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01-12-2020 | Gastric Cancer | Research

CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer

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

Published in: Molecular Cancer | Issue 1/2020

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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Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMed

Pavlova NN, Thompson CB. The emerging hallmarks of Cancer metabolism. Cell Metab. 2016;23:27–47.PubMedPubMedCentralCrossRef

Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, et al. Ferroptosis: a regulated cell death Nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.PubMedPubMedCentralCrossRef

Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, Dai X, Li Z, Wu G. Ferroptosis: a novel anti-tumor action for Cisplatin. Cancer Res Treat. 2018;50:445–60.PubMedCrossRef

Jiang L, Kon N, Li TY, Wang SJ, Su T, Hibshoosh H, Baer R, Gu W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57.PubMedPubMedCentralCrossRef

Zhang YL, Shi JJ, Liu XG, Feng L, Gong ZH, Koppula P, Sirohi K, Li X, Wei YK, Lee H, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018;20:1181.PubMedPubMedCentralCrossRef

Sun XF, Niu XH, Chen RC, He WY, Chen D, Kang R, Tang DL. Metallothionein-1G facilitates Sorafenib resistance through inhibition of Ferroptosis. Hepatology. 2016;64:488–500.PubMedCrossRef

Anderson AR, Weaver AM, Cummings PT, Quaranta V. Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell. 2006;127:905–15.PubMedCrossRef

Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, Kaminker J, Ferrara N. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15:21–34.PubMedCrossRef

10.

Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18:1359.PubMedPubMedCentralCrossRef

11.

Ligorio M, Sil S, Malagon-Lopez J, Nieman LT, Misale S, Di Pilato M, Ebright RY, Karabacak MN, Kulkarni AS, Liu A, et al. Stromal microenvironment shapes the Intratumoral architecture of pancreatic Cancer. Cell. 2019;178:160–175 e127.PubMedCrossRefPubMedCentral

12.

Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015;25:198–213.PubMedCrossRef

13.

Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, Hodi FS, Martin-Algarra S, Mandal R, Sharfman WH, et al. Tumor and microenvironment evolution during immunotherapy with Nivolumab. Cell. 2017;171:934–49 e916.PubMedPubMedCentralCrossRef

14.

Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.PubMedCrossRef

15.

Zhang H, Deng T, Ge S, Liu Y, Bai M, Zhu K, Fan Q, Li J, Ning T, Tian F, et al. Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene. 2019;38:2844–59.PubMedCrossRef

16.

Zhang H, Deng T, Liu R, Bai M, Zhou L, Wang X, Li S, Yang H, Li J, Ning T, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun. 2017;8:15016.PubMedPubMedCentralCrossRef

17.

Qin X, Guo H, Wang X, Zhu X, Yan M, Xu Q, Shi J, Lu E, Chen W, Zhang J. Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5. Genome Biol. 2019;20:12.PubMedPubMedCentralCrossRef

18.

Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159:499–513.PubMedPubMedCentralCrossRef

19.

Bhome R, Goh RW, Bullock MD, Pillar N, Thirdborough SM, Mellone M, Mirnezami R, Galea D, Veselkov K, Gu Q, et al. Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. Aging (Albany NY). 2017;9:2666–94.CrossRef

20.

Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770–8.PubMedCrossRef

21.

Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRef

22.

Felicetti F, De Feo A, Coscia C, Puglisi R, Pedini F, Pasquini L, Bellenghi M, Errico MC, Pagani E, Care A. Exosome-mediated transfer of miR-222 is sufficient to increase tumor malignancy in melanoma. J Transl Med. 2016;14:56.PubMedPubMedCentralCrossRef

23.

Wei Y, Li M, Cui S, Wang D, Zhang CY, Zen K, Li L. Shikonin inhibits the proliferation of human breast Cancer cells by reducing tumor-derived Exosomes. Molecules. 2016;21.

24.

Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.PubMedCrossRef

25.

Qin X, Yan M, Wang X, Xu Q, Zhu X, Shi J, Li Z, Zhang J, Chen W. Cancer-associated fibroblast-derived IL-6 promotes head and neck Cancer progression via the Osteopontin-NF-kappa B signaling pathway. Theranostics. 2018;8:921–40.PubMedPubMedCentralCrossRef

26.

Gong BD, Xie Q, Wang L, Xiang XG, Lin LY, Zhao GD, Wang H, Yu H. Real-time quantification of microRNAs in Huh7 cells by stem-loop reverse transcriptase polymerase chain reaction. Zhonghua Gan Zang Bing Za Zhi. 2009;17:603–6.PubMed

27.

Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005;33:e179.PubMedPubMedCentralCrossRef

28.

Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Radmark O, Wurst W, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–48.PubMedCrossRef

29.

Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.PubMedCrossRef

30.

Ou Y, Wang SJ, 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:E6806–12.PubMedPubMedCentralCrossRef

31.

