The Role of The Tissue-Level Yap–Taz Pathway in Glioma Development

Year 2025, Volume: 15 Issue: 3, 690 - 694

Sinan Findik , Ebru Arslan , Pınar Ata , Yaşar Bayri , Adnan Dağçınar

Abstract

Objective: The aim of this research is to evaluate the tissue-level expression of LATS1, YAP1, PI3KCG, and WWTR1 genes, which are key components of the Hippo-YAP/TAZ signaling pathway, in relation to glioma development.
Methods: This research included tissue samples collected from 30 patients aged between 18 and 80 years who underwent neurosurgical resection at the institution’s affiliated hospital with a diagnosis of glioma. Tumor tissue samples were processed for total RNA isolation. Complementary DNA (cDNA) synthesis was subsequently performed, followed by quantitative polymerase chain reaction (qPCR) analysis to assess the relative expression levels of the selected genes. All procedures were conducted in compliance with standardized molecular protocols, and data were statistically analyzed using appropriate methods to determine expression differences.
Results: Among the genes analyzed, YAP1 demonstrated a statistically significant 2.6-fold downregulation in glioma tissues compared to adjacent non-tumoral tissues (p = 0.03). Expression changes in other genes were observed, but did not reach statistical significance within the scope of this study.
Conclusion: Our findings suggest that YAP1 may play a critical role in glioma pathogenesis. The observed downregulation indicates a potential dysregulation of the Hippo-YAP/TAZ signaling pathway in tumor development. These results underscore the importance of further investigating YAP1 and related signaling components as potential therapeutic targets in glioma and other central nervous system tumors. Future studies with larger patient cohorts and functional analyses are warranted to validate these preliminary findings.

Keywords

Glioma , YAP/TAZ , Hippo signaling pathway , gene expression

Ethical Statement

We hereby confirm that our doctoral thesis research titled “The Role of the Tissue-Level YAP–TAZ Pathway in Glioma Development” was reviewed and approved by the Marmara University Faculty of Medicine Non-Drug and Medical Device Research Ethics Committee, in accordance with international ethical standards and guidelines. The study received official ethics approval on September 20, 2024, under Protocol Number: 09.2024.1069.

Supporting Institution

This research received no external funding.

Thanks

The authors thank all contributors who supported this work.

