JAK/STAT信号通路与神经胶质瘤的研究进展
Research Progress on the JAK/STAT Signaling Pathway in Gliomas
DOI: 10.12677/acm.2025.1551661, PDF,    科研立项经费支持
作者: 毛 奇, 鞠海涛*:内蒙古医科大学附属医院神经外科,内蒙古 呼和浩特
关键词: JAK/STAT信号通路神经胶质瘤靶向治疗JAK/STAT Signal Pathway Glioma Targeting Therapy
摘要: 神经胶质瘤是一类发源于中枢神经系统的恶性肿瘤,起源于神经胶质细胞。它们在神经系统中具有严重的侵袭性和生存率低的特点。尽管目前的治疗方法包括手术切除、放疗和化疗,但这些方法往往不能带来理想的治疗效果,特别是对于高度恶性的胶质母细胞瘤。因此,寻找新的治疗靶点和策略对于改善脑胶质瘤患者的预后至关重要。JAK/STAT信号通路是一种关键的细胞信号传导通路,调控许多生理过程,如细胞生长、分化、凋亡和免疫反应等。近年来,研究者们发现JAK/STAT信号通路在神经胶质瘤的发生、发展和耐药性等方面具有重要作用。因此,深入探讨JAK/STAT信号通路与神经胶质瘤之间的关系对于理解脑胶质瘤的发病机制、识别新的治疗靶点和开发新型药物具有重要意义。本综述旨在总结近年来关于JAK/STAT信号通路在神经胶质瘤中的研究进展,包括信号通路异常激活的分子机制、信号通路在胶质瘤生物学行为中的作用以及针对JAK/STAT信号通路的治疗策略。
Abstract: Gliomas are a class of malignant tumors originating from the central nervous system, specifically from neuroglial cells. They are characterized by severe invasiveness in the nervous system and low survival rates. Although current treatment methods include surgical resection, radiation, and chemotherapy, these often do not yield satisfactory results, particularly in the case of highly malignant glioblastomas. Therefore, identifying new therapeutic targets and strategies is crucial for improving the prognosis of patients with brain gliomas. The JAK/STAT signaling pathway is a key cellular signaling pathway that regulates numerous physiological processes, such as cell growth, differentiation, apoptosis, and immune responses. Recently, researchers have found that the JAK/STAT signaling pathway plays an important role in the pathogenesis, progression, and drug resistance of gliomas. Therefore, a thorough exploration of the relationship between the JAK/STAT signaling pathway and gliomas is significant for understanding the pathogenesis of brain gliomas, identifying new therapeutic targets, and developing novel drugs. This review aims to summarize recent advances in research on the JAK/STAT signaling pathway in gliomas, including the molecular mechanisms of abnormal pathway activation, the role of this pathway in glioma biology, and therapeutic strategies targeting the JAK/STAT signaling pathway.
文章引用:毛奇, 鞠海涛. JAK/STAT信号通路与神经胶质瘤的研究进展[J]. 临床医学进展, 2025, 15(5): 2632-2640. https://doi.org/10.12677/acm.2025.1551661

参考文献

[1] O’Shea, J.J., Schwartz, D.M., Villarino, A.V., et al. (2015) The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention. Annual Review of Medicine, 66, 311-328.
[2] Yu, Y. and Wang, Z. (2010) Advances of the Correlation between JAK-STAT3 Signaling Pathway and the Biological Behavior of Non-Small Cell Lung Cancer. Chinese Journal of Lung Cancer, 13, 160-164.
[3] Xin, P., Xu, X., Deng, C., Liu, S., Wang, Y., Zhou, X., et al. (2020) The Role of JAK/STAT Signaling Pathway and Its Inhibitors in Diseases. International Immunopharmacology, 80, Article ID: 106210. [Google Scholar] [CrossRef] [PubMed]
[4] 邹雪, 张丽卿. Janus激酶抑制剂及其在类风湿关节炎治疗中的作用研究进展[J]. 山东医药, 2022, 62(31): 107-110.
[5] 黄永富, 余世庆, 许文荣. 支气管哮喘候选基因的表达与信号转导途径的调控[J]. 国际检验医学杂志, 2011, 32(3): 350-352.
