MicroRNA‑766 inhibits the malignant biological behaviours of pancreatic ductal adenocarcinoma by directly targeting ETS1

Li,Shiquan; Yan,Guoqiang; Yue,Meng; Kang,Zhenhua; Wang,Lei

doi:10.3892/mmr.2018.9770

MicroRNA‑766 inhibits the malignant biological behaviours of pancreatic ductal adenocarcinoma by directly targeting ETS1

Authors:
- Shiquan Li
- Guoqiang Yan
- Meng Yue
- Zhenhua Kang
- Lei Wang
View Affiliations

Affiliations: Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: December 14, 2018 https://doi.org/10.3892/mmr.2018.9770
Pages: 1380-1387

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

Increasing evidence indicates that numerous microRNAs (miRNAs) are altered in pancreatic ductal adenocarcinoma (PDAC), and their alterations significantly influence the malignant behaviour of PDAC. Therefore, identifying miRNAs associated with PDAC and their biological roles in the disease may provide promising therapeutic opportunities. Alteration of the expression of miRNA‑766 (miR‑766) has been previously reported in several types of human malignancy. However, to the best of our knowledge, whether miR‑766 exhibits different expression patterns in PDAC and its underlying functions in the progression of PDAC remain to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect miR‑766 expression levels in PDAC tissues and cell lines. The effects of miR‑766 upregulation on PDAC cell proliferation and invasion were evaluated using MTT and invasion assays, respectively. The mechanisms underlying the role of miR‑766 in PDAC cells were explored using bioinformatics analysis, luciferase reporter assay, RT‑qPCR and western blot analysis. It was found that miR‑766 was significantly downregulated in PDAC tissues and cell lines. The detailed roles of miR‑766 in the progression of PDAC were characterised using Panc‑1 and Aspc‑1 cell lines. The results revealed that the upregulation of miR‑766 restricted the proliferation and invasion of PDAC cells. Through a series of experiments, it was found that E26 transformation specific‑1 (ETS1) was a direct target of miR‑766 in PDAC cells. Furthermore, ETS1 knockdown simulated the inhibitory effects of the overexpression of miR‑766 on PDAC cells, whereas the effects of miR‑766 restoration on the PDAC cells were reversed by overexpressing ETS1. In conclusion, the findings of the present study demonstrate that miR‑766 offers potential as a therapeutic target for patients with PDAC.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Modolell I, Guarner L and Malagelada JR: Vagaries of clinical presentation of pancreatic and biliary tract cancer. Ann Oncol. 10 Suppl 4:S82–S84. 1999. View Article : Google Scholar
3	Hidalgo M: Pancreatic cancer. N Engl J Med. 362:1605–1617. 2010. View Article : Google Scholar : PubMed/NCBI
4	Winter JM, Brennan MF, Tang LH, D'Angelica MI, Dematteo RP, Fong Y, Klimstra DS, Jarnagin WR and Allen PJ: Survival after resection of pancreatic adenocarcinoma: Results from a single institution over three decades. Ann Surg Oncol. 19:169–175. 2012. View Article : Google Scholar : PubMed/NCBI
5	Cho K, Ishiwata T, Uchida E, Nakazawa N, Korc M, Naito Z and Tajiri T: Enhanced expression of keratinocyte growth factor and its receptor correlates with venous invasion in pancreatic cancer. Am J Pathol. 170:1964–1974. 2007. View Article : Google Scholar : PubMed/NCBI
6	Cleary SP, Gryfe R, Guindi M, Greig P, Smith L, Mackenzie R, Strasberg S, Hanna S, Taylor B, Langer B and Gallinger S: Prognostic factors in resected pancreatic adenocarcinoma: Analysis of actual 5-year survivors. J Am Coll Surg. 198:722–731. 2004. View Article : Google Scholar : PubMed/NCBI
7	Galasso M, Sandhu SK and Volinia S: MicroRNA expression signatures in solid malignancies. Cancer J. 18:238–243. 2012. View Article : Google Scholar : PubMed/NCBI
8	Zhu W, Wang Y, Zhang D, Yu X and Leng X: MiR-7-5p functions as a tumor suppressor by targeting SOX18 in pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun. 497:963–970. 2018. View Article : Google Scholar : PubMed/NCBI
9	Xiong J, Wang D, Wei A, Ke N, Wang Y, Tang J, He S, Hu W and Liu X: MicroRNA-410-3p attenuates gemcitabine resistance in pancreatic ductal adenocarcinoma by inhibiting HMGB1-mediated autophagy. Oncotarget. 8:107500–107512. 2017. View Article : Google Scholar : PubMed/NCBI
10	Wu Z, Zhou L, Ding G and Cao L: Overexpressions of miR-212 are associated with poor prognosis of patients with pancreatic ductal adenocarcinoma. Cancer Biomark. 18:35–39. 2017. View Article : Google Scholar : PubMed/NCBI
11	Fan Y, Shi C, Li T and Kuang T: microRNA-454 shows anti-angiogenic and anti-metastatic activity in pancreatic ductal adenocarcinoma by targeting LRP6. Am J Cancer Res. 7:139–147. 2017.PubMed/NCBI
