Skip to main content

Advertisement

SpringerLink
Log in

Stress-induced phosphoprotein 1 facilitates breast cancer cell progression and indicates poor prognosis for breast cancer patients

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

Abstract

Breast cancer (BC) threatened the life health of a tremendous amount of the population, and the estimated number of death is still rising nowadays. We found that stress-induced phosphoprotein 1 (STIP1) is overexpressed in BC tissues compared to non-tumorous breast tissues. Our study is to validate the prognostic value of STIP1 and investigate its biological role in BC. We verified the upregulation of STIP1 in multiple databases, proved that STIP1 is upregulated in BC tissues and cell lines using real-time quantitative PCR (qRT-PCR). We used small interfering RNA to examine the function of STIP1 in BC cell lines (BT-549, MDA-MB-231, Hs-578 T) and explored the mechanism of function of STIP1 in BC cells using Western blotting and qRT-PCR. Analyses of multiple databases indicated that high STIP1 expression is a marker that effectively distinguishes BC patients from healthy control and predicts worse clinical outcomes in BC. The loss-of-function experiments showed that STIP1 silencing results in inhibition of cell proliferation and migration, inducing cell apoptosis, and S-phase arrest in vitro. Our study also showed that STIP1 downregulation inhibited the JAK2/STAT3 pathway and epithelial-mesenchymal transition process. Rescue experiments demonstrated that the oncogenic effect of STIP1 is partially dependent on mediating JAK2 expression. This study verified that STIP1 is an oncogenic gene that promotes BC progression and serves as a valuable diagnostic and outcome-related marker of BC.

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

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.

    Article  PubMed  Google Scholar 

  2. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:5. https://doi.org/10.1093/jnci/dju055.

    Article  Google Scholar 

  3. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70 https://doi.org/10.1038/nature11412.

  4. Moo TA, Sanford R, Dang C, Morrow M. Overview of breast cancer therapy. PET Clin. 2018;13(3):339–54. https://doi.org/10.1016/j.cpet.2018.02.006.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Krug D, Baumann R, Budach W, Dunst J, Feyer P, Fietkau R, et al. Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer : a systematic review. Strahlenther Onkol Organ Deutschen Rontgengesellschaft. 2018;194(7):607–18. https://doi.org/10.1007/s00066-018-1270-x.

    Article  Google Scholar 

  6. Freedman RA. Treatment of breast cancer in the elderly. Curr Oncol Rep. 2015;17(11):51. https://doi.org/10.1007/s11912-015-0475-8.

    Article  CAS  PubMed  Google Scholar 

  7. Harbeck N, Gnant M. Breast cancer. Lancet (Lond Engl). 2017;389(10074):1134–50. https://doi.org/10.1016/S0140-6736(16)31891-8.

    Article  Google Scholar 

  8. Noone AM HN, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) SEER cancer statistics review, 1975–2015, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER web site, April 2018. Accessed 26 July 2020.

  9. Bhandari A, Zheng C, Sindan N, Quan R, Xia E, Thapa Y, et al. COPB2 is up-regulated in breast cancer and plays a vital role in the metastasis via N-cadherin and Vimentin. J Cell Mol Med. 2019;23(8):5235–45. https://doi.org/10.1111/jcmm.14398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guan Y, Bhandari A, Xia E, Yang F, Xiang J, Wang O. lncRNA FOXD3-AS1 is associated with clinical progression and regulates cell migration and invasion in breast cancer. Cell Biochem Funct. 2019;37(4):239–44. https://doi.org/10.1002/cbf.3393.

    Article  CAS  PubMed  Google Scholar 

  11. Song Y, Masison DC. Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). J Biol Chem. 2005;280(40):34178–85. https://doi.org/10.1074/jbc.M505420200.

    Article  CAS  PubMed  Google Scholar 

  12. Odunuga OO, Longshaw VM, Blatch GL. Hop: more than an Hsp70/Hsp90 adaptor protein. BioEssays. 2004;26(10):1058–68. https://doi.org/10.1002/bies.20107.

