IL-6 induces tumor suppressor protein tyrosine phosphatase receptor type D by inhibiting miR-34a to prevent IL-6 signaling overactivation

Abstract

Protein tyrosine phosphatase receptor type D (PTPRD) is a tumor suppressor gene that is epigenetically silenced and mutated in several cancers, including breast cancer. Since IL-6/STAT3 signaling is often hyperactivated in breast cancer and STAT3 is a direct PTPRD substrate, we investigated the role of PTPRD in breast cancer and the association between PTPRD and IL-6/STAT3 signaling. We found that PTPRD acts as a tumor suppressor in breast cancer tissues and that high PTPRD expression is positively associated with tumor size, lymph node metastasis, PCNA expression, and patient survival. Moreover, breast cancers with high PTPRD expression tend to exhibit high IL-6 and low phosphorylated-STAT3 expression. IL-6 was found to inhibit miR-34a transcription and induce PTPRD expression in breast cancer and breast epithelial cells, whereas PTPRD was shown to mediate activated STAT3 dephosphorylation and to be a conserved, direct target of miR-34a. IL-6-induced PTPRD upregulation was blocked by miR-34a mimics, whereas experimental PTPRD overexpression suppressed MDA-MB-231 cell migration, invasion, and epithelial to mesenchymal transition, decreased STAT3 phosphorylation, and increased miR-34a transcription. Our findings suggest that PTPRD mediates activated STAT3 dephosphorylation and is induced by the IL-6/STAT3-mediated transcriptional inhibition of miR-34a, thereby establishing a negative feedback loop that inhibits IL-6/STAT3 signaling overactivation.

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

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

Data availability

Any materials and data are available from the corresponding author on reasonable request.

References

  1. 1.

    Lee EY, Muller WJ (2010) Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol 2:a003236. https://doi.org/10.1101/cshperspect.a003236

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Zhu K, Liu Q, Zhou Y, Tao C, Zhao Z, Sun J, Xu H (2015) Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. BMC Genomics 16(Suppl 7):S8. https://doi.org/10.1186/1471-2164-16-s7-s8

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Wang D, Wang L, Zhou J, Pan J, Qian W, Fu J, Zhang G, Zhu Y, Liu C, Wang C, Jin Z, He Z, Wu J, Shi B (2014) Reduced expression of PTPRD correlates with poor prognosis in gastric adenocarcinoma. PLoS ONE 9:e113754. https://doi.org/10.1371/journal.pone.0113754

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Ortiz B, Fabius AW, Wu WH, Pedraza A, Brennan CW, Schultz N, Pitter KL, Bromberg JF, Huse JT, Holland EC, Chan TA (2014) Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis. Proc Natl Acad Sci USA 111:8149–8154. https://doi.org/10.1073/pnas.1401952111

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Kohno T, Otsuka A, Girard L, Sato M, Iwakawa R, Ogiwara H, Sanchez-Cespedes M, Minna JD, Yokota J (2010) A catalog of genes homozygously deleted in human lung cancer and the candidacy of PTPRD as a tumor suppressor gene. Genes Chromosomes Cancer 49:342–352. https://doi.org/10.1002/gcc.20746

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Szaumkessel M, Wojciechowska S, Janiszewska J, Zemke N, Byzia E, Kiwerska K, Kostrzewska-Poczekaj M, Ustaszewski A, Jarmuz-Szymczak M, Grenman R, Wierzbicka M, Bartochowska A, Szyfter K, Giefing M (2017) Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma. Tumour Biol 39:1010428317691427. https://doi.org/10.1177/1010428317691427

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Lyu J, Song Z, Chen J, Shepard MJ, Song H, Ren G, Li Z, Guo W, Zhuang Z, Shi Y (2018) Whole-exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets. J Pathol 244:358–366. https://doi.org/10.1002/path.5017

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Budczies J, Bockmayr M, Denkert C, Klauschen F, Lennerz JK, Gyorffy B, Dietel M, Loibl S, Weichert W, Stenzinger A (2015) Classical pathology and mutational load of breast cancer—integration of two worlds. J Pathol Clin Res 1:225–238. https://doi.org/10.1002/cjp2.25

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Van Renne N, Roca Suarez AA, Duong FHT, Gondeau C, Calabrese D, Fontaine N, Ababsa A, Bandiera S, Croonenborghs T, Pochet N, De Blasi V, Pessaux P, Piardi T, Sommacale D, Ono A, Chayama K, Fujita M, Nakagawa H, Hoshida Y, Zeisel MB, Heim MH, Baumert TF, Lupberger J (2018) miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis. Gut 67:953–962. https://doi.org/10.1136/gutjnl-2016-312270

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Hsu HC, Lapke N, Chen SJ, Lu YJ, Jhou RS, Yeh CY, Tsai WS, Hung HY, Hsieh JC, Yang TS, Thiam TK, You JF (2018) PTPRT and PTPRD deleterious mutations and deletion predict bevacizumab resistance in metastatic colorectal cancer patients. Cancers (Basel). https://doi.org/10.3390/cancers10090314

    Article  PubMed Central  Google Scholar 

  11. 11.

