Pterostilbene increases PTEN expression through the targeted downregulation of microRNA-19a in hepatocellular carcinoma

Qian,Yu‑Yuan; Liu,Zhi‑Su; Zhang,Zidong; Levenson,Anait  S.; Li,Kun

doi:10.3892/mmr.2018.8515

Pterostilbene increases PTEN expression through the targeted downregulation of microRNA-19a in hepatocellular carcinoma

Authors:
- Yu‑Yuan Qian
- Zhi‑Su Liu
- Zidong Zhang
- Anait S. Levenson
- Kun Li
View Affiliations

Affiliations: Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Surgery, School of Medicine, Saint Louis University, St. Louis, MO 63103, USA, Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39762, USA
Published online on: January 29, 2018 https://doi.org/10.3892/mmr.2018.8515
Pages: 5193-5201
Copyright: © Qian 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

Pterostilbene (Pter) is reported to exhibit an anticancer effect in hepatocellular carcinoma (HCC). In order to explore the anticancer mechanism in HCC cells, the present study aimed to investigate whether pterostilbene (Pter) may increase phosphatase and tensin homolog (PTEN) expression through targeted downregulation of microRNA (miRNA/miR)-19a in hepatocellular carcinoma (HCC). The proliferation, apoptosis and cell cycle was analyzed in the SMMC‑7721 HCC cell line by MTT assays and flow cytometry methods. Cells were divided into five treatment groups: Pter treatment, miR‑19a inhibitor transfection, Pter + miR‑19a inhibitor, negative control transfection and blank control. The expression of miR‑19a and PTEN was detected by reverse transcription‑quantitative polymerase chain reaction and western blot analysis following treatment. Furthermore, a luciferase reporter gene assay was performed to determine whether the PTEN gene was a direct target of miR‑19a. The results demonstrated that Pter treatment or miR‑19a inhibitor transfection downregulated miR‑19a and induced PTEN/Akt pathway regulation, which led to proliferation inhibition, cell cycle arrest in the S phase, increased apoptosis and reduced cell invasion. These results indicated that Pter may increase PTEN expression through the direct downregulation of miR‑19a in HCC. Therefore, miR‑19a may have potential as a novel molecular marker for HCC and Pter may be a promising clinical target with the potential to be developed as a HCC therapy.

