Vitamin D3 mediates miR‑15a‑5p inhibition of liver cancer cell proliferation via targeting E2F3

Li,Yulong; Lin,Qiang; Chang,Su'e; Zhang,Rong; Wang,Jingjie

doi:10.3892/ol.2020.11572

Vitamin D3 mediates miR‑15a‑5p inhibition of liver cancer cell proliferation via targeting E2F3

Authors:
- Yulong Li
- Qiang Lin
- Su'e Chang
- Rong Zhang
- Jingjie Wang
View Affiliations

Affiliations: Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China, Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: April 24, 2020 https://doi.org/10.3892/ol.2020.11572
Pages: 292-298
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vitamin D3 has been demonstrated to suppress the development and progression of liver cancer, but the mechanism is unclear. The effects of vitamin D3 and microRNA (miR)‑15a‑5p on liver cancer cells were investigated in the present study using MTT and colony formation assays, flow cytometry, western blotting and reverse transcription‑quantitative PCR. A dual‑luciferase reporter assay was performed to determine whether E2F transcription factor 3 (E2F3) was a target of miR‑15a‑5p. The effects of silencing the E2F3 gene expression in liver cancer cells were investigated using a small interfering RNA. Vitamin D3 suppressed liver cancer cell proliferation, induced apoptosis and increased miR‑15a‑5p expression. Treatment with the miR‑15a‑5p mimics significantly suppressed liver cancer cell proliferation compared with that of the controls. Bioinformatics analysis and a dual‑luciferase reporter assay demonstrated that E2F3 was a target of miR‑15a‑5p and that silencing E2F3 inhibited liver cancer cell proliferation. Therefore, Vitamin D3 suppressed cell proliferation by miR‑15a‑5p‑mediated silencing of E2F3 gene expression. These findings suggested a role for vitamin D3 and E2F3 targeting as potential novel liver cancer therapies.