[6] Horvath, C.M. (2000) STAT Proteins and Transcriptional Responses to Extracellular Signals. Trends in Biochemical Sciences, 25, 496-502. [Google Scholar] [CrossRef] [PubMed]
[7] Kawata, T., Shevchenko, A., Fukuzawa, M., Jermyn, K.A., Totty, N.F., Zhukovskaya, N.V., et al. (1997) SH2 Signaling in a Lower Eukaryote: A STAT Protein That Regulates Stalk Cell Differentiation in Dictyostelium. Cell, 89, 909-916. [Google Scholar] [CrossRef] [PubMed]
[8] Barahmand-Pour, F., Meinke, A., Groner, B. and Decker, T. (1998) Jak2-Stat5 Interactions Analyzed in Yeast. Journal of Biological Chemistry, 273, 12567-12575. [Google Scholar] [CrossRef] [PubMed]
[9] Durham, G.A., Williams, J.J.L., Nasim, M.T. and Palmer, T.M. (2019) Targeting SOCS Proteins to Control JAK-STAT Signalling in Disease. Trends in Pharmacological Sciences, 40, 298-308. [Google Scholar] [CrossRef] [PubMed]
[10] Yu, H. and Jove, R. (2004) The Stats of Cancer—New Molecular Targets Come of Age. Nature Reviews Cancer, 4, 97-105. [Google Scholar] [CrossRef] [PubMed]
[11] Verhoeven, Y., Tilborghs, S., Jacobs, J., De Waele, J., Quatannens, D., Deben, C., et al. (2020) The Potential and Controversy of Targeting STAT Family Members in Cancer. Seminars in Cancer Biology, 60, 41-56. [Google Scholar] [CrossRef] [PubMed]
[12] Jatiani, S.S., Cosenza, S.C., Reddy, M.V.R., Ha, J.H., Baker, S.J., Samanta, A.K., et al. (2010) A Non-ATP-Competitive Dual Inhibitor of JAK2V617F and BCR-ABLT315I Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition. Genes & Cancer, 1, 331-345. [Google Scholar] [CrossRef] [PubMed]
[13] Wang (2010) Knockdown of STAT3 Expression by RNAi Suppresses Growth and Induces Apoptosis and Differentiation in Glioblastoma Stem Cells. International Journal of Oncology, 37, 103-110. [Google Scholar] [CrossRef
[14] Iwamaru, A., Szymanski, S., Iwado, E., Aoki, H., Yokoyama, T., Fokt, I., et al. (2006) A Novel Inhibitor of the STAT3 Pathway Induces Apoptosis in Malignant Glioma Cells Both in Vitro and in Vivo. Oncogene, 26, 2435-2444. [Google Scholar] [CrossRef] [PubMed]
[15] Chen, F., Xu, Y., Luo, Y., Zheng, D., Song, Y., Yu, K., et al. (2010) Down-Regulation of Stat3 Decreases Invasion Activity and Induces Apoptosis of Human Glioma Cells. Journal of Molecular Neuroscience, 40, 353-359. [Google Scholar] [CrossRef] [PubMed]
[16] Lo, H., Cao, X., Zhu, H. and Ali-Osman, F. (2008) Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and Alkylators. Clinical Cancer Research, 14, 6042-6054. [Google Scholar] [CrossRef] [PubMed]
[17] Schaefer, L.K., Ren, Z., Fuller, G.N. and Schaefer, T.S. (2002) Constitutive Activation of Stat3α in Brain Tumors: Localization to Tumor Endothelial Cells and Activation by the Endothelial Tyrosine Kinase Receptor (VEGFR-2). Oncogene, 21, 2058-2065. [Google Scholar] [CrossRef] [PubMed]
[18] Fetell, M.R., Housepian, E.M., Oster, M.W., Cote, D.N., Sisti, M.B., Marcus, S.G., et al. (1990) Intratumor Administration of Beta-Interferon in Recurrent Malignant Gliomas. A Phase I Clinical and Laboratory Study. Cancer, 65, 78-83. [Google Scholar] [CrossRef
[19] Han, E.S., Wen, W., Dellinger, T.H., Wu, J., Lu, S.A., Jove, R., et al. (2018) Ruxolitinib Synergistically Enhances the Anti-Tumor Activity of Paclitaxel in Human Ovarian Cancer. Oncotarget, 9, 24304-24319. [Google Scholar] [CrossRef] [PubMed]
[20] Fogelman, D., Cubillo, A., García‐Alfonso, P., Mirón, M.L.L., Nemunaitis, J., Flora, D., et al. (2018) Randomized, Double‐Blind, Phase Two Study of Ruxolitinib plus Regorafenib in Patients with Relapsed/Refractory Metastatic Colorectal Cancer. Cancer Medicine, 7, 5382-5393. [Google Scholar] [CrossRef] [PubMed]
