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

  • Dongying Liu
  • Haiyang Zhang
  • Shaohua Ge
  • Dan Lin
  • Jiayi Han
  • Guoguang YingEmail author
  • Yi BaEmail author
PRECLINICAL STUDIES
  • 22 Downloads

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.

Keywords

miR-15a/16/195 Gastric cancer Proliferation Migration HGF 

Abbreviations

GC

gastric cancer

HGF

Hepatocyte growth factor

IHC

immunohistochemical assays

Notes

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.

Compliance with ethical standards

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.

Ethics approval

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386CrossRefGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29CrossRefGoogle Scholar
  3. 3.
    Koh SA, Kim MK, Lee KH, Kim SW, Kim JR (2014) RhoGDI2 is associated with HGF-mediated tumor invasion through VEGF in stomach cancer. Clin Exp Metastasis 31(7):805–815CrossRefGoogle Scholar
  4. 4.
    Yang X, Zhang XF, Lu X, Jia HL, Liang L, Dong QZ, Ye QH, Qin LX (2014) MicroRNA-26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factor-cMet pathway. Hepatology. 59(5):1874–1885CrossRefGoogle Scholar
  5. 5.
    Wu CW, Li AF, Chi CW, Chung WW, Liu TY, Lui WY et al (1998) Hepatocyte growth factor and met/HGF receptors in patients with gastric adenocarcinoma. Oncol Rep 5(4):817–822Google Scholar
  6. 6.
    Fajardo-Puerta AB, Mato Prado M, Frampton AE, Jiao LR (2016) Gene of the month: HGF. J Clin Pathol 69(7):575–579CrossRefGoogle Scholar
  7. 7.
    Husmann K, Ducommun P, Sabile AA, Pedersen EM, Born W, Fuchs B (2015) Signal transduction and downregulation of C-MET in HGF stimulated low and highly metastatic human osteosarcoma cells. Biochem Biophys Res Commun 464(4):1222–1227CrossRefGoogle Scholar
  8. 8.
    Cao HH, Cheng CY, Su T, Fu XQ, Guo H, Li T, Tse AKW, Kwan HY, Yu H, Yu ZL (2015) Quercetin inhibits HGF/c-met signaling and HGF-stimulated melanoma cell migration and invasion. Mol Cancer 14:103CrossRefGoogle Scholar
  9. 9.
    Li M, Xin X, Wu T, Hua T, Wang H. (2015) HGF and c-Met in pathogenesis of endometrial carcinoma. Front Biosci (Landmark Ed). 2015; 20:635–43Google Scholar
  10. 10.
    Ciamporcero E, Miles KM, Adelaiye R, Ramakrishnan S, Shen L, Ku S, Pizzimenti S, Sennino B, Barrera G, Pili R (2015) Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models. Mol Cancer Ther 14(1):101–110CrossRefGoogle Scholar
  11. 11.
    Hu HJ, Lin XL, Liu MH, Fan XJ, Zou WW (2016) Curcumin mediates reversion of HGF-induced epithelial-mesenchymal transition via inhibition of c-met expression in DU145 cells. Oncol Lett 11(2):1499–1505CrossRefGoogle Scholar
  12. 12.
    Han TS, Hur K, Xu G, Choi B, Okugawa Y, Toiyama Y, Oshima H, Oshima M, Lee HJ, Kim VN, Chang AN, Goel A, Yang HK (2015) MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1. Gut. 64(2):203–214CrossRefGoogle Scholar
  13. 13.
    Su ZX, Zhao J, Rong ZH, Wu YG, Geng WM, Qin CK (2014) Diagnostic and prognostic value of circulating miR-18a in the plasma of patients with gastric cancer. Tumour Biol 35(12):12119–12125CrossRefGoogle Scholar
  14. 14.
    Xu L, Hou Y, Tu G, Chen Y, Du YE, Zhang H et al (2017) Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer. Cell Death Dis 8(3):e2642CrossRefGoogle Scholar
  15. 15.
    Zhu X, Lv M, Wang H, Guan W (2014) Identification of circulating microRNAs as novel potential biomarkers for gastric cancer detection: a systematic review and meta-analysis. Dig Dis Sci 59(5):911–919CrossRefGoogle Scholar