12	Chang JC and Kundranda M: Novel diagnostic and predictive biomarkers in pancreatic adenocarcinoma. Int J Mol Sci. 18:E6672017. View Article : Google Scholar : PubMed/NCBI
13	Diab M, Muqbil I, Mohammad RM, Azmi AS and Philip PA: The role of microRNAs in the diagnosis and treatment of pancreatic adenocarcinoma. J Clin Med. 5:E592016. View Article : Google Scholar : PubMed/NCBI
14	Song B, Zhang C, Li G, Jin G and Liu C: MiR-940 inhibited pancreatic ductal adenocarcinoma growth by targeting MyD88. Cell Physiol Biochem. 35:1167–1177. 2015. View Article : Google Scholar : PubMed/NCBI
15	Keklikoglou I, Hosaka K, Bender C, Bott A, Koerner C, Mitra D, Will R, Woerner A, Muenstermann E, Wilhelm H, et al: MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene. 34:4867–4878. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zhang R, Leng H, Huang J, Du Y, Wang Y, Zang W, Chen X and Zhao G: miR-337 regulates the proliferation and invasion in pancreatic ductal adenocarcinoma by targeting HOXB7. Diagn Pathol. 9:1712014. View Article : Google Scholar : PubMed/NCBI
17	Chen C, Xue S, Zhang J, Chen W, Gong D and Zheng J, Ma J, Xue W, Chen Y, Zhai W and Zheng J: DNA-methylation-mediated repression of miR-766-3p promotes cell proliferation via targeting SF2 expression in renal cell carcinoma. Int J Cancer. 141:1867–1878. 2017. View Article : Google Scholar : PubMed/NCBI
18	Li YC, Li CF, Chen LB, Li DD, Yang L, Jin JP and Zhang B: MicroRNA-766 targeting regulation of SOX6 expression promoted cell proliferation of human colorectal cancer. Onco Targets Ther. 8:2981–2988. 2015. View Article : Google Scholar : PubMed/NCBI
19	Li X, Shi Y, Yin Z, Xue X and Zhou B: An eight-miRNA signature as a potential biomarker for predicting survival in lung adenocarcinoma. J Transl Med. 12:1592014. View Article : Google Scholar : 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	Park JY, Helm J, Coppola D, Kim D, Malafa M and Kim SJ: MicroRNAs in pancreatic ductal adenocarcinoma. World J Gastroenterol. 17:817–827. 2011. View Article : Google Scholar : PubMed/NCBI
22	Mardin WA and Mees ST: MicroRNAs: Novel diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma? Ann Surg Oncol. 16:3183–3189. 2009. View Article : Google Scholar : PubMed/NCBI
23	Frampton AE, Krell J, Jacob J, Stebbing J, Jiao LR and Castellano L: microRNAs as markers of survival and chemoresistance in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther. 11:1837–1842. 2011. View Article : Google Scholar : PubMed/NCBI
24	Oh K and Lee DS: In vivo validation of metastasis-regulating microRNA-766 in human triple-negative breast cancer cells. Lab Anim Res. 33:256–263. 2017. View Article : Google Scholar : PubMed/NCBI
25	Afgar A, Fard-Esfahani P, Mehrtash A, Azadmanesh K, Khodarahmi F, Ghadir M and Teimoori-Toolabi L: MiR-339 and especially miR-766 reactivate the expression of tumor suppressor genes in colorectal cancer cell lines through DNA methyltransferase 3B gene inhibition. Cancer Biol Ther. 17:1126–1138. 2016. View Article : Google Scholar : PubMed/NCBI
26	Dittmer J: The role of the transcription factor Ets1 in carcinoma. Semin Cancer Biol. 35:20–38. 2015. View Article : Google Scholar : PubMed/NCBI
27	Ito T, Nakayama T, Ito M, Naito S, Kanematsu T and Sekine I: Expression of the ets-1 proto-oncogene in human pancreatic carcinoma. Mod Pathol. 11:209–215. 1998.PubMed/NCBI
28	Lefter LP, Dima S, Sunamura M, Furukawa T, Sato Y, Abe M, Chivu M, Popescu I and Horii A: Transcriptional silencing of ETS-1 efficiently suppresses angiogenesis of pancreatic cancer. Cancer Gene Ther. 16:137–148. 2009. View Article : Google Scholar : PubMed/NCBI
29	Khanna A, Mahalingam K, Chakrabarti D and Periyasamy G: Ets-1 expression and gemcitabine chemoresistance in pancreatic cancer cells. Cell Mol Biol Lett. 16:101–113. 2011. View Article : Google Scholar : PubMed/NCBI
30	Li C, Wang Z, Chen Y, Zhou M, Zhang H, Chen R, Shi F, Wang C and Rui Z: Transcriptional silencing of ETS-1 abrogates epithelial-mesenchymal transition resulting in reduced motility of pancreatic cancer cells. Oncol Rep. 33:559–565. 2015. View Article : Google Scholar : PubMed/NCBI
31	Li Z, Lin P, Gao C, Peng C, Liu S, Gao H, Wang B, Wang J, Niu J and Niu W: Integrin β6 acts as an unfavorable prognostic indicator and promotes cellular malignant behaviors via ERK-ETS1 pathway in pancreatic ductal adenocarcinoma (PDAC). Tumour Biol. 37:5117–5131. 2016. View Article : Google Scholar : PubMed/NCBI
32	Christopher AF, Kaur RP, Kaur G, Kaur A, Gupta V and Bansal P: MicroRNA therapeutics: Discovering novel targets and developing specific therapy. Perspect Clin Res. 7:68–74. 2016. View Article : Google Scholar : PubMed/NCBI