鑑定腦部疾病的生物標誌物和治療目標：重點研究輕度頭部外傷和多形性膠質母細胞瘤

Identification of Biomarkers and Therapeutic Target Toward Brain Diseases: Focusing on Mild Traumatic Brain Injury and Glioblastoma Multiforme

李薰華(Hsun-Hua Lee)

指導教授 ： 胡朝榮

共同指導教授 ： 林源峰(Yuan-Feng Lin)

臺北醫學大學/醫學院/臨床醫學研究所/博士(2020年)

摘要

腦部疾病，例如輕度頭部外傷和腦瘤仍然是當前重要的疾病及致死原因。儘管當前已有一些非侵入性或侵入性的治療策略來治療輕度頭部外傷和腦腫瘤，但是仍然沒有有效、可用的生物標記物能夠預測這些患者的治療預後。因此，發現新的生物標誌物可有效控制輕度頭部外傷和預測腦腫瘤的預後是重要的課題
通過使用單一核苷酸多型性，我們發現ASIC3的Pro536（G到A）的突變和前庭和本體感覺系統中、與平衡功能相關，並與輕度頭部外傷後的平衡功能受損程度高度相關。
另一方面多形性膠質母細胞瘤是最惡性的腦腫瘤，且患者預後最差。 Temozolomide（TMZ）是目前治療GBM患者的主要化療藥物，但大多數患者治療反應不佳，因此增加了癌症進展的風險。本研究利用TCGA數據庫，初步發現H2AFJ於GBM腫瘤之中呈現高表現，且與 GBM的腫瘤惡性程度有因果關係。在檢測到的癌細胞中，我們發現H2AFJ與TMZ抗性高度相關，並調控proneural-mesenchymal transition和 TNF-NFB and IL6/STAT3 的路徑。
我們的發現表明，ASIC3多型性和H2AFJ可能是不良的預後生物標誌物，可能分別成為mTBI和GBM患者的新的治療目標地。

關鍵字

腦部疾病 ； 生物標誌物 ； 治療目標 ； 輕度頭部外傷 ； 多形性膠質母細胞瘤 ； ASIC3 ； H2AFJ

並列摘要

Brain disorders, e.g. mild traumatic brain injury (mTBI) and brain tumors, are still the important causes for risking the life span of patients in current clinics. Although several non-invasive or invasive strategies have been developed to treat mTBI and brain tumors, there are still no available biomarkers enabling to predict the prognosis of those patients after the treatments. Moreover, identifying a druggable target to more efficiently govern mTBI and brain tumors is urgently needed.
By using Single Nucleotide Polymorphism (SNP), we found that the mutations of acid-sensing ion channel 3 (ASIC3), expressed in the vestibular and proprioceptive systems and associated with balance functions, at Pro536 (G to A) are highly associated with impaired balance functions and dizziness questionnaires in mild TBI (mTBI) and non-mTBI patients compared to the control cohort. On the other hand, our results revealed that histone 2A family member J (H2AFJ), a component of nucleosome, is extensively upregulated in the most aggressive brain tumors, glioblastoma multiforme (GBM), and serves as a poor prognostic factor for GBM patients receiving temozolomide (TMZ) treatment. Moreover, the knockdown of endogenous H2AFJ gene expression dramatically enhanced but the enforced expression of exogenous H2AFJ gene predominantly reduced the responsiveness of the tested GBM cells to TMZ treatment. By performing an in silico gene set enrichment analysis, we found that H2AFJ upregulation significantly correlates with the activation of intracellular signaling cascades relaying proneural-mesenchymal transition and TNF-NFB and IL6/STAT3 pathways. These computational simulations were further validated in GBM cells without or with H2AFJ knockdown or overexpression.
Our findings suggest that ASIC3 polymorphism and H2AFJ upregulation could be the poor prognostic biomarkers and might be new therapeutic targets in mTBI and GBM patients, respectively.

並列關鍵字

Brain Diseases ； Biomarkers ； Therapeutic Target ； Mild Traumatic Brain Injury ； Glioblastoma Multiforme

參考文獻

Aguirre-Gamboa, R., Gomez-Rueda, H., Martínez-Ledesma, E., Martínez-Torteya, A., Chacolla-Huaringa, R., Rodriguez-Barrientos, A., …Trevino, V. (2013). SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PloS One, 8(9).

Akin, F. W., Murnane, O. D., Hall, C. D., &Riska, K. M. (2017). Vestibular consequences of mild traumatic brain injury and blast exposure: a review. Brain Injury, 31(9), 1188–1194.

Alabert, C., Jasencakova, Z., &Groth, A. (2017). Chromatin replication and histone dynamics. In DNA Replication (pp. 311–333). Springer.

Arnold, B. L., &Schmitz, R. J. (1998). Examination of balance measures produced by the biodex stability system. Journal of Athletic Training, 33(4), 323.

Balss, J., Meyer, J., Mueller, W., Korshunov, A., Hartmann, C., &vonDeimling, A. (2008). Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathologica, 116(6), 597–602.