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MiR-181a, a new regulator of TGF-β signaling, can promote cell migration and proliferation in gastric cancer

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Summary

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.

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Data availability

The datasets supporting the conclusions of this article are included within the article.

Abbreviations

3’-UTR:

3′-untranslated region

CCK-8:

Cell Counting Kit-8

cDNA:

complementary deoxyribonucleic acid

EdU:

5-ethynyl-2-deoxyuridine

HER-2:

epidermal growth factor receptor-2

miRNA:

microRNA

RT-qPCR:

real-time quantitative polymerase chain reaction

siRNA:

small interfering RNA

TGF-β:

transforming growth factor-beta

TGFβR2:

TGF-β receptor 2

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Funding

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).

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Author notes

  1. Shaohua Ge, Haiyang Zhang and Ting Deng contributed equally to this work.

Authors and Affiliations

  1. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, 300060, China

    Shaohua Ge, Haiyang Zhang, Ting Deng, Wu Sun, Tao Ning, Qian Fan, Yi Wang, Xinyi Wang, Qiumo Zhang, Zhengyang Zhou, Haiou Yang, Guoguang Ying & Yi Ba

Authors
  1. Shaohua Ge
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  2. Haiyang Zhang
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  3. Ting Deng
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  4. Wu Sun
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  5. Tao Ning
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  7. Yi Wang
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Contributions

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.

Corresponding authors

Correspondence to Guoguang Ying or Yi Ba.

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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.

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Written informed consent for publication was obtained from all participants.

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The authors have no competing interests to declare.

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Ge, S., Zhang, H., Deng, T. et al. MiR-181a, a new regulator of TGF-β signaling, can promote cell migration and proliferation in gastric cancer. Invest New Drugs 37, 923–934 (2019). https://doi.org/10.1007/s10637-018-0695-5

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  • DOI: https://doi.org/10.1007/s10637-018-0695-5

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