MiR-143 Targeting TAK1 Attenuates Pancreatic Ductal Adenocarcinoma Progression via MAPK and NF-κB Pathway In Vitro
Authors: Yuan-Hua Li
Wen-Jie Cheng
Shi-Neng Zhang
Juan-Fei Peng
Feng-Ting Huang
Wen-Ying Chen
Ling-Yun Wang
Yan-Yan Zhuang
Chu-Qiang Li
Jian Tang
Journal: Digestive Diseases and Sciences (2017)
Discipline: CLINICAL MEDICINE
Keywords: MAPK; MiR-143; NF-κB; Pancreatic ductal adenocarcinoma; TAK1.
Affiliations: 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., Department of Ultrasound, the Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong Province, People's Republic of China., Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong Province, People's Republic of China., 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. .

Abstract:  Background: 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). Aims: To identify the interaction between TAK1 and miR-143 in PDA. Methods: 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. Results: 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 G1/S arrest. Moreover, TAK1 depletion inactivated MAPK and NF-κB pathway, mimicking the function of miR-143. Conclusions: 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. 

Retracted: No

PubPeer comments:
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