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Gastric cancer stem cell-derived exosomes promoted tobacco smoke-triggered development of gastric cancer by inducing the expression of circ670

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Abstract

As one of the most common malignant cancers in the world, gastric cancer is caused by mang factors among which tobacco smoke is an important risk factor. Gastric cancer stem cells (GCSCs) and the derived exosomes play a key role in the occurrence and development of gastric cancer, and exosomal circRNA is considered as a new regulatory factor in the development of gastric cancer. However, it is unclear whether tobacco smoke can affect exosomes and their transport circRNAs to promote the development of gastric cancer. Herein, we provided a new insight into tobacco smoke promoting the progression of gastric cancer. In the present study, we demonstrated that tobacco smoke-induced exosomes promoted the spheroidizing ability, stemness genes expression, and epithelial–mesenchymal transition (EMT) process of GCSCs. We further found that hsa-circRNA-000670 (circ670) was up-regulated in tissues of gastric cancer patients with smoking history, tobacco smoke-induced GCSCs, and their exosomes. Functional assays have shown that circ670 knockdown inhibited the stemness and EMT process of GCSCs, whereas circ670 overexpression appeared to have an opposite effect. Our findings indicated that exosomal circ670 promotes the development of tobacco smoke-induced gastric cancer, which may provide insight into the mechanism of tobacco smoke promoting the progression of gastric cancer.

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References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  Google Scholar 

  2. Li J, Xu HL, Yao BD, Li WX, Fang H, Xu DL, Zhang ZF. Environmental tobacco smoke and cancer risk, a prospective cohort study in a Chinese population. Environ Res. 2020;191:110015.

    Article  CAS  Google Scholar 

  3. Mezzoiuso AG, Odone A, Signorelli C, Russo AG. Association between smoking and cancers among women: results from the FRiCaM multisite cohort study. J Cancer. 2021;12:3136–44.

    Article  Google Scholar 

  4. Lu L, Chen J, Li M, Tang L, Wu R, Jin L, Liang Z. betacarotene reverses tobacco smokeinduced gastric EMT via Notch pathway in vivo. Oncol Rep. 2018;39:1867–73.

    CAS  Google Scholar 

  5. Dong J, Thrift AP. Alcohol, smoking and risk of oesophago-gastric cancer. Best Pract Res Clin Gastroenterol. 2017;31:509–17.

    Article  Google Scholar 

  6. Praud D, Rota M, Pelucchi C, Bertuccio P, Rosso T, Galeone C, Zhang ZF, Matsuo K, Ito H, Hu J, Johnson KC, Yu GP, Palli D, Ferraroni M, Muscat J, Lunet N, Peleteiro B, Malekzadeh R, Ye W, Song H, Zaridze D, Maximovitch D, Aragones N, Castano-Vinyals G, Vioque J, Navarrete-Munoz EM, Pakseresht M, Pourfarzi F, Wolk A, Orsini N, Bellavia A, Hakansson N, Mu L, Pastorino R, Kurtz RC, Derakhshan MH, Lagiou A, Lagiou P, Boffetta P, Boccia S, Negri E, La Vecchia C. Cigarette smoking and gastric cancer in the Stomach Cancer Pooling (StoP) Project. Eur J Cancer Prev. 2018;27:124–33.

    Article  Google Scholar 

  7. Ferro A, Morais S, Rota M, Pelucchi C, Bertuccio P, Bonzi R, Galeone C, Zhang ZF, Matsuo K, Ito H, Hu J, Johnson KC, Yu GP, Palli D, Ferraroni M, Muscat J, Malekzadeh R, Ye W, Song H, Zaridze D, Maximovitch D, Aragones N, Castano-Vinyals G, Vioque J, Navarrete-Munoz EM, Pakseresht M, Pourfarzi F, Wolk A, Orsini N, Bellavia A, Hakansson N, Mu L, Pastorino R, Kurtz RC, Derakhshan MH, Lagiou A, Lagiou P, Boffetta P, Boccia S, Negri E, La Vecchia C, Peleteiro B, Lunet N. Tobacco smoking and gastric cancer: meta-analyses of published data versus pooled analyses of individual participant data (StoP Project). Eur J Cancer Prev. 2018;27:197–204.

