MicroRNA-101 inhibits the metastasis of osteosarcoma cells by downregulation of EZH2 expression

Zhang,Kailiang; Zhang,Yinglong; Ren,Kun; Zhao,Guangyi; Yan,Kang; Ma,Baoan

doi:10.3892/or.2014.3459

MicroRNA-101 inhibits the metastasis of osteosarcoma cells by downregulation of EZH2 expression

Authors:
- Kailiang Zhang
- Yinglong Zhang
- Kun Ren
- Guangyi Zhao
- Kang Yan
- Baoan Ma
View Affiliations

Affiliations: Department of Orthopedic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: September 2, 2014 https://doi.org/10.3892/or.2014.3459
Pages: 2143-2149

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

MicroRNAs (miRNAs) are a class of small non‑coding RNA molecules, which play regulatory roles at the post-transcriptional level by suppressing the translation of protein‑coding genes or inducing mRNA cleavage. Dysregulated expression of miRNAs is involved in multiple types of cancers and plays important roles in regulating various biological processes including metastasis. miR-101 is downregulated in various types of cancer and functions as a suppressor of cell migration and invasion. Meanwhile, enhancer of zeste homolog 2 (EZH2) is associated with the metastatic potential of several aggressive tumors. In the present study, we reported that ectopic overexpression of miR-101 downregulated the expression level of EZH2 and significantly inhibited migration and invasion of osteosarcoma cells. In addition, knockdown of EZH2 by siRNA showed the same effect of miR-101 on migration and invasion. To conclude, these results indicate that miR-101 may act as a tumor suppressor in osteosarcoma, as it has a suppressive role in cell migration and invasion by targeting EZH2.

