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Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma.

ABSTRACT: Drug resistance and disease recurrence are important contributors for the poor prognosis of glioblastoma multiforme (GBM). Temozolomide (TMZ), the standard chemotherapy for GBM treatment, can methylate DNA and cause the formation of double-strand breaks (DSBs). X-ray repair cross complementing 5 (XRCC5), also known as Ku80 or Ku86, is required for the repair of DSBs. The present study identified novel determinants that sensitize cells to TMZ, using an array-based short hairpin (sh)RNA library. Then, cBioportal, Oncomine, and R2 databases were used to analyze the association between gene expression levels and clinical characteristics. Subsequently, lentiviral shRNA or pCMV was used to knockdown or overexpress the gene of interest, and the effects on TMZ sensitivity were determined using a MTT assay and western blot analysis. TMZ-resistant cells were also established and were used in in vitro and in vivo experiments to analyze the role of the gene of interest in TMZ resistance. The results indicated that XRCC5 was effective in enhancing TMZ cytotoxicity. The results from the bioinformatics analysis revealed that XRCC5 mRNA expression levels were associated with clinical deterioration and lower overall survival rates. In addition, XRCC5 knockdown could significantly increase TMZ sensitivity in GBM cells, while XRCC5 overexpression caused the cancer cells to be resistant to TMZ. Both the in vivo and in vitro experiments showed that TMZ treatment could induce expression of XRCC5 in TMZ-resistant cells. Taken together these findings suggested that XRCC5 could be a promising target for GBM treatment and could also be used as a diagnostic marker for refractory GBM.

SUBMITTER: Lee IN

PROVIDER: S-EPMC8045174 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOur previous studies have indicated that miR-198 reduces cellular methylguanine DNA methyltransferase (MGMT) levels to enhance temozolomide sensitivity. Transforming growth factor beta 1 (TGF-β1) switches off miR-198 expression by repressing K-homology splicing regulatory protein (KSRP) expression in epidermal keratinocytes. However, the underlying role of TGF-β1 in temozolomide resistance has remained unknown.MethodsThe distribution of KSRP was detected by western blotting and immunofluorescence. Microarray analysis was used to compare the levels of long noncoding RNAs (lncRNAs) between TGF-β1-treated and untreated cells. RNA immunoprecipitation was performed to verify the relationship between RNAs and KSRP. Flow cytometry and orthotopic and subcutaneous xenograft tumor models were used to determine the function of TGF-β1 in temozolomide resistance.ResultsOverexpression of TGF-β1 contributed to temozolomide resistance in MGMT promoter hypomethylated glioblastoma cells in vitro and in vivo. TGF-β1 treatment reduced cellular MGMT levels through suppressing the expression of miR-198. However, TGF-β1 upregulation did not affect KSRP expression in glioma cells. We identified and characterized 2 lncRNAs (H19 and HOXD-AS2) that were upregulated by TGF-β1 through Smad signaling. H19 and HOXD-AS2 exhibited competitive binding to KSRP and prevented KSRP from binding to primary miR-198, thus decreasing miR-198 expression. HOXD-AS2 or H19 upregulation strongly promoted temozolomide resistance and MGMT expression. Moreover, KSRP depletion abrogated the effects of TGF-β1 and lncRNAs on miR-198 and MGMT. Finally, we found that patients with low levels of TGF-β1 or lncRNA expression benefited from temozolomide therapy.ConclusionsOur results reveal an underlying mechanism by which TGF-β1 confers temozolomide resistance. Furthermore, our findings suggest that a novel combination of temozolomide with a TGF-β inhibitor may serve as an effective therapy for glioblastomas.

Project description:Background: Glioblastoma (GBM) prognosis remains extremely poor despite standard treatment that includes temozolomide (TMZ) chemotherapy. To discover new GBM drug targets and biomarkers, genes signatures associated with survival and TMZ resistance in GBM patients treated with TMZ were identified. Methods: GBM cases in The Cancer Genome Atlas who received TMZ (n = 221) were stratified into subgroups that differed by median overall survival (mOS) using network-based stratification to cluster patients whose somatic mutations affected genes in similar modules of a gene interaction network. Gene signatures formed from differentially mutated genes in the subgroup with the longest mOS were used to confirm their association with survival and TMZ resistance in independent datasets. Somatic mutations in these genes also were assessed for an association with OS in an independent group of 37 GBM cases. Results: Among the four subgroups identified, subgroup four (n = 71 subjects) exhibited the longest mOS at 18.3 months (95% confidence interval: 16.2, 34.1; p = 0.0324). Subsets of the 86 genes that were differentially mutated in this subgroup formed 20-gene and 8-gene signatures that predicted OS in two independent datasets (Spearman's rho of 0.64 and 0.58 between actual and predicted OS; p < 0.001). Patients with mutations in five of the 86 genes had longer OS in a small, independent sample of 37 GBM cases, but this association did not reach statistical significance (p = 0.07). Thirty-one of the 86 genes formed signatures that distinguished TMZ-resistant GBM samples from controls in three independent datasets (area under the curve ≥ 0.75). The prognostic and TMZ-resistance signatures had eight genes in common (ANG, BACH1, CDKN2C, HMGA1, IFI16, PADI4, SDF4, and TP53INP1). The latter three genes have not been associated with GBM previously. Conclusion: PADI4, SDF4, and TP53INP1 are novel therapy and biomarker candidates for GBM. Further investigation of their oncologic functions may provide new insight into GBM treatment resistance mechanisms.

Project description:BackgroundMedullary thyroid carcinoma (MTC) patients have poor survival, tumor/node/metastasis (TNM) stage and biochemical prognosis are the most important factors. We investigated the clinical significance of calcitonin (Ctn) to assess the biochemical prognosis of MTC.MethodsThis retrospective observational study enrolled 77 MTC patients with complete information and primary surgery at the Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University between 2009 and 2020. Patient and MTC characteristics were recorded. All patients were divided into remission, stable, and progression according to biochemical prognosis. We analyzed the correlation between preoperative serum Ctn, TNM stage and biochemical prognosis.ResultsElevated preoperative serum Ctn was positively correlated with TNM stage. Patients with higher Ctn, multifocality, and bilateral tumors were associated with a higher TNM stage. Multivariate logistic regression analysis showed that preoperative serum Ctn level was an independent risk factor for TNM stage. Receiver operating characteristic (ROC) analysis found the best Ctn cut-off value for predicting TNM III was 45.88 pg/mL, which had a sensitivity of 87.2% and a specificity of 65.8%. The best Ctn cut-off value for predicting TNM IV was 167.00 pg/mL, with a sensitivity of 92.9% and a specificity of 77.6%. In univariate analysis, patients with higher preoperative serum Ctn, multifocality, bilateral tumors, and higher TNM stage were more likely to progress. The optimal cut-off value for progression was 195.5 pg/mL, which had a sensitivity of 80.0% and a specificity of 70.2%. For every 1-unit increase in preoperative serum Ctn levels, the risk of progression increased by 1.004 times (P=0.008), and patients with TNM stage III [hazard ratio (HR) =9.663; 95% confidence interval (CI): 1.411, 66.156] were nearly 9.7-fold more likely to progress than those in TNM stage I/II.ConclusionsElevated preoperative serum Ctn predicted poor clinical outcomes in MTC.

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Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma.

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