STAT5b is a marker of poor prognosis, rather than a therapeutic target in glioblastomas

Dubois,Nadège; Dubois,Nadège; Berendsen,Sharon; Berendsen,Sharon; Tan,Katherine; Tan,Katherine; Schoysmans,Laurent; Schoysmans,Laurent; Spliet,Wim; Spliet,Wim; Seute,Tatjana; Seute,Tatjana; Bours,Vincent; Bours,Vincent; Robe,Pierre A.; Robe,Pierre A.

doi:10.3892/ijo.2022.5414

STAT5b is a marker of poor prognosis, rather than a therapeutic target in glioblastomas

Authors:
- Nadège Dubois
- Sharon Berendsen
- Katherine Tan
- Laurent Schoysmans
- Wim Spliet
- Tatjana Seute
- Vincent Bours
- Pierre A. Robe
View Affiliations

Affiliations: Department of Neurology and Neurosurgery, and The T&P Bohnenn Laboratory for Neuro‑Oncology, University Medical Center of Utrecht, 3584CX Utrecht, The Netherlands, Department of Radiology, University Medical Center of Liège, 4000 Liege, Belgium, Department of Pathology, University Medical Center of Utrecht, 3584CX Utrecht, The Netherlands, Human Genetics Laboratory, GIGA‑Cancer Center, University of Liège, 4000 Liege, Belgium
Published online on: September 5, 2022 https://doi.org/10.3892/ijo.2022.5414
Article Number: 124
Copyright: © Dubois et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The copy number and mRNA expression of STAT5b were assessed in samples from the TCGA repository of glioblastomas (GBM). The activation of this transcription factor was analyzed on tissue microarrays comprising 392 WHO 2016 GBM samples from our clinical practice. These data were correlated with patient survival using multivariable Cox analysis and, for a subset of 167 tumors, with signs of tumor invasiveness on the MRI. The effects of STAT5b knockdown by siRNA were assessed on the growth, therapeutic resistance, invasion and migration of GBM cell lines U87, U87‑EGFRVIII and LN18 and primary cultures GM2 and GM3. The activation, but not the copy number or the mRNA expression of nuclear transcription factor STAT5b expression correlated inversely with patient survival independently of IDH1R132H status, age, Karnofsky Performance Score, treatment and tumor volume. STAT5b inhibition neither altered the cell proliferation nor reduced the clonogenic proliferative potency of GBM cells, and did not sensitize them to the cytotoxic effect of ionizing radiation and temozolomide in vitro. STAT5b inhibition significantly increased GBM cell migration, but decreased the invasion of some GBM cells in vitro. There was no correlation between the activation of STAT5b in clinical tumors and the extent of invasion on MRI OF patients. In conclusion, STAT5b is frequently activated in GBM and correlates inversely with patient survival. It does not contribute to the growth and resistance of these tumors, and is thus rather a potential prognostic marker than a therapeutic target in these tumors.

