Department of Pathology, IRCCS Neuromed, Pozzilli, Italy.
Oncogene. 2011 Sep 1;30(35):3813-20. doi: 10.1038/onc.2011.99. Epub 2011 Apr 18.
Dual-specificity phosphatase 6 (DUSP6, mitogen-activated protein kinase (MAPK) phosphatase 3 or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on extracellular signal-regulated kinase (ERK1/2; MAPK1/2) to inactivate the ERK1/2 kinase. DUSP6 is a critical regulator of the ERK signaling cascade and has been implicated as a tumor suppressor. We report here experimental evidences that DUSP6 is transcriptionally upregulated in primary and long-term cultures of human glioblastoma, as assayed by northern hybridization and real-time quantitative PCR, producing constitutive high level of protein expression. Functional assays were performed with adenovirus-mediated expression of DUSP6 in glioblastoma cultures. Protein overexpression inhibits growth by inducing G1-phase delay and increased mitogenic/anchorage dependence and clonogenic potential in vitro. Changes in cell morphology were associated with an increased tumor growth in vivo. Chemoresistance is a major cause of treatment failure and poor outcome in human glioblastomas. Importantly, DUSP6 overexpression increased resistance to cisplatin-mediated cell death in vitro and in vivo. Antisense-mediated depletion of DUSP6 acted in lowering the threshold to anticancer DNA-damaging drugs. We conclude that upregulation of DUSP6 exerts a tumor-promoting role in human glioblastomas exacerbating the malignant phenotype.
双特异性磷酸酶 6（DUSP6，丝裂原活化蛋白激酶（MAPK）磷酸酶 3 或 PYST1）去磷酸化细胞外信号调节激酶（ERK1/2；MAPK1/2）上的磷酸酪氨酸和磷酸苏氨酸残基，从而使 ERK1/2 激酶失活。DUSP6 是 ERK 信号级联的关键调节剂，并且已被暗示为肿瘤抑制因子。我们在这里报告了实验证据，即通过 northern 杂交和实时定量 PCR 检测，DUSP6 在人神经胶质瘤的原代和长期培养物中转录上调，产生组成型高水平的蛋白表达。通过腺病毒介导的 DUSP6 在神经胶质瘤培养物中的表达进行功能测定。蛋白过表达通过诱导 G1 期延迟和增加有丝分裂/锚定依赖性以及体外集落形成潜力来抑制生长。细胞形态的变化与体内肿瘤生长增加有关。化疗耐药是人类神经胶质瘤治疗失败和预后不良的主要原因。重要的是，DUSP6 过表达增加了体外和体内顺铂介导的细胞死亡的耐药性。反义介导的 DUSP6 耗竭可降低抗癌 DNA 损伤药物的阈值。我们得出结论，DUSP6 的上调在人类神经胶质瘤中发挥了促进肿瘤的作用，加剧了恶性表型。
