MicroRNA-449a Enhances Radiosensitivity in Lung Adenocarcinoma Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Tsai Mong-Hsun
PROVIDER: S-ECPF-GEOD-40602 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Lung cancer is the leading cause of cancer-related mortality worldwide. Radiotherapy is often applied for treating lung cancer, but it often fails because of the relative non-susceptibility of lung cancer cells to radiation. MicroRNAs (miRNAs) have been reported to modulate the radiosensitivity of lung cancer cells and have the potential to improve the efficacy of radiotherapy. The purpose of this study was to identify a miRNA that can adjust radiosensitivity in lung adenocarcinoma cells. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5) with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips. Twenty-six miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation.
| S-EPMC3629161 | biostudies-literature
Project description:Twenty-five miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation. MiR-449a might be a novel radiosensitizer for clinical applications. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5) with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips.
2012-12-30 | E-GEOD-40602 | biostudies-arrayexpress
Project description:Twenty-five miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation. MiR-449a might be a novel radiosensitizer for clinical applications.
2012-12-30 | GSE40602 | GEO
Project description:Lung adenocarcinoma is recognized as one of the most recurrent tumours in adults. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts and have been demonstrated to regulate biological functions during tumorigenesis. Our study aims to investigate the underlying molecular mechanisms of LINC00461/microRNA-195 (miR-195)/HOXA10 responsible for its involvement in lung adenocarcinoma. We firstly selected differentially expressed lncRNAs and genes by the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO). The functional role of LINC00461 in lung adenocarcinoma was then determined using ectopic expression, knockdown and reporter assay experiments. Besides, we detected the expression profiles of LINC00461, miR-195, HOXA10 and apoptosis- and invasion-related genes. Cell proliferation, migration and invasion were evaluated. In vivo tumour formation ability was analysed. Overexpressed LINC00461 and HOXA10 but down-regulated miR-195 were observed in primary and metastatic lung adenocarcinoma. LINC00461 negatively regulated miR-195, while miR-195 negatively regulated HOXA10. Forced LINC00461 expression decreased expression of miR-195 and Bax, increased expression of HOXA10, MMP-2, MMP-9 and Bcl-2, promoted cell proliferation, migration and invasion as well as tumour formation, and enhanced radiosensitivity of lung adenocarcinoma cells. However, these effects were reversed by lentivirus-mediated miR-195-forced expression, thereby suggesting that miR-195 could antagonize the harmful effect of LINC00461 on lung adenocarcinoma cells. Collectively, the present study provides evidence supporting the inhibitory effect of LINC00461 silencing on lung adenocarcinoma, which suppresses lung adenocarcinoma cell migration, invasion and radiosensitivity via HOXA10 by binding to miR-195, which provides a promising basis for the targeted intervention treatment for human lung adenocarcinoma.
| S-EPMC7077533 | biostudies-literature
Project description:ObjectiveTo explore the effects of miR-195-5p and its target gene HOXA10 on the biological behaviors and radiosensitivity of lung adenocarcinoma (LUAD) cells.MethodsThe effects of miR-195-5p on LUAD cell proliferation, migration, invasion, cycle arrest, apoptosis, and radiosensitivity were investigated by in vitro experiments. The bioinformatics analysis was used to assess its clinical value and predict target genes. Double-luciferase experiments were used to verify whether the miR-195-5p directly targeted HOXA10. A xenograft tumor-bearing mouse model was used to examine its effects on the radiosensitivity of LUAD in vivo.ResultsBoth gain- and loss-of-function assays demonstrated that miR-195-5p inhibited LUAD cell proliferation, invasion, and migration, induced G1 phase arrest and apoptosis, and enhanced radiosensitivity. Double-luciferase experiments confirmed that miR-195-5p directly targeted HOXA10. Downregulation of HOXA10 also inhibited LUAD cell proliferation, migration, and invasion, induced G1 phase arrest and apoptosis, and enhanced radiosensitivity. The protein levels of β-catenin, c-myc, and Wnt1 were decreased by miR-195-5p and increased by its inhibitor. Moreover, the effects of the miR-195-5p inhibitor could be eliminated by HOXA10-siRNA. Furthermore, miR-195-5p improved radiosensitivity of LUAD cells in vivo.ConclusionmiR-195-5p has excellent antitumor effects via inhibiting cancer cell growth, invasion, and migration, arresting the cell cycle, promoting apoptosis, and sensitizing LUAD cells to X-ray irradiation by targeting HOXA10. Thus, miR-195-5p may serve as a potential candidate for the treatment of LUAD.