View Figures

View References

1	Bellissimo F, Pinzone MR, Cacopardo B and Nunnari G: Diagnostic and therapeutic management of hepatocellular carcinoma. World J Gastroenterol. 21:12003–12021. 2015. View Article : Google Scholar : PubMed/NCBI
2	Liu CY, Chen KF and Chen PJ: Treatment of liver cancer. Cold Spring Harb Perspect Med. 5:a0215352015. View Article : Google Scholar : PubMed/NCBI
3	Yang J, Zhu S, Lin G, Song C and He Z: Vitamin D enhances omega-3 polyunsaturated fatty acids-induced apoptosis in breast cancer cells. Cell Biol Int. 41:890–897. 2017. View Article : Google Scholar : PubMed/NCBI
4	Dormoy V, Beraud C, Lindner V, Coquard C, Barthelmebs M, Brasse D, Jacqmin D, Lang H and Massfelder T: Vitamin D3 triggers antitumor activity through targeting hedgehog signaling in human renal cell carcinoma. Carcinogenesis. 33:2084–2093. 2012. View Article : Google Scholar : PubMed/NCBI
5	Pan L, Matloob AF, Du J, Pan H, Dong Z, Zhao J, Feng Y, Zhong Y, Huang B and Lu J: Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A/sodium butyrate-induced and 5-aza-2′-deoxycytidine-induced PTEN upregulation. FEBS J. 277:989–999. 2010. View Article : Google Scholar : PubMed/NCBI
6	Zhao Y, Chen C, Pan W, Gao M, He W, Mao R, Lin T and Huang J: Comparative efficacy of vitamin D status in reducing the risk of bladder cancer: A systematic review and network meta-analysis. Nutrition. 32:515–523. 2016. View Article : Google Scholar : PubMed/NCBI
7	Louka ML, Fawzy AM, Naiem AM, Elseknedy MF, Abdelhalim AE and Abdelghany MA: Vitamin D and K signaling pathways in hepatocellular carcinoma. Gene. 629:108–116. 2017. View Article : Google Scholar : PubMed/NCBI
8	Caputo A, Pourgholami MH, Akhter J and Morris DL: 1,25-Dihydroxyvitamin D(3) induced cell cycle arrest in the human primary liver cancer cell line HepG2. Hepatol Res. 26:34–39. 2003. View Article : Google Scholar : PubMed/NCBI
9	Iseki K, Tatsuta M, Uehara H, Iishi H, Yano H, Sakai N and Ishiguro S: Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer. 81:730–733. 1999. View Article : Google Scholar : PubMed/NCBI
10	Zhang Y, Guo Q, Zhang Z, Bai N, Liu Z, Xiong M, Wei Y, Xiang R and Tan X: VDR status arbitrates the prometastatic effects of tumor-associated macrophages. Mol Cancer Res. 12:1181–1191. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zeljic K, Supic G and Magic Z: New insights into vitamin D anticancer properties: Focus on miRNA modulation. Mol Genet Genomics. 292:511–524. 2017. View Article : Google Scholar : PubMed/NCBI
12	Peng Y and Croce CM: The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 1:150042016. View Article : Google Scholar : PubMed/NCBI
13	Ying J, Yu X, Ma C, Zhang Y and Dong J: MicroRNA-363-3p is downregulated in hepatocellular carcinoma and inhibits tumorigenesis by directly targeting specificity protein 1. Mol Med Rep. 16:1603–1611. 2017. View Article : Google Scholar : PubMed/NCBI
14	Dou C, Liu Z, Xu M, Jia Y, Wang Y, Li Q, Yang W, Zheng X, Tu K and Liu Q: miR-187-3p inhibits the metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting S100A4. Cancer Lett. 381:380–390. 2016. View Article : Google Scholar : PubMed/NCBI
15	Li D, Liu X, Lin L, Hou J, Li N, Wang C, Wang P, Zhang Q, Zhang P, Zhou W, et al: MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma. J Biol Chem. 286:36677–36685. 2011. View Article : Google Scholar : PubMed/NCBI
16	Xue F, Yin J, Xu L and Wang B: MicroRNA-143 inhibits tumorigenesis in hepatocellular carcinoma by downregulating GATA6. Exp Ther Med. 13:2667–2674. 2017. View Article : Google Scholar : PubMed/NCBI
17	Bandyopadhyay S, Mitra R, Maulik U and Zhang MQ: Development of the human cancer MicroRNA network. Silence. 1:62010. View Article : Google Scholar : PubMed/NCBI
18	Long J, Jiang C, Liu B, Fang S and Kuang M: MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. Tumour Biol. 37:5821–5828. 2016. View Article : Google Scholar : PubMed/NCBI
19	Liu B, Sun T, Wu G, Shang-Guan H, Jiang ZJ, Zhang JR and Zheng YF: MiR-15a suppresses hepatocarcinoma cell migration and invasion by directly targeting cMyb. Am J Transl Res. 9:520–532. 2017.PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Feng Z, Peng C, Li D, Zhang D, Li X, Cui F, Chen Y and He Q: E2F3 promotes cancer growth and is overexpressed through copy number variation in human melanoma. Onco Targets Ther. 11:5303–5313. 2018. View Article : Google Scholar : PubMed/NCBI
22	Sun FB, Lin Y, Li SJ, Gao J, Han B and Zhang CS: MiR-210 knockdown promotes the development of pancreatic cancer via upregulating E2F3 expression. Eur Rev Med Pharmacol Sci. 22:8640–8648. 2018.PubMed/NCBI
23	Jeon SM and Shin EA: Exploring Vitamin D metabolism and function in cancer. Exp Mol Med. 50:202018. View Article : Google Scholar : PubMed/NCBI
24	Ting HJ, Messing J, Yasmin-Karim S and Lee YF: Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by Vitamin D. J Biol Chem. 288:1–9. 2013. View Article : Google Scholar : PubMed/NCBI
25	Kasiappan R, Shen Z, Tse AK, Jinwal U, Tang J, Lungchukiet P, Sun Y, Kruk P, Nicosia SV, Zhang X and Bai W: 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through MicroRNA-498. J Biol Chem. 287:41297–41309. 2012. View Article : Google Scholar : PubMed/NCBI
26	Wang ZM, Wan XH, Sang GY, Zhao JD, Zhu QY and Wang DM: miR-15a-5p suppresses endometrial cancer cell growth via Wnt/β-catenin signaling pathway by inhibiting WNT3A. Eur Rev Med Pharmacol Sci. 21:4810–4818. 2017.PubMed/NCBI
27	Kontos CK, Tsiakanikas P, Avgeris M, Papadopoulos IN and Scorilas A: miR-15a-5p, A novel prognostic biomarker, predicting recurrent colorectal adenocarcinoma. Mol Diagn Ther. 21:453–464. 2017. View Article : Google Scholar : PubMed/NCBI
28	John B, Enright AJ, Aravin A, Tuschl T, Sander C and Marks DS: Human MicroRNA targets. Plos Biol. 2:e3632004. View Article : Google Scholar : PubMed/NCBI
29	Zhan L, Zhang Y, Wang W, Song E, Fan Y and Wei B: E2F1: A promising regulator in ovarian carcinoma. Tumour Biol. 37:2823–2831. 2016. View Article : Google Scholar : PubMed/NCBI
30	Gong W, Li J, Wang Y, Meng J and Zheng G: miR-221 promotes lens epithelial cells apoptosis through interacting with SIRT1 and E2F3. Chem Biol Interact. 306:39–46. 2019. View Article : Google Scholar : PubMed/NCBI
31	Zhong Q, Huang J, Wei J and Wu R: Circular RNA CDR1as sponges miR-7-5p to enhance E2F3 stability and promote the growth of nasopharyngeal carcinoma. Cancer Cell Int. 19:2522019. View Article : Google Scholar : PubMed/NCBI
32	Yang H, Zheng W, Shuai X, Chang RM, Yu L, Fang F and Yang LY: MicroRNA-424 inhibits Akt3/E2F3 axis and tumor growth in hepatocellular carcinoma. Oncotarget. 6:27736–27750. 2015.PubMed/NCBI
33	Feber A, Clark J, Goodwin G, Dodson AR, Smith PH, Fletcher A, Edwards S, Flohr P, Falconer A, Roe T, et al: Amplification and overexpression of E2F3 in human bladder cancer. Oncogene. 23:1627–1630. 2003. View Article : Google Scholar
34	Zeng X, Yin F, Liu X, Xu J, Xu Y, Huang J, Nan Y and Qiu X: Upregulation of E2F transcription factor 3 is associated with poor prognosis in hepatocellular carcinoma. Oncol Rep. 31:1139–1146. 2014. View Article : Google Scholar : PubMed/NCBI