MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS

Xiao,Yi; Deng,Taoran; Su,Changliang; Shang,Zhen

doi:10.3892/ol.2017.6076

MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS

Authors:
- Yi Xiao
- Taoran Deng
- Changliang Su
- Zhen Shang
View Affiliations

Affiliations: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: April 24, 2017 https://doi.org/10.3892/ol.2017.6076
Pages: 4986-4994

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

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder derived from the myeloid hematopoietic cells that accounts for ~80% of all adult acute leukemia. Numerous studies have shown that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to identify the mechanisms behind chemoresistance and seek therapeutic strategies to enhance efficacy in AML chemotherapy. MicroRNA (miR)‑217 has been recognized as a tumor suppressor that is downregulated in various types of cancer, however the mechanisms behind the expression and function of miR‑217 in AML have not yet been recognized. The expression of miR‑217 was determined by quantitative polymerase chain reaction (qPCR). Following transfection with miR‑217 mimics, an MTT assay, chemosensitivity assay, cell apoptosis assay and western blot analysis were performed in AML cell lines. Functional assays were also performed to explore the effects of endogenous Kirsten rat sarcoma viral oncogene homolog (KRAS) in AML. The results revealed that miR‑217 was downregulated in patients with AML. Overexpression of miR‑217 inhibited cellular proliferation and enhanced cell chemosensitivity to doxorubicin by the cell apoptosis pathway in AML cells. A dual‑luciferase reporter assay demonstrated that KRAS was a direct target gene of miR‑217 in vitro. qPCR and western blot analysis revealed that miR‑217 negatively regulated KRAS protein expression, but had no impact on KRAS mRNA expression. Knockdown of KRAS expression markedly suppressed AML cellular proliferation, and enhanced cell chemosensitivity to doxorubicin via the cell apoptosis pathway. These findings indicate that miR‑217 functions as a tumor suppressor in AML by directly targeting KRAS. Therefore, miR‑217‑based therapeutic strategies may provide a novel strategy for the enhancement of efficacy in the treatment of AML.

View Figures

View References

1	Das RP, Konkimalla VB, Rath SN, Hansa J and Jagdeb M: Elucidation of the molecular interaction between miRNAs and the HOXA9 gene, involved in acute myeloid leukemia, by the assistance of argonaute protein through a computational approach. Genomics Inform. 13:45–52. 2015. View Article : Google Scholar : PubMed/NCBI
2	Estey EH: Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol. 88:318–327. 2013. View Article : Google Scholar : PubMed/NCBI
3	Ferrara F and Schiffer CA: Acute myeloid leukaemia in adults. Lancet. 381:484–495. 2013. View Article : Google Scholar : PubMed/NCBI
4	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
5	Gregory TK, Wald D, Chen Y, Vermaat JM, Xiong Y and Tse W: Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics. J Hematol Oncol. 2:232009. View Article : Google Scholar : PubMed/NCBI
6	Burnett A, Wetzler M and Löwenberg B: Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 29:487–494. 2011. View Article : Google Scholar : PubMed/NCBI
7	Stanisic S and Kalaycio M: Treatment of refractory and relapsed acute myelogenous leukemia. Expert Rev Anticancer Ther. 2:287–295. 2002. View Article : Google Scholar : PubMed/NCBI
8	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
9	Ameres SL and Zamore PD: Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 14:475–488. 2013. View Article : Google Scholar : PubMed/NCBI
10	Berindan-Neagoe I, Pdel C Monroig, Pasculli B and Calin GA: MicroRNAome genome: A treasure for cancer diagnosis and therapy. CA Cancer J Clin. 64:311–336. 2014. View Article : Google Scholar : PubMed/NCBI
11	Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W, et al: Relation between microRNA expression and progression and prognosis of gastric cancer: A microRNA expression analysis. Lancet Oncol. 11:136–146. 2010. View Article : Google Scholar : PubMed/NCBI
12	Braun J and Hüttelmaier S: Pathogenic mechanisms of deregulated microRNA expression in thyroid carcinomas of follicular origin. Thyroid Res. 4 Suppl 1:S12011. View Article : Google Scholar : PubMed/NCBI
13	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
14	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
15	Bhardwaj A, Singh S and Singh AP: MicroRNA-based cancer therapeutics: Big hope from small RNAs. Mol Cell Pharmacol. 2:213–219. 2010.PubMed/NCBI
16	Ryan BM, Robles AI and Harris CC: Genetic variation in microRNA networks: The implications for cancer research. Nat Rev Cancer. 10:389–402. 2010. View Article : Google Scholar : PubMed/NCBI
17	Lu F, Zhang J, Ji M, Li P, Du Y, Wang H, Zang S, Ma D, Sun X and Ji C: miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1. Int J Oncol. 45:383–392. 2014.PubMed/NCBI
18	Nagano H, Tomimaru Y, Eguchi H, Hama N, Wada H, Kawamoto K, Kobayashi S, Mori M and Doki Y: MicroRNA-29a induces resistance to gemcitabine through the Wnt/β-catenin signaling pathