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Identification of miR-135b as a novel regulator of TGFβ pathway in gastric cancer

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Abstract

Gastric cancer (GC) is a common malignant tumor worldwide, with a high incidence and low survival rate. The transforming growth factor-beta (TGFβ) signaling pathway usually plays a tumor-suppressive role and is normally quietened in GC. The downregulation of transforming growth factor-beta receptor II (TGFBR2) affects TGFβ signaling pathway, which exerts an immense effect on tumor cell proliferation and metastasis. Although the effect of the TGFβ signaling pathway on cancer cells is well studied, little is known about the mechanism by which TGFBR2 expression is downregulated. Here, we showed that TGFBR2 protein, but not TGFBR2 mRNA, was consistently downregulated in GC, suggesting that post-transcriptional mechanism is involved in the regulation of TGFBR2. Bioinformatics analysis and luciferase reporter analysis proved that miR-135b combines precisely with the 3′-UTR of TGFBR2 mRNA. EdU assays and cell migration assays respectively showed that miR-135b overexpression induced the growth and invasion of GC cells. However, the overexpression of TGFBR2 had the opposite effect. TGFBR2 acted as the direct target for miR-135b and was downregulated in gastric cancer cells. Therefore, miR-135b promotes proliferation and migration of GC cells by negatively regulating TGFBR2 expression, displaying an oncomiR effect. Altogether, this conclusive evidence supported that miR-135b mediates the progression of GC by targeting TGFBR2 and miR-135b/TGFBR2 axis can be used in future targeted therapy for GC.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81772629) and the Demonstrative Research Platform of Clinical Evaluation Technology for New Anticancer Drugs (No. 2018ZX09201015). This work was also supported by the Tianjin Science Foundation (No. 18JCYBJC92000) and the Science & Technology Development Fund of the Tianjin Education Commission for Higher Education (2018KJ046).

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  1. Ming Bai, Peiyun Wang, Jiayu Yang and Mengsi Zuo 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, 300060, China

    Ming Bai, Peiyun Wang, Jiayu Yang, Mengsi Zuo & Yi Ba

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  1. Ming Bai
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Correspondence to Yi Ba.

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All animal studies were performed by skilled laboratory personnel with the approval of the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (Tianjin, China), and informed consent was obtained from all patients. All experimental procedures were performed under approved protocols following the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Key points

1. miR-135b showed a high expression pattern in GC.

2. The interaction between miR-135b and TGFBR2 contributed to the invasion and metastasis of gastric cancer cells.

3. Our results illustrated that inhibition of miR-135b in GC serves as a new method for clinical treatment.

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Bai, M., Wang, P., Yang, J. et al. Identification of miR-135b as a novel regulator of TGFβ pathway in gastric cancer. J Physiol Biochem 76, 549–560 (2020). https://doi.org/10.1007/s13105-020-00759-9

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