Skip to main content

Advertisement

SpringerLink
Log in

Extracellular vesicles derived from cancer-associated fibroblasts carry tumor-promotive microRNA-1228-3p to enhance the resistance of hepatocellular carcinoma cells to sorafenib

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) can promote tumor progression by delivering microRNA (miRNA). Whether EVs could transfer miR-1228-3p into hepatocellular carcinoma (HCC) cells to affect chemoresistance was discussed in this study. Normal fibroblasts (NFs) and CAFs were isolated from tissue samples of HCC patients. We assessed the functions of HCC cells after co-culturing with NFs and CAFs. miR-1228-3p gain-of-function experiments were conducted. Next, functional assays were carried out to determine the binding of miR-1228-3p to placenta associated 8 (PLAC8). In vivo models were constructed for validation. CAFs-derived EVs exerted promoting effect on proliferative, migrating, invading potential of HCC cells and their resistance to sorafenib. PLAC8 was demonstrated as a direct target of miR-1228-3p. By targeting PLAC8, miR-1228-3p activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In addition, the transfer of miR-1228-3p from CAFs-derived EVs into HCC cells boosted chemoresistance of HCC cells, which was reversed by restoring PLAC8. All in all, CAF-EV-carried miR-1228-3p strengthens the chemoresistance of HCC through activating PLAC8-mediated PI3K/AKT pathway. This finding contributes to the development of EV-based therapies overcoming the chemoresistance of HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Date availability

The datasets generated for this study are available on request to the corresponding author.

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.

    Article  Google Scholar 

  2. Ikeda M, Morizane C, Ueno M, et al. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol. 2018;48:103–14. https://doi.org/10.1093/jjco/hyx180.

    Article  Google Scholar 

  3. Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87. https://doi.org/10.1038/s41392-020-0187-x.

    Article  Google Scholar 

  4. Xia S, Pan Y, Liang Y, Xu J, Cai X. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine. 2020;51: 102610. https://doi.org/10.1016/j.ebiom.2019.102610.

    Article  Google Scholar 

  5. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:714–26. https://doi.org/10.1038/nrc3599.

    Article  CAS  Google Scholar 

  6. Sukowati CH, Rosso N, Croce LS, Tiribelli C. Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma. World J Hepatol. 2010;2:114–26. https://doi.org/10.4254/wjh.v2.i3.114.

    Article  Google Scholar 

  7. Maacha S, Bhat AA, Jimenez L, et al. Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance. Mol Cancer. 2019;18:55. https://doi.org/10.1186/s12943-019-0965-7.

    Article  Google Scholar 

  8. Samuel P, Fabbri M, Carter DRF. Mechanisms of drug resistance in cancer: the role of extracellular vesicles. Proteomics. 2017. https://doi.org/10.1002/pmic.201600375.

    Article  Google Scholar 

  9. Takahashi RU, Prieto-Vila M, Hironaka A, Ochiya T. The role of extracellular vesicle microRNAs in cancer biology. Clin Chem Lab Med. 2017;55:648–56. https://doi.org/10.1515/cclm-2016-0708.

    Article  CAS  Google Scholar 

  10. Zhang Y, Dai J, Deng H, et al. miR-1228 promotes the proliferation and metastasis of hepatoma cells through a p53 forward feedback loop. Br J Cancer. 2015;112:365–74. https://doi.org/10.1038/bjc.2014.593.

    Article  CAS  Google Scholar 

  11. Cabreira-Cagliari C, Dias NC, Bohn B, et al. Revising the PLAC8 gene family: from a central role in differentiation, proliferation, and apoptosis in mammals to a multifunctional role in plants. Genome. 2018;61:857–65. https://doi.org/10.1139/gen-2018-0035.

    Article  CAS  Google Scholar 

  12. Zou L, Chai J, Gao Y, et al. Down-regulated PLAC8 promotes hepatocellular carcinoma cell proliferation by enhancing PI3K/Akt/GSK3beta/Wnt/beta-catenin signaling. Biomed Pharmacother. 2016;84:139–46. https://doi.org/10.1016/j.biopha.2016.09.015.

