Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide‑resistant glioblastoma

Chen,Wu-Fu; Chen,Wu-Fu; Chuang,Jimmy Ming‑Jung; Chuang,Jimmy Ming‑Jung; Yang,San-Nan; Yang,San-Nan; Chen,Nan-Fu; Chen,Nan-Fu; Bhattacharya,Manojit; Bhattacharya,Manojit; Liu,Hsin-Tzu; Liu,Hsin-Tzu; Dhama,Kuldeep; Dhama,Kuldeep; Chakraborty,Chiranjib; Chakraborty,Chiranjib; Wen,Zhi-Hong; Wen,Zhi-Hong

doi:10.3892/ol.2024.14511

Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide‑resistant glioblastoma

Authors:
- Wu-Fu Chen
- Jimmy Ming‑Jung Chuang
- San-Nan Yang
- Nan-Fu Chen
- Manojit Bhattacharya
- Hsin-Tzu Liu
- Kuldeep Dhama
- Chiranjib Chakraborty
- Zhi-Hong Wen
View Affiliations

Affiliations: Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan, R.O.C., Department of Pediatrics, E‑DA Hospital, School of Medicine, College of Medicine I‑Shou University, Kaohsiung 82445, Taiwan, R.O.C., Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan, R.O.C., Department of Zoology, Fakir Mohan University, Balasore, Odisha 756089, India, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan, R.O.C., Division of Pathology, Indian Council of Agriculture Research‑Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243122, India, Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal 700126, India, Department of Marine Biotechnology and Resources, National Sun Yat‑sen University, Kaohsiung 80424, Taiwan, R.O.C.
Published online on: June 17, 2024 https://doi.org/10.3892/ol.2024.14511
Article Number: 378
Copyright: © Chen 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

Glioblastoma multiforme (GBM) is an aggressive brain cancer that occurs more frequently than other brain tumors. The present study aimed to reveal a novel mechanism of temozolomide resistance in GBM using bioinformatics and wet lab analyses, including meta‑Z analysis, Kaplan‑Meier survival analysis, protein‑protein interaction (PPI) network establishment, cluster analysis of co‑expressed gene networks, and hierarchical clustering of upregulated and downregulated genes. Next‑generation sequencing and quantitative PCR analyses revealed downregulated [tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 1 (TIE1), calcium voltage‑gated channel auxiliary subunit α2Δ1 (CACNA2D1), calpain 6 (CAPN6) and a disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6)] and upregulated [serum amyloid (SA)A1, SAA2, growth differentiation factor 15 (GDF15) and ubiquitin specific peptidase 26 (USP26)] genes. Different statistical models were developed for these genes using the Z‑score for P‑value conversion, and Kaplan‑Meier plots were constructed using several patient cohorts with brain tumors. The highest number of nodes was observed in the PPI network was for ADAMTS6 and TIE1. The PPI network model for all genes contained 35 nodes and 241 edges. Immunohistochemical staining was performed using isocitrate dehydrogenase (IDH)‑wild‑type or IDH‑mutant GBM samples from patients and a significant upregulation of TIE1 (P<0.001) and CAPN6 (P<0.05) protein expression was demonstrated in IDH‑mutant GBM in comparison with IDH‑wild‑type GBM. Structural analysis revealed an IDH‑mutant model demonstrating the mutant residues (R132, R140 and R172). The findings of the present study will help the future development of novel biomarkers and therapeutics for brain tumors.

