CAF Secreted MiR-522 Suppresses Ferroptosis and Promotes Acquired Chemo-resistance in Gastric Cancer

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2020 Feb 29

PMID 32106859

Citations 472

Authors

Haiyang Zhang

Ting Deng

Rui Liu

Tao Ning

Haiou Yang

Dongying Liu

Qiumo Zhang

Dan Lin

Shaohua Ge

Ming Bai

Xinyi Wang

Le Zhang

Hongli Li

Yuchong Yang

Zhi Ji

Hailong Wang

Guoguang Ying

Yi Ba

Affiliations

Soon will be listed here.

Abstract

Background: Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic.

Methods: Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential.

Results: Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity.

Conclusions: The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC.

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References

Hughes R, Simons B, Khan H, Miller R, Kugler V, Torquato S . Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression. Cancer Res. 2019; 79(14):3636-3650. PMC: 6734938. DOI: 10.1158/0008-5472.CAN-18-2931. View

Ou Y, Wang S, Li D, Chu B, Gu W . Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci U S A. 2016; 113(44):E6806-E6812. PMC: 5098629. DOI: 10.1073/pnas.1607152113. View

Shi Y, Qi B, Liu X, Ding H . Upregulation of miR-522 is associated with poor outcome of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2016; 20(15):3194-8. View

Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C . Ferroptosis: A Novel Anti-tumor Action for Cisplatin. Cancer Res Treat. 2017; 50(2):445-460. PMC: 5912137. DOI: 10.4143/crt.2016.572. View

Qin X, Yan M, Wang X, Xu Q, Wang X, Zhu X . Cancer-associated Fibroblast-derived IL-6 Promotes Head and Neck Cancer Progression via the Osteopontin-NF-kappa B Signaling Pathway. Theranostics. 2018; 8(4):921-940. PMC: 5817102. DOI: 10.7150/thno.22182. View

Chen C, Ridzon D, Broomer A, Zhou Z, Lee D, Nguyen J . Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005; 33(20):e179. PMC: 1292995. DOI: 10.1093/nar/gni178. View

Wu B, Su S, Patil D, Liu H, Gan J, Jaffrey S . Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun. 2018; 9(1):420. PMC: 5789076. DOI: 10.1038/s41467-017-02770-z. View

Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z . PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2008; 15(1):21-34. DOI: 10.1016/j.ccr.2008.12.004. View

Conrad M, Sandin A, Forster H, Seiler A, Frijhoff J, Dagnell M . 12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases. Proc Natl Acad Sci U S A. 2010; 107(36):15774-9. PMC: 2936618. DOI: 10.1073/pnas.1007909107. View

10.

Rebollido-Rios R, Venton G, Sanchez-Redondo S, Iglesias I Felip C, Fournet G, Gonzalez E . Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer. Oncogene. 2020; 39(13):2756-2771. PMC: 7098886. DOI: 10.1038/s41388-020-1184-9. View

11.

Zhang H, Deng T, Ge S, Liu Y, Bai M, Zhu K . Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene. 2018; 38(15):2844-2859. PMC: 6484761. DOI: 10.1038/s41388-018-0619-z. View

12.

Jiang L, Kon N, Li T, Wang S, Su T, Hibshoosh H . Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015; 520(7545):57-62. PMC: 4455927. DOI: 10.1038/nature14344. View

13.

Shi J, Ma H, Wang H, Zhu W, Jiang S, Dou R . Overexpression of LINC00261 inhibits non-small cell lung cancer cells progression by interacting with miR-522-3p and suppressing Wnt signaling. J Cell Biochem. 2019; 120(10):18378-18387. DOI: 10.1002/jcb.29149. View

14.

Val S, Krueger A, Poley M, Cohen A, Brown K, Panigrahi A . Nontypeable Haemophilus influenzae lysates increase heterogeneous nuclear ribonucleoprotein secretion and exosome release in human middle-ear epithelial cells. FASEB J. 2017; 32(4):1855-1867. PMC: 5893168. DOI: 10.1096/fj.201700248RR. View

15.

Alim I, Caulfield J, Chen Y, Swarup V, Geschwind D, Ivanova E . Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell. 2019; 177(5):1262-1279.e25. DOI: 10.1016/j.cell.2019.03.032. View

16.

Shin D, Kim E, Lee J, Roh J . Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018; 129:454-462. DOI: 10.1016/j.freeradbiomed.2018.10.426. View

17.

Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P . BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018; 20(10):1181-1192. PMC: 6170713. DOI: 10.1038/s41556-018-0178-0. View

18.

Bhome R, Goh R, Bullock M, Pillar N, Thirdborough S, Mellone M . Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. Aging (Albany NY). 2017; 9(12):2666-2694. PMC: 5764398. DOI: 10.18632/aging.101355. View

19.

Hao S, Yu J, He W, Huang Q, Zhao Y, Liang B . Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells. Neoplasia. 2017; 19(12):1022-1032. PMC: 5686465. DOI: 10.1016/j.neo.2017.10.005. View

20.

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View