    Article  CAS  Google Scholar 

  13. Zhang XL, Jia Q, Lv L, Deng T, Gao J. Tumorspheres derived from HCC cells are enriched with cancer stem cell-like cells and present high chemoresistance dependent on the akt pathway. Anticancer Agents Med Chem. 2015;15:755–63. https://doi.org/10.2174/1871520615666150202111721.

    Article  CAS  Google Scholar 

  14. Kilkenny C, Browne W, Cuthill IC, et al. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577–9. https://doi.org/10.1111/j.1476-5381.2010.00872.x.

    Article  CAS  Google Scholar 

  15. Fang T, Lv H, Lv G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191. https://doi.org/10.1038/s41467-017-02583-0.

    Article  CAS  Google Scholar 

  16. Qin X, Guo H, Wang X, et al. 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. https://doi.org/10.1186/s13059-018-1604-0.

    Article  Google Scholar 

  17. Yuan JH, Yang F, Wang F, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81. https://doi.org/10.1016/j.ccr.2014.03.010.

    Article  CAS  Google Scholar 

  18. Yan W, Wu X, Zhou W, et al. Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol. 2018;20:597–609. https://doi.org/10.1038/s41556-018-0083-6.

    Article  CAS  Google Scholar 

  19. Hu M, Guo G, Huang Q, et al. The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes. Cell Death Dis. 2018;9:357. https://doi.org/10.1038/s41419-018-0392-5.

    Article  CAS  Google Scholar 

  20. Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS ONE. 2014;9: e88685. https://doi.org/10.1371/journal.pone.0088685.

    Article  CAS  Google Scholar 

  21. Zhang Y, Zhang D, Li W, et al. A novel real-time quantitative PCR method using attached universal template probe. Nucleic Acids Res. 2003;31: e123. https://doi.org/10.1093/nar/gng123.

    Article  CAS  Google Scholar 

  22. Gonul Baltaci N, Guler C, Ceylan H, et al. In vitro and in vivo effects of iron on the expression and activity of glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reductase in rat spleen. J Biochem Mol Toxicol. 2018. https://doi.org/10.1002/jbt.22229.

    Article  Google Scholar 

  23. Liu Y, Xu W, Zhai T, You J, Chen Y. Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway. Acta Pharm Sin B. 2019;9:745–57. https://doi.org/10.1016/j.apsb.2019.02.006.

    Article  Google Scholar 

  24. Liu C, Liu R, Zhang D, et al. MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes. Nat Commun. 2017;8:14270. https://doi.org/10.1038/ncomms14270.

    Article  CAS  Google Scholar 

  25. Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018. https://doi.org/10.1126/science.aan5931.

    Article  Google Scholar 

  26. Zhang P, Zhang L, Qin Z, et al. Genetically engineered liposome-like nanovesicles as active targeted transport platform. Adv Mater. 2018. https://doi.org/10.1002/adma.201705350.

    Article  Google Scholar 

  27. Hu JL, Wang W, Lan XL, et al. CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Mol Cancer. 2019;18:91. https://doi.org/10.1186/s12943-019-1019-x.

    Article  CAS  Google Scholar 

  28. Zhang H, Deng T, Liu R, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19:43. https://doi.org/10.1186/s12943-020-01168-8.

    Article  CAS  Google Scholar 

  29. Zhang Z, Li X, Sun W, et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett. 2017;397:33–42. https://doi.org/10.1016/j.canlet.2017.03.004.

    Article  CAS  Google Scholar 

  30. Mao M, Chen Y, Jia Y, et al. PLCA8 suppresses breast cancer apoptosis by activating the PI3k/AKT/NF-kappaB pathway. J Cell Mol Med. 2019;23:6930–41. https://doi.org/10.1111/jcmm.14578.

    Article  CAS  Google Scholar 

  31. Yang Q, Diamond MP, Al-Hendy A. The emerging role of extracellular vesicle-derived miRNAs: implication in cancer progression and stem cell related diseases. J Clin Epigenet. 2016;2(1):13. Epub 2016 Jan 31.

  32. Borrelli DA, Yankson K, Shukla N, et al. Extracellular vesicle therapeutics for liver disease. J Control Release. 2018;273:86–98. https://doi.org/10.1016/j.jconrel.2018.01.022.

