Velmurugan Bharath K, Lee Chien-Hung, Chiang Shang-Lun, Hua Chun-Hung, Chen Mei-Chung, Lin Shu-Hui, Yeh Kun-Tu, Ko Ying-Chin
Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsuing, Taiwan.
J Cell Physiol. 2018 Feb;233(2):1300-1311. doi: 10.1002/jcp.26001. Epub 2017 Jun 12.
Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3-stage (aOR = 2.1, 95%CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR = 2.2, 95%CI: 1.2-4.0) and lower 10-year overall survival (p = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated in oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC.
蛋白磷酸酶2A（PP2A）是一种肿瘤抑制基因，在多种癌症中经常被失活。然而，其在口腔鳞状细胞癌（OSCC）中的分子和临床相关性仍不清楚。在此我们表明，PP2A失活在口腔癌细胞中是常见事件，其酪氨酸307（Y307）残基的过度磷酸化导致PP2A失活。用FTY720处理恢复PP2A可降低细胞生长并减少糖原合成酶激酶-3β（GSK-3β）的磷酸化，而不会显著改变其他PP2A靶点。我们进一步检测了262例OSCC组织中的PP2A磷酸化情况。肿瘤组织中p-PP2A表达增加与更高的N2/N3分期显著相关（调整后比值比[aOR]=2.1，95%置信区间[CI]：1.2-3.8）。p-PP2A高表达患者的总生存率低于低表达患者。风险比分析表明，在淋巴结转移中，p-PP2A高表达与死亡密度显著相关（aOR=2.2，95%CI：1.2-4.0）且10年总生存率较低（P=0.027）。然而，未观察到p-PP2A表达与淋巴结转移之间存在相互作用。我们所有的结果表明，PP2A在口腔癌中经常失活并决定不良预后，通过FTY720恢复其表达可能是OSCC的一种替代治疗方法。