View Figures

View References

1	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
2	Peters L and Meister G: Argonaute proteins: mediators of RNA silencing. Mol Cell. 26:611–623. 2007. View Article : Google Scholar : PubMed/NCBI
3	Carthew RW and Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell. 136:642–655. 2009. View Article : Google Scholar : PubMed/NCBI
4	Jansson MD and Lund AH: MicroRNA and cancer. Mol Oncol. 6:590–610. 2012. View Article : Google Scholar
5	Chen PS, Su JL and Hung MC: Dysregulation of microRNAs in cancer. J Biomed Sci. 19:902012. View Article : Google Scholar : PubMed/NCBI
6	Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar
7	Hammond SM: MicroRNAs as tumor suppressors. Nat Genet. 39:582–583. 2007. View Article : Google Scholar : PubMed/NCBI
8	Qin X, Yan L, Zhao X, Li C and Fu Y: microRNA-21 overexpression contributes to cell proliferation by targeting PTEN in endometrioid endometrial cancer. Oncol Lett. 4:1290–1296. 2012.PubMed/NCBI
9	Rather MI, Nagashri MN, Swamy SS, Gopinath KS and Kumar A: Oncogenic microRNA-155 downregulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics. J Biol Chem. 288:608–618. 2013. View Article : Google Scholar : PubMed/NCBI
10	Liu L, Yu X, Guo X, et al: miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol Med Rep. 5:753–760. 2012.PubMed/NCBI
11	Frampton AE, Krell J, Jacob J, Stebbing J, Castellano L and Jiao LR: Loss of miR-126 is crucial to pancreatic cancer progression. Expert Rev Anticancer Ther. 12:881–884. 2012. View Article : Google Scholar : PubMed/NCBI
12	Liu X, Jiang L, Wang A, Yu J, Shi F and Zhou X: MicroRNA-138 suppresses invasion and promotes apoptosis in head and neck squamous cell carcinoma cell lines. Cancer Lett. 286:217–222. 2009. View Article : Google Scholar : PubMed/NCBI
13	Link MP: Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy. Cancer Treat Res. 62:383–385. 1993.PubMed/NCBI
14	Jaffe N: Osteosarcoma: review of the past, impact on the future. The American experience. Cancer Treat Res. 152:239–262. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ferguson WS and Goorin AM: Current treatment of osteosarcoma. Cancer Invest. 19:292–315. 2001. View Article : Google Scholar : PubMed/NCBI
16	Novello C, Pazzaglia L, Cingolani C, et al: miRNA expression profile in human osteosarcoma: role of miR-1 and miR-133b in proliferation and cell cycle control. Int J Oncol. 42:667–675. 2013.PubMed/NCBI
17	Zhao H, Guo M, Zhao G, et al: miR-183 inhibits the metastasis of osteosarcoma via downregulation of the expression of Ezrin in F5M2 cells. Int J Mol Med. 30:1013–1020. 2012.PubMed/NCBI
18	Yan K, Gao J, Yang T, et al: MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo. PLoS One. 7:e337782012. View Article : Google Scholar : PubMed/NCBI
19	Fan L, Wu Q, Xing X, Wei Y and Shao Z: MicroRNA-145 targets vascular endothelial growth factor and inhibits invasion and metastasis of osteosarcoma cells. Acta Biochim Biophys Sin. 44:407–414. 2012. View Article : Google Scholar : PubMed/NCBI
20	Osaki M, Takeshita F, Sugimoto Y, et al: MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Mol Ther. 19:1123–1130. 2011. View Article : Google Scholar : PubMed/NCBI
21	Cho HM, Jeon HS, Lee SY, et al: microRNA-101 inhibits lung cancer invasion through the regulation of enhancer of zeste homolog 2. Exp Ther Med. 2:963–967. 2011.PubMed/NCBI
22	Wang HJ, Ruan HJ, He XJ, et al: MicroRNA-101 is downregulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 46:2295–2303. 2010. View Article : Google Scholar : PubMed/NCBI
23	Wang R, Wang HB, Hao CJ, et al: MiR-101 is involved in human breast carcinogenesis by targeting Stathmin1. PLoS One. 7:e461732012. View Article : Google Scholar : PubMed/NCBI
24	Smits M, Nilsson J, Mir SE, et al: miR-101 is downregulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget. 1:710–720. 2010.PubMed/NCBI
25	He LJ, Cai MY, Xu GL, et al: Prognostic significance of overexpression of EZH2 and H3k27me3 proteins in gastric cancer. Asian Pac J Cancer Prev. 13:3173–3178. 2012. View Article : Google Scholar : PubMed/NCBI
26	Ren G, Baritaki S, Marathe H, et al: Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res. 72:3091–3104. 2012. View Article : Google Scholar : PubMed/NCBI
27	Rao ZY, Cai MY, Yang GF, et al: EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-beta1 and is a predictor of outcome in ovarian carcinoma patients. Carcinogenesis. 31:1576–1583. 2010. View Article : Google Scholar : PubMed/NCBI
28	Chen X, Yang TT, Wang W, et al: Establishment and characterization of human osteosarcoma cell lines with different pulmonary metastatic potentials. Cytotechnology. 61:37–44. 2009. View Article : Google Scholar : PubMed/NCBI
29	Negrini M and Calin GA: Breast cancer metastasis: a microRNA story. Breast Cancer Res. 10:2032008. View Article : Google Scholar : PubMed/NCBI
30	Watahiki A, Wang Y, Morris J, et al: MicroRNAs associated with metastatic prostate cancer. PLoS One. 6:e249502011. View Article : Google Scholar : PubMed/NCBI
31	Wada T, Isu K, Takeda N, Usui M, Ishii S and Yamawaki S: A preliminary report of neoadjuvant chemotherapy NSH-7 study in osteosarcoma: preoperative salvage chemotherapy based on clinical tumor response and the use of granulocyte colony-stimulating factor. Oncology. 53:221–227. 1996. View Article : Google Scholar
32	Sauvageau M and Sauvageau G: Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 7:299–313. 2010. View Article : Google Scholar : PubMed/NCBI
33	Varambally S, Dhanasekaran SM, Zhou M, et al: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 419:624–629. 2002. View Article : Google Scholar : PubMed/NCBI
34	Hussein YR, Sood AK, Bandyopadhyay S, et al: Clinical and biological relevance of enhancer of zeste homolog 2 in triple-negative breast cancer. Hum Pathol. 43:1638–1644. 2012. View Article : Google Scholar : PubMed/NCBI
35	Changchien YC, Tatrai P, Papp G, et al: Poorly differentiated synovial sarcoma is associated with high expression of enhancer of zeste homologue 2 (EZH2). J Transl Med. 10:2162012. View Article : Google Scholar : PubMed/NCBI
36	Wang H, Albadine R, Magheli A, et al: Increased EZH2 protein expression is associated with invasive urothelial carcinoma of the bladder. Urol Oncol. 30:428–433. 2012. View Article : Google Scholar : PubMed/NCBI
37	Fluge Ø, Gravdal K, Carlsen E, et al: Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Cancer. 101:1282–1289. 2009.PubMed/NCBI
38	Guo SQ and Zhang YZ: Overexpression of enhancer of zests homolog 2 in lymphoma. Chin Med J. 125:3735–3739. 2012.PubMed/NCBI
39	Sasaki H, Setoguchi T, Matsunoshita Y, Gao H, Hirotsu M and Komiya S: The knock-down of overexpressed EZH2 and BMI-1 does not prevent osteosarcoma growth. Oncol Rep. 23:677–684. 2010.PubMed/NCBI
40	Tong ZT, Cai MY, Wang XG, et al: EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. 31:583–594. 2012.PubMed/NCBI
41	Liu DC and Yang ZL: Overexpression of EZH2 and loss of expression of PTEN is associated with invasion, metastasis, and poor progression of gallbladder adenocarcinoma. Pathol Res Pract. 207:472–478. 2011. View Article : Google Scholar : PubMed/NCBI
42	Alford SH, Toy K, Merajver SD and Kleer CG: Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. Breast Cancer Res Treat. 132:429–437. 2012. View Article : Google Scholar : PubMed/NCBI
43	Song QC, Shi ZB, Zhang YT, et al: Downregulation of microRNA-26a is associated with metastatic potential and the poor prognosis of osteosarcoma patients. Oncol Rep. 31:1263–1270. 2014.PubMed/NCBI
44	Sakurai T, Bilim VN, Ugolkov AV, et al: The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells. Biochem Biophys Res Commun. 422:607–614. 2012. View Article : Google Scholar : PubMed/NCBI
45	Varambally S, Cao Q, Mani RS, et al: Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 322:1695–1699. 2008. View Article : Google Scholar : PubMed/NCBI
46	Banerjee R, Mani RS, Russo N, et al: The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. Oncogene. 30:4339–4349. 2011. View Article : Google Scholar : PubMed/NCBI
47	Friedman JM, Liang G, Liu CC, et al: The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 69:2623–2629. 2009. View Article : Google Scholar : PubMed/NCBI