Journal
ONCOTARGET
Volume 7, Issue 16, Pages 22339-22354Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7970
Keywords
miR-101; ZFX; EMT; TGF-beta; gallbladder carcinoma
Categories
Funding
- National Natural Science Foundation of China [81172026, 81272402, 81301816, 81172029, 91440203, 81402403, 81502433, 31501127]
- National High Technology Research and Development Program (863 Program) [2012AA022606]
- Foundation for Interdisciplinary Research of Shanghai Jiao Tong University [YG2011ZD07]
- Shanghai Science and Technology Commission Intergovernmental International Cooperation Project [12410705900]
- Shanghai Science and Technology Commission Medical Guiding Project [12401905800]
- Program for Changjiang Scholars
- Natural Science Research Foundation of Shanghai Jiao Tong University School of Medicine [13XJ10037]
- Leading Talent program of Shanghai and Specialized Research Foundation [20130073130014]
- Interdisciplinary Program of Shanghai Jiao Tong University [14JCRY05]
- Shanghai Rising-Star Program [15QA1403100]
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Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR-101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-beta-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-beta-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management.
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