    (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70. https://doi.org/10.1038/nature11412

  12. 12.

    Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, Cope L, Herman JG, Velculescu V, Schuebel KE, Ahuja N, Baylin SB (2008) Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5:e114. https://doi.org/10.1371/journal.pmed.0050114

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14:736–746. https://doi.org/10.1038/nrc3818

    CAS  Article  Google Scholar 

  14. 14.

    Wendt MK, Balanis N, Carlin CR, Schiemann WP (2014) STAT3 and epithelial-mesenchymal transitions in carcinomas. Jakstat 3:e28975. https://doi.org/10.4161/jkst.28975

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Zhang F, Li L, Yang X, Wang B, Zhao J, Lu S, Yu X (2015) Expression and activation of EGFR and STAT3 during the multistage carcinogenesis of intrahepatic cholangiocarcinoma induced by 3'-methyl-4 dimethylaminoazobenzene in rats. J Toxicol Pathol 28:79–87. https://doi.org/10.1293/tox.2014-0047

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Banerjee K, Resat H (2016) Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer 138:2570–2578. https://doi.org/10.1002/ijc.29923

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Zhang N, Zhang M, Wang Z, Gao W, Sun ZG (2020) Activated STAT3 could reduce survival in patients with esophageal squamous cell carcinoma by up-regulating VEGF and cyclin D1 expression. J Cancer 11:1859–1868. https://doi.org/10.7150/jca.38798

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Chun J, Park MK, Ko H, Lee K, Kim YS (2018) Bioassay-guided isolation of cantharidin from blister beetles and its anticancer activity through inhibition of epidermal growth factor receptor-mediated STAT3 and Akt pathways. J Nat Med 72:937–945. https://doi.org/10.1007/s11418-018-1226-6

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Zhang S, Yang Y, Huang S, Deng C, Zhou S, Yang J, Cao Y, Xu L, Yuan Y, Yang J, Chen G, Zhou L, Lv Y, Wang L, Zou X (2019) SIRT1 inhibits gastric cancer proliferation and metastasis via STAT3/MMP-13 signaling. J Cell Physiol 234:15395–15406. https://doi.org/10.1002/jcp.28186

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Wu Y, Diab I, Zhang X, Izmailova ES, Zehner ZE (2004) Stat3 enhances vimentin gene expression by binding to the antisilencer element and interacting with the repressor protein, ZBP-89. Oncogene 23:168–178. https://doi.org/10.1038/sj.onc.1207003

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Tutar L, Ozgur A, Tutar Y (2018) Involvement of miRNAs and Pseudogenes in cancer. Methods Mol Biol 1699:45–66. https://doi.org/10.1007/978-1-4939-7435-1_3

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, Kaller M, Horst D, Ziegler PK, Schwitalla S, Slotta-Huspenina J, Bader FG, Greten FR, Hermeking H (2014) IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 124:1853–1867. https://doi.org/10.1172/jci73531

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Li F, Li XJ, Qiao L, Shi F, Liu W, Li Y, Dang YP, Gu WJ, Wang XG, Liu W (2014) miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6. Exp Mol Med 46:e116. https://doi.org/10.1038/emm.2014.63

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Xiang M, Birkbak NJ, Vafaizadeh V, Walker SR, Yeh JE, Liu S, Kroll Y, Boldin M, Taganov K, Groner B, Richardson AL, Frank DA (2014) STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-kappaB to IL-6 signaling axis and STAT3-driven cancer phenotypes. Sci Signal 7:ra11. https://doi.org/10.1126/scisignal.2004497

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Zhu X, Shen H, Yin X, Long L, Chen X, Feng F, Liu Y, Zhao P, Xu Y, Li M, Xu W, Li Y (2017) IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells. Oncotarget 8:39154–39166. https://doi.org/10.18632/oncotarget.16610

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K (2010) STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 39:493–506. https://doi.org/10.1016/j.molcel.2010.07.023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M, Ulrich S, Speich R, Huber LC (2009) Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res 104:1184–1191. https://doi.org/10.1161/circresaha.109.197491

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Guo L, Chen C, Shi M, Wang F, Chen X, Diao D, Hu M, Yu M, Qian L, Guo N (2013) Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition. Oncogene 32:5272–5282. https://doi.org/10.1038/onc.2012.573

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Lin X, Lin BW, Chen XL, Zhang BL, Xiao XJ, Shi JS, Lin JD, Chen X (2017) PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in Non-small cell lung cancer. Biochem Biophys Res Commun 493:1464–1470. https://doi.org/10.1016/j.bbrc.2017.10.014

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Shi X, Kaller M, Rokavec M, Kirchner T, Horst D, Hermeking H (2020) Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal Cancer. Cell Mol Gastroenterol Hepatol. https://doi.org/10.1016/j.jcmgh.2020.04.002

    Article  PubMed  Google Scholar 

  31. 31.

