Stemness Is Enhanced in Gastric Cancer by a SET/PP2A/E2F1 Axis
Stemness Is Enhanced in Gastric Cancer by a SET/PP2A/E2F1 Axis
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DOI：
10.1158/1541-7786.mcr-17-0393
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发表时间：
2018-03-01
影响因子：
5.2
通讯作者：
Sato, Koichi
中科院分区：
文献类型：
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作者：
Enjoji, Shuhei;Yabe, Ryotaro;Sato, Koichi
胃癌是世界范围内第五大常见恶性肿瘤和第三大癌症相关死亡原因。针对胃癌的化疗通常失败，癌症复发可能是由于癌症干细胞的持续存在。肿瘤中这种独特的细胞亚群具有自我更新和去分化的能力。这些癌症干细胞对于癌症的起始、维持、转移和复发至关重要;然而，支持癌症干细胞性的分子机制在很大程度上仍然未知。激酶活性增加和磷酸酶活性降低是致癌信号传导的标志。蛋白磷酸酶2A（PP 2A）作为一种肿瘤抑制酶发挥作用，SET/I2 PP 2A（一种内源性PP 2A蛋白抑制剂）水平升高与几种人类癌症的预后不良相关。在此，确定了SET表达在胃癌小鼠模型系统中的肿瘤组织中升高，并且SET表达与人胃癌患者的不良存活正相关。机制上，SET敲低降低了E2 F1水平并抑制了癌细胞系的干性。免疫沉淀显示SET与PP 2A-B56复合物相关，B56亚基与E2 F1转录因子相互作用。用SET靶向药物OP 449处理胃癌细胞增加了PP 2A活性，降低了E2 F1蛋白水平，并抑制了癌细胞的干性。这些数据表明，SET/PP 2A/E2 F1轴调节癌细胞的干细胞性，是胃癌治疗的潜在靶点。
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Chemotherapies against gastric cancer often fail, with cancer recurrence due potentially to the persistence of cancer stem cells. This unique subpopulation of cells in tumors possesses the ability to self-renew and dedifferentiate. These cancer stem cells are critical for initiation, maintenance, metastasis, and relapse of cancers; however, the molecular mechanisms supporting cancer stemness remain largely unknown. Increased kinase and decreased phosphatase activity are hallmarks of oncogenic signaling. Protein phosphatase 2A (PP2A) functions as a tumor-suppressor enzyme, and elevated levels of SET/I2PP2A, an endogenous PP2A protein inhibitor, are correlated with poor prognosis of several human cancers. Here, it was determined that SET expression was elevated in tumor tissue in a gastric cancer mouse model system, and SET expression was positively correlated with poor survival of human gastric cancer patients. Mechanistically, SET knockdown decreased E2F1 levels and suppressed the stemness of cancer cell lines. Immunoprecipitations show SET associated with the PP2A-B56 complex, and the B56 subunit interacted with the E2F1 transcription factor. Treatment of gastric cancer cells with the SET-targeting drug OP449 increased PP2A activity, decreased E2F1 protein levels, and suppressed stemness of cancer cells. These data indicate that a SET/PP2A/E2F1 axis regulates cancer cell stemness and is a potential target for gastric cancer therapy.