View Figures

View References

1	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
2	Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, et al: Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA. 314:2535–2543. 2015. View Article : Google Scholar : PubMed/NCBI
3	Bell EH, Pugh SL, McElroy JP, Gilbert MR, Mehta M, Klimowicz AC, Magliocco A, Bredel M, Robe P, Grosu AL, et al: Molecular-based recursive partitioning analysis model for glioblastoma in the temozolomide era: A correlative analysis based on NRG oncology RTOG 0525. JAMA Oncol. 3:784–792. 2017. View Article : Google Scholar : PubMed/NCBI
4	Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, et al: Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 372:2499–2508. 2015. View Article : Google Scholar : PubMed/NCBI
5	Maurer B, Kollmann S, Pickem J, Hoelbl-Kovacic A and Sexl V: STAT5A and STAT5B-twins with different personalities in hematopoiesis and leukemia. Cancers (Basel). 11:17262019. View Article : Google Scholar
6	Kuo YH, Chen YT, Tsai HP, Chai CY and Kwan AL: Nucleophosmin overexpression is associated with poor survival in astrocytoma. APMIS. 123:515–522. 2015. View Article : Google Scholar : PubMed/NCBI
7	Liang QC, Xiong H, Zhao ZW, Jia D, Li WX, Qin HZ, Deng JP, Gao L, Zhang H and Gao GD: Inhibition of transcription factor STAT5b suppresses proliferation, induces G1 cell cycle arrest and reduces tumor cell invasion in human glioblastoma multiforme cells. Cancer Lett. 273:164–171. 2009. View Article : Google Scholar
8	Latha K, Li M, Chumbalkar V, Gururaj A, Hwang Y, Dakeng S, Sawaya R, Aldape K, Cavenee WK, Bogler O and Furnari FB: Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. Int J Cancer. 132:509–520. 2013. View Article : Google Scholar :
9	Cao S, Wang C, Zheng Q, Qiao Y, Xu K, Jiang T and Wu A: STAT5 regulates glioma cell invasion by pathways dependent and independent of STAT5 DNA binding. Neurosci Lett. 487:228–233. 2011. View Article : Google Scholar
10	Lin JX and Leonard WJ: The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene. 19:2566–2576. 2000. View Article : Google Scholar : PubMed/NCBI
11	Chumbalkar V, Latha K, Hwang Y, Maywald R, Hawley L, Sawaya R, Diao L, Baggerly K, Cavenee WK, Furnari FB and Bogler O: Analysis of phosphotyrosine signaling in glioblastoma identifies STAT5 as a novel downstream target of ΔEGFR. J Proteome Res. 10:1343–1352. 2011. View Article : Google Scholar : PubMed/NCBI
12	Roos A, Dhruv HD, Peng S, Tuncali S, Pineda M, Millard N, Mayo Z, Eschbacher JM, Loftus JC, Winkles JA and Tran NL: EGFRvIII-Stat5 signaling enhances glioblastoma cell migration and survival. Mol Cancer Res. 16:1185–1195. 2018. View Article : Google Scholar : PubMed/NCBI
13	Tan C, Dai Y, Liu X, Zhao G, Wang W, Li J and Qi L: STAT5A induced LINC01198 promotes proliferation of glioma cells through stabilizing DGCR8. Aging (Albany NY). 12:5675–5692. 2020. View Article : Google Scholar
14	Zhang Y, Kim J, Mueller AC, Dey B, Yang Y, Lee DH, Hachmann J, Finderle S, Park DM, Christensen J, et al: Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma. Cell Death Differ. 21:720–734. 2014. View Article : Google Scholar : PubMed/NCBI
15	Sawada T, Arai D, Jing X, Miyajima M, Frank SJ and Sakaguchi K: Molecular interactions of EphA4, growth hormone receptor, Janus kinase 2, and signal transducer and activator of transcription 5B. PLoS One. 12:e01807852017. View Article : Google Scholar : PubMed/NCBI
16	Liu YL, Liu PF, Liu HE, Ma LX and Li G: Association between STAT5 polymorphisms and glioblastoma risk in Han Chinese population. Pathol Res Pract. 210:582–585. 2014. View Article : Google Scholar : PubMed/NCBI
17	Televantou D, Karkavelas G, Hytiroglou P, Lampaki S, Iliadis G, Selviaridis P, Polyzoidis KS, Fountzilas G and Kotoula V: DARPP32, STAT5 and STAT3 mRNA expression ratios in glioblastomas are associated with patient outcome. Pathol Oncol Res. 19:329–343. 2013. View Article : Google Scholar
18	Berendsen S, Spliet WGM, Geurts M, Van Hecke W, Seute T, Snijders TJ, Bours V, Bell EH, Chakravarti A and Robe PA: Epilepsy associates with decreased HIF-1α/STAT5b signaling in glioblastoma. Cancers (Basel). 11:412019. View Article : Google Scholar
19	Berendsen S, Varkila M, Kroonen J, Seute T, Snijders TJ, Kauw F, Spliet WG, Willems M, Poulet C, Broekman ML, et al: Prognostic relevance of epilepsy at presentation in glioblastoma patients. Neuro Oncol. 18:700–706. 2016. View Article : Google Scholar :
20	Robe PA, Bentires-Alj M, Bonif M, Rogister B, Deprez M, Haddada H, Khac MT, Jolois O, Erkmen K, Merville MP, et al: In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res. 10:5595–5603. 2004. View Article : Google Scholar : PubMed/NCBI
21	Fan QW, Cheng CK, Gustafson WC, Charron E, Zipper P, Wong RA, Chen J, Lau J, Knobbe-Thomsen C, Weller M, et al: EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell. 24:438–449. 2013. View Article : Google Scholar : PubMed/NCBI
22	Yang C, Huang W, Yan L, Wang Y, Wang W, Liu D and Zuo X: Downregulation of the expression of B-cell lymphoma-extra large by RNA interference induces apoptosis and enhances the radiosensitivity of nonsmall cell lung cancer cells. Mol Med Rep. 12:449–455. 2015. View Article : Google Scholar : PubMed/NCBI
23	Hsia DA, Mitra SK, Hauck CR, Streblow DN, Nelson JA, Ilic D, Huang S, Li E, Nemerow GR, Leng J, et al: Differential regulation of cell motility and invasion by FAK. J Cell Biol. 160:753–767. 2003. View Article : Google Scholar : PubMed/NCBI
24	Gressot LV, Doucette TA, Yang Y, Fuller GN, Heimberger AB, Bögler O, Rao A, Latha K and Rao G: Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis. Int J Cancer. 136:2047–2054. 2015. View Article : Google Scholar :
25	Bredel M, Scholtens DM, Yadav AK, Alvarez AA, Renfrow JJ, Chandler JP, Yu IL, Carro MS, Dai F, Tagge MJ, et al: NFKBIA deletion in glioblastomas. N Engl J Med. 364:627–637. 2011. View Article : Google Scholar