View Figures

View References

1	Grech N, Dalli T, Mizzi S, Meilak L, Calleja N and Zrinzo A: Rising incidence of glioblastoma multiforme in a well-defined population. Cureus. 12:e81952020.PubMed/NCBI
2	Miller KD, Ostrom QT, Kruchko C, Patil N, Tihan T, Cioffi G, Fuchs HE, Waite KA, Jemal A, Siegel RL and Barnholtz-Sloan JS: Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin. 71:381–406. 2021. View Article : Google Scholar : PubMed/NCBI
3	Ostrom QT, Cioffi G, Waite K, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2014–2018. Neuro Oncol. 23 (12 Suppl 2):iii1–iii105. 2021. View Article : Google Scholar : PubMed/NCBI
4	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
5	Kleihues P and Ohgaki H: Primary and secondary glioblastomas: From concept to clinical diagnosis. Neuro Oncol. 1:44–51. 1999. View Article : Google Scholar : PubMed/NCBI
6	Lin D, Wang M, Chen Y, Gong J, Chen L, Shi X, Lan F, Chen Z, Xiong T, Sun H and Wan S: Trends in Intracranial glioma incidence and mortality in the United States, 1975–2018. Front Oncol. 11:7480612021. View Article : Google Scholar : PubMed/NCBI
7	Upadhyaya SA, Ghazwani Y, Wu S, Broniscer A, Boop FA, Gajjar A and Qaddoumi I: Mortality in children with low-grade glioma or glioneuronal tumors: A single-institution study. Pediatr Blood Cancer. 65:10.1002/pbc.26717. 2018. View Article : Google Scholar
8	Yao M, Li S, Wu X, Diao S, Zhang G, He H, Bian L and Lu Y: Cellular origin of glioblastoma and its implication in precision therapy. Cell Mol Immunol. 15:737–739. 2018. View Article : Google Scholar : PubMed/NCBI
9	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
10	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
11	Olivier C, Oliver L, Lalier L and Vallette FM: Drug resistance in glioblastoma: The two faces of oxidative stress. Front Mol Biosci. 7:6206772021. View Article : Google Scholar : PubMed/NCBI
12	Mansoori B, Mohammadi A, Davudian S, Shirjang S and Baradaran B: The different mechanisms of cancer drug resistance: A brief review. Adv Pharm Bull. 7:339–348. 2017. View Article : Google Scholar : PubMed/NCBI
13	Jakoby WB: The glutathione S-transferases: A group of multifunctional detoxification proteins. Adv Enzymol Relat Areas Mol Biol. 46:383–414. 1978.PubMed/NCBI
14	Oliver L, Lalier L, Salaud C, Heymann D, Cartron PF and Vallette FM: Drug resistance in glioblastoma: Are persisters the key to therapy? Cancer Drug Resist. 3:287–301. 2020.PubMed/NCBI
15	Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, Lee YK and Kwon HY: Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018:54169232018. View Article : Google Scholar : PubMed/NCBI
16	Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL and Yu JS: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 5:672006. View Article : Google Scholar : PubMed/NCBI
17	Behnan J, Finocchiaro G and Hanna G: The landscape of the mesenchymal signature in brain tumours. Brain. 142:847–866. 2019. View Article : Google Scholar : PubMed/NCBI
18	Yu Z, Chen Y, Wang S, Li P, Zhou G and Yuan Y: Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression. Cancer Lett. 428:77–89. 2018. View Article : Google Scholar : PubMed/NCBI
19	Yao L, Li J, Zhang X, Zhou L and Hu K: Downregulated ferroptosis-related gene SQLE facilitates temozolomide chemoresistance, and invasion and affects immune regulation in glioblastoma. CNS Neurosci Ther. 28:2104–2115. 2022. View Article : Google Scholar : PubMed/NCBI
20	Cohen AL, Holmen SL and Colman H: IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 13:3452013. View Article : Google Scholar : PubMed/NCBI
21	Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 352:997–1003. 2005. View Article : Google Scholar : PubMed/NCBI
22	Perez A and Huse JT: The evolving classification of diffuse gliomas: World Health Organization updates for 2021. Curr Neurol Neurosci Rep. 21:672021. View Article : Google Scholar : PubMed/NCBI
23	Sun X and Turcan S: From laboratory studies to clinical trials: Temozolomide use in IDH-mutant gliomas. Cells. 10:12252021. View Article : Google Scholar : PubMed/NCBI
24	Han S, Liu Y, Cai SJ, Qian M, Ding J, Larion M, Gilbert MR and Yang C: IDH mutation in glioma: Molecular mechanisms and potential therapeutic targets. Br J Cancer. 122:1580–1589. 2020. View Article : Google Scholar : PubMed/NCBI
