SNHG15-mediated feedback loop interplays with HNRNPA1/SLC7A11/GPX4 pathway to promote gastric cancer progression.

Autor: Duan Y; Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China., Yan Y; Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China., Fu H; Department of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China., Dong Y; Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China., Li K; Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China., Ye Z; Department of Gastrointestinal Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China., Dou Y; Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China., Huang B; Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China., Kang W; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China., Wei GH; Fudan University Shanghai Cancer Center; MOE Key Laboratory of Metabolism and Molecular Medicine & Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China., Cai Q; MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China., Xu D; Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China., Zhou D; Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2024 Jul; Vol. 115 (7), pp. 2269-2285. Date of Electronic Publication: 2024 May 08.
DOI: 10.1111/cas.16181
Abstrakt: Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.
(© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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