2. Academic Validation
  3. CPSF3 regulates alternative polyadenylation of CNIH2 to promote esophageal squamous cell carcinoma progression

CPSF3 regulates alternative polyadenylation of CNIH2 to promote esophageal squamous cell carcinoma progression

  • Cancer Lett. 2024 May 6:593:216925. doi: 10.1016/j.canlet.2024.216925.
Ying Zhang 1,  Dongchen Liu 2,  Dan Guo 3,  Wenting Lin 3,  Weiqing Lu 4,  Lan Hu 4,  Shuqin Chen 5,  Chuangzhen Chen 6
Affiliations

Affiliations

  • 1 Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China; Department of Clinical Research Center, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China. Electronic address: yzhangmimazi@stu.edu.cn.
  • 2 Department of Clinical Research Center, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China.
  • 3 Department of Pathology, Shantou University Medical College, No.22 Xinling Road, Shantou, Guangdong, 515041, China.
  • 4 Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China.
  • 5 Department of Pathology, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China.
  • 6 Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China. Electronic address: czchen2@stu.edu.cn.
PMID: 38718887 DOI: 10.1016/j.canlet.2024.216925
Abstract

Alternative polyadenylation (APA), an important post-transcriptional regulatory mechanism, is aberrantly activated in Cancer，but how APA functions in tumorigenesis remains elusive. We analyzed APA events in RNA-seq data in TCGA and reported 3'UTR alterations associated with esophageal squamous cell carcinoma (ESCC) patient prognosis and gene expression changes involving loss of tumor-suppressive miRNA binding sites. Moreover, we investigated the expression and function of cleavage and polyadenylation specific factor 3 (CPSF3), a key APA regulator in ESCC. By immunohistochemistry and qRT-PCR, we found that CPSF3 was highly expressed in ESCC tissues and associated with poor patient prognosis. Overexpression of CPSF3 enhanced, while knockdown of CPSF3 inhibited ESCC cell proliferation and migration in vitro and in vivo, as determined by colony formation, transwell assays and animal experiments. Iso-Seq and RNA-seq data analysis indicated that knockdown of CPSF3 favored use of the distal poly (A) site in the 3'UTR of Cornichon family AMPA Receptor auxiliary protein 2 (CNIH2), resulting in a long-3'UTR CNIH2 isoform that produced less CNIH2 protein due to miR-125a-5p targeting and downregulating CNIH2 mRNA through a miR-125a-5p binding site in the long CNIH2 mRNA 3'UTR. Moreover, CPSF3-induced ESCC tumorigenicity was mediated by CNIH2. Taken together, CPSF3 promotes ESCC progression by upregulating CNIH2 expression through loss of miR-125a-5p-mediated CNIH2 repression through alternative splicing and polyadenylation of the CNIH2 mRNA 3'UTR.

Keywords

Alternative polyadenylation; CNIH2; CPSF3; ESCC.

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