Identification and Validation of TSPAN13 As a Novel Temozolomide Resistance-related Gene Prognostic Biomarker in Glioblastoma

Overview

Journal PLoS One

Date 2025 Feb 4

PMID 39903772

Authors

Haofei Wang

Zhen Liu

Zesheng Peng

Peng Lv

Peng Fu

Xiaobing Jiang

Affiliations

Soon will be listed here.

Abstract

Glioblastoma (GBM) is the most lethal primary tumor of the central nervous system, with its resistance to treatment posing significant challenges. This study aims to develop a comprehensive prognostic model to identify biomarkers associated with temozolomide (TMZ) resistance. We employed a multifaceted approach, combining differential expression and univariate Cox regression analyses to screen for TMZ resistance-related differentially expressed genes (TMZR-RDEGs) in GBM. Using LASSO Cox analysis, we selected 12 TMZR-RDEGs to construct a risk score model, which was evaluated for performance through survival analysis, time-dependent ROC, and stratified analyses. Functional enrichment and mutation analyses were conducted to explore the underlying mechanisms of the risk score and its relationship with immune cell infiltration levels in GBM. The prognostic risk score model, based on the 12 TMZR-RDEGs, demonstrated high efficacy in predicting GBM patient outcomes and emerged as an independent predictive factor. Additionally, we focused on the molecule TSPAN13, whose role in GBM is not well understood. We assessed cell proliferation, migration, and invasion capabilities through in vitro assays (including CCK-8, Edu, wound healing, and transwell assays) and quantitatively analyzed TSPAN13 expression levels in clinical glioma samples using tissue microarray immunohistochemistry. The impact of TSPAN13 on TMZ resistance in GBM cells was validated through in vitro experiments and a mouse orthotopic xenograft model. Notably, TSPAN13 was upregulated in GBM and correlated with poorer patient prognosis. Knockdown of TSPAN13 inhibited GBM cell proliferation, migration, and invasion, and enhanced sensitivity to TMZ treatment. This study provides a valuable prognostic tool for GBM and identifies TSPAN13 as a critical target for therapeutic intervention.

References

Berger Y, Dehmlow H, Blum-Kaelin D, Kitas E, Loffler B, Aebi J . Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells. J Med Chem. 2005; 48(2):483-98. DOI: 10.1021/jm040857x. View

Alhamzawi R, Mohammad Ali H . The Bayesian adaptive lasso regression. Math Biosci. 2018; 303:75-82. DOI: 10.1016/j.mbs.2018.06.004. View

Lorente M, Torres S, Salazar M, Carracedo A, Hernandez-Tiedra S, Rodriguez-Fornes F . Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ. 2011; 18(6):959-73. PMC: 3131933. DOI: 10.1038/cdd.2010.170. View

Kamil M, Shinsato Y, Higa N, Hirano T, Idogawa M, Takajo T . High filamin-C expression predicts enhanced invasiveness and poor outcome in glioblastoma multiforme. Br J Cancer. 2019; 120(8):819-826. PMC: 6474268. DOI: 10.1038/s41416-019-0413-x. View

Zhao Z, Zhang K, Wang Q, Li G, Zeng F, Zhang Y . Chinese Glioma Genome Atlas (CGGA): A Comprehensive Resource with Functional Genomic Data from Chinese Glioma Patients. Genomics Proteomics Bioinformatics. 2021; 19(1):1-12. PMC: 8498921. DOI: 10.1016/j.gpb.2020.10.005. View

Brennan C, Verhaak R, McKenna A, Campos B, Noushmehr H, Salama S . The somatic genomic landscape of glioblastoma. Cell. 2013; 155(2):462-77. PMC: 3910500. DOI: 10.1016/j.cell.2013.09.034. View

Zhang H, Wang Y, Zhao Y, Liu T, Wang Z, Zhang N . PTX3 mediates the infiltration, migration, and inflammation-resolving-polarization of macrophages in glioblastoma. CNS Neurosci Ther. 2022; 28(11):1748-1766. PMC: 9532932. DOI: 10.1111/cns.13913. View

Louis D, Perry A, Wesseling P, Brat D, Cree I, Figarella-Branger D . The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021; 23(8):1231-1251. PMC: 8328013. DOI: 10.1093/neuonc/noab106. View

Cheng S, Liu L, Wang D, Li Y, Li S, Yuan J . Upregulation of the ZNF148/PTX3 axis promotes malignant transformation of dendritic cells in glioma stem-like cells microenvironment. CNS Neurosci Ther. 2023; 29(9):2690-2704. PMC: 10401131. DOI: 10.1111/cns.14213. View

10.

Oliva C, Halloran B, Hjelmeland A, Vazquez A, Bailey S, Sarkaria J . IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling. Cell Commun Signal. 2018; 16(1):61. PMC: 6148802. DOI: 10.1186/s12964-018-0273-7. View

11.

Minchenko D, Kharkova A, Karbovskyi L, Minchenko O . Expression of insulin-like growth factor binding protein genes and its hypoxic regulation in U87 glioma cells depends on ERN1 mediated signaling pathway of endoplasmic reticulum stress. Endocr Regul. 2015; 49(2):73-83. DOI: 10.4149/endo_2015_02_73. View

12.

Reifenberger G, Wirsching H, Knobbe-Thomsen C, Weller M . Advances in the molecular genetics of gliomas - implications for classification and therapy. Nat Rev Clin Oncol. 2016; 14(7):434-452. DOI: 10.1038/nrclinonc.2016.204. View

13.

Choo M, Mai V, Kim H, Kim D, Ku J, Lee S . Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide. Acta Pharmacol Sin. 2022; 44(3):670-679. PMC: 9958008. DOI: 10.1038/s41401-022-00984-6. View

14.

Mayakonda A, Lin D, Assenov Y, Plass C, Koeffler H . Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018; 28(11):1747-1756. PMC: 6211645. DOI: 10.1101/gr.239244.118. View

15.

Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A . MGMT testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol. 2014; 10(7):372-85. DOI: 10.1038/nrneurol.2014.100. View

16.

Liu Y, Hsu J, Lin H, Lai S, Huang B, Tsai C . Bradykinin B1 receptor contributes to interleukin-8 production and glioblastoma migration through interaction of STAT3 and SP-1. Neuropharmacology. 2018; 144:143-154. DOI: 10.1016/j.neuropharm.2018.10.033. View

17.

Jaiswal R, Kumar P, Kumar M, Yadava P . hTERT promotes tumor progression by enhancing TSPAN13 expression in osteosarcoma cells. Mol Carcinog. 2018; 57(8):1038-1054. DOI: 10.1002/mc.22824. View

18.

Zhang K, Liu X, Li G, Chang X, Li S, Chen J . Clinical management and survival outcomes of patients with different molecular subtypes of diffuse gliomas in China (2011-2017): a multicenter retrospective study from CGGA. Cancer Biol Med. 2022; 19(10). PMC: 9630520. DOI: 10.20892/j.issn.2095-3941.2022.0469. View

19.

Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A . Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015; 129(6):829-48. DOI: 10.1007/s00401-015-1432-1. View

20.

Blanche P, Dartigues J, Jacqmin-Gadda H . Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks. Stat Med. 2013; 32(30):5381-97. DOI: 10.1002/sim.5958. View