Huang Feng-Ting, Peng Juan-Fei, Cheng Wen-Jie, Zhuang Yan-Yan, Wang Ling-Yun, Li Chu-Qiang, Tang Jian, Chen Wen-Ying, Li Yuan-Hua, Zhang Shi-Neng
Department of Gastroenterology and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China.
Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China.
Dig Dis Sci. 2017 Apr;62(4):944-957. doi: 10.1007/s10620-017-4472-7. Epub 2017 Feb 13.
Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is one of the major regulators of inflammation-induced cancer cell growth and progression. MiR-143 dysregulation is a common event in a variety of human diseases including pancreatic ductal adenocarcinoma (PDA).
To identify the interaction between TAK1 and miR-143 in PDA.
Data mining of TAK1 expression in PDA patient gene profiling was conducted. QRT-PCR and western blot were performed to detect the expression of TAK1 in PDA tissues and cell lines. Ectopic miR-143 and TAK1 were introduced to PDA cells. Cell growth, apoptosis and migration were examined. Xenograft models were used to examine the function of TAK1 in vivo. Western blot and luciferase assay were carried out to investigate the direct target of miR-143.
PDA patient gene profiling data (GSE15471 and GSE16515) showed that TAK1 mRNA was aberrantly up-regulated in PDA tissues. TAK1 protein levels were overexpressed in PDA tissues and cell lines. Overexpression of TAK1 was strongly associated with positive lymph node metastasis. Inhibition of TAK1 suppressed cell growth, migration, and induced cell apoptosis in vitro and in vivo. Further studies demonstrated that TAK1 was a direct target gene of miR-143. MiR-143 also inhibited PDA cells proliferation and migration, induced apoptosis and G/S arrest. Moreover, TAK1 depletion inactivated MAPK and NF-κB pathway, mimicking the function of miR-143.
The study highlights that miR-143 acts as a tumor suppressor in PDA through directly targeting TAK1, and their functional regulation may provide potential therapeutic strategies in clinics.
转化生长因子（TGF）-β激活激酶1（TAK1）是炎症诱导的癌细胞生长和进展的主要调节因子之一。MiR-143失调在包括胰腺导管腺癌（PDA）在内的多种人类疾病中是常见事件。
确定PDA中TAK1与miR-143之间的相互作用。
对PDA患者基因谱中TAK1的表达进行数据挖掘。采用实时定量PCR（QRT-PCR）和蛋白质印迹法检测PDA组织和细胞系中TAK1的表达。将异位miR-143和TAK1导入PDA细胞。检测细胞生长、凋亡和迁移情况。利用异种移植模型在体内检测TAK1的功能。进行蛋白质印迹和荧光素酶测定以研究miR-143的直接靶点。
PDA患者基因谱数据（GSE15471和GSE16515）显示，PDA组织中TAK1 mRNA异常上调。TAK1蛋白水平在PDA组织和细胞系中过表达。TAK1的过表达与阳性淋巴结转移密切相关。抑制TAK1在体外和体内均抑制细胞生长、迁移并诱导细胞凋亡。进一步研究表明，TAK1是miR-143的直接靶基因。MiR-143还抑制PDA细胞增殖和迁移，诱导凋亡和G/S期阻滞。此外，TAK1缺失使丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路失活，模拟了miR-143的功能。
该研究强调miR-143通过直接靶向TAK1在PDA中发挥肿瘤抑制作用，它们的功能调节可能为临床提供潜在的治疗策略。