25	Nobusawa S, Watanabe T, Kleihues P and Ohgaki H: IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 15:6002–6007. 2009. View Article : Google Scholar : PubMed/NCBI
26	Govindarajan V, Shah AH, Di L, Rivas S, Suter RK, Eichberg DG, Luther E, Lu V, Morell AA, Ivan ME, et al: Systematic review of epigenetic therapies for treatment of IDH-mutant glioma. World Neurosurg. 162:47–56. 2022. View Article : Google Scholar : PubMed/NCBI
27	Qi S, Lei Y, Si G, YanQing D, HuiXia H, XueLin Z, LanXiao W and Fei Y: IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci. 103:269–273. 2012. View Article : Google Scholar : PubMed/NCBI
28	Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL and Rameshwar P: Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids. 2:e1262013. View Article : Google Scholar : PubMed/NCBI
29	Bolger AM, Lohse M and Usadel B: Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 30:2114–2120. 2014. View Article : Google Scholar : PubMed/NCBI
30	Pertea M, Kim D, Pertea GM, Leek JT and Salzberg SL: Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 11:1650–1667. 2016. View Article : Google Scholar : PubMed/NCBI
31	Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, Pimentel H, Salzberg SL, Rinn JL and Pachter L: Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 7:562–578. 2012. View Article : Google Scholar : PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
33	Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, Nair VS, Xu Y, Khuong A, Hoang CD, et al: The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 21:938–945. 2015. View Article : Google Scholar : PubMed/NCBI
34	Dudley WN, Wickham R and Coombs N: An introduction to survival statistics: Kaplan-Meier analysis. J Adv Pract Oncol. 7:91–100. 2016.PubMed/NCBI
35	Lubbock ALR, Katz E, Harrison DJ and Overton IM: TMA navigator: Network inference, patient stratification and survival analysis with tissue microarray data. Nucleic Acids Res. 41((Web Server Issue)): W562–W568. 2013. View Article : Google Scholar : PubMed/NCBI
36	Stelzer G, Dalah I, Stein TI, Satanower Y, Rosen N, Nativ N, Oz-Levi D, Olender T, Belinky F, Bahir I, et al: In-silico human genomics with GeneCards. Hum Genomics. 5:709–717. 2011. View Article : Google Scholar : PubMed/NCBI
37	Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein TI, Nudel R, Lieder I, Mazor Y, et al: The GeneCards suite: From gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics. 54:1.30.1–1.30.33. 2016. View Article : Google Scholar : PubMed/NCBI
38	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43((Database Issue)): D447–D452. 2015. View Article : Google Scholar : PubMed/NCBI
39	Maglott D, Ostell J, Pruitt KD and Tatusova T: Entrez gene: Gene-centered information at NCBI. Nucleic Acids Res. 33((Database Issue)): D54–D58. 2005.PubMed/NCBI
40	Crowe AR and Yue W: Semi-quantitative determination of protein expression using immunohistochemistry staining and analysis: An Integrated Protocol. Bio Protoc. 9:e34652019. View Article : Google Scholar : PubMed/NCBI
41	Yuan JX and Munson JM: Quantitative immunohistochemistry of the cellular microenvironment in patient glioblastoma resections. J Vis Exp. 560252017.PubMed/NCBI
42	Burley SK, Berman HM, Kleywegt GJ, Markley JL, Nakamura H and Velankar S: Protein data bank (PDB): The single global macromolecular structure archive. Methods Mol Biol. 1607:627–641. 2017. View Article : Google Scholar : PubMed/NCBI
43	Yuan S, Chan HCS, Filipek S and Vogel H: PyMOL and inkscape bridge the data and the data visualization. Structure. 24:2041–2042. 2016. View Article : Google Scholar : PubMed/NCBI
44	Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, et al: Highly accurate protein structure prediction with AlphaFold. Nature. 596:583–589. 2021. View Article : Google Scholar : PubMed/NCBI
45	de Beer TAP, Berka K, Thornton JM and Laskowski RA: PDBsum additions. Nucleic Acids Res. 42((Database Issue)): D292–D296. 2014. View Article : Google Scholar : PubMed/NCBI
46	Hammer Ø, Harper DAT and Ryan PD: PAST: Paleontological statistics software package for education and data analysis. Palaeontol Electron. 4:92001.
47	MATLAB, . High performance numeric computation and visualization software: User's guide: For UNIX workstations. Mathworks Incorporated. 2003.
