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TRIB2 contributes to cisplatin resistance in small cell lung cancer.

ABSTRACT: 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.

SUBMITTER: Liang Y

PROVIDER: S-EPMC5752545 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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TRIB2 contributes to cisplatin resistance in small cell lung cancer.

Liang Yuanxin Y Yu Dong D Perez-Soler Roman R Klostergaard Jim J Zou Yiyu Y

Oncotarget 20171127 65

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 ...[more]

PMID: 29312632

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Project description:BackgroundCisplatin (DDP) is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and long-term DDP stimulation increased resistance of NSCLC cells to this drug by enriching cancer stem cells (CSCs), which contributed to recurrence and worse prognosis of NSCLC, but the molecular mechanisms are still not fully delineated.MethodsReal-Time qPCR and Western Blot analysis were conducted to examine gene expressions at mRNA and protein levels, respectively. Dual-luciferase reporter gene system was used to validate the targeting sites among circRNA CDR1as, miR-641 and HOXA9 mRNA. Cell growth was evaluated by CCK-8 assay, trypan blue staining assay and colony formation assay. The Annexin V-FITC/PI double staining method was employed to measure cell apoptosis ratio. Spheroid formation and flow cytometer assay was used to evaluate cell stemness. Xenograft mice models were established to measure tumorgenicity in vivo, and Ki67 expressions in mice tumor tissues were examined by immunohistochemistry (IHC).ResultsHere we identified a novel circRNA CDR1as/miR-641/Homeobox protein Hox-A9 (HOXA9) pathway regulated stemness and DDP chemoresistance in NSCLC. Mechanistically, circRNA CDR1as and HOXA9 were high-expressed, while miR-641 was low-expressed in DDP-resistant NSCLC cells, instead of their corresponding parental DDP-sensitive NSCLC cells. Additionally, we validated that circRNA CDR1as positively regulated HOXA9 in NSCLC cells by serving as an RNA sponge for miR-641, and knock-down of circRNA CDR1as increased the sensitivity of DDP-resistant NSCLC cells, which were reversed by downregulating miR-641 and upregulating HOXA9. Consistently, overexpression of circRNA CDR1as increased drug resistance of DDP-sensitive NSCLC cells by regulating miR-641/HOXA9 axis. In addition, the expression levels of stemness signatures (SOX2, OCT4 and Nanog) were higher in DDP-resistant NSCLC cells, which also tended to form spheres and enrich CD44+CD166+ population compared to their parental DDP-sensitive NSCLC cells, suggesting that CSCs were enriched in DDP-resistant NSCLC cells. Notably, knock-down of circRNA CDR1as inhibited stemness of DDP-resistant NSCLC cells by inhibiting HOXA9 through upregulating miR-641.ConclusionsTaken together, this study identified that circRNA CDR1as regulated stemness and DDP chemoresistance in NSCLC cells by targeting miR-641/HOXA9 axis.

Project description:Background: Cisplatin is the basis of the primary treatment for SCLC chemotherapy. However, the limited objective response rate and definite drug resistance greatly restrict the clinical potential and therapeutic benefits of cisplatin use. Therefore, it is essential to identify biomarkers that can discern the sensitivity of SCLC patients to cisplatin treatment. Methods: We collected two SCLC cohorts treated with cisplatin that included mutation data, prognosis data and expression data. The sensitivity of cisplatin was evaluated by the pRRophetic algorithm. MCPcounter, quanTIseq, and xCell algorithms were used to evaluate immune cell score. GSEA and ssGSEA algorithms were used to calculate immune-related pathway scores. Univariate and multivariate Cox regression models were employed, and survival analysis was used to evaluate the prognostic value of the candidate genes. Results: MMP9-High is related to improved clinical prognoses of patients with SCLC (HR = 0.425, p = 0.0085; HR = 0.365, p = 0.0219). Multivariate results showed that MMP-High could be used as an independent predictor of the prognosis of SCLC after cisplatin treatment (HR = 0.216, p = 0.00153; HR = 0.352; p = 0.0199). In addition, MMP9-High displayed a significantly lower IC50 value of cisplatin and higher immunogenicity than MMP9-Low SCLC. Compared with MMP9-Low SCLC, MMP9-High included significantly increased levels of T-cells, cytoxic lymphocytes, B-cells, NK-cells, and dense cells (DCS). Similarly, the activity of cytokine binding, B-cell, NK-cell mediated immune response chemokine binding, and antigen presentation pathways in MMP9-High was significantly higher than that in MMP9-Low. Conclusion: In this study, we identified that MMP9-High could be potentially considered a novel biomarker used to ascertain the improved prognosis of SCLC patients after cisplatin treatment. Furthermore, we indicated that the tumor immune microenvironment of MMP9-High SCLC is mainly characterized by a large number of infiltrated activated immune cells as well as activated immune-related pathways.

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TRIB2 contributes to cisplatin resistance in small cell lung cancer.

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TRIB2 contributes to cisplatin resistance in small cell lung cancer.

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