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  2. APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly

APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly

  • Adv Sci (Weinh). 2022 Oct;9(28):e2201889. doi: 10.1002/advs.202201889.
Qiang Wang 1 2 Chen Chen 3 Xiao Xu 4 Chuanjun Shu 5 Changchang Cao 6 Zhangding Wang 7 Yao Fu 8 Lei Xu 7 Kaiyue Xu 1 Jiawen Xu 3 Anliang Xia 1 Bo Wang 1 Guifang Xu 7 Xiaoping Zou 7 Ruibao Su 6 Wei Kang 9 Yuanchao Xue 6 Ran Mo 4 Beicheng Sun 1 2 Shouyu Wang 1 3 10
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China.
  • 2 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 3 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210000, China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210000, China.
  • 5 Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 210000, China.
  • 6 Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 7 Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China.
  • 8 Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, China.
  • 9 Department of Anatomical and Cellular Pathology, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, 999077, China.
  • 10 Center for Public Health Research, Medical School of Nanjing University, Nanjing, 210000, China.
Abstract

Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease-activating factor 1 (APAF1)-binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell Apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA-binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3-mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase-9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.

Keywords

ABL; IGF2BP1; apoptosis; apoptotic protease-activating factor 1 (APAF1); drug resistance; gastric cancer; m6A.

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