48	Singh N, Miner A, Hennis L and Mittal S: Mechanisms of temozolomide resistance in glioblastoma-a comprehensive review. Cancer Drug Resist. 4:17–43. 2021.PubMed/NCBI
49	Chen X, Zhang M, Gan H, Wang H, Lee JH, Fang D, Kitange GJ, He L, Hu Z, Parney IF, et al: A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nat Commun. 9:29492018. View Article : Google Scholar : PubMed/NCBI
50	Bukowski K, Kciuk M and Kontek R: Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 21:32332020. View Article : Google Scholar : PubMed/NCBI
51	Rapin N, Bagger FO, Jendholm J, Mora-Jensen H, Krogh A, Kohlmann A, Thiede C, Borregaard N, Bullinger L, Winther O, et al: Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. Blood. 123:894–904. 2014. View Article : Google Scholar : PubMed/NCBI
52	Cheng SY, Chen NF, Wen ZH, Yao ZK, Tsui KH, Kuo HM and Chen WF: Glutathione S-transferase M3 is associated with glycolysis in intrinsic temozolomide-resistant glioblastoma multiforme cells. Int J Mol Sci. 22:70802021. View Article : Google Scholar : PubMed/NCBI
53	Gordinier ME, Schau GF, Pollock SB, Shields LBE and Talwalkar S: Genomic characterization of vulvar squamous cell carcinoma reveals differential gene expression based on clinical outcome. Gynecol Oncol. 180:111–117. 2024. View Article : Google Scholar : PubMed/NCBI
54	Hu G, Wei B, Wang L, Wang L, Kong D, Jin Y and Sun Z: Analysis of gene expression profiles associated with glioma progression. Mol Med Rep. 12:1884–1890. 2015. View Article : Google Scholar : PubMed/NCBI
55	Kothari C, Osseni MA, Agbo L, Ouellette G, Déraspe M, Laviolette F, Corbeil J, Lambert JP, Diorio C and Durocher F: Machine learning analysis identifies genes differentiating triple negative breast cancers. Sci Rep. 10:104642020. View Article : Google Scholar : PubMed/NCBI
56	Kumar SU, Kumar DT, Siva R, Doss CGP and Zayed H: Integrative bioinformatics approaches to map potential novel genes and pathways involved in ovarian cancer. Front Bioeng Biotechnol. 7:3912019. View Article : Google Scholar : PubMed/NCBI
57	Chakraborty C, Sharma AR, Bhattacharya M, Zayed H and Lee SS: Understanding gene expression and transcriptome profiling of COVID-19: An initiative towards the mapping of protective immunity genes against SARS-CoV-2 infection. Front Immunol. 12:7249362021. View Article : Google Scholar : PubMed/NCBI
58	Chakraborty C, Bhattacharya M, Dhama K and Lee SS: Evaluation of differentially expressed genes during replication using gene expression landscape of monkeypox-infected MK2 cells: A bioinformatics and systems biology approach to understanding the genomic pattern of viral replication. J Infect Public Health. 16:399–409. 2023. View Article : Google Scholar : PubMed/NCBI
59	Dunn SL, Soul J, Anand S, Schwartz JM, Boot-Handford RP and Hardingham TE: Gene expression changes in damaged osteoarthritic cartilage identify a signature of non-chondrogenic and mechanical responses. Osteoarthritis Cartilage. 24:1431–1440. 2016. View Article : Google Scholar : PubMed/NCBI
60	Chen SJ, Liao DL, Chen CH, Wang TY and Chen KC: Construction and analysis of protein-protein interaction network of heroin use disorder. Sci Rep. 9:49802019. View Article : Google Scholar : PubMed/NCBI
61	Raman K: Construction and analysis of protein-protein interaction networks. Autom Exp. 2:22010. View Article : Google Scholar : PubMed/NCBI
62	Silverbush D and Sharan R: A systematic approach to orient the human protein-protein interaction network. Nat Commun. 10:30152019. View Article : Google Scholar : PubMed/NCBI
63	Lee SY: Temozolomide resistance in glioblastoma multiforme. Genes Dis. 3:198–210. 2016. View Article : Google Scholar : PubMed/NCBI
