tumor-specific biomolecules. Although several protein- and RNA-based salivary biomarkers have been proposed for the detection of OSCC, the results of the studies show large differences. Our goal was to clarify which salivary microRNAs (miRNA) show reliably high expression in the saliva of OSCC patients, to be used as cancer-specific biomarkers, and potentially as early diagnostic biomarkers. Based on a detailed literature search, we selected six miRNAs commonly overexpressed in OSCC, and analyzed their expression in saliva samples of cancer patients and controls by real-time quantitative PCR. Our results suggest that miR-345 and miR-31-5p are consistently upregulated salivary biomarkers for OSCC, and a three-miRNA panel of miR-345, miR-31-5p, and miR-424-3p can distinguish cancer and control patients with high sensitivity.
| S-EPMC8876825 | biostudies-literature
Project description:ObjectiveThis study aims to explore the mechanism of the miR-424-5p/E2F7 axis in hepatocellular carcinoma (HCC) and provide new ideas for targeted therapy of HCC.MethodsBioinformatics analysis was used to identify the target differentially expressed miRNA in HCC and predict its target gene. qRT-PCR was employed to verify the expression of miR-424-5p and E2F7 mRNA in HCC cells. Western blot was performed to detect the effect of miR-424-5p ectopic expression on the protein expression of E2F7. CCK-8 was used to detect proliferative activity of HCC cells and flow cytometry was carried out for analyzing cell cycle distribution. Dual luciferase reporter assay was conducted to verify the direct targeting relationship between miR-424-5p and E2F7.ResultsWe observed that miR-424-5p was down-regulated in HCC cells. CCK-8 showed that overexpression of miR-424-5p inhibited cell proliferation, and flow cytometry showed that miR-424-5p could block cells in G0/G1 phase. E2F7 was up-regulated in HCC cells, and E2F7 overexpression could facilitate the proliferative ability of HCC cells and promote the cell cycle progressing from G0/G1 to S phase. Furthermore, dual-luciferase reporter assay indicated that miR-424-5p could directly down-regulate E2F7 expression. Analysis on cell function demonstrated that miR-424-5p inhibited the proliferation of HCC cells and blocked cell cycle at G0/G1 phase by targeting E2F7.ConclusionOur results proved that E2F7 was a direct target of miR-424-5p, and miR-424-5p could regulate cell cycle and further inhibit the proliferation of HCC cells by targeting E2F7.
| S-EPMC7671513 | biostudies-literature