    Article  CAS  PubMed  Google Scholar 

  13. Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP, et al. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene. 2013;32(25):3101–10. https://doi.org/10.1038/onc.2012.314.

    Article  CAS  PubMed  Google Scholar 

  14. Jing Y, Liang W, Liu J, Zhang L, Wei J, Zhu Y, et al. Stress-induced phosphoprotein 1 promotes pancreatic cancer progression through activation of the FAK/AKT/MMP signaling axis. Pathol Res Pract. 2019;215(11):152564. https://doi.org/10.1016/j.prp.2019.152564.

    Article  CAS  PubMed  Google Scholar 

  15. Sun X, Cao N, Mu L, Cao W. Stress induced phosphoprotein 1 promotes tumor growth and metastasis of melanoma via modulating JAK2/STAT3 pathway. Biomed Pharmacother. 2019;116:108962. https://doi.org/10.1016/j.biopha.2019.108962.

    Article  CAS  PubMed  Google Scholar 

  16. Wang TH, Chao A, Tsai CL, Chang CL, Chen SH, Lee YS, et al. Stress-induced phosphoprotein 1 as a secreted biomarker for human ovarian cancer promotes cancer cell proliferation. Mol Cell Proteomics. 2010;9(9):1873–84. https://doi.org/10.1074/mcp.M110.000802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tsai CL, Tsai CN, Lin CY, Chen HW, Lee YS, Chao A, et al. Secreted stress-induced phosphoprotein 1 activates the ALK2-SMAD signaling pathways and promotes cell proliferation of ovarian cancer cells. Cell Rep. 2012;2(2):283–93. https://doi.org/10.1016/j.celrep.2012.07.002.

    Article  CAS  PubMed  Google Scholar 

  18. Huang L, Zhai E, Cai S, Lin Y, Liao J, Jin H, et al. Stress-inducible Protein-1 promotes metastasis of gastric cancer via Wnt/beta-catenin signaling pathway. J Exp Clin Cancer Res. 2018;37(1):6. https://doi.org/10.1186/s13046-018-0676-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu R, Liu F, Peng P, Qiu H, Xiong H, Yu S, et al. Tumor stress-induced phosphoprotein 1 as a prognostic biomarker for breast cancer. Ann Transl Med. 2018;6(15):302. https://doi.org/10.21037/atm.2018.06.46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77(21):e108–10. https://doi.org/10.1158/0008-5472.CAN-17-0307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, et al. Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res. 2006;66(21):10292–301. https://doi.org/10.1158/0008-5472.CAN-05-4414.

    Article  CAS  PubMed  Google Scholar 

  22. Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, et al. Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 2005;7(6):R953–64. https://doi.org/10.1186/bcr1325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lance D, Miller JS, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. PNAS. 2005;102(38):13550–5.

    Article  Google Scholar 

  24. Nagy A, Lanczky A, Menyhart O, Gyorffy B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep. 2018;8(1):9227. https://doi.org/10.1038/s41598-018-27521-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat. 2010;123(3):725–31. https://doi.org/10.1007/s10549-009-0674-9.

    Article  CAS  PubMed  Google Scholar 

  26. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52. https://doi.org/10.1038/nature10983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stefan GluCk JSR, Royce M, Edward F, Jr. McKenna, Perou CM, Avisar E, Lin W. TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine—trastuzumab. Breast Cancer Res Treat. 2012;132:781–91. https://doi.org/10.1007/s10549-011-1412-7.

    Article  CAS  PubMed  Google Scholar 

  28. Chandrashekar D, Bashel B, Balasubramanya S, Creighton C, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia (New York, NY). 2017;19(8):649–58. https://doi.org/10.1016/j.neo.2017.05.002.