64	Mrugala MM and Chamberlain MC: Mechanisms of disease: Temozolomide and glioblastoma-look to the future. Nat Clin Pract Oncol. 5:476–486. 2008. View Article : Google Scholar : PubMed/NCBI
65	Woo PYM, Li Y, Chan AHY, Ng SCP, Loong HHF, Chan DTM, Wong GKC and Poon WS: A multifaceted review of temozolomide resistance mechanisms in glioblastoma beyond O-6-methylguanine-DNA methyltransferase. Glioma. 2:68–82. 2019. View Article : Google Scholar
66	Kitange GJ, Carlson BL, Schroeder MA, Grogan PT, Lamont JD, Decker PA, Wu W, James CD and Sarkaria JN: Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro Oncol. 11:281–291. 2009. View Article : Google Scholar : PubMed/NCBI
67	Barthel FP, Johnson KC, Varn FS, Moskalik AD, Tanner G, Kocakavuk E, Anderson KJ, Abiola O, Aldape K, Alfaro KD, et al: Longitudinal molecular trajectories of diffuse glioma in adults. Nature. 576:112–120. 2019. View Article : Google Scholar : PubMed/NCBI
68	Jonsson P, Lin AL, Young RJ, DiStefano NM, Hyman DM, Li BT, Berger MF, Zehir A, Ladanyi M, Solit DB, et al: Genomic correlates of disease progression and treatment response in prospectively characterized gliomas. Clin Cancer Res. 25:5537–5547. 2019. View Article : Google Scholar : PubMed/NCBI
69	Ohba S, Mukherjee J, See WL and Pieper RO: Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance. Cancer Res. 74:4836–4844. 2014. View Article : Google Scholar : PubMed/NCBI
70	Chen T, Wang J, Xue B, Kong Q, Liu Z and Yu B: Identification and characterization of a novel porcine endothelial cell-specific Tie1 promoter. Xenotransplantation. 20:438–448. 2013. View Article : Google Scholar : PubMed/NCBI
71	Rodewald HR and Sato TN: Tie1, a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. Oncogene. 12:397–404. 1996.PubMed/NCBI
72	Woo KV and Baldwin HS: Role of Tie1 in shear stress and atherosclerosis. Trends Cardiovasc Med. 21:118–123. 2011. View Article : Google Scholar : PubMed/NCBI
73	Meltzer M, Eliash N, Azoulay Z, Hadad U and Papo N: In vitro inhibition of cancer angiogenesis and migration by a nanobody that targets the orphan receptor Tie1. Cell Mol Life Sci. 79:3122022. View Article : Google Scholar : PubMed/NCBI
74	Dolphin AC: Voltage-gated calcium channel α ₂δ subunits: an assessment of proposed novel roles. F1000Res. 7:F1000 Faculty Rev. –1830. 2018. View Article : Google Scholar : PubMed/NCBI
75	Panebianco M, Al-Bachari S, Hutton JL and Marson AG: Gabapentin add-on treatment for drug-resistant focal epilepsy. Cochrane Database Syst Rev. 1:CD0014152021.PubMed/NCBI
76	Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D and Moore RA: Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 1:CD0070762019.PubMed/NCBI
77	Alles SRA, Cain SM and Snutch TP: Pregabalin as a pain therapeutic: Beyond calcium channels. Front Cell Neurosci. 14:832020. View Article : Google Scholar : PubMed/NCBI
78	Verma V, Singh N and Singh Jaggi A: Pregabalin in neuropathic pain: Evidences and possible mechanisms. Curr Neuropharmacol. 12:44–56. 2014. View Article : Google Scholar : PubMed/NCBI
79	Tonami K, Kurihara Y, Aburatani H, Uchijima Y, Asano T and Kurihara H: Calpain 6 is involved in microtubule stabilization and cytoskeletal organization. Mol Cell Biol. 27:2548–2561. 2007. View Article : Google Scholar : PubMed/NCBI
80	Ono Y and Sorimachi H: Calpains: An elaborate proteolytic system. Biochim Biophys Acta. 1824:224–236. 2012. View Article : Google Scholar : PubMed/NCBI
81	Chen L, Xiao D, Tang F, Gao H and Li X: CAPN6 in disease: An emerging therapeutic target (review). Int J Mol Med. 46:1644–1652. 2020.PubMed/NCBI
82	Kelwick R, Desanlis I, Wheeler GN and Edwards DR: The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. Genome Biol. 16:1132015. View Article : Google Scholar : PubMed/NCBI
