MiR-181a, a new regulator of TGF-β signaling, can promote cell migration and proliferation in gastric cancer
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Transforming growth factor-beta (TGF-β) signaling pathway plays pivotal roles in various types of cancer. TGF-β receptor 2 (TGFβR2) contains a kinase domain that phosphorylates and activates the downstream of the TGF-β signaling pathway. Our previous microarray analysis revealed marked changes in miR-181a expression in gastric cancers, and the bioinformatics analysis suggested that miR-181a negatively regulated TGFβR2. In order to verify the effect of miR-181a on TGFβR2 and clarify the influence of miR-181a on the migration and proliferation of gastric cancer, studies in gastric cancer cell lines and xenograft mouse models were carried out. We found that a reduced expression of TGFβR2 and an increased expression miR-181a in gastric cancer tissues compared to adjacent noncancerous tissues. A luciferase reporter assay confirmed that TGFβR2 was a target of miR-181a. In addition, we found that miR-181a mimics, which increased the level of miR-181a, downregulated the expression of TGFβR2 in the gastric cancer cell line SGC-7901. Moreover, both the overexpression of miR-181a and the downregulation of TGFβR2 promoted the migration and proliferation of SGC-7901 cells. Conversely, SGC-7901 cell migration and proliferation were inhibited by the downregulation of miR-181a and the overexpression of TGFβR2. Furthermore, the increased expression of miR-181a and the decreased expression of TGFβR2 also enhanced the tumor growth in mice bearing gastric cancer. Our results herein indicated that miR-181a promoted the migration and proliferation of gastric cancer cells by downregulating TGFβR2 at the posttranscriptional level. The present study suggests that miR-181a is a novel negative regulator of TGFβR2 in the TGF-β signaling pathway and thus represents a potential new therapeutic target for gastric cancer.
KeywordsTGFβR2 miR-181a Gastric cancer Posttranscriptional regulation Molecular targeted therapy
Cell Counting Kit-8
complementary deoxyribonucleic acid
epidermal growth factor receptor-2
real-time quantitative polymerase chain reaction
small interfering RNA
transforming growth factor-beta
TGF-β receptor 2
SG and HZ performed most of the experiments, analyzed the data, and wrote the manuscript. TD, WS and TN reviewed and edited the manuscript. QF performed some experiments. YB and GY designed the experiments and edited the manuscript. YB is the guarantor of this work and has unlimited access to all of the data in the study and thus takes responsibility for the integrity of the data and the accuracy of the data analysis.
This work was supported by the National Natural Science Foundation of China (nos. 81,772,629, 81,602,158, 81,602,156, 81,702,275 and 81,702,437) and the Tianjin Health and Family Planning Commission Foundation of Science and Technology (no. 15KG142).
Compliance with ethical standards
Ethics approval and consent to participate
Animal care and experiments were performed in accordance with guidelines of the Institutional Animal Use Committee of Tianjin Medical University, and the procedures were approved by the Institutional Animal Care and Use Committee.
Consent for publication
Written informed consent for publication was obtained from all participants.
The authors have no competing interests to declare.
- 4.Sun N, Xue Y, Dai T, Li X, Zheng N (2017) Tripartite motif containing 25 promotes proliferation and invasion of colorectal cancer cells through TGF-beta signaling. Biosci Rep 37(4)Google Scholar
- 6.Jin B, Liu Y, Wang H (2016) Antagonism of miRNA-21 sensitizes human gastric Cancer cells to paclitaxel. Cell Biochem Biophys 72(1):275–282Google Scholar
- 20.Liu J, Wu CP, Lu BF, Jiang JT (2014) Mechanism of T cell regulation by microRNAs. Cancer Biol Med 10(3):131–137Google Scholar
- 27.Petrillo M, Zannoni GF, Beltrame L, Martinelli E, DiFeo A, Paracchini L, Craparotta I, Mannarino L, Vizzielli G, Scambia G, D'Incalci M, Romualdi C, Marchini S (2016) Identification of high-grade serous ovarian cancer miRNA species associated with survival and drug response in patients receiving neoadjuvant chemotherapy: a retrospective longitudinal analysis using matched tumor biopsies. Ann Oncol 27(4):625–634PubMedGoogle Scholar