    Lee HM, Kim TS, Jo EK (2016) MiR-146 and miR-125 in the regulation of innate immunity and inflammation. BMB Rep 49:311–318. https://doi.org/10.5483/bmbrep.2016.49.6.056

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Senfter D, Madlener S, Krupitza G, Mader RM (2016) The microRNA-200 family: still much to discover. Biomol Concepts 7:311–319. https://doi.org/10.1515/bmc-2016-0020

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Veeriah S, Brennan C, Meng S, Singh B, Fagin JA, Solit DB, Paty PB, Rohle D, Vivanco I, Chmielecki J, Pao W, Ladanyi M, Gerald WL, Liau L, Cloughesy TC, Mischel PS, Sander C, Taylor B, Schultz N, Major J, Heguy A, Fang F, Mellinghoff IK, Chan TA (2009) The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. Proc Natl Acad Sci USA 106:9435–9440. https://doi.org/10.1073/pnas.0900571106

    Article  PubMed  Google Scholar 

  34. 34.

    Funato K, Yamazumi Y, Oda T, Akiyama T (2011) Tyrosine phosphatase PTPRD suppresses colon cancer cell migration in coordination with CD44. Exp Ther Med 2:457–463. https://doi.org/10.3892/etm.2011.231

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Pulido R, Serra-Pagès C, Tang M, Streuli M (1995) The LAR/PTP delta/PTP sigma subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTP delta, and PTP sigma isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proc Natl Acad Sci USA 92:11686–11690. https://doi.org/10.1073/pnas.92.25.11686

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Chaudhary F, Lucito R, Tonks NK (2015) Missing-in-metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity. Biochem J 465:89–101. https://doi.org/10.1042/bj20140573

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Gonzalez-Quevedo R, Shoffer M, Horng L, Oro AE (2005) Receptor tyrosine phosphatase-dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4. J Cell Biol 168:453–463. https://doi.org/10.1083/jcb.200409078

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Walia V, Prickett TD, Kim JS, Gartner JJ, Lin JC, Zhou M, Rosenberg SA, Elble RC, Solomon DA, Waldman T, Samuels Y (2014) Mutational and functional analysis of the tumor-suppressor PTPRD in human melanoma. Hum Mutat 35:1301–1310. https://doi.org/10.1002/humu.22630

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Wu A, Yang X, Zhang B, Wang S, Li G (2019) miR-516a-3p promotes proliferation, migration, and invasion and inhibits apoptosis in lung adenocarcinoma by targeting PTPRD. Int J Clin Exp Pathol 12:4222–4231

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Ortiz B, White JR, Wu WH, Chan TA (2014) Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Oncotarget 5:6976–6982. https://doi.org/10.18632/oncotarget.2106

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Mohammady M, Ghetmiri SI, Baharizade M, Morowvat MH, Torabi S (2019) Expanding the biotherapeutics realm via miR-34a: "Potent Clever Little" agent in breast cancer therapy. Curr Pharm Biotechnol 20:665–673. https://doi.org/10.2174/1389201020666190617162042

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Adams BD, Parsons C, Slack FJ (2016) The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. Expert Opin Ther Targets 20:737–753. https://doi.org/10.1517/14728222.2016.1114102

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Li MX, Bi XY, Huang Z, Zhao JJ, Han Y, Li ZY, Zhang YF, Li Y, Chen X, Hu XH, Zhao H, Cai JQ (2015) Prognostic role of phospho-STAT3 in patients with cancers of the digestive system: a systematic review and meta-analysis. PLoS ONE 10:e0127356. https://doi.org/10.1371/journal.pone.0127356

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Liu Y, Huang J, Li W, Chen Y, Liu X, Wang J (2018) Meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with breast cancer. Oncotarget 9:13060–13067. https://doi.org/10.18632/oncotarget.23962

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Wu P, Wu D, Zhao L, Huang L, Shen G, Huang J, Chai Y (2016) Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis. Oncotarget 7:19863–19883. https://doi.org/10.18632/oncotarget.7887

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant Number #81272430).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Xiaotang Yu or Lianhong Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest concerning this article.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 250 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, F., Wang, B., Qin, T. et al. IL-6 induces tumor suppressor protein tyrosine phosphatase receptor type D by inhibiting miR-34a to prevent IL-6 signaling overactivation. Mol Cell Biochem (2020). https://doi.org/10.1007/s11010-020-03803-w

Download citation

Keywords

  • Interleukin-6
  • Signal transducer and activator of transcription 3
  • Protein tyrosine phosphatase receptor type D
  • MicroRNA-34a