    Article  Google Scholar 

  8. Butt J, Varga MG, Wang T, Tsugane S, Shimazu T, Zheng W, Abnet CC, Yoo KY, Park SK, Kim J, Jee SH, Qiao YL, Shu XO, Waterboer T, Pawlita M, Epplein M. Smoking, helicobacter pylori serology, and gastric cancer risk in prospective Studies from China, Japan, and Korea. Cancer Prev Res (Phila). 2019;12:667–74.

    Article  CAS  Google Scholar 

  9. Lu L, Chen J, Tang H, Bai L, Lu C, Wang K, Li M, Yan Y, Tang L, Wu R, Ye Y, Jin L, Liang Z. EGCG suppresses ERK5 activation to reverse tobacco smoke-triggered gastric epithelial-mesenchymal transition in BALB/c mice. Nutrients. 2016;8:380.

    Article  Google Scholar 

  10. Liang Z, Wu R, Xie W, Geng H, Zhao L, Xie C, Wu J, Geng S, Li X, Zhu M, Zhu W, Zhu J, Huang C, Ma X, Zhong C, Han H. Curcumin suppresses MAPK pathways to reverse tobacco smoke-induced gastric epithelial-mesenchymal transition in mice. Phytother Res. 2015;29:1665–71.

    Article  CAS  Google Scholar 

  11. Hayakawa Y, Nakagawa H, Rustgi AK, Que J, Wang TC. Stem cells and origins of cancer in the upper gastrointestinal tract. Cell Stem Cell. 2021;28:1343–61.

    Article  CAS  Google Scholar 

  12. Chang W, Wang H, Kim W, Liu Y, Deng H, Liu H, Jiang Z, Niu Z, Sheng W, Napoles OC, Sun Y, Xu J, Sepulveda A, Hayakawa Y, Bass AJ, Wang TC. Hormonal suppression of stem cells inhibits symmetric cell division and gastric tumorigenesis. Cell Stem Cell. 2020;26(739–754):e8.

    Google Scholar 

  13. Lang T, Xu J, Zhou L, Zhang Z, Ma X, Gu J, Liu J, Li Y, Ding D, Qiu J. Disruption of KDM4C-ALDH1A3 feed-forward loop inhibits stemness, tumorigenesis and chemoresistance of gastric cancer stem cells. Signal Transduct Target Ther. 2021;6:336.

    Article  CAS  Google Scholar 

  14. Zhu YD, Ba H, Chen J, Zhang M, Li P. Celastrus orbiculatus extract reduces stemness of gastric cancer stem cells by targeting PDCD4 and EIF3H. Integr Cancer Ther. 2021;20:15347354211058168.

    Article  CAS  Google Scholar 

  15. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.

    Article  CAS  Google Scholar 

  16. Isaac R, Reis FCG, Ying W, Olefsky JM. Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metab. 2021;33:1744–62.

    Article  CAS  Google Scholar 

  17. Morrissey SM, Zhang F, Ding C, Montoya-Durango DE, Hu X, Yang C, Wang Z, Yuan F, Fox M, Zhang HG, Guo H, Tieri D, Kong M, Watson CT, Mitchell RA, Zhang X, McMasters KM, Huang J, Yan J. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab. 2021;33(2040–2058):e10.

    Google Scholar 

  18. Wu H, Fu M, Liu J, Chong W, Fang Z, Du F, Liu Y, Shang L, Li L. The role and application of small extracellular vesicles in gastric cancer. Mol Cancer. 2021;20:71.

    Article  CAS  Google Scholar 

  19. Tang XH, Guo T, Gao XY, Wu XL, Xing XF, Ji JF, Li ZY. Exosome-derived noncoding RNAs in gastric cancer: functions and clinical applications. Mol Cancer. 2021;20:99.

