[go: up one dir, main page]

Skip to main content

Advertisement

Log in

IFN-γ inhibits ovarian cancer progression via SOCS1/JAK/STAT signaling pathway

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Ovarian cancer (OC) is a common malignancy, and IFN-γ, a multifunctional cytokine, is unveiled to impede the multiplication and enhance apoptosis in diverse tumor cells in previous research. Nonetheless, its function and mechanism in OC are blurred.

Methods

OC cell lines SKOV3 and OVCAR3 were dealt with different concentrations (0–40 ng/ml) of IFN-γ. CCK-8 experiment was utilized to examine cell multiplication; Flow cytometry was executed to detect apoptosis and cell cycle; Wound healing assay was utilized to detect cell migration; and Transwell experiment was implemented to examine cell invasion. qRT-PCR analysis was applied to detect STAT5, STAT3, JAK2 and JAK3 mRNA expression in OC cell lines. Western blot experiment was applied to detect the protein and phosphorylation levels of SOCS1, STAT5 and STAT3.

Results

IFN-γ suppressed OC cell multiplication in a concentration-dependent manner. Relative to the control group, IFN-γ restrained OC cell migration, invasion, enhanced apoptosis and prevented cell transformation from G0/G1 to S phase. Further analysis revealed that IFN-γ up-modulated SOCS1 expression and impeded STAT5 and STAT3 protein phosphorylation levels, and knockdown of SOCS1 partially counteracted the inhibitory effect of IFN-γ on STAT5 and STAT3 protein phosphorylation levels.

Conclusion

IFN-γ represses OC progression by facilitating SOCS1 to suppress STAT3 and STAT5 protein phosphorylation.

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

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References:

  1. Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Primers. 2016;2:16061.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    Article  Google Scholar 

  3. DiSilvestro P, Alvarez SA. Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time? Cancer Treat Rev. 2018;69:53–65.

    Article  CAS  Google Scholar 

  4. Gomez-Lomeli P, Bravo-Cuellar A, Hernandez-Flores G, et al. Increase of IFN-gamma and TNF-alpha production in CD107a + NK-92 cells co-cultured with cervical cancer cell lines pre-treated with the HO-1 inhibitor. Cancer Cell Int. 2014;14:100.

    Article  Google Scholar 

  5. Kursunel MA, Esendagli G. The untold story of IFN-gamma in cancer biology. Cytokine Growth Factor Rev. 2016;31:73–81.

    Article  Google Scholar 

  6. Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-gamma in tumor progression and regression: a review. Biomark Res. 2020;8:49.

    Article  Google Scholar 

  7. Wall L, Burke F, Barton C, Smyth J, Balkwill F. IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro. Clin Cancer Res. 2003;9:2487–96.

    CAS  PubMed  Google Scholar 

  8. Duncan TJ, Rolland P, Deen S, Scott IV, Liu DT, Spendlove I, Durrant LG. Loss of IFN gamma receptor is an independent prognostic factor in ovarian cancer. Clin Cancer Res. 2007;13:4139–45.

    Article  CAS  Google Scholar 

  9. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28.

    Article  CAS  Google Scholar 

  10. Owen KL, Brockwell NK, Parker BS. JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression. Cancers (Basel). 2019;11:2002.

    Article  CAS  Google Scholar 

  11. Ruan Z, Yang X, Cheng W. OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells. Cancer Manag Res. 2019;11:389–99.

    Article  CAS  Google Scholar 

  12. Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signaling pathway. Semin Cell Dev Biol. 2008;19:414–22.

    Article  CAS  Google Scholar 

  13. Li Y, Chu N, Rostami A, Zhang GX. Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo. J Immunol. 2006;177:1679–88.

    Article  CAS  Google Scholar 

  14. Yang M, Chen H, Zhou L, Huang X, Su F, Wang P. Identification of SOCS family members with prognostic values in human ovarian cancer. Am J Transl Res. 2020;12:1824–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Mojic M, Takeda K, Hayakawa Y. The dark side of IFN-gamma: its role in promoting cancer immunoevasion. Int J Mol Sci. 2017;19:89.

