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Identification of HGF as a novel target of miR-15a/16/195 in gastric cancer

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Summary

Background Gastric malignancy is the third most frequently encountered cancer globally and have been documented to confer extremely poor prognosis, given their limited treatment options. The up-regulation of hepatocyte growth factor (HGF) has been found in various tumor tissues, including GC tissue, and has been linked with tumor development. Nevertheless, the pathways leading to HGF upregulation have yet to be fully explored. Methods Immunohistochemistry (IHC) assay was used to detect HGF expression in human gastric tumor tissues, while western blotting allowed quantification of protein levels. Bioinformatics tools were used to predict potential miRNA that may target HGF mRNA. Relative levels of miR-15a/16/195 as well as the target mRNA levels were analyzed with qRT-PCR. Direct targeting between miRNA and mRNA was then validated by luciferase assay. Finally, a mouse xenograft tumor model was selected to demonstrate the in vivo effects of miR-15a/16/195. Results HGF protein expressions were markedly raised, while miR-15a/16/195 levels were dramatically down-regulated in tumor tissues of GC. miR-15a/16/195 were shown to directly bind with the 3′-UTR of HGF mRNA. This study demonstrated that HGF can be repressed by overexpressed miR-15a/16/195, which resulted in the suppression of GC cell proliferation and migration. Furthermore, in the xenograft mouse model, miR-15a/16/195 were also found to have a tumor growth suppression effect. Conclusions miR-15a/16/195 suppresses tumorigenesis by targeting HGF and may have a potential therapeutic application in the clinical treatment of GC.

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Abbreviations

GC:

gastric cancer

HGF:

Hepatocyte growth factor

IHC:

immunohistochemical assays

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81772629, 81602158, 81602156, 81702275, 81802363, 81702431, 81702437, 81772843) 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 (Nos. 18JCQNJC81900, 18JCYBJC92000, 18JCYBJC25400, 16PTSYJC00170) and the Science & Technology Development Fund of the Tianjin Education Commission for Higher Education (2018KJ046, 2017KJ227). The funders had no role in the study design, the data collection and analysis, the interpretation of the data, the writing of the report, and the decision to submit this article for publication.

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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, China

    Dongying Liu, Haiyang Zhang, Shaohua Ge, Dan Lin, Jiayi Han, Guoguang Ying & Yi Ba

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  1. Dongying Liu
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Correspondence to Guoguang Ying or Yi Ba.

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Conflict of interest

Dongying Liu declares that he has no conflict of interest. Haiyang Zhang declares that he has no conflict of interest. Shaohua Ge declares that he has no conflict of interest. Dan Lin declares that he has no conflict of interest. Jiayi Han declares that he has no conflict of interest. Guoguang Ying declares that he has no conflict of interest. Yi Ba declares that he has no conflict of interest.

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All applicable international, national, or institutional guidelines for the care and use of animals were followed. Animal experiments were approved by the Animal Research Committee of Tianjin Medical University Cancer Institute and Hospital and were performed in accordance with established guidelines. The use of human tissues was reviewed and approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital, and patient informed consent was obtained. Samples were retrospectively acquired from the surgical pathology archives of Tianjin Medical University Cancer Institute and Hospital.

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Liu, D., Zhang, H., Ge, S. et al. Identification of HGF as a novel target of miR-15a/16/195 in gastric cancer. Invest New Drugs 38, 922–933 (2020). https://doi.org/10.1007/s10637-019-00834-z

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