Chang Vincent Hung-Shu, Tsai Yi-Chih, Tsai Ya-Li, Peng Shu-Ling, Chen Su-Liang, Chang Tsung Ming, Yu Winston Chun-Yuan, Ch'ang Hui-Ju
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
National Institute of Cancer Research, National Health Research Institutes, Miaoli County , Taiwan.
Radiother Oncol. 2017 Mar;122(3):476-484. doi: 10.1016/j.radonc.2017.01.001. Epub 2017 Jan 16.
Krüpple-like factor 10 (Klf10), an early response gene of TGFβ, was reported to be a prognostic biomarker for pancreatic cancer survival. The role of Klf10 in predicting tumor response to cancer treatment is unknown.
Genetically manipulated MiaPaCa and Panc-1 cells were established to evaluate clonogenic survival, autophagy, apoptosis and DNA repair after radiation. The interaction between Klf10 and UV radiation resistance-associated gene (UVRAG) was demonstrated by ChiP-PCR and luciferase reporter assay. Orthotopic murine tumor model and clinical specimens were used to evaluate radio-sensitivity of pancreatic cancer.
We found Klf10 silencing correlates with enhanced pancreatic cancer clonogenic survival and murine tumor growth after radiation. UVRAG was an essential down-stream mediator transcriptionally suppressed by Klf10. Silencing UVRAG mRNA in Klf10 depleted Panc-1 cells reversed the radio-resistant phenotypes including decreased apoptosis and enhanced DNA repair as well as autophagy. Metformin, an anti-diabetic agent, was found to increase Klf10 and suppress UVRAG expression to improve radiation cytotoxicity in pancreatic cancer. The predictive value of Klf10 in radiation response and the inverse correlation with UVRAG were confirmed in cohorts of pancreatic cancer patients.
Klf10 is a potential biomarker in predicting and sensitizing radiation effect in pancreatic cancer.
据报道，Krüpple样因子10（Klf10）是转化生长因子β（TGFβ）的早期反应基因，是胰腺癌生存的预后生物标志物。Klf10在预测肿瘤对癌症治疗反应中的作用尚不清楚。
构建基因操作的MiaPaCa和Panc-1细胞，以评估辐射后的克隆形成存活、自噬、凋亡和DNA修复。通过染色质免疫沉淀聚合酶链反应（ChiP-PCR）和荧光素酶报告基因检测证明Klf10与紫外线辐射抗性相关基因（UVRAG）之间的相互作用。采用原位小鼠肿瘤模型和临床标本评估胰腺癌的放射敏感性。
我们发现Klf10沉默与辐射后胰腺癌克隆形成存活增强和小鼠肿瘤生长相关。UVRAG是Klf10转录抑制的重要下游介质。在Klf10缺失的Panc-1细胞中沉默UVRAG mRNA可逆转放射抗性表型，包括凋亡减少、DNA修复增强以及自噬增强。二甲双胍是一种抗糖尿病药物，被发现可增加Klf10并抑制UVRAG表达，从而提高胰腺癌的放射细胞毒性。在胰腺癌患者队列中证实了Klf10在辐射反应中的预测价值以及与UVRAG的负相关。
Klf10是预测和增强胰腺癌放射效应的潜在生物标志物。