    Article  CAS  Google Scholar 

  33. Tetta C, Ghigo E, Silengo L, Deregibus MC, Camussi G. Extracellular vesicles as an emerging mechanism of cell-to-cell communication. Endocrine. 2013;44:11–9. https://doi.org/10.1007/s12020-012-9839-0.

    Article  CAS  Google Scholar 

  34. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28. https://doi.org/10.1038/nrm.2017.125.

    Article  CAS  Google Scholar 

  35. Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol. 2018;6:18. https://doi.org/10.3389/fcell.2018.00018.

    Article  Google Scholar 

  36. Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest. 2016;126:1139–43. https://doi.org/10.1172/JCI87316.

    Article  Google Scholar 

  37. Zhao H, Achreja A, Iessi E, et al. The key role of extracellular vesicles in the metastatic process. Biochim Biophys Acta Rev Cancer. 2018;1869:64–77. https://doi.org/10.1016/j.bbcan.2017.11.005.

    Article  CAS  Google Scholar 

  38. Yan B, Zhao JL. miR-1228 prevents cellular apoptosis through targeting of MOAP1 protein. Apoptosis. 2012;17:717–24.

    Article  CAS  Google Scholar 

  39. Lin L, Liu D, Liang H, et al. MiR-1228 promotes breast cancer cell growth and metastasis through targeting SCAI protein. Int J Clin Exp Pathol. 2015;8:6646–55.

    Google Scholar 

  40. Pascut D, Cavalletto L, Pratama MY, et al. Serum miRNA are promising biomarkers for the detection of early hepatocellular carcinoma after treatment with direct-acting antivirals. Cancers (Basel). 2019. https://doi.org/10.3390/cancers11111773.

    Article  Google Scholar 

  41. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11:597–610. https://doi.org/10.1038/nrg2843.

    Article  CAS  Google Scholar 

  42. Grate LR. Many accurate small-discriminatory feature subsets exist in microarray transcript data: biomarker discovery. BMC Bioinform. 2005;6:97. https://doi.org/10.1186/1471-2105-6-97.

    Article  CAS  Google Scholar 

  43. Fang X, Yang D, Luo H, et al. SNORD126 promotes HCC and CRC cell growth by activating the PI3K-AKT pathway through FGFR2. J Mol Cell Biol. 2017;9:243–55. https://doi.org/10.1093/jmcb/mjw048.

    Article  CAS  Google Scholar 

  44. Xia S, Yu S, Fu Q, et al. Inhibiting PI3K/Akt pathway increases DNA damage of cervical carcinoma HeLa cells by drug radiosensitization. J Huazhong Univ Sci Technol Med Sci. 2010;30:360–4. https://doi.org/10.1007/s11596-010-0357-0.

    Article  CAS  Google Scholar 

  45. Zhou Q, Lui VW, Yeo W. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Future Oncol. 2011;7:1149–67. https://doi.org/10.2217/fon.11.95.

    Article  CAS  Google Scholar 

  46. Mourtada-Maarabouni M, Watson D, Munir M, Farzaneh F, Williams GT. Apoptosis suppression by candidate oncogene PLAC8 is reversed in other cell types. Curr Cancer Drug Targets. 2013;13:80–91.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110000, Liaoning Province, People’s Republic of China

    Yijie Zhang, Qi Pan & Zigong Shao

  2. The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang, 110000, Liaoning Province, People’s Republic of China

    Yijie Zhang, Qi Pan & Zigong Shao

Authors
  1. Yijie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zigong Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed research: YZ. Performed experiments: YZ. Analyzed data: YZ and QP. Interpreted results of experiments: QP and ZShao; prepared figures: Qi Pan and Zigong S. Drafted manuscript: QP. Edited and revised manuscript: YZ and ZS. Approved final version of manuscript: YZ, QP and ZS.

Corresponding author

Correspondence to Zigong Shao.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 677 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Pan, Q. & Shao, Z. Extracellular vesicles derived from cancer-associated fibroblasts carry tumor-promotive microRNA-1228-3p to enhance the resistance of hepatocellular carcinoma cells to sorafenib. Human Cell 36, 296–311 (2023). https://doi.org/10.1007/s13577-022-00800-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-022-00800-7

Keywords

Search

Navigation