最近的研究發(fā)現(xiàn),，人類嗜神經(jīng)病毒JCV廣泛存在于包括成神經(jīng)管細(xì)胞瘤的大多數(shù)腦瘤。
已知T抗原是JCV的一種早期蛋白,，在細(xì)胞培養(yǎng)及轉(zhuǎn)基因小鼠中由于它的轉(zhuǎn)化活性,，導(dǎo)致了廣泛的神經(jīng)嵴腫瘤及神經(jīng)膠質(zhì)瘤的發(fā)生。
T抗原與廣泛的腫瘤抑制蛋白（包括p53,、pRb以及信號(hào)分子β-catenin及IRS-1）的聯(lián)系,，在JCV T抗原的致癌功能中起著重要作用。
成神經(jīng)管細(xì)胞瘤細(xì)胞及膠質(zhì)母細(xì)胞瘤異種移植都能內(nèi)源性的表達(dá)T抗原,。來自美國天普大學(xué)醫(yī)學(xué)院院長的研究人員最近發(fā)現(xiàn),，在這兩種瘤細(xì)胞中，T抗原的表達(dá)通過葡萄糖剝奪（glucose deprivation）被抑制,。
AMP激酶(AMPK)是細(xì)胞內(nèi)一個(gè)重要的AMP/ATP感受器,，研究表明，葡萄糖剝奪介導(dǎo)的T抗原的抑制作用在一定程度上受到5′激活的AMP激酶(AMPK)的影響,。
而且在葡萄糖剝奪期間,，T抗原阻止了G1停滯，并維持細(xì)胞在G2期,。在功能水平上,，葡萄糖剝奪期間T抗原的下調(diào)在一定程度上依賴于活性氧(ROS)的水平，T抗原阻止了ROS的誘導(dǎo),，導(dǎo)致ATP的消耗,，隨即表現(xiàn)出了細(xì)胞毒性。
此外,，研究人員已經(jīng)發(fā)現(xiàn),，T抗原被下調(diào)通過一個(gè)糖酵解抑制劑（2-脫氧-D-葡萄糖(2-DG)）以及戊糖磷酸酶抑制劑（6-氨基煙酰胺及羥基硫胺素）。T抗原調(diào)節(jié)了糖酵解酶,、己糖激酶2(HK2),、戊糖磷酸酶及醛羧移轉(zhuǎn)酶1(TALDO1)的表達(dá)，表明了T抗原與代謝調(diào)節(jié)之間一個(gè)潛在的聯(lián)系,。
這些研究指出了JCV T抗原在成神經(jīng)管細(xì)胞瘤增殖和代謝表型之間可能的聯(lián)系,。該研究增強(qiáng)了對(duì)病毒蛋白在糖分解代謝中的作用的理解，也提供了有用的由病毒引起的腫瘤的治療靶點(diǎn),。相關(guān)論文發(fā)表在4月9日的Plos One,。（生物谷Deepblue編譯）
doi: 10.1371/journal.pone.0035054
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JC Virus T-Antigen Regulates Glucose Metabolic Pathways in Brain Tumor Cells
Evan Noch, Ilker Kudret Sariyer, Jennifer Gordon, Kamel Khalili.
Recent studies have reported the detection of the human neurotropic virus, JCV, in a significant population of brain tumors, including medulloblastomas.
Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin.Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as β-catenin and IRS-1, plays a role in the oncogenic function of JCV T-antigen.We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells and in glioblastoma xenografts that both endogenously express T-antigen.Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by 5′-activated AMP kinase (AMPK), an important sensor of the AMP/ATP ratio in cells.In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation.Furthermore, T-antigen prevents G1 arrest and sustains cells in the G2 phase during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on reactive oxygen species (ROS) production during glucose deprivation, and T-antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation.Additionally, we have found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamide and oxythiamine, and that T-antigen modulates expression of the glycolytic enzyme, hexokinase 2 (HK2), and the pentose phosphate enzyme, transaldolase-1 (TALDO1), indicating a potential link between T-antigen and metabolic regulation.These studies point to the possible involvement of JCV T-antigen in medulloblastoma proliferation and the metabolic phenotype and may enhance our understanding of the role of viral proteins in glycolytic tumor metabolism, thus providing useful targets for the treatment of virus-induced tumors.