View Figures

View References

1	Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, et al: Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 47:505–511. 2015. View Article : Google Scholar : PubMed/NCBI
2	Zhang B, Pan X, Cobb GP and Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 302:1–12. 2007. View Article : Google Scholar : PubMed/NCBI
3	Urtasun R, Elizalde M, Azkona M, Latasa MU, García-Irigoyen O, Uriarte I, Fernández-Barrena MG, Vicent S, Alonso MM, Muntané J, et al: Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression. Oncogene. 35:4719–4729. 2016. View Article : Google Scholar : PubMed/NCBI
4	Zhu H, Han C and Wu T: MiR-17-92 cluster promotes hepatocarcinogenesis. Carcinogenesis. 36:1213–1222. 2015. View Article : Google Scholar : PubMed/NCBI
5	Filipowicz W, Bhattacharyya SN and Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 9:102–114. 2008. View Article : Google Scholar : PubMed/NCBI
6	Sapre N and Selth LA: Circulating MicroRNAs as biomarkers of prostate cancer: The state of play. Prostate Cancer. 2013:5396802013. View Article : Google Scholar : PubMed/NCBI
7	Li L, Song W, Yan X, Li A, Zhang X, Li W, Wen X, Zhou L, Yu D, Hu JF and Cui J: Friend leukemia virus integration 1 promotes tumorigenesis of small cell lung cancer cells by activating the miR-17-92 pathway. Oncotarget. 8:41975–41987. 2017.PubMed/NCBI
8	Dhar S, Hicks C and Levenson AS: Resveratrol and prostate cancer: Promising role for microRNAs. Mol Nutr Food Res. 55:1219–1229. 2011. View Article : Google Scholar : PubMed/NCBI
9	Liu F, Zhang F, Li X, Liu Q, Liu W, Song P, Qiu Z, Dong Y and Xiang H: Prognostic role of miR-17-92 family in human cancers: Evaluation of multiple prognostic outcomes. Oncotarget. 8:69125–69138. 2017.PubMed/NCBI
10	Strickertsson JA, Rasmussen LJ and Friis-Hansen L: Enterococcus faecalis infection and reactive oxygen species Down-regulates the miR-17-92 cluster in gastric adenocarcinoma cell culture. Genes (Basel). 5:726–738. 2014. View Article : Google Scholar : PubMed/NCBI
11	Knudsen KN, Nielsen BS, Lindebjerg J, Hansen TF, Holst R and Sorensen FB: microRNA-17 Is the Most Up-Regulated member of the miR-17-92 cluster during early colon cancer evolution. PLoS One. 10:e01405032015. View Article : Google Scholar : PubMed/NCBI
12	Zou P, Ding J and Fu S: Elevated expression of microRNA-19a predicts a poor prognosis in patients with osteosarcoma. Pathol Res Pract. 213:194–198. 2017. View Article : Google Scholar : PubMed/NCBI
13	Zhou B, Wang J, Zheng G and Qiu Z: Methylated urolithin A, the modified ellagitannin-derived metabolite, suppresses cell viability of DU145 human prostate cancer cells via targeting miR-21. Food Chem Toxicol. 97:375–384. 2016. View Article : Google Scholar : PubMed/NCBI
14	Song L, Liu S, Zhang L, Yao H, Gao F, Xu D and Li Q: MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1α feedback loop and the Akt-mTOR signaling pathway. Tumour Biol. 37:12161–12168. 2016. View Article : Google Scholar : PubMed/NCBI
15	Li C, Song L, Zhang Z, Bai XX, Cui MF and Ma LJ: MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression. Oncotarget. 7:66989–67003. 2016.PubMed/NCBI
16	Fang H, Xie J, Zhang M, Zhao Z, Wan Y and Yao Y: miRNA-21 promotes proliferation and invasion of triple-negative breast cancer cells through targeting PTEN. Am J Transl Res. 9:953–961. 2017.PubMed/NCBI
17	Dhar S, Kumar A, Rimando AM, Zhang X and Levenson AS: Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in prostate cancer. Oncotarget. 6:27214–27226. 2015. View Article : Google Scholar : PubMed/NCBI
18	Zhao D, Chen Y, Chen S, Zheng C, Hu J and Luo S: MiR-19a regulates the cell growth and apoptosis of osteosarcoma stem cells by targeting PTEN. Tumour Biol. 39:10104283177053412017. View Article : Google Scholar : PubMed/NCBI
19	Yu G, Chen X, Chen S, Ye W, Hou K and Liang M: MiR-19a, miR-122 and miR-223 are differentially regulated by hepatitis B virus X protein and involve in cell proliferation in hepatoma cells. J Transl Med. 14:1222016. View Article : Google Scholar : PubMed/NCBI
20	Ma Q, Peng Z, Wang L, Li Y, Wang K, Zheng J, Liang Z and Liu T: miR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Int J Oncol. 49:2589–2599. 2016. View Article : Google Scholar : PubMed/NCBI
21	Liu K, Liu S, Zhang W, Jia B, Tan L, Jin Z and Liu Y: miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN. Oncol Rep. 34:1003–1010. 2015. View Article : Google Scholar : PubMed/NCBI
22	Zhang X, Chen Y, Zhao P, Zang L, Zhang Z and Wang X: MicroRNA-19a functions as an oncogene by regulating PTEN/AKT/pAKT pathway in myeloma. Leuk Lymphoma. 58:932–940. 2017. View Article : Google Scholar : PubMed/NCBI
23	Li X, Xie W, Xie C, Huang C, Zhu J, Liang Z, Deng F, Zhu M, Zhu W, Wu R, et al: Curcumin modulates miR-19/PTEN/AKT/p53 axis to suppress bisphenol A-induced MCF-7 breast cancer cell proliferation. Phytother Res. 28:1553–1560. 2014. View Article : Google Scholar : PubMed/NCBI
24	Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S and Takada Y: Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Res. 24:2783–2840. 2004.PubMed/NCBI
25	Wang G, Dai F, Yu K, Jia Z, Zhang A, Huang Q, Kang C, Jiang H and Pu P: Resveratrol inhibits glioma cell growth via targeting oncogenic microRNAs and multiple signaling pathways. Int J Oncol. 46:1739–1747. 2015. View Article : Google Scholar : PubMed/NCBI
26	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
27	Dhar S, Kumar A, Li K, Tzivion G and Levenson AS: Resveratrol regulates PTEN/Akt pathway through inhibition of MTA1/HDAC unit of the NuRD complex in prostate cancer. Biochim Biophys Acta. 1853:265–275. 2015. View Article : Google Scholar : PubMed/NCBI
28	Luo H, Yang Y, Duan J, Wu P, Jiang Q and Xu C: PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 4:e4812013. View Article : Google Scholar : PubMed/NCBI
29	Kumar A, Rimando AM and Levenson AS: Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer. Ann N Y Acad Sci. 1403:15–26. 2017. View Article : Google Scholar : PubMed/NCBI
30	Li Y, Kong D, Wang Z and Sarkar FH: Regulation of microRNAs by natural agents: An emerging field in chemoprevention and chemotherapy research. Pharm Res. 27:1027–1041. 2010. View Article : Google Scholar : PubMed/NCBI
31	Milenkovic D, Jude B and Morand C: miRNA as molecular target of polyphenols underlying their biological effects. Free Radic Biol Med. 64:40–51. 2013. View Article : Google Scholar : PubMed/NCBI
32	Wu YR, Qi HJ, Deng DF, Luo YY and Yang SL: MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer. Tumour Biol. 37:12061–12070. 2016. View Article : Google Scholar : PubMed/NCBI
33	Wang G, Li Y, Wang P, Liang H, Cui M, Zhu M, Guo L, Su Q, Sun Y, McNutt MA and Yin Y: PTEN regulates RPA1 and protects DNA replication forks. Cell Res. 25:1189–1204. 2015. View Article : Google Scholar : PubMed/NCBI
34	Chang RM, Xu JF, Fang F, Yang H and Yang LY: MicroRNA-130b promotes proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling. Tumour Biol. 37:10609–10619. 2016. View Article : Google Scholar : PubMed/NCBI
35	Li P, Mao WM, Zheng ZG, Dong ZM and Ling ZQ: Down-regulation of PTEN expression modulated by dysregulated miR-21 contributes to the progression of esophageal cancer. Dig Dis Sci. 58:3483–3493. 2013. View Article : Google Scholar : PubMed/NCBI
36	Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658. 2007. View Article : Google Scholar : PubMed/NCBI
37	Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV and Cheng JQ: MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 68:425–433. 2008. View Article : Google Scholar : PubMed/NCBI