    Article  CAS  Google Scholar 

  20. Xie M, Yu T, Jing X, Ma L, Fan Y, Yang F, Ma P, Jiang H, Wu X, Shu Y, Xu T. Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation. Mol Cancer. 2020;19:112.

    Article  CAS  Google Scholar 

  21. Zhang X, Wang S, Wang H, Cao J, Huang X, Chen Z, Xu P, Sun G, Xu J, Lv J, Xu Z. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer. 2019;18:20.

    Article  Google Scholar 

  22. Shi H, Huang S, Qin M, Xue X, Guo X, Jiang L, Hong H, Fang J, Gao L. Exosomal circ_0088300 derived from cancer-associated fibroblasts acts as a miR-1305 sponge and promotes gastric carcinoma cell tumorigenesis. Front Cell Dev Biol. 2021;9:676319.

    Article  Google Scholar 

  23. Zhang Y, Jiang J, Zhang J, Shen H, Wang M, Guo Z, Zang X, Shi H, Gao J, Cai H, Fang X, Qian H, Xu W, Zhang X. CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability. Mol Cancer. 2021;20:101.

    Article  CAS  Google Scholar 

  24. Wang M, Zhao X, Qiu R, Gong Z, Huang F, Yu W, Shen B, Sha X, Dong H, Huang J, Wang L, Zhu W, Xu W. Lymph node metastasis-derived gastric cancer cells educate bone marrow-derived mesenchymal stem cells via YAP signaling activation by exosomal Wnt5a. Oncogene. 2021;40:2296–308.

    Article  CAS  Google Scholar 

  25. Lu L, Fang S, Zhang Y, Jin L, Xu W, Liang Z. Exosomes and exosomal circRNAs: the rising stars in the progression, diagnosis and prognosis of gastric cancer. Cancer Manag Res. 2021;13:8121–9.

    Article  CAS  Google Scholar 

  26. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.

    Article  CAS  Google Scholar 

  27. Goodall GJ, Wickramasinghe VO. RNA in cancer. Nat Rev Cancer. 2021;21:22–36.

    Article  CAS  Google Scholar 

  28. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu YM, Dhanasekaran SM, Engelke CG, Cao X, Robinson DR, Nesvizhskii AI, Chinnaiyan AM. The landscape of circular RNA in cancer. Cell. 2019;176(869–881): e13.

    Google Scholar 

  29. Guarnerio J, Zhang Y, Cheloni G, Panella R, MaeKaton J, Simpson M, Matsumoto A, Papa A, Loretelli C, Petri A, Kauppinen S, Garbutt C, Nielsen GP, Deshpande V, Castillo-Martin M, Cordon-Cardo C, Dimitrios S, Clohessy JG, Batish M, Pandolfi P. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res. 2019;29:628–40.

    Article  Google Scholar 

  30. Shan C, Zhang Y, Hao X, Gao J, Chen X, Wang K. Biogenesis, functions and clinical significance of circRNAs in gastric cancer. Mol Cancer. 2019;18:136.

    Article  Google Scholar 

  31. Jiang T, Xia Y, Lv J, Li B, Li Y, Wang S, Xuan Z, Xie L, Qiu S, He Z, Wang L, Xu Z. A novel protein encoded by circMAPK1 inhibits progression of gastric cancer by suppressing activation of MAPK signaling. Mol Cancer. 2021;20:66.

    Article  CAS  Google Scholar 

  32. Yu T, Ran L, Zhao H, Yin P, Li W, Lin J, Mao H, Cai D, Ma Q, Pan X, Wang X, Wu J, Zeng H, Zhang W, Lu D, Luo P, Zou Q, Xiao B. Circular RNA circ-TNPO3 suppresses metastasis of GC by acting as a protein decoy for IGF2BP3 to regulate the expression of MYC and SNAIL. Mol Ther Nucleic Acids. 2021;26:649–64.

