期刊
CANCER RESEARCH
卷 81, 期 22, 页码 5638-5651出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-1201
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资金
- National Science Fund for Distinguished Young Scholars [81725015]
- Medical and Health Technology Innovation Project of Chinese Academy of Medical Sciences [2016-I2M-3-019, 2016-I2M-4-002, 2019-I2M-2-001, 2016-I2M-1-001, 2019-12M-1-003]
- Beijing Outstanding Young Scientist Program [BJJWZYJH01201910023027]
- National Natural Science Foundation of China [81988101]
- Department of Biochemistry and Molecular Biology at UTMB
High-throughput analysis revealed that the recurrent shortening of the BID 3'UTR is a driver of disease progression in esophageal squamous cell carcinoma.
The majority of human genes have multiple polyadenylation sites, which are differentially used through the process of alternative polyadenylation (APA). Dysregulation of APA contributes to numerous diseases, including cancer. However, specific genes subject to APA that impact oncogenesis have not been well characterized, and many cancer APA landscapes remain under-explored. Here, we used dynamic analyses of APA from RNA-seq (DaPars) to define both the 3'UTR APA profile in esophageal squamous cell carcinoma (ESCC) and to identify 3'UTR shortening events that may drive tumor progression. In four distinct squamous cell carcinoma datasets, BID 3'UTRs were recurrently shortened and BID mRNA levels were significantly upregulated. Moreover, system correlation analysis revealed that CstF64 is a candidate upstream regulator of BID 3'UTR length. Mechanistically, a shortened BID 3'UTR promoted proliferation of ESCC cells by disrupting competing endogenous RNA (ceRNA) cross-talk, resulting in downregulation of the tumor suppressor gene ZFP36L2. These in vitro and in vivo results were supported by human patient data whereby 3'UTR shortening of BID and low expression of ZFP36L2 are prognostic factors of survival in ESCC. Collectively, these findings demonstrate that a key ceRNA network is disrupted through APA and promotes ESCC tumor progression. Significance: High-throughput analysis of alternative polyadenylation in esophageal squamous cell carcinoma identifies recurrent shortening of the BID 3'UTR as a driver of disease progression.
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