    Article  Google Scholar 

  16. Yang SL, Tan HX, Niu TT, et al. The IFN-gamma-IDO1-kynureine pathway-induced autophagy in cervical cancer cell promotes phagocytosis of macrophage. Int J Biol Sci. 2021;17:339–52.

    Article  CAS  Google Scholar 

  17. Su Z, Sun Y, Zhu H, et al. Th17 cell expansion in gastric cancer may contribute to cancer development and metastasis. Immunol Res. 2014;58:118–24.

    Article  CAS  Google Scholar 

  18. Li J, Zeng M, Yan K, Yang Y, Li H, Xu X. IL-17 promotes hepatocellular carcinoma through inhibiting apoptosis induced by IFN-gamma. Biochem Biophys Res Commun. 2020;522:525–31.

    Article  CAS  Google Scholar 

  19. Barton C, Davies D, Balkwill F, Burke F. Involvement of both intrinsic and extrinsic pathways in IFN-gamma-induced apoptosis that are enhanced with cisplatin. Eur J Cancer. 2005;41:1474–86.

    Article  CAS  Google Scholar 

  20. Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020;80:106210.

    Article  CAS  Google Scholar 

  21. Wen W, Liang W, Wu J, et al. Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer. Mol Cancer Ther. 2014;13:3037–48.

    Article  CAS  Google Scholar 

  22. Ruan Z, Yang X, Cheng W. OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells. Cancer Manag Res. 2018;11:389–99.

    Article  Google Scholar 

  23. Delen E, Doğanlar O. The dose dependent effects of ruxolitinib on the invasion and tumorigenesis in gliomas cells via inhibition of interferon gamma-depended JAK/STAT signaling pathway. J Korean Neurosurg Soc. 2020;63:444–54.

    Article  CAS  Google Scholar 

  24. Darnell JJ. STATs and gene regulation. Science. 1997;277:1630–5.

    Article  CAS  Google Scholar 

  25. Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.

    Article  CAS  Google Scholar 

  26. Silver DL, Naora H, Liu J, Cheng W, Montell DJ. Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res. 2004;64:3550–8.

    Article  CAS  Google Scholar 

  27. Rosen DG, Mercado-Uribe I, Yang G, et al. The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis. Cancer. 2006;107:2730–40.

    Article  CAS  Google Scholar 

  28. Wu CJ, Sundararajan V, Sheu BC, Huang RY, Wei LH. Activation of STAT3 and STAT5 signaling in epithelial ovarian cancer progression: mechanism and therapeutic opportunity. Cancers (Basel). 2019;12:24.

    Article  Google Scholar 

  29. Bachmann J, Raue A, Schilling M, et al. Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range. Mol Syst Biol. 2011;7:516.

    Article  Google Scholar 

  30. Lindemann C, Hackmann O, Delic S, Schmidt N, Reifenberger G, Riemenschneider MJ. SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol. 2011;122:241–51.

    Article  CAS  Google Scholar 

  31. Liang Y, Xu WD, Peng H, Pan HF, Ye DQ. SOCS signaling in autoimmune diseases: molecular mechanisms and therapeutic implications. Eur J Immunol. 2014;44:1265–75.

    Article  CAS  Google Scholar 

  32. Liu H, Wang W, Liu C. Increased expression of IFN-γ in preeclampsia impairs human trophoblast invasion via a SOCS1/JAK/STAT1 feedback loop. Exp Ther Med. 2021;21:112.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by Suzhou science and technology development plan (application basis) (SYS201729) and Jiangsu province maternal and child health research project (F201709).

Author information

Authors and Affiliations

Authors

Contributions

AHG designed the study and drafted the manuscript. AHG and YRH were responsible for the collection and analysis of the experimental data. YRH and WPZ revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Y. R. Hu or W. P. Zhu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by Ethical Committee of the Second Affiliated Hospital of Soochow University and conducted in accordance with the ethical standards.

Informed consent

Subjects signed the informed consent.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, A.H., Hu, Y.R. & Zhu, W.P. IFN-γ inhibits ovarian cancer progression via SOCS1/JAK/STAT signaling pathway. Clin Transl Oncol 24, 57–65 (2022). https://doi.org/10.1007/s12094-021-02668-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-021-02668-9

Keywords

Navigation