干擾素誘導四肽重複蛋白5（IFIT5）調控多型性膠質母細胞瘤進程之探討

Abstract

多型性膠質母細胞瘤（glioblastoma multiforme, GBM）是目前最致命的原發性腦癌，生存期短且預後不佳，現今尚未找到治療多型性膠質母細胞瘤的最佳方法。有研究發現多型性膠質母細胞瘤癌幹細胞之存在與治療效果不佳有關係，包括造成癌細胞增生、遷移，並且容易復發，若能了解多型性膠質母細胞瘤之癌幹細胞生長機制，將會是開發新療法的關鍵。干擾素誘導四肽重複蛋白5（Interferon-induced protein with tetratricopeptide repeats 5, IFIT5），屬於IFIT蛋白家族，在細胞中扮演重要角色，包括調控細胞增殖、遷移、信號傳遞和病毒複製。我們實驗室從TCGA資料庫分析中發現，在多型性膠質母細胞瘤的病人中，IFIT5表現量高的病人平均存活時間較長，另外我們先前研究中也發現，過度表現IFIT5可以抑制多型性膠質母細胞瘤細胞株U87-MG的增殖及遷移。為了更進一步確認IFIT5在多型性膠質母細胞瘤及其癌幹細胞中的功能，本研究使用過度表現IFIT5之多型性膠質母細胞瘤細胞株U251-MG和U373-MG來進一步確認IFIT5對於多型性膠質母細胞瘤細胞增殖、遷移等影響。實驗結果發現，過度表現IFIT5會抑制多型性膠質母細胞瘤之細胞及癌幹細胞的增殖及抑制類癌幹細胞球形成能力，在細胞週期分析中發現過度表現IFIT5會造成細胞週期G1期停滯。並且發現過度表現IFIT5可以抑制多型性膠質母細胞瘤癌細胞的上皮間質轉化以及抑制細胞遷移。總而言之，IFIT5有潛力可以成為治療GBM新策略。

Glioblastoma multiforme (GBM) is currently the most malignant primary brain cancer with low survival rates and poor prognosis. Studies have found that cancer stem cells (CSCs) of GBM are associated with poor treatment effects, since they increase cancer cell proliferation and migration. Understanding how cancer stem cells are regulated in glioblastoma multiforme is the crux for the development of novel therapeutics. Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5), which belongs to the IFIT protein family, plays an important role in regulation of cell functions, including cell proliferation, migration, signal transduction and virus replication. We have found that GBM patients with high expression of IFIT5 had a longer average overall survival from TCGA database analysis. Our previous studies have also found that overexpression of IFIT5 inhibited cell proliferation and migration in GBM cell line U87-MG. To further confirm the function of IFIT5 in GBM cells and cancer stem cells, we established GBM cell line U251-MG and U373-MG overexpressing IFIT5 for examination of the cell proliferation and migration. The results showed that overexpression of IFIT5 inhibited cell proliferation and inhibit the sphere-forming ability of these two GBM cells and their spheroid cells. In cell cycle analysis, overexpression of IFIT5 caused G1 arrest. Moreover, overexpression of IFIT5 inhibit EMT and cell migration of GBM cells. In summary, IFIT5 may have the potential to develop a novel therapeutic strategy for GBM.