    Article  CAS  Google Scholar 

  33. Ma C, Wang X, Yang F, Zang Y, Liu J, Wang X, Xu X, Li W, Jia J, Liu Z. Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit. Mol Cancer. 2020;19:157.

    Article  CAS  Google Scholar 

  34. Wang H, Zeng X, Zheng Y, Wang Y, Zhou Y. Exosomal circRNA in digestive system tumors: the main player or coadjuvants? Front Oncol. 2021;11:614462.

    Article  Google Scholar 

  35. Bai J, Deng J, Han Z, Cui Y, He R, Gu Y, Zhang Q. CircRNA_0026344 via exosomal miR-21 regulation of Smad7 is involved in aberrant cross-talk of epithelium-fibroblasts during cigarette smoke-induced pulmonary fibrosis. Toxicol Lett. 2021;347:58–66.

    Article  CAS  Google Scholar 

  36. Ma H, Lu L, Xia H, Xiang Q, Sun J, Xue J, Xiao T, Cheng C, Liu Q, Shi A. Circ0061052 regulation of FoxC1/Snail pathway via miR-515-5p is involved in the epithelial-mesenchymal transition of epithelial cells during cigarette smoke-induced airway remodeling. Sci Total Environ. 2020;746:141181.

    Article  CAS  Google Scholar 

  37. Zhao J, Xia H, Wu Y, Lu L, Cheng C, Sun J, Xiang Q, Bian T, Liu Q. CircRNA_0026344 via miR-21 is involved in cigarette smoke-induced autophagy and apoptosis of alveolar epithelial cells in emphysema. Cell Biol Toxicol, 2021. https://doi.org/10.1007/s10565-021-09654-5

    Article  Google Scholar 

  38. Qiao D, Hu C, Li Q, Fan J. Circ-RBMS1 knockdown alleviates CSE-induced apoptosis, inflammation and oxidative stress via up-regulating FBXO11 through miR-197-3p in 16HBE cells. Int J Chron Obstruct Pulmon Dis. 2021;16:2105–18.

    Article  CAS  Google Scholar 

  39. Ni SJ, Zhao LQ, Wang XF, Wu ZH, Hua RX, Wan CH, Zhang JY, Zhang XW, Huang MZ, Gan L, Sun HL, Dimri GP, Guo WJ. CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-kappaB-miR-21 pathways. J Hematol Oncol. 2018;11:17.

    Article  Google Scholar 

  40. Zhang H, Wang M, He Y, Deng T, Liu R, Wang W, Zhu K, Bai M, Ning T, Yang H, Liu Y, Wang J, Ba Y. Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells. Cell Death Dis. 2021;12:1116.

    Article  CAS  Google Scholar 

  41. Shaheen S, Ahmed M, Lorenzi F, Nateri AS. Spheroid-formation (Colonosphere) assay for in vitro assessment and expansion of stem cells in colon cancer. Stem Cell Rev Rep. 2016;12:492–9.

    Article  CAS  Google Scholar 

  42. Cao W, Li Y, Sun H, Yang C, Zhu J, Xie C, Li X, Wu J, Geng S, Wang L, Sun L, Geng G, Han H, Zhong C. Apatinib suppresses gastric cancer stem cells properties by inhibiting the sonic hedgehog pathway. Front Cell Dev Biol. 2021;9:679806.

    Article  Google Scholar 

  43. Ghosh P, Mandal S, Mitra Mustafi S, Murmu N. Clinicopathological characteristics and incidence of gastric cancer in Eastern India: a retrospective study. J Gastrointest Cancer. 2021;52:863–71.

    Article  Google Scholar 

  44. Gao J, Li S, Xu Q, Zhang X, Huang M, Dai X, Liu L. Exosomes promote pre-metastatic niche formation in gastric cancer. Front Oncol. 2021;11:652378.

    Article  Google Scholar 

  45. Fu M, Gu J, Jiang P, Qian H, Xu W, Zhang X. Exosomes in gastric cancer: roles, mechanisms, and applications. Mol Cancer. 2019;18:41.

