微原纤维相关蛋白3在调控胶质瘤干细胞间充质表型转化中的作用

doi:10.6040/j.issn.1671-7554.0.2023.1040

摘要/Abstract

摘要： 目的探讨微原纤维相关蛋白3(microfibril-associated protein 3, MFAP3)在胶质母细胞瘤(glioblastoma, GBM)中的表达与临床意义,以及对于胶质瘤干细胞(glioma stem cells, GSCs)恶性生物学行为的影响。方法利用TCGA数据和CGGA数据分析GBM中MFAP3表达情况及其与患者预后相关性;使用Western blotting检测胶质瘤干细胞系中MFAP3蛋白表达水平;探究敲减及过表达MFAP3对胶质瘤干细胞自我更新能力和表型的影响。结果 MFAP3在GBM中高表达,且与患者不良预后相关。间充质型GSCs中MFAP3的表达水平高于前神经元型GSCs。MFAP3敲减后,GSCs自我更新能力减弱,间充质表型标志物CD44、YKL40蛋白水平均降低,过表达与之相反。结论 MFAP3对GBM恶性生物学进展具有重要调控作用,有望成为新的GBM临床诊断标志物和治疗干预靶点。

Abstract: Objective To investigate the expression and clinical significance of microfibril-associated protein 3(MFAP3)in glioblastoma(GBM)and its influence on the malignant biological behavior of glioma stem cells(GSCs). Methods TCGA data and CGGA data were used to analyze the expression of MFAP3 in GBM and its correlation with patient prognosis. Western blotting was used to detect the protein expression level of MFAP3 in GSCs. The effects of MFAP3 knockdown and overexpression on the self-renewal ability and phenotype of GSCs were explored. Results MFAP3 was highly expressed in GBM and correlated with poor prognosis. The expression level of MFAP3 in mesenchymal GSCs was higher than that in preneuronal GSCs. After MFAP3 knockdown, the self-renewal ability of GSCs was weakened, and the protein levels of mesenchymal phenotype markers CD44 and YKL40 were decreased, whereas overexpression exhibited the opposite trends. Conclusion MFAP3 plays an important role in regulating the malignant biological progression of GBM and is expected to be a new clinical diagnostic marker and therapeutic intervention target for GBM.

Key words: Microfibril-associated protein 3, Glioma stem cells, Phenotype transition, Self-renewal, Prognosis

中图分类号:

R739.41

郭姝画,樊扬,田风,王传新,杜鲁涛,李培龙,郭兴,徐硕. 微原纤维相关蛋白3在调控胶质瘤干细胞间充质表型转化中的作用[J]. 山东大学学报 (医学版), 2024, 62(6): 9-16.

GUO Shuhua, FAN Yang, TIAN Feng, WANG Chuanxin, DU Lutao, LI Peilong, GUO Xing, XU Shuo. Role of microfibril-associated protein 3 in regulating mesenchymal transition of glioma stem cells[J]. Journal of Shandong University (Health Sciences), 2024, 62(6): 9-16.

