2. Academic Validation
  3. hsa_circ_0007919 induces LIG1 transcription by binding to FOXA1/TET1 to enhance the DNA damage response and promote gemcitabine resistance in pancreatic ductal adenocarcinoma

hsa_circ_0007919 induces LIG1 transcription by binding to FOXA1/TET1 to enhance the DNA damage response and promote gemcitabine resistance in pancreatic ductal adenocarcinoma

  • Mol Cancer. 2023 Dec 4;22(1):195. doi: 10.1186/s12943-023-01887-8.
Lei Xu # 1 2 3,  Xiao Ma # 1 2 4,  Xiuzhong Zhang # 1,  Chong Zhang 1,  Yi Zhang 1,  Shuai Gong 1,  Nai Wu 1,  Peng Zhang 1 2 5,  Xinyu Feng 1 2,  Jiaxuan Guo 1 2,  Mengmeng Zhao 1 2,  Zeqiang Ren 6,  Pengbo Zhang 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 2 Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China.
  • 3 Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, China.
  • 4 Department of General Surgery, Xuzhou First People's Hospital, Xuzhou, China.
  • 5 Department of General Surgery, Shangqiu Municipal Hospital, Shangqiu, China.
  • 6 Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. rzq0805@163.com.
  • 7 Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. zpb_ok@126.com.
  • # Contributed equally.
PMID: 38044421 DOI: 10.1186/s12943-023-01887-8
Abstract

Background: Circular RNAs (circRNAs) play important roles in the occurrence and development of Cancer and chemoresistance. DNA damage repair contributes to the proliferation of Cancer cells and resistance to chemotherapy-induced Apoptosis. However, the role of circRNAs in the regulation of DNA damage repair needs clarification.

Methods: RNA Sequencing analysis was applied to identify the differentially expressed circRNAs. qRT-PCR was conducted to confirm the expression of hsa_circ_0007919, and CCK-8, FCM, single-cell gel electrophoresis and IF assays were used to analyze the proliferation, Apoptosis and gemcitabine (GEM) resistance of pancreatic ductal adenocarcinoma (PDAC) cells. Xenograft model and IHC experiments were conducted to confirm the effects of hsa_circ_0007919 on tumor growth and DNA damage in vivo. RNA Sequencing and GSEA were applied to confirm the downstream genes and pathways of hsa_circ_0007919. FISH and nuclear-cytoplasmic RNA fractionation experiments were conducted to identify the cellular localization of hsa_circ_0007919. ChIRP, RIP, Co-IP, ChIP, MS-PCR and luciferase reporter assays were conducted to confirm the interaction among hsa_circ_0007919, FOXA1, TET1 and the LIG1 promoter.

Results: We identified a highly expressed circRNA, hsa_circ_0007919, in GEM-resistant PDAC tissues and cells. High expression of hsa_circ_0007919 correlates with poor overall survival (OS) and disease-free survival (DFS) of PDAC patients. Hsa_circ_0007919 inhibits the DNA damage, accumulation of DNA breaks and Apoptosis induced by GEM in a LIG1-dependent manner to maintain cell survival. Mechanistically, hsa_circ_0007919 recruits FOXA1 and TET1 to decrease the methylation of the LIG1 promoter and increase its transcription, further promoting base excision repair, mismatch repair and nucleotide excision repair. At last, we found that GEM enhanced the binding of QKI to the introns of hsa_circ_0007919 pre-mRNA and the splicing and circularization of this pre-mRNA to generate hsa_circ_0007919.

Conclusions: Hsa_circ_0007919 promotes GEM resistance by enhancing DNA damage repair in a LIG1-dependent manner to maintain cell survival. Targeting hsa_circ_0007919 and DNA damage repair pathways could be a therapeutic strategy for PDAC.

Keywords

DNA damage repair; LIG1; Pancreatic ductal adenocarcinoma; QKI; hsa_circ_0007919.

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