Conrad M, Sandin A, Forster H, Seiler A, Frijhoff J, Dagnell M, Bornkamm GW, Radmark O, van Huijsduijnen RH, Aspenstrom P, et al. 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;107:15774–9.PubMedPubMedCentralCrossRef

32.

Shi J, Ma H, Wang H, Zhu W, Jiang S, Dou R, Yan B. 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;120:18378–387.

33.

Shuai F, Wang B, Dong SX. miR-522-3p promotes tumorigenesis in human colorectal Cancer via targeting bloom syndrome protein. Oncol Res. 2018;26:1113–21.PubMedCrossRefPubMedCentral

34.

Shi YH, Qi BB, Liu XB, Ding HM. Upregulation of miR-522 is associated with poor outcome of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2016;20:3194–8.PubMed

35.

Cancer-Associated Fibroblasts Contribute to PDAC Heterogeneity. Cancer Discov 2019;9:993.

36.

Hughes RM, Simons BW, Khan H, Miller R, Kugler V, Torquato S, Theodros D, Haffner MC, Lotan TL, Huang J, et al. Asporin restricts Mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression. Cancer Res. 2019;79:3636–50.PubMedCrossRefPubMedCentral

37.

Wu B, Su S, Patil DP, Liu H, Gan J, Jaffrey SR, Ma J. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun. 2018;9:420.PubMedPubMedCentralCrossRef

38.

Val S, Krueger A, Poley M, Cohen A, Brown K, Panigrahi A, Preciado D. Nontypeable Haemophilus influenzae lysates increase heterogeneous nuclear ribonucleoprotein secretion and exosome release in human middle-ear epithelial cells. FASEB J. 2018;32:1855–67.PubMedPubMedCentralCrossRef

39.

Alim I, Caulfield JT, Chen Y, Swarup V, Geschwind DH, Ivanova E, Seravalli J, Ai Y, Sansing LH, Ste Marie EJ, et al. Selenium drives a transcriptional adaptive program to block Ferroptosis and treat stroke. Cell. 2019;177:1262–79 e1225.CrossRefPubMed

40.

Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, Possemato R. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551:639–43.PubMedPubMedCentralCrossRef

41.

Wang W, Green M, Choi JE, Gijon M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.PubMedPubMedCentralCrossRef

42.

Guo JP, Xu BF, Han Q, Zhou HX, Xia Y, Gong CW, Dai XF, Li ZY, Wu G. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science. 2018;50:445–460.

43.

Long KB, Collier AI, Beatty GL. Macrophages: key orchestrators of a tumor microenvironment defined by therapeutic resistance. Mol Immunol. 2019;110:3–12.PubMedCrossRef

44.

Teh JLF, Aplin AE. Arrested developments: CDK4/6 inhibitor resistance and alterations in the tumor immune microenvironment. Clin Cancer Res. 2019;25:921–7.PubMedCrossRef

45.

Hao S, Yu J, He W, Huang Q, Zhao Y, Liang B, Zhang S, Wen Z, Dong S, Rao J, et al. Cysteine Dioxygenase 1 mediates Erastin-induced Ferroptosis in human gastric Cancer cells. Neoplasia. 2017;19:1022–32.PubMedPubMedCentralCrossRef

46.

Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76.PubMedCrossRef

47.

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.PubMedPubMedCentralCrossRef

48.

Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, Tseng YY, Deasy R, Kost-Alimova M, Dancik V, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019;10:1617.PubMedPubMedCentralCrossRef

49.

Shin D, Kim EH, Lee J, Roh JL. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018;129:454–62.PubMedCrossRef

50.

Zhai J, Shen J, Xie G, Wu J, He M, Gao L, Zhang Y, Yao X, Shen L. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett. 2019;454:37–43.PubMedCrossRef

51.

Shao L, Chen Z, Soutto M, Zhu S, Lu H, Romero-Gallo J, Peek R, Zhang S, El-Rifai W. Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer. FASEB J. 2019;33:264–74.PubMedCrossRef

52.

Kwon CH, Park HJ, Choi Y, Won YJ, Lee SJ, Park DY. TWIST mediates resistance to paclitaxel by regulating Akt and Bcl-2 expression in gastric cancer cells. Tumour Biol. 2017;39:1010428317722070.PubMed

53.

Rebollido-Rios R, Venton G, Sanchez-Redondo S, Iglesias IFC, Fournet G, Gonzalez E, Romero Fernandez W, Borroto Escuela DO, Di Stefano B, Penarroche-Diaz R, et al. Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer. FASEB J. 2019;33:264–274.

54.

Silva MM, Rocha CRR, Kinker GS, Pelegrini AL, Menck CFM. The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. Sci Rep. 2019;9.

Title: CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer
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
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Gastric Cancer
Gastric Cancer
Cytostatic Therapy
Published in: Molecular Cancer / Issue 1/2020
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/s12943-020-01168-8

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