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AID modulates carcinogenesis network via DNA demethylation in bladder urothelial cell carcinoma.

ABSTRACT: Bladder cancer is one of the most common malignant diseases in the urinary system, with poor survival after metastasis. Activation-induced cytidine deaminase (AID), a versatile enzyme involved in antibody diversification, is an oncogenic gene that induces somatic hypermutation and class-switch recombination (CSR). However, the contribution of AID-mediated DNA demethylation to bladder urothelial cell carcinoma (BUCC) remains unclear. Herein, we evaluated the impact on BUCC caused by AID and explored the gene network downstream of AID by using a proteomic approach. Lentiviral vector containing AID-specific shRNA significantly reduced AID expression in T24 and 5637 cells. Silencing AID expression remarkably inhibited tumour malignancies, including cell proliferation, invasion and migration. We used Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics analysis technology to study the underpinning mechanism in monoclonal T24 cells, with or without AID knockdown. Among the 6452 proteins identified, 99 and 142 proteins in shAICDA-T24 cells were significantly up- or downregulated, respectively (1.2-fold change) compared with the NC-T24 control. After a pipeline of bioinformatics analyses, we identified three tumour-associated factors, namely, matrix metallopeptidase 14 (MMP14), C-X-C motif chemokine ligand 12 and wntless Wnt ligand secretion mediator, which were further confirmed in human BUCC tissues. Nonetheless, only MMP14 was sensitive to the DNA demethylation molecule 5-aza-2'-deoxycytidine (5-azadC; 5??M), which reversed the inhibition of carcinogenesis by AID silence in T24 and 5637 cells. Overall, AID is an oncogene that mediates tumourigenesis via DNA demethylation. Our findings provide novel insights into the clinical treatment for BUCC.

SUBMITTER: Li H

PROVIDER: S-EPMC6420503 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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AID modulates carcinogenesis network via DNA demethylation in bladder urothelial cell carcinoma.

Li Haoyong H Li Qi Q Ma Zhe Z Zhou Zhiyan Z Fan Jinfeng J Jin Yingxia Y Wu Yaoxi Y Cheng Fan F Liang Peiyu P

Cell death & disease 20190315 4

Bladder cancer is one of the most common malignant diseases in the urinary system, with poor survival after metastasis. Activation-induced cytidine deaminase (AID), a versatile enzyme involved in antibody diversification, is an oncogenic gene that induces somatic hypermutation and class-switch recombination (CSR). However, the contribution of AID-mediated DNA demethylation to bladder urothelial cell carcinoma (BUCC) remains unclear. Herein, we evaluated the impact on BUCC caused by AID and explo ...[more]

PMID: 30874539

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Project description:BackgroundDifferent genomic characterization in urothelial carcinoma (UC) by site of origin may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity.Materials and methodsWe prospectively sequenced 118 tumors and matched blood DNA from Chinese patients with UC using next-generation sequencing techniques, including 45 UTUC and 73 UCB. Two hundred twenty-six patients with UTUC and 350 patients with UCB for The Cancer Genome Atlas were acquired from the cbioportal.ResultsThere were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared with UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. Patients with UTUC had lower PD-L1 than those with UCB. There was no significant difference in the number of DDR mutations, copy number variation counts, and tumor mutational burden between UTUC and UCB.ConclusionUTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.Implications for practiceThis study's findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.

Dataset Information

AID modulates carcinogenesis network via DNA demethylation in bladder urothelial cell carcinoma.

Publications

AID modulates carcinogenesis network via DNA demethylation in bladder urothelial cell carcinoma.

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