    Article  CAS  Google Scholar 

  29. Guo X, Yan Z, Zhang G, Wang X, Pan Y, Huang M. STIP1 regulates proliferation and migration of lung adenocarcinoma through JAK2/STAT3 signaling pathway. Cancer Manag Res. 2019;11:10061–72. https://doi.org/10.2147/CMAR.S233758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jin W. Role of JAK/STAT3 signaling in the regulation of metastasis, the transition of cancer stem cells, and chemoresistance of cancer by epithelial-mesenchymal transition. Cells. 2020;9:1. https://doi.org/10.3390/cells9010217.

    Article  CAS  Google Scholar 

  31. Tsai CL, Chao A, Jung SM, Tsai CN, Lin CY, Chen SH, et al. Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells. Oncotarget. 2016;7(31):50548–63. https://doi.org/10.18632/oncotarget.10500.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lehmann BD, Pietenpol JA. Clinical implications of molecular heterogeneity in triple negative breast cancer. Breast. 2015;24(Suppl 2):S36-40. https://doi.org/10.1016/j.breast.2015.07.009.

    Article  PubMed  Google Scholar 

  33. Baindur-Hudson S, Edkins AL, Blatch GL. Hsp70/Hsp90 organising protein (hop): beyond interactions with chaperones and prion proteins. Subcell Biochem. 2015;78:69–90. https://doi.org/10.1007/978-3-319-11731-7_3.

    Article  CAS  PubMed  Google Scholar 

  34. Beraldo FH, Soares IN, Goncalves DF, Fan J, Thomas AA, Santos TG, et al. Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. FASEB J. 2013;27(9):3594–607. https://doi.org/10.1096/fj.13-232280.

    Article  CAS  PubMed  Google Scholar 

  35. Yin H, Deng Z, Li X, Li Y, Yin W, Zhao G, et al. Down-regulation of STIP1 regulate apoptosis and invasion of glioma cells via TRAP1/AKT signaling pathway. Cancer Genet. 2019;237:1–9. https://doi.org/10.1016/j.cancergen.2019.05.006.

    Article  CAS  PubMed  Google Scholar 

  36. Luo X, Liu Y, Ma S, Liu L, Xie R, Li M, et al. STIP1 is over-expressed in hepatocellular carcinoma and promotes the growth and migration of cancer cells. Gene. 2018;662:110–7. https://doi.org/10.1016/j.gene.2018.03.076.

    Article  CAS  PubMed  Google Scholar 

  37. Krafft U, Tschirdewahn S, Hess J, Harke NN, Hadaschik BA, Nyirady P, et al. STIP1 tissue expression is associated with survival in chemotherapy-treated bladder cancer patients. Pathol Oncol Res. 2020;26(2):1243–9. https://doi.org/10.1007/s12253-019-00689-y.

    Article  CAS  PubMed  Google Scholar 

  38. Jiang YZ, Ma D, Suo C, Shi J, Xue M, Hu X, et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell. 2019;35(3):428–40. https://doi.org/10.1016/j.ccell.2019.02.001.

    Article  CAS  PubMed  Google Scholar 

  39. Miklossy G, Hilliard TS, Turkson J. Therapeutic modulators of STAT signalling for human diseases. Nat Rev Drug Discov. 2013;12(8):611–29. https://doi.org/10.1038/nrd4088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chang R, Song L, Xu Y, Wu Y, Dai C, Wang X, et al. Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis. Nat Commun. 2018;9(1):3486. https://doi.org/10.1038/s41467-018-05852-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lin WH, Dai WG, Xu XD, Yu QH, Zhang B, Li J, et al. Downregulation of DPF3 promotes the proliferation and motility of breast cancer cells through activating JAK2/STAT3 signaling. Biochem Biophys Res Commun. 2019;514(3):639–44. https://doi.org/10.1016/j.bbrc.2019.04.170.

    Article  CAS  PubMed  Google Scholar 

  42. Groner B, von Manstein V. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol. 2017;451:1–14. https://doi.org/10.1016/j.mce.2017.05.033.