| S-EPMC8672108 | biostudies-literature
Project description:Radiotherapy is a common method for the treatment of lung adenocarcinoma, but it often fails due to the relative non-susceptibility of lung adenocarcinoma cells to radiation. We aimed to discuss the related mechanisms by which miR-126-5p might mediate radiosensitivity of lung adenocarcinoma cells. The binding affinity between miR-126-5p and EZH2 and between KLF2 and BIRC5 was identified using multiple assays. A549 and H1650 cells treated with X-ray were transfected with miR-126-5p mimic/inhibitor, oe-EZH2, or si-KLF2 to detect cell biological functions and radiosensitivity. Finally, lung adenocarcinoma nude mouse models were established. miR-126-5p and KLF2 were poorly expressed, while EZH2 and BIRC5 were upregulated in lung adenocarcinoma tissues and cells. miR-126-5p targeted EZH2 to promote the KLF2 expression so as to inhibit BIRC5 activation. Both in vitro and in vivo experiments verified that elevated miR-126-5p inhibited cell migration and promoted apoptosis to enhance the sensitivity of lung adenocarcinoma cells to radiotherapy via the EZH2/KLF2/BIRC5 axis. Collectively, miR-126-5p downregulated EZH2 to facilitate the sensitivity of lung adenocarcinoma cells to radiotherapy via KLF2/BIRC5.
| S-EPMC9077299 | biostudies-literature
Project description:MicroRNAs (miRNAs) have been reported to be involved in DNA damage response induced by ionizing radiation (IR). c-Myc is reduced when cells treated with IR or other DNA damaging agents. It is unknown whether miRNAs participate in c-Myc downregulation in response to IR. In the present study, we found that miR-449a enhanced radiosensitivity in vitro and in vivo by targeting c-Myc in prostate cancer (LNCaP) cells. MiR-449a was upregulated and c-Myc was downregulated in response to IR in LNCaP cells. Overexpression of miR-449a or knockdown of c-Myc promoted the sensitivity of LNCaP cells to IR. By establishing c-Myc as a direct target of miR-449a, we revealed that miR-449a enhanced radiosensitivity by repressing c-Myc expression in LNCaP cells. Furthermore, we showed that miR-449a enhanced radiation-induced G2/M phase arrest by directly downregulating c-Myc, which controlled the Cdc2/CyclinB1 cell cycle signal by modulating Cdc25A. These results highlight an unrecognized mechanism of miR-449a-mediated c-Myc regulation in response to IR and may provide alternative therapeutic strategies for the treatment of prostate cancer.
| S-EPMC4890029 | biostudies-literature
Project description:Prostate cancer is the second leading cause of cancer-related death worldwide. Radiotherapy is often applied for the treatment, but radioresistance is a challenge in some patients. MicroRNAs have been reported to be involved in the DNA damage response induced by ionizing radiation and recent studies have reported microRNA-mediated radiosensitivity. In the present study, we found microRNA-107 (miR-107) enhanced radiosensitivity by regulating granulin (GRN) in prostate cancer (PC-3) cells. MiR-107 was downregulated and GRN was upregulated in response to ionizing radiation in PC-3 cells. Overexpression of miR-107 and knockdown of GRN promoted the sensitivity of PC3 cells to ionizing radiation. By rescue experiments of GRN, we revealed that radiosensitivity enhanced by miR-107 can be attenuated by GRN overexpression in PC-3 cells. Furthermore, we showed miR-107 enhanced radiation-induced G1/S phase arrest and G2/M phase transit, and identify delayed apoptosis by suppressing p21 and phosphorylation of CHK2. Collectively, these results highlight an unrecognized mechanism of miR-107-mediated GRN regulation in response to ionizing radiation and may advance therapeutic strategies for the treatment of prostate cancer.
| S-EPMC7471693 | biostudies-literature
Project description:BackgroundAs one of the most common malignancy, lung adenocarcinoma (LUAD) is characterized by low 5-year survival rate. This research aimed to investigate the effects of ribonucleotide reductase regulatory subunit M2 (RRM2) on malignant biological behaviors and activation of cGAS/STING pathway. We also explored the synergistic sensitization mechanisms of RRM2 and radiotherapy.MethodsBioinformatic tools were used to evaluate the clinical significance of RRM2 in LUAD patients. The roles of RRM2 in malignant phenotype and DNA damage in LUAD cells were investigated with cell proliferation, colony formation, immunofluorescence, modified Boyden chamber and comet assays. The mouse models were used to evaluate the biological significance of RRM2 in vivo. Cytotoxic T cell infiltration was evaluated via flow cytometric analysis and immunohistochemistry staining in C57BL/6 mice. We also explored the synergistic effects of RRM2 silencing and radiation on LUAD cells with apoptosis assay and immunoblotting in vitro.ResultsBioinformatic analysis revealed that RRM2 had diagnostic values for LUAD patients. Higher levels of RRM2 predicted worse prognosis. RRM2 silencing inhibited LUAD cell proliferation, invasion and migration. RRM2 knockdown induced S phase arrest and DNA damage. RRM2 silencing induced cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, and the downstream targets were regulated in a STING-dependent manner. Knockdown of RRM2 suppressed tumor growth in the xenograft tumor models. RRM2 deficiency increased CD8 + T cells in the tumor tissues and spleens. Furthermore, RRM2 silencing had synergistic effects with radiation on inhibiting cell proliferation and promoting apoptosis. Meanwhile, this combination promoted the activation of cGAS/STING signaling pathway synergistically, and simultaneously increased expression of IFNβ, CCL5 and CXCL10.ConclusionOur results demonstrated that RRM2 silencing had anti-tumor values and activated the cGAS/STING signaling pathway. RRM2 silencing increased CD8 + T cells infiltration. RRM2 silencing cooperated with radiation to inhibit LUAD cell proliferation, promote apoptosis and enhance the activation of cGAS/STING signaling pathway. RRM2 could be a promising target for tumor regression through cancer immunotherapy in LUAD.
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Project description:Seven cardenolides isolated from the ethanol extract of the stems of Calotropis gigantea were evaluated in vitro against human cancer cells and the structure-activity relationships were discussed. The results demonstrated that a compound, named CGN (coroglaucigenin), had better anti-proliferative activity with the IC50 value less than 6 ?M among these compounds. Further, we found that CGN displayed much lower cytotoxicity to normal lung epithelial cells (BEAS-2B) than cancer cells (A549). Especially, our results demonstrated that treatment with CGN (1 ?M) combined with X-ray irradiation induced higher radiosensitivity in human lung cancer cells (A549, NCI-H460, NCI-H446) but not in BEAS-2B. The expression levels of nuclear transcription factor Nrf2 and Nrf2-driven antioxidant molecule NQO-1 reduced in A549 cells after combined treatment compared to the radiation only. However, CGN had no toxicity and the levels of antioxidant molecules expression were higher in BEAS-2B cells when given the similar treatment as A549 cells. These results suggest that CGN is a very promising potential sensitizer for cancer radiotherapy, which not only inhibits the proliferation of cancer cells but also enhances the radiosensitivity of cancer cells through suppressing the expression of antioxidant molecules while there is no influence for normal cells.
| S-EPMC5464829 | biostudies-other