Dataset Information

Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells.

ABSTRACT:

Background

To investigate the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer.

Methods

We assessed three bladder cancer cell lines (5637, J82, and TCCSUP) for their sensitivity to chemoradiotherapy. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression of specific genes after chemoradiotherapy or combined with olaparib. The Genome Cancer Atlas (TGCA) database was used to analyze possible radioresistance-related genes and the relationship between their expression and bladder cancer survival and prognostic indicators.

Results

The 5637 cell line showed the most significant sensitivity to chemoradiotherapy. The expression levels of DNA damage repair genes in 5637 cells did not significantly change after chemoradiotherapy. In contrast, the expression levels of BRCA1 and RBBP8 genes significantly increased in J82 and TCCSUP cells after chemoradiotherapy. After combination with olaparib, which is a poly (ADP-ribose) polymerase inhibitor that initiates DNA repair, 5637 cells were significantly inhibited by chemoradiotherapy. However, chemoradiotherapy inhibition on J82 cells was weakened when combined with olaparib. A high reactive expression of BRCA1 and RBBP8 after combination with olaparib suggested that olaparib was ineffective because it did not induce synthetic lethality in which inhibiting PARP by olaparib coincided with suppression of BRCA1/2 expression result in cancer cell death.

Conclusions

The expression levels of RBBP8 and BRCA1 genes were associated with sensitivity to radiotherapy and chemotherapy in bladder cancer, and an increase in reactive expression after treatment led to worse sensitivity. Therefore, the reactive expression levels of BRCA1 and RBBP8 after chemoradiotherapy may be useful in evaluating the efficacy of olaparib combination therapy.

SUBMITTER: Sun S

PROVIDER: S-EPMC9547156 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells.

Sun Shujun S Jiang Kehua K Zeng Jin J

Translational andrology and urology 20220901 9

<h4>Background</h4>To investigate the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer.<h4>Methods</h4>We assessed three bladder cancer cell lines (5637, J82, and TCCSUP) for their sensitivity to chemoradiotherapy. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression of specific genes after chemoradiotherapy or combined with olaparib. The Genome Cancer Atlas (TGCA) database was used to analyze possible radioresistance-related gene ...[more]

PMID: 36217404

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Project description:Bladder cancer (BCa) is the tenth most common tumor in humans. DNA damage repair genes (DDRGs) play important roles in many malignant tumors; thus, their functions in BCa should also be explored. We performed a comprehensive analysis of the expression profiles of DDRGs in 410 BCa tumors and 19 normal tissues from The Cancer Genome Atlas database. We identified 123 DDRGs differentially expressed between BCa tumors and normal tissues, including 95 upregulated and 28 downregulated genes. We detected 22 DDRGs associated with overall survival (OS) of patients with BCa by performing univariate Cox regression analysis. To explore the interactions between OS-associated DDRGs, we constructed a PPI network, which showed that the top six DDRGs (CDCA2, FOXM1, PBK, RRM2, ORC1, and HDAC4) with the highest scores in the PPI network might play significant roles in OS of BCa. Moreover, to investigate the latent regulatory mechanism of these OS-associated DDRGs, we analyzed the transcription factors (TFs)-DDRGs regulatory network. The core seven TFs (NCAPG, DNMT1, LMNB1, BRCA1, E2H2, CENPA, and E2F7) were shown to be critical regulators of the OS-related DDRGs. The 22 DDRGs were incorporated into a stepwise multivariable Cox analysis. Then, we built the index of risk score based on the expression of 8 DDRGs (CAD, HDAC10, JDP2, LDLR, PDGFRA, POLA2, SREBF1, and STAT1). The p-value < 0.0001 in the Kaplan-Meier survival plot and an area under the ROC curve (AUC) of 0.771 in TCGA-BLCA training dataset suggested the high specificity and sensitivity of the prognostic index. Furthermore, we validated the risk score in the internal TCGA-BLCA and an independent GSE32894 dataset, with AUC of 0.743 and 0.827, respectively. More importantly, the multivariate Cox regression and stratification analysis demonstrated that the predictor was independent of various clinical parameters, including age, tumor stage, grade, and number of positive tumor lymph nodes. In summary, a panel of 8 DNA damage repair genes associated with overall survival in bladder cancer may be a useful prognostic tool.

Project description:BackgroundChemicals from occupational exposure and components of cigarette smoke can cause DNA damage in bladder urothelium. Failure to repair DNA damage by DNA repair proteins may result in mutations leading to genetic instability and the development of bladder cancer. Immunohistochemistry studies have shown DNA damage signal activation in precancerous bladder lesions which is lost on progression, suggesting that the damage signalling mechanism acts as a brake to further tumorigenesis. Single nucleotide polymorphisms (SNPs) in DSB signalling genes may alter protein function. We hypothesized that SNPs in DSB signalling genes may modulate predisposition to bladder cancer and influence the effects of environmental exposures.MethodsWe recruited 771 cases and 800 controls (573 hospital-based and 227 population-based from a previous case-control study) and interviewed them regarding their smoking habits and occupational history. DNA was extracted from a peripheral blood sample and genotyping of 24 SNPs in MRE11, NBS1, RAD50, H2AX and ATM was undertaken using an allelic discrimination method (Taqman).ResultsSmoking and occupational dye exposure were strongly associated with bladder cancer risk. Using logistic regression adjusting for age, sex, smoking and occupational dye exposure, there was a marginal increase in risk of bladder cancer for an MRE11 3'UTR SNP (rs2155209, adjusted odds ratio 1.54 95% CI (1.13-2.08, p = 0.01) for individuals homozygous for the rare allele compared to those carrying the common homozygous or heterozygous genotype). However, in the hospital-based controls, the genotype distribution for this SNP deviated from Hardy-Weinberg equilibrium. None of the other SNPs showed an association with bladder cancer and we did not find any significant interaction between any of these polymorphisms and exposure to smoking or dye exposure.ConclusionApart from a possible effect for one MRE11 3'UTR SNP, our study does not support the hypothesis that SNPs in DSB signaling genes modulate predisposition to bladder cancer.

Dataset Information

Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells.

Background

Methods

Results

Conclusions

Publications

Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells.

Similar Datasets

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