    Article  CAS  PubMed  Google Scholar 

  43. Cho KH, Jeong KJ, Shin SC, Kang J, Park CG, Lee HY. STAT3 mediates TGF-beta1-induced TWIST1 expression and prostate cancer invasion. Cancer Lett. 2013;336(1):167–73. https://doi.org/10.1016/j.canlet.2013.04.024.

    Article  CAS  PubMed  Google Scholar 

  44. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18(2):189–218. https://doi.org/10.1038/sj.leu.2403241.

    Article  CAS  PubMed  Google Scholar 

  45. Wu Y, Sarkissyan M, Vadgama JV. Epithelial-mesenchymal transition and breast cancer. J Clin Med. 2016;5:2. https://doi.org/10.3390/jcm5020013.

    Article  CAS  Google Scholar 

  46. Chen Z, Xu L, Su T, Ke Z, Peng Z, Zhang N, et al. Autocrine STIP1 signaling promotes tumor growth and is associated with disease outcome in hepatocellular carcinoma. Biochem Biophys Res Commun. 2017;493(1):365–72. https://doi.org/10.1016/j.bbrc.2017.09.016.

    Article  CAS  PubMed  Google Scholar 

  47. Tsai C, Tsai C, Lin C, Chen H, Lee Y, Chao A, et al. Secreted stress-induced phosphoprotein 1 activates the ALK2-SMAD signaling pathways and promotes cell proliferation of ovarian cancer cells. Cell reports. 2012;2(2):283–93. https://doi.org/10.1016/j.celrep.2012.07.002.

    Article  CAS  PubMed  Google Scholar 

  48. Wang J, Gong C, Guo F, Zhou X, Zhang M, Qiu H, et al. Knockdown of STIP1 inhibits the invasion of CD133-positive cancer stem-like cells of the osteosarcoma MG63 cell line via the PI3K/Akt and ERK1/2 pathways. Int J Mol Med. 2020;46(6):2251–9. https://doi.org/10.3892/ijmm.2020.4764.

    Article  CAS  PubMed  Google Scholar 

  49. Wang T, Chao A, Tsai C, Chang C, Chen S, Lee Y, et al. Stress-induced phosphoprotein 1 as a secreted biomarker for human ovarian cancer promotes cancer cell proliferation. Mol Cell Proteom MCP. 2010;9(9):1873–84. https://doi.org/10.1074/mcp.M110.000802.

    Article  CAS  Google Scholar 

Download references

Funding

This study was funded by the National Natural Science Foundation of China (No. 81572291), the Natural Science Foundation of Zhejiang Province (LGF18H160031, LY18H160053), and the Science And Technology Project of Wenzhou (Y20190204, Y20170740).

Author information

Author notes

  1. Lizhi Lin and Jialiang Wen contributed equally to this work.

Authors and Affiliations

  1. Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China

    Lizhi Lin, Jialiang Wen, Bangyi Lin, Erjie Xia, Chen Zheng, Yinghao Wang, Ouchen Wang & Yizuo Chen

  2. Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China

    Lechi Ye

Authors
  1. Lizhi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jialiang Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bangyi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erjie Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lechi Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yinghao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ouchen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yizuo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LL and JW wrote the manuscript. JW and BL did the main experiments. EX and CZ analyzed the raw data. YW and LY revised the manuscript. YC and OW designed and funded the whole work.

Corresponding author

Correspondence to Yizuo Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The ethics approval of this study was acquired from the Institutional Review Board of First Affiliated Hospital of Wenzhou Medical University (Approval no. 2012‐57).

Informed consent

All patients provided written informed consent.

Additional information

Publisher's Note

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

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, L., Wen, J., Lin, B. et al. Stress-induced phosphoprotein 1 facilitates breast cancer cell progression and indicates poor prognosis for breast cancer patients. Human Cell 34, 901–917 (2021). https://doi.org/10.1007/s13577-021-00507-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-021-00507-1

Keywords

Search

Navigation