83	Xie Y, Gou Q, Xie K, Wang Z, Wang Y and Zheng H: ADAMTS6 suppresses tumor progression via the ERK signaling pathway and serves as a prognostic marker in human breast cancer. Oncotarget. 7:61273–61283. 2016. View Article : Google Scholar : PubMed/NCBI
84	Mori M, Tian G, Ishikawa A and Higuchi K: Diversity and complexity of the mouse Saa1 and Saa2 genes. Exp Anim. 63:99–106. 2014. View Article : Google Scholar : PubMed/NCBI
85	Jumeau C, Awad F, Assrawi E, Cobret L, Duquesnoy P, Giurgea I, Valeyre D, Grateau G, Amselem S, Bernaudin JF and Karabina SA: Expression of SAA1, SAA2 and SAA4 genes in human primary monocytes and monocyte-derived macrophages. PLoS One. 14:e02170052019. View Article : Google Scholar : PubMed/NCBI
86	Li W, Wang W, Zuo R, Liu C, Shu Q, Ying H and Sun K: Induction of pro-inflammatory genes by serum amyloid A1 in human amnion fibroblasts. Sci Rep. 7:6932017. View Article : Google Scholar : PubMed/NCBI
87	Abouelasrar Salama S, De Bondt M, De Buck M, Berghmans N, Proost P, Oliveira VLS, Amaral FA, Gouwy M, Van Damme J and Struyf S: Serum amyloid A1 (SAA1) revisited: Restricted leukocyte-activating properties of homogeneous SAA1. Front Immunol. 11:8432020. View Article : Google Scholar : PubMed/NCBI
88	Li S, Cheng Y, Cheng G, Xu T, Ye Y, Miu Q, Cao Q, Yang X, Ruan H and Zhang X: High SAA1 expression predicts advanced tumors in renal cancer. Front Oncol. 11:6497612021. View Article : Google Scholar : PubMed/NCBI
89	Sack GH Jr: Serum amyloid A-a review. Mol Med. 24:462018. View Article : Google Scholar : PubMed/NCBI
90	Kim YJ, Gallien S, El-Khoury V, Goswami P, Sertamo K, Schlesser M, Berchem G and Domon B: Quantification of SAA1 and SAA2 in lung cancer plasma using the isotype-specific PRM assays. Proteomics. 15:3116–3125. 2015. View Article : Google Scholar : PubMed/NCBI
91	Wischhusen J, Melero I and Fridman WH: Growth/differentiation factor-15 (GDF-15): From biomarker to novel targetable immune checkpoint. Front Immunol. 11:9512020. View Article : Google Scholar : PubMed/NCBI
92	Arinaga-Hino T, Ide T, Akiba J, Suzuki H, Kuwahara R, Amano K, Kawaguchi T, Sano T, Inoue E, Koga H, et al: Growth differentiation factor 15 as a novel diagnostic and therapeutic marker for autoimmune hepatitis. Sci Rep. 12:87592022. View Article : Google Scholar : PubMed/NCBI
93	Gkretsi V, Louca M, Stylianou A, Minadakis G, Spyrou GM and Stylianopoulos T: Inhibition of breast cancer cell invasion by ras suppressor-1 (RSU-1) silencing is reversed by growth differentiation factor-15 (GDF-15). Int J Mol Sci. 20:1632019. View Article : Google Scholar : PubMed/NCBI
94	Sakai K, Ito C, Wakabayashi M, Kanzaki S, Ito T, Takada S, Toshimori K, Sekita Y and Kimura T: Usp26 mutation in mice leads to defective spermatogenesis depending on genetic background. Sci Rep. 9:137572019. View Article : Google Scholar : PubMed/NCBI
95	Guo L, Chen Y, Hu S, Gao L, Tang N, Liu R, Qin Y, Ren C and Du S: GDF15 expression in glioma is associated with malignant progression, immune microenvironment, and serves as a prognostic factor. CNS Neurosci Ther. 28:158–171. 2022. View Article : Google Scholar : PubMed/NCBI
96	Zhang H, Xu Y, Deng G, Yuan F, Tan Y, Gao L, Sun Q, Qi Y, Yang K, Geng R and Jiang H: SAA1 knockdown promotes the apoptosis of glioblastoma cells via downregulation of AKT signaling. J Cancer. 12:2756–2767. 2021. View Article : Google Scholar : PubMed/NCBI
97	Tommasini-Ghelfi S, Murnan K, Kouri FM, Mahajan AS, May JL and Stegh AH: Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease. Sci Adv. 5:eaaw45432019. View Article : Google Scholar : PubMed/NCBI