  16. 16.
    Ni J, Yang Y, Liu D, Sun H, Jin S, Li J (2017) MicroRNA-429 inhibits gastric cancer migration and invasion through the downregulation of specificity protein 1. Oncol Lett 13(5):3845–3849CrossRefGoogle Scholar
  17. 17.
    Shi J, Chen P, Sun J, Song Y, Ma B, Gao P, Chen X, Wang Z (2017) MicroRNA-1258: an invasion and metastasis regulator that targets heparanase in gastric cancer. Oncol Lett 13(5):3739–3745CrossRefGoogle Scholar
  18. 18.
    Wang J, Li L, Jiang M, Li Y (2017) MicroRNA-195 inhibits human gastric cancer by directly targeting basic fibroblast growth factor. Clin Transl Oncol 19(11):1320–1328CrossRefGoogle Scholar
  19. 19.
    Janaki Ramaiah M, Lavanya A, Honarpisheh M, Zarea M, Bhadra U, Bhadra MP (2014) MiR-15/16 complex targets p70S6 kinase 1 and controls cell proliferation in MDA-MB-231 breast cancer cells. Gene. 552(2):255–264CrossRefGoogle Scholar
  20. 20.
    Zidan HE, Abdul-Maksoud RS, Elsayed WSH, Desoky EAM (2018) Diagnostic and prognostic value of serum miR-15a and miR-16-1 expression among egyptian patients with prostate cancer. IUBMB Life 70(5):437–444CrossRefGoogle Scholar
  21. 21.
    Rassenti LZ, Balatti V, Ghia EM, Palamarchuk A, Tomasello L, Fadda P, Pekarsky Y, Widhopf GF II, Kipps TJ, Croce CM (2017) MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 114(40):10731–10736CrossRefGoogle Scholar
  22. 22.
    Ho-Yen CM, Jones JL, Kermorgant S (2015) The clinical and functional significance of c-met in breast cancer: a review. Breast Cancer Res 17:52CrossRefGoogle Scholar
  23. 23.
    Li Y, Liu H, Chen J (2014) Dysregulation of HGF/c-met signal pathway and their targeting drugs in lung cancer. Zhongguo Fei Ai Za Zhi 17(8):625–634Google Scholar
  24. 24.
    Hartmann S, Bhola NE, Grandis JR (2016) HGF/met signaling in head and neck Cancer: impact on the tumor microenvironment. Clin Cancer Res 22(16):4005–4013CrossRefGoogle Scholar
  25. 25.
    Graziano F, Galluccio N, Lorenzini P, Ruzzo A, Canestrari E, D'Emidio S, Catalano V, Sisti V, Ligorio C, Andreoni F, Rulli E, di Oto E, Fiorentini G, Zingaretti C, de Nictolis M, Cappuzzo F, Magnani M (2011) Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer. J Clin Oncol 29(36):4789–4795CrossRefGoogle Scholar
  26. 26.
    Wang WX, Kyprianou N, Wang X, Nelson PT (2010) Dysregulation of the mitogen granulin in human cancer through the miR-15/107 microRNA gene group. Cancer Res 70(22):9137–9142CrossRefGoogle Scholar
  27. 27.
    Finnerty JR, Wang WX, Hebert SS, Wilfred BR, Mao G, Nelson PT (2010) The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol 402(3):491–509CrossRefGoogle Scholar
  28. 28.
    Takeshita F, Patrawala L, Osaki M, Takahashi RU, Yamamoto Y, Kosaka N et al (2010) Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther 18(1):181–187CrossRefGoogle Scholar
  29. 29.
    Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353(17):1793–1801CrossRefGoogle Scholar
  30. 30.
    Bandi N, Zbinden S, Gugger M, Arnold M, Kocher V, Hasan L, Kappeler A, Brunner T, Vassella E (2009) miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res 69(13):5553–5559CrossRefGoogle Scholar
  31. 31.
    Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D, Wang Y (2009) Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol 24(4):652–657CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 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 TherapyTianjin Medical UniversityTianjinChina

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