参考文献

[1] Alexander BM, Cloughesy TF. Adult glioblastoma[J]. J Clin Oncol, 2017, 35(21): 2402-2409.
[2] Huang BY, Li XS, Li YT, et al. Current immunotherapies for glioblastoma multiforme[J]. Front Immunol, 2021, 11: 603911. doi:10.3389/fimmu.2020.603911.
[3] Lah TT, Novak M, Breznik B. Brain malignancies: glioblastoma and brain metastases[J]. Semin Cancer Bio, 2020, 60: 262-273. doi: 10.1016/j.semcancer.2019.10.010.
[4] Tan AC, Ashley DM, López GY, et al. Management of glioblastoma: state of the art and future directions[J]. CA Cancer J Clin, 2020, 70(4): 299-312.
[5] Shaim H, Shanley M, Basar R, et al. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells[J]. J Clin Invest, 2021, 131(14): e142116. doi:10.1172/JCI142116.
[6] Mohile NA, Messersmith H, Gatson NT, et al. Therapy for diffuse astrocytic and oligodendroglial tumors in adults: ASCO-SNO guideline[J]. J Clin Oncol, 2022, 40(4): 403-426.
[7] Suvà ML, Tirosh I. The glioma stem cell model in the era of single-cell genomics[J]. Cancer Cell, 2020, 37(5): 630-636.
[8] Fan Y, Gao ZJ, Xu JY, et al. SPI1-mediated MIR222HG transcription promotes proneural-to-mesenchymal transition of glioma stem cells and immunosuppressive polarization of macrophages[J]. Theranostics, 2023, 13(10): 3310-3329.
[9] Gao ZJ, Xu JY, Fan Y, et al. ARPC1B promotes mesenchymal phenotype maintenance and radiotherapy resistance by blocking TRIM21-mediated degradation of IFI16 and HuR in glioma stem cells[J]. J Exp Clin Cancer Res, 2022, 41(1): 323. doi:10.1186/s13046-022-02526-8.
[10] Chen ZH, Wang HZ, Zhang ZP, et al. Cell surface GRP78 regulates BACE2 via lysosome-dependent manner to maintain mesenchymal phenotype of glioma stem cells[J]. J Exp Clin Cancer Res, 2021, 40(1): 20. doi:10.1186/s13046-020-01807-4.
[11] Gao ZJ, Xu JY, Fan Y, et al. PDIA3P1 promotes Temozolomide resistance in glioblastoma by inhibiting C/EBPβ degradation to facilitate proneural-to-mesenchymal transition[J]. J Exp Clin Cancer Res, 2022, 41(1): 223. doi:10.1186/s13046-022-02431-0.
[12] Zhu SP, Ye L, Bennett S, et al. Molecular structure and function of microfibrillar-associated proteins in skeletal and metabolic disorders and cancers[J]. J Cell Physiol, 2021, 236(1): 41-48.
[13] Olson JE, Wang X, Goode EL, et al. Variation in genes required for normal mitosis and risk of breast cancer[J]. Breast Cancer Res Treat, 2010, 119(2): 423-430.
[14] Li M, Zhang HY, Zhang RG. MFAP2 enhances cisplatin resistance in gastric cancer cells by regulating autophagy[J]. PeerJ, 2023, 11: e15441. doi:10.7717/peerj.15441.
[15] Zhang H, Shen S, Feng C, et al. MFAP2 promotes the progression of oral squamous cell carcinoma by activating the Wnt/β-catenin signaling pathway through autophagy[J]. Acta Biochim Biophys Sin, 2023, 55(9): 1445-1455.
[16] Han Y, Xia K, Su T. Exploration of the important role of microfibril-associated protein 4 gene in oral squamous cell carcinoma[J]. Med Sci Monit, 2021, 27: e931238. doi:10.12659/MSM.931238.
[17] Li J, Wang JG, Liu ZK, et al. Tumor-suppressive role of microfibrillar associated protein 4 and its clinical significance as prognostic factor and diagnostic biomarker in hepatocellular carcinoma[J]. J Cancer Res Ther, 2022, 18(7): 1919-1925.
[18] Zhou Z, Cui D, Sun MH, et al. CAFs-derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling[J]. FASEB J, 2020, 34(6): 7970-7988.
[19] Duan Y, Zhang XZ, Ying HG, et al. Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix[J]. Oncogene, 2023, 42(25): 2061-2073.
[20] Abrams WR, Ma RI, Kucich U, et al. Molecular cloning of the microfibrillar protein MFAP3 and assignment of the gene to human chromosome 5q32-q33.2[J]. Genomics, 1995, 26(1): 47-54.
[21] Uddin MN, Wang XS. Identification of key tumor stroma-associated transcriptional signatures correlated with survival prognosis and tumor progression in breast cancer[J]. Breast Cancer, 2022, 29(3): 541-561.
[22] Lou XM, Kang B, Zhang J, et al. MFAP3L activation promotes colorectal cancer cell invasion and metastasis[J]. Biochim Biophys Acta, 2014, 1842(9): 1423-1432.
[23] Ye JH, Luo WJ, Luo LL, et al. MicroRNA-671-5p inhibits cell proliferation, migration and invasion in non-small cell lung cancer by targeting MFAP3L[J]. Mol Med Rep, 2022, 25(1): 30. doi:10.3892/mmr.2021.12546.
[24] Jiang L, Hao YJ, Shao CW, et al. ADAR1-mediated RNA editing links ganglioside catabolism to glioblastoma stem cell maintenance[J]. J Clin Invest, 2022, 132(6): e143397. doi:10.1172/JCI143397.
[25] Dixit D, Prager BC, Gimple RC, et al. The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells[J]. Cancer Discov, 2021, 11(2): 480-499.
[26] Joseph JV, Conroy S, Pavlov K, et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis[J]. Cancer Lett, 2015, 359(1): 107-116.
[27] Suvà ML, Rheinbay E, Gillespie SM, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells[J]. Cell, 2014, 157(3): 580-594.
[28] Narayanan A, Gagliardi F, Gallotti AL, et al. The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1[J]. Cell Death Differ, 2019, 26(9): 1813-1831.
[29] Minata M, Audia A, Shi JF, et al. Phenotypic plasticity of invasive edge glioma stem-like cells in response to ionizing radiation[J]. Cell Rep, 2019, 26(7): 1893-1905.

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