98	Immanuel SRC, Ghanate AD, Parmar DS, Yadav R, Uthup R, Panchagnula V and Raghunathan A: Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells. NPJ Syst Biol Appl. 7:22021. View Article : Google Scholar : PubMed/NCBI
99	Lee JY, Hall JA, Kroehling L, Wu L, Najar T, Nguyen HH, Lin WY, Yeung ST, Silva HM, Li D, et al: Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell. 180:79–91.e16. 2020. View Article : Google Scholar : PubMed/NCBI
100	Takehara M, Sato Y, Kimura T, Noda K, Miyamoto H, Fujino Y, Miyoshi J, Nakamura F, Wada H, Bando Y, et al: Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression. Cancer Sci. 111:2883–2894. 2020. View Article : Google Scholar : PubMed/NCBI
101	Kang YE, Kim JM, Lim MA, Lee SE, Yi S, Kim JT, Oh C, Liu L, Jin Y, Jung SN, et al: Growth differentiation factor 15 is a cancer cell-induced mitokine that primes thyroid cancer cells for invasiveness. Thyroid. 31:772–786. 2021. View Article : Google Scholar : PubMed/NCBI
102	Wosnitzer MS, Mielnik A, Dabaja A, Robinson B, Schlegel PN and Paduch DA: Ubiquitin specific protease 26 (USP26) expression analysis in human testicular and extragonadal tissues indicates diverse action of USP26 in cell differentiation and tumorigenesis. PLoS One. 9:e986382014. View Article : Google Scholar : PubMed/NCBI
103	Parker SJ and Metallo CM: Metabolic consequences of oncogenic IDH mutations. Pharmacol Ther. 152:54–62. 2015. View Article : Google Scholar : PubMed/NCBI
104	Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 462:739–744. 2009. View Article : Google Scholar : PubMed/NCBI
105	Turkalp Z, Karamchandani J and Das S: IDH mutation in glioma: New insights and promises for the future. JAMA Neurol. 71:1319–1325. 2014. View Article : Google Scholar : PubMed/NCBI
106	Peng H, Li Z, Fu J and Zhou R: Growth and differentiation factor 15 regulates PD-L1 expression in glioblastoma. Cancer Manag Res. 11:2653–2661. 2019. View Article : Google Scholar : PubMed/NCBI
107	Wang S, Yao F, Lu X, Li Q, Su Z, Lee JH, Wang C and Du L: Temozolomide promotes immune escape of GBM cells via upregulating PD-L1. Am J Cancer Res. 9:1161–1171. 2019.PubMed/NCBI
108	Jin Y, Cui D, Ren J, Wang K, Zeng T and Gao L: CACNA2D3 is downregulated in gliomas and functions as a tumor suppressor. Mol Carcinog. 56:945–959. 2017. View Article : Google Scholar : PubMed/NCBI
109	Nie C, Qin X, Li X, Tian B, Zhao Y, Jin Y, Li Y, Wang Q, Zeng D, Hong A and Chen X: CACNA2D3 enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin via inducing Ca²⁺-mediated apoptosis and suppressing PI3K/Akt pathways. Front Oncol. 9:1852019. View Article : Google Scholar : PubMed/NCBI
110	Dai X, Tian X, Gu S, Yang Y, Li H, Gao P, Lan Q and Cheng H: Hybrid biofabrication of neurosecretory structures as a model for neurosecretion. Int J Bioprint. 9:6592022. View Article : Google Scholar : PubMed/NCBI
111	Dai X, Shao Y, Tian X, Cao X, Ye L, Gao P, Cheng H and Wang X: Fusion between glioma stem cells and mesenchymal stem cells promotes malignant progression in 3D-bioprinted models. ACS Appl Mater Interfaces. 14:35344–35356. 2022. View Article : Google Scholar : PubMed/NCBI
112	Dai X, Ye L, Li H, Dong X, Tian H, Gao P, Dong J and Cheng H: Crosstalk between microglia and neural stem cells influences the relapse of glioblastoma in GBM immunological microenvironment. Clin Immunol. 251:1093332023. View Article : Google Scholar : PubMed/NCBI
113	Liu D, Dai X, Zhang W, Zhu X, Zha Z, Qian H, Cheng L and Wang X: Liquid exfoliation of ultrasmall zirconium carbide nanodots as a noninflammatory photothermal agent in the treatment of glioma. Biomaterials. 292:1219172023. View Article : Google Scholar : PubMed/NCBI