    Article  Google Scholar 

  46. Benedikter BJ, Volgers C, van Eijck PH, Wouters EFM, Savelkoul PHM, Reynaert NL, Haenen G, Rohde GGU, Weseler AR, Stassen FRM. Cigarette smoke extract induced exosome release is mediated by depletion of exofacial thiols and can be inhibited by thiol-antioxidants. Free Radic Biol Med. 2017;108:334–44.

    Article  CAS  Google Scholar 

  47. He S, Chen D, Hu M, Zhang L, Liu C, Traini D, Grau GE, Zeng Z, Lu J, Zhou G, Xie L, Sun S. Bronchial epithelial cell extracellular vesicles ameliorate epithelial-mesenchymal transition in COPD pathogenesis by alleviating M2 macrophage polarization. Nanomedicine. 2019;18:259–71.

    Article  CAS  Google Scholar 

  48. Wang L, Chen Q, Yu Q, Xiao J, Zhao H. Cigarette smoke extract-treated airway epithelial cells-derived exosomes promote M1 macrophage polarization in chronic obstructive pulmonary disease. Int Immunopharmacol. 2021;96:107700.

    Article  CAS  Google Scholar 

  49. Xu H, Ling M, Xue J, Dai X, Sun Q, Chen C, Liu Y, Zhou L, Liu J, Luo F, Bian Q, Liu Q. Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking. Theranostics. 2018;8:5419–33.

    Article  CAS  Google Scholar 

  50. Serban KA, Rezania S, Petrusca DN, Poirier C, Cao D, Justice MJ, Patel M, Tsvetkova I, Kamocki K, Mikosz A, Schweitzer KS, Jacobson S, Cardoso A, Carlesso N, Hubbard WC, Kechris K, Dragnea B, Berdyshev EV, McClintock J, Petrache I. Structural and functional characterization of endothelial microparticles released by cigarette smoke. Sci Rep. 2016;6:31596.

    Article  CAS  Google Scholar 

  51. Liu Y, Luo F, Wang B, Li H, Xu Y, Liu X, Shi L, Lu X, Xu W, Lu L, Qin Y, Xiang Q, Liu Q. STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells. Cancer Lett. 2016;370:125–35.

    Article  CAS  Google Scholar 

  52. Liu P, Cai S, Li N. Circular RNA-hsa-circ-0000670 promotes gastric cancer progression through the microRNA-384/SIX4 axis. Exp Cell Res. 2020;394:112141.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by project of social development in Zhenjiang (No. SH2021045), the Foundation for excellent young teachers of Jiangsu university, and Suzhou science and technology town hospital pre-Research Fund (No. szkjcyy2022002).

Funding

This study was supported by Suzhou science and technology town hospital pre-Research Fund (Grant Number szkjcyy2022002), Major Project of Philosophy and Social Science Research in Colleges and Universities of Jiangsu Province (Grant Number SH2021045), and the Foundation for excellent young teachers of Jiangsu university.

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  1. Zhao feng Liang, Yue Zhang and Wenhao Guo have contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People’s Republic of China

    Zhao feng Liang, Yue Zhang, Bei Chen, Shikun Fang & Hui Qian

  2. Department of Laboratory, Taicang Affiliated Hospital of Soochow University, The First People’s Hospital of Taichang, Suzhou, 215400, Jiangsu, People’s Republic of China

    Wenhao Guo

  3. Suzhou Science and Technology Town Hospital, Suzhou, 215153, Jiangsu, People’s Republic of China

    Bei Chen

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ZL and WG designed research and wrote the paper. YZ and WG performed research. XZ and YX analyzed the data. SF assisted in experimental operation. HQ contributed to the writing and revision of the manuscript.

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Correspondence to Zhao feng Liang.

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Liang, Z.f., Zhang, Y., Guo, W. et al. Gastric cancer stem cell-derived exosomes promoted tobacco smoke-triggered development of gastric cancer by inducing the expression of circ670. Med Oncol 40, 24 (2023). https://doi.org/10.1007/s12032-022-01906-6

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