Exosomal lncRNA ROR1-AS1 from cancer-associated fibroblasts inhibits ferroptosis of lung cancer cells through the IGF2BP1/SLC7A11 signal axis

Fei Yao; Yongxiang Zhao; Guangyao Wang; Mei Zhao; Xiaohua Hong; Zhifu Ye; Fuqiang Dong; Wanjin Li; Qianyu Deng

doi:10.1016/j.cellsig.2024.111221

Exosomal lncRNA ROR1-AS1 from cancer-associated fibroblasts inhibits ferroptosis of lung cancer cells through the IGF2BP1/SLC7A11 signal axis

Cell Signal. 2024 May 8:120:111221. doi: 10.1016/j.cellsig.2024.111221. Online ahead of print.

Authors

Fei Yao¹, Yongxiang Zhao², Guangyao Wang³, Mei Zhao³, Xiaohua Hong⁴, Zhifu Ye⁵, Fuqiang Dong⁶, Wanjin Li⁶, Qianyu Deng⁶

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530203, Guangxi Zhuang Autonomous Region, PR China. Electronic address: yaofei@sr.gxmu.edu.cn.
² National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China.
³ Department of Respiratory and Critical Care, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530203, Guangxi Zhuang Autonomous Region, PR China.
⁴ College of Pharmacy, Guangxi Medical University, Nanning 530203, Guangxi Zhuang Autonomous Region, PR China.
⁵ Department of Oncology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530203, Guangxi Zhuang Autonomous Region, PR China.
⁶ The First Clinical Faculty, Guangxi University of Chinese Medicine, Nanning 530203, Guangxi Zhuang Autonomous Region, PR China.

PMID: 38729321
DOI: 10.1016/j.cellsig.2024.111221

Abstract

Background: Targeting ferroptosis is a potential strategy for cancer treatment. Activated cancer-associated fibroblasts (CAFs) can affect the progression of lung cancer through exosomes. This study investigated the mechanism by which exosomal lncRNA ROR1-AS1 derived from CAFs affects ferroptosis of lung cancer cells.

Methods: CAFs were identified by western blot and immunofluorescence. Exosomes derived from CAFs (CAF-exo) were analyzed by transmission electron microscope, nanoparticle tracking analysis and western blot. The expression levels of ROR1-AS1, IGF2BP1 and SLC7A11 in lung cancer were analyzed by bioinformatics analysis and detected by qPCR and western blot. The lung cancer cells were treated with Erastin and/or CAF-exo, then cell viability was detected by cell counting kit-8, and the ferroptosis-related indicators were detected by corresponding kits. The relationship between IGF2BP1 and ROR1-AS1 or SLC7A11 was determined by RNA pull down and RNA immunoprecipitation, and their effects on cell ferroptosis were confirmed by rescue experiments. Xenotransplantation experiment was used to determine the effect of CAF-exo on tumor growth and ferroptosis in vivo. Immunohistochemistry was used to identify the Ki-67 and 4-HNE expression.

Results: ROR1-AS1, IGF2BP1 and SLC7A11 were upregulated in lung cancer and indicated poor prognosis. LncRNA ROR1-AS1 increased the stability of SLC7A11 mRNA by interacting with IGF2BP1. Exosomal ROR1-AS1 from CAFs inhibited ferroptosis of lung cancer cells in vitro and in vivo. The effect of ROR1-AS1 overexpression or IGF2BP1 overexpression on ferroptosis of lung cancer cells was partially reversed by IGF2BP1 silencing or SLC7A11 inhibition.

Conclusions: CAFs secrete exosomal ROR1-AS1 to promote the expression of SLC7A11 by interacting with IGF2BP1, thereby inhibiting ferroptosis of lung cancer cells.

Keywords: Exosomes; Ferroptosis; Lung cancer; cancer-associated fibroblasts; lncRNA ROR1-AS1.