Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Mitochondrion. 2020 Nov;55:154-163. doi: 10.1016/j.mito.2020.10.001. Epub 2020 Oct 10.
Mitochondrial DNA (mtDNA) content in several solid tumors was found to be lower than in their normal counterparts. However, there is paucity of literature on the clinical significance of mtDNA content in glioblastoma and its effect on treatment response. Hence, we studied the prognostic significance of mtDNA content in glioblastoma tumor tissue and the effect of mtDNA depletion in glioblastoma cells on response to treatment.
130 newly diagnosed glioblastomas, 32 paired newly diagnosed and recurrent glioblastomas and 35 non-neoplastic brain tissues were utilized for the study. mtDNA content in the patient tumor tissue was assessed and compared with known biomarkers and patient survival. mtDNA was chemically depleted in malignant glioma cell lines, U87, LN229. The biology and treatment response of parent and depleted cells were compared.
Lower range of mtDNA copy number in glioblastoma was associated with poor overall survival (p = 0.01), progression free survival (p = 0.04) and also with wild type IDH (p = 0.02). In recurrent glioblastoma, mtDNA copy number was higher than newly diagnosed glioblastoma in the patients who received RT (p = 0.01). mtDNA depleted U87 and LN229 cells showed higher survival fraction post radiation exposure when compared to parent lines. The IC50 of TMZ was also higher for mtDNA depleted U87 and LN229 cells. The depleted cells formed more neurospheres than their parent counterparts, thus showing increased stemness of mtDNA depleted cells.
Low mtDNA copy number in glioblastoma is associated with poor patient survival and treatment resistance in cell lines possibly by impacting stemness of the glioblastoma cells.
在几种实体瘤中发现线粒体 DNA（mtDNA）含量低于其正常对应物。然而，关于胶质母细胞瘤中 mtDNA 含量的临床意义及其对治疗反应的影响的文献很少。因此，我们研究了胶质母细胞瘤肿瘤组织中 mtDNA 含量的预后意义以及 mtDNA 耗竭对胶质母细胞瘤细胞对治疗反应的影响。
研究中使用了 130 例新诊断的胶质母细胞瘤、32 对新诊断和复发性胶质母细胞瘤以及 35 例非肿瘤性脑组织。评估了患者肿瘤组织中的 mtDNA 含量，并与已知的生物标志物和患者生存情况进行了比较。在恶性神经胶质瘤细胞系 U87、LN229 中用化学方法耗尽 mtDNA。比较了亲本细胞和耗竭细胞的生物学和治疗反应。
胶质母细胞瘤中 mtDNA 拷贝数较低与总生存期（p=0.01）、无进展生存期（p=0.04）差以及野生型 IDH（p=0.02）差相关。在接受放疗的复发性胶质母细胞瘤患者中，mtDNA 拷贝数高于新诊断的胶质母细胞瘤（p=0.01）。与亲本系相比，mtDNA 耗竭的 U87 和 LN229 细胞在接受辐射后显示出更高的存活分数。mtDNA 耗竭的 U87 和 LN229 细胞的 TMZ IC50 也更高。耗竭细胞形成的神经球比亲本细胞多，因此显示出 mtDNA 耗竭细胞的干性增加。
胶质母细胞瘤中 mtDNA 拷贝数较低与患者生存不良和细胞系治疗耐药有关，可能通过影响胶质母细胞瘤细胞的干性。