[21] Cheng, Z., Fu, J., Liu, G., Zhang, L., Xu, Q. and Wang, S. (2017) Angiogenesis in JAK2 V617F Positive Myeloproliferative Neoplasms and Ruxolitinib Decrease VEGF, HIF-1 Enesis in JAK2 V617F Positive Cells. Leukemia & Lymphoma, 59, 196-203. [Google Scholar] [CrossRef] [PubMed]
[22] Delen, E. and Doğanlar, O. (2020) The Dose Dependent Effects of Ruxolitinib on the Invasion and Tumorigenesis in Gliomas Cells via Inhibition of Interferon Gamma-Depended JAK/STAT Signaling Pathway. Journal of Korean Neurosurgical Society, 63, 444-454. [Google Scholar] [CrossRef] [PubMed]
[23] Goker Bagca, B., Ozates, N.P. and Biray Avci, C. (2022) Ruxolitinib Enhances Cytotoxic and Apoptotic Effects of Temozolomide on Glioblastoma Cells by Regulating WNT Signaling Pathway-Related Genes. Medical Oncology, 40, Article No. 37. [Google Scholar] [CrossRef] [PubMed]
[24] Rahaman, S.O., Harbor, P.C., Chernova, O., Barnett, G.H., Vogelbaum, M.A. and Haque, S.J. (2002) Inhibition of Constitutively Active Stat3 Suppresses Proliferation and Induces Apoptosis in Glioblastoma Multiforme Cells. Oncogene, 21, 8404-8413. [Google Scholar] [CrossRef] [PubMed]
[25] Senft, C., Priester, M., Polacin, M., Schröder, K., Seifert, V., Kögel, D., et al. (2010) Inhibition of the JAK-2/STAT3 Signaling Pathway Impedes the Migratory and Invasive Potential of Human Glioblastoma Cells. Journal of Neuro-Oncology, 101, 393-403. [Google Scholar] [CrossRef] [PubMed]
[26] Sun, Y., Niu, W., Du, F., Du, C., Li, S., Wang, J., et al. (2016) Safety, Pharmacokinetics, and Antitumor Properties of Anlotinib, an Oral Multi-Target Tyrosine Kinase Inhibitor, in Patients with Advanced Refractory Solid Tumors. Journal of Hematology & Oncology, 9, Article No. 105. [Google Scholar] [CrossRef] [PubMed]
[27] Lin, B., Song, X., Yang, D., Bai, D., Yao, Y. and Lu, N. (2018) Anlotinib Inhibits Angiogenesis via Suppressing the Activation of VEGFR2, PDGFRβ and FGFR1. Gene, 654, 77-86. [Google Scholar] [CrossRef] [PubMed]
[28] Liang, L., Hui, K., Hu, C., Wen, Y., Yang, S., Zhu, P., et al. (2019) Autophagy Inhibition Potentiates the Anti-Angiogenic Property of Multikinase Inhibitor Anlotinib through JAK2/STAT3/VEGFA Signaling in Non-Small Cell Lung Cancer Cells. Journal of Experimental & Clinical Cancer Research, 38, Article No. 71. [Google Scholar] [CrossRef] [PubMed]
[29] He, C., Wu, T. and Hao, Y. (2018) Anlotinib Induces Hepatocellular Carcinoma Apoptosis and Inhibits Proliferation via Erk and Akt Pathway. Biochemical and Biophysical Research Communications, 503, 3093-3099. [Google Scholar] [CrossRef] [PubMed]
[30] Wang, G., Sun, M., Jiang, Y., Zhang, T., Sun, W., Wang, H., et al. (2019) Anlotinib, a Novel Small Molecular Tyrosine Kinase Inhibitor, Suppresses Growth and Metastasis via Dual Blockade of VEGFR2 and MET in Osteosarcoma. International Journal of Cancer, 145, 979-993. [Google Scholar] [CrossRef] [PubMed]
[31] Chen, X., Zhu, M., Zou, X., Mao, Y., Niu, J., Jiang, J., et al. (2022) CCl2-Targeted Ginkgolic Acid Exerts Anti-Glioblastoma Effects by Inhibiting the JAK3-STAT1/PI3K-AKT Signaling Pathway. Life Sciences, 311, Article ID: 121174. [Google Scholar] [CrossRef] [PubMed]
[32] Yuan, Z., Yang, Z., Li, W., Wu, A., Su, Z., Jiang, B., et al. (2022) Triphlorethol‐a Attenuates U251 Human Glioma Cancer Cell Proliferation and Ameliorates Apoptosis through JAK2/STAT3 and P38 MAPK/ERK Signaling Pathways. Journal of Biochemical and Molecular Toxicology, 36, e23138. [Google Scholar] [CrossRef] [PubMed]
[33] Feng, Y., Wang, J., Cai, B., et al. (2022) Ivermectin Accelerates Autophagic Death of Glioma Cells by Inhibiting Glycolysis through Blocking GLUT4 Mediated JAK/STAT Signaling Pathway Activation. Environmental Toxicology, 37, 754-764.