References

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. https://doi.org/10.1056/NEJMoa043330
• Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro Oncol. 2020;22(Suppl 2):iv1-iv96. https://doi.org/10.1093/neuonc/noaa200
• Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: An updated version. Genes Dev. 2010;24(9):862-874. https://doi.org/10.1101/gad.1909210
• Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246-257. https://doi.org/10.1038/nrc3458
• Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15(2):73-79. https://doi.org/10.1038/nrc3876
• Panciera T, Azzolin L, Cordenonsi M, Piccolo S. Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol. 2017;18(12):758-770. https://doi.org/10.1038/nrm.2017.87
• Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O'Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander ES, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477. https://doi.org/10.1016/j.cell.2013.09.034
• Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323-331. https://doi.org/10.1016/S0092-8674(00)81871-1
• Knudsen ES, Wang JY. Targeting the RB-pathway in cancer therapy. Clin Cancer Res. 2010;16(4):1094-1099. https://doi.org/10.1158/1078-0432.CCR-09-0787
• Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G. Wnt/β-catenin signalling: Function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3. https://doi.org/10.1038/s41392-021-00762-6
• Takezaki T, Hide T, Takanaga H, Nakamura H, Kuratsu J, Kondo T. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci. 2011;102(7):1306-1312. https://doi.org/10.1111/j.1349-7006.2011.01943.x
• Puliyappadamba VT, Hatanpaa KJ, Chakraborty S, Habib AA. The role of NF-κB in the pathogenesis of glioma. Mol Cell Oncol. 2014;1(3):e963478. https://doi.org/10.4161/23723548.2014.963478
• Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29(6):783-803. https://doi.org/10.1016/j.ccell.2016.05.005
• Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163(4):811-828. https://doi.org/10.1016/j.cell.2015.10.044
• Casati G, Giunti L, Iorio AL, Marturano A, Galli L, Sardi I. Hippo pathway in regulating drug resistance of glioblastoma. Int J Mol Sci. 2021;22(24):13431. https://doi.org/10.3390/ijms222413431
• Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: Hippo signaling and beyond. Physiol Rev. 2014;94(4):1287-1312. https://doi.org/10.1152/physrev.00005.2014
• Dey A, Varelas X, Guan KL. Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat Rev Drug Discov. 2020;19(7):480-494. https://doi.org/10.1038/s41573-020-0070-z
• Calses PC, Crawford JJ, Lill JR, Dey A. Hippo pathway in cancer: Aberrant regulation and therapeutic opportunities. Trends Cancer 2019;5(5):297-307. https://doi.org/10.1016/j.trecan.2019.04.001
• Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, David KK, Huang B, Yabuta N, Nojima H, Anders RA, Pan D. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev. 2015;29(12):1285-1297. https://doi.org/10.1101/gad.264234.115
• Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I, Yu FX, Wang K, Ho SB, Boland BS, Chang JT, Sandborn WJ, Hardiman G, Raz E, Maehara Y, Yoshimura A, Zucman-Rossi J, Guan KL, Karin M. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature. 2015;519(7541):57-62. https://doi.org/10.1038/nature14228
• Cai J, Zhang N, Zheng Y, de Wilde RF, Maitra A, Pan D. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 2010;24(21):2383-2388. https://doi.org/10.1101/gad.1978810
• Curto M, McClatchey AI. Nf2/Merlin: A coordinator of receptor signalling and intercellular contact. Br J Cancer. 2008;98(2):256-262. https://doi.org/10.1038/sj.bjc.6604002
• Zhang J, You Q, Wang Y, Ji J. LncRNA GAS5 modulates the progression of glioma through repressing miR-135b-5p and upregulating APC. Biologics 2024;18:129-142. https://doi.org/10.2147/BTT.S454058
• Pan D. The Hippo signaling pathway in development and cancer. Dev Cell. 2010;19(4):491-505. https://doi.org/10.1016/j.devcel.2010.09.011
• Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120-1133. https://doi.org/10.1016/j.cell.2007.07.019
• Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell. 2005;122(3):421-434. https://doi.org/10.1016/j.cell.2005.06.007
• Wu H, Liu Y, Jiang XW, Li WF, Guo G, Gong JP, Ding X. Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma. Tumour Biol. 2016;37(10):13499-13508. https://doi.org/10.1007/s13277-016-5211-y
• Wu S, Huang J, Dong J, Pan D. Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with Salvador and Warts. Cell. 2003;114(4):445-456. https://doi.org/10.1016/S0092-8674(03)00549-X
• Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, Manfrin A, Ingallina E, Sommaggio R, Piazza S, Rosato A, Piccolo S, Del Sal G. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol. 2014;16(4):357-366. https://doi.org/10.1038/ncb2936
• Yang Q, Jiang W, Hou P. Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Semin Cancer Biol. 2019;59:112-124. https://doi.org/10.1016/j.semcancer.2019.04.001
• Masliantsev K, Karayan-Tapon L, Guichet PO. Hippo signaling pathway in gliomas. Cells. 2021;10(1):184. https://doi.org/10.3390/cells10010184
• Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the Hippo pathway. Mol Cell Biol. 2008;28(7):2426-2436. https://doi.org/10.1128/MCB.01874-07
• Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012;5(1):102-114. https://doi.org/10.2174/1874467211205010102
• Li Y, Xu J, Lin S, Wu S, Zheng Y. Role of the Hippo pathway in glioma development and progression. J Cell Mol Med. 2021;25(15):7173-7185. https://doi.org/10.1111/jcmm.16723
• Vigneswaran K, Boyd NH, Oh SY, Lallani S, Boucher A, Neill SG, Olson JJ, Read RD. YAP/TAZ transcriptional coactivators create therapeutic vulnerability to verteporfin in EGFR-mutant glioblastoma. Clin Cancer Res. 2021;27(5):1553-1569. https://doi.org/10.1158/1078-0432.CCR-20-0018
• Rodrigo JP, Rodríguez-Santamarta T, Corte D, García-de-la-Fuente V, Rodríguez-Torres N, Lequerica-Fernández P, Lorz C, García-Pedrero JM, de Vicente JC. Hippo-YAP signaling activation and cross-talk with PI3K in oral cancer: a retrospective cohort study. Oral Dis. 2024;30(1):149-162. https://doi.org/10.1111/odi.14350
• Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palazon A, Zhang J, Kluwe J, Govaere O, Zhang H, Brown M, Karin M, Sasik R, Peinado H, Rowbotham DA, Ruffell B, van Ginderachter JA, De Palma M, Christofk HR, Newman JW, Aerts JL, Hackett NR, DiRenzo J, Lowy AM, Offringa R, Lieberman J, Koong AC, Jain RK, Mellinghoff IK, Graeber TG, Cheresh DA, Karin M, Lawrence T, Natoli G, Underhill DM, Hanahan D, Joyce JA, Coussens LM, Hedrick CC, Verginis P, DeNardo DG, Ruffell B. PI3Kγ is a molecular switch that controls immune suppression. Nature 2016;539(7629):437-442. https://doi.org/10.1038/nature19834
• Strepkos D, Markouli M, Papavassiliou KA, Papavassiliou AG, Piperi C. Emerging roles for the YAP/TAZ transcriptional regulators in brain tumour pathology and targeting options. Neuropathol Appl Neurobiol. 2022;48(2):e12762. https://doi.org/10.1111/nan.12762
• Ji T, Zhang L, Chen Y, Xiao J, Zhang J, Cheng J, Chen Z, Zhang Q, Hu H. Decreased expression of LATS1 is correlated with the progression and prognosis of glioma. J Exp Clin Cancer Res. 2012;31(1):67. https://doi.org/10.1186/1756-9966-31-67
• Li W, Dong S, Wei W, Wang G, Zhang A, Pu P, Jia Z. The role of transcriptional coactivator TAZ in gliomas. Oncotarget 2016;7(50):82686-82699. https://doi.org/10.18632/oncotarget.12625