LNX1 Contributes to Cell Cycle Progression and Cisplatin Resistance.
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ABSTRACT:
SUBMITTER: Jang M
PROVIDER: S-EPMC8394373 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung cancer is one of the main causes of tumor lethality worldwide. Circular RNAs (circRNAs) have essential roles in tumor progression. However, in non-small cell lung carcinoma (NSCLC), the role of circRNAs remains unknown. In the present study, the expression, function and molecular mechanisms of a new circRNA, circRNA_103615, were investigated in NSCLC. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect circRNA_103615 expression levels in NSCLC and normal tissues, as well as in NSCLC cell lines. MTT assay, flow cytometric assay, colony formation assay, and cell migration and invasion assays were used to examine the function of circRNA_103615 in NSCLC cells. MTT assay, colony formation assay, RT-qPCR, and western blotting were used to detect the effect of circRNA_103615 on cisplatin resistance. The results demonstrated that NSCLC cell lines and tissues had increased levels of circRNA_103615 compared with normal cells and normal tissues, respectively. Functionally, silencing of circRNA_103615 by small interfering RNA resulted in suppression of cell growth, migration, and invasion, but promotion of cell apoptosis. In addition, the cisplatin resistance of NSCLC was reversed by the silencing of circRNA_103615. Notably, ATP binding cassette subfamily Bmember 1 (ABCB1) expression was significantly decreased following circRNA_103615 knockdown, and ABCB1 overexpression reversed the effects of circRNA_103615 silencing on NSCLC cisplatin resistance. Thus, the present study indicated that circRNA_103615 may serve as a critical oncogene and potential novel biomarker in NSCLC, as well as a potential cisplatin resistance promoter, by regulating ABCB1 expression.
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Project description:Background Ovarian cancer recurrence and chemotherapy resistance are still urgent issues, and exploring the mechanisms of metastasis and chemotherapy resistance is beneficial to the development of therapeutic methods. Caspase recruitment domain family member 9 (CARD9) and homeobox B5 (HOXB5) are related and both are upregulated in ovarian cancer. This study aimed to define their functions in ovarian cancer cell proliferation, migration, and cisplatin sensitivity. Results The levels of CARD9 were detected in acquired ovarian cancer tissues and cell lines. CARD9 was indeed abnormally upregulated in them. CARD9 knockdown significantly suppressed cell proliferation, colony formation, migration, cycle arrest, and cisplatin sensitivity. HOXB5 bound to the CARD9 promoter, and HOXB5 overexpression reversed the regulation by CARD9 knockdown in cells, as well as the activation of NF-κB signaling. This indicated that CARD9 was positively regulated by HOXB5 in ovarian cancer cells. Conclusion Together, CARD9 is involved in ovarian cancer cell proliferation, migration, and cisplatin sensitivity via NF-κB signaling after transcriptional activation by HOXB5. Supplementary Information The online version contains supplementary material available at 10.1186/s12860-022-00447-0.
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Project description:Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype and so far, no favorable therapeutic strategy has been established for chemo-resistant SCLC. Cisplatin is one of the most important components among all standard poly-chemotherapeutic regimens for SCLC; therefore, this study focused on revealing Cisplatin-resistance mechanism(s) in this disease. Cisplatin-resistant SCLC cells were generated in the NCI-H69 xenograft model in nude mice by continuous intravenous administration of Cisplatin; Cisplatin resistance of the tumor cells was confirmed by in vitro and in vivo tests, and the gene expression profile of the resistant cells was determined using microarray analysis. A significantly higher expression of tribbles pseudokinase 2 (TRIB2) mRNA in the Cisplatin-resistant cells was found compared to parental H69 cells. Further, the Cisplatin-resistance level was decreased when TRIB2 expression was knocked down. The mRNA and protein levels of CCAAT/enhancer binding protein alpha (CEBPA), known to be a transcription factor regulating cell differentiation and a target for degradation by TRIB2, as well as selected cancer stem cell makers in the Cisplatin-resistant cells, were measured. We found that CEBPA protein levels could be upregulated by knocking down the overexpressed TRIB2, which also reversed the Cisplatin-resistance of these cells; further, the Cisplatin-resistant SCLC cells demonstrated certain cancer stem cell-like properties. Similar patterns were also observed in limited human tumor specimens of chemo-resistant SCLC patients: namely, overexpressed TRIB2 and undetected CEBPA proteins. Our study revealed a possible molecular mechanism for Cisplatin-resistant SCLC involving induced TRIB2 overexpression and downregulation of CEBPA protein. We propose that this mechanism is a potential therapeutic target to circumvent chemo-resistance in SCLC.
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Project description:The PHD zinc finger protein Jade-1S is a component of the HBO1 histone acetyltransferase complex and binds chromatin in a cell cycle-dependent manner. Jade-1S also acts as an E3 ubiquitin ligase for the canonical Wnt effector protein ?-catenin and is influenced by CK1?-mediated phosphorylation. To further elucidate the functional impact of this phosphorylation, we used a stable, low-level expression system to express either wild-type or mutant Jade-1S lacking the N-terminal CK1? phosphorylation motif. Interactome analyses revealed that the Jade-1S mutant unable to be phosphorylated by CK1? has an increased binding affinity to proteins involved in chromatin remodelling, histone deacetylation, transcriptional repression, and ribosome biogenesis. Interestingly, cells expressing the mutant displayed an elongated cell shape and a delay in cell cycle progression. Finally, phosphoproteomic analyses allowed identification of a Jade-1S site phosphorylated in the presence of CK1? but closely resembling a PLK1 phosphorylation motif. Our data suggest that Jade-1S phosphorylation at an N-terminal CK1? motif creates a PLK1 phospho-binding domain. We propose CK1? phosphorylation of Jade 1S to serve as a molecular switch, turning off chromatin remodelling functions of Jade-1S and allowing timely cell cycle progression. As Jade-1S protein expression in the kidney is altered upon renal injury, this could contribute to understanding mechanisms underlying epithelial injury repair.
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Project description:MicroRNAs (miRs) have been reported to be associated with the development of numerous types of cancer. However, the function of miRs in human ovarian carcinoma chemoresistance remains largely undefined. In the present study, cell chemotherapy combined with a Cell Counting Kit-8 assay demonstrated that miR-20a performed important roles in ovarian cancer cells chemoresistance. Flow cytometry, cellular proliferation assays and Transwell assays results revealed that the proliferation and migration rates of OVCAR3/DDP cells were increased in comparison with parental cells. Western blot analysis results suggested that epithelial-mesenchymal transition (EMT) activated by miR-20a contributed to OVCAR3/DDP cell migration. The present study highlighted the importance of miR-20a in regulating the chemoresistant properties of OVCAR3 cells and promoting cisplatin-resistant cell migration by activating EMT. The results of present study may therefore provide novel insights into reversing the chemoresistance of ovarian cancer and improving its treatment.
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Project description:This study is to investigate transcription factors involved in cisplatin resistance in ovarian cancer cells. The transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372. Ovarian transcriptome data GSE62944 was downloaded from TCGA and applied for transcription regulatory network analysis. The analysis results were confirmed using quantitative polymerase chain reaction. The roles of SREBP2 in cisplatin-resistant cells were investigated by RNA inference and cell viability analysis. Transcription regulatory network analysis found that 12 transcription factors and their targets were involved in cisplatin resistant in A2780 cells. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes between cisplatin resistant and cisplatin sensitive cells. Their targets were enriched mainly in cell cycle and cholesterol metabolic process, respectively. Bioinformatic analysis illustrated three known targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines. Additionally, the three genes and SREBP2 were also elevated in live cells after cisplatin treatment via quantitative polymerase chain reaction. Importantly, RNA inference of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and cholesterol metabolic process might be a novel target for cancer therapy. Impact statement Transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372 and TCGA. Twelve transcription factors and their targets were involved in cisplatin resistant. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes. Their targets were enriched mainly in cell cycle and cholesterol metabolic process. Three targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines and were found elevated in live cells after cisplatin treatment via qPCR. RNAi of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and might be a novel target for cancer therapy.
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Project description:Lung cancer is one of the leading causes of cancer mortality worldwide. The therapeutic effect of chemotherapy is limited due to the resistance of cancer cells, which remains a challenge in cancer therapeutics. In this work, we found that flap endonuclease 1 (FEN1) is overexpressed in lung cancer cells. FEN1 is a major component of the base excision repair pathway for DNA repair systems and plays important roles in maintaining genomic stability through DNA replication and repair. We showed that FEN1 is critical for the rapid proliferation of lung cancer cells. Suppression of FEN1 resulted in decreased DNA replication and accumulation of DNA damage, which subsequently induced apoptosis. Manipulating the amount of FEN1 altered the response of lung cancer cells to chemotherapeutic drugs. A small-molecule inhibitor (C20) was used to target FEN1 and this enhanced the therapeutic effect of cisplatin. The FEN1 inhibitor significantly suppressed cell proliferation and induced DNA damage in lung cancer cells. In mouse models, the FEN1 inhibitor sensitized lung cancer cells to a DNA damage-inducing agent and efficiently suppressed cancer progression in combination with cisplatin treatment. Our study suggests that targeting FEN1 may be a novel and efficient strategy for a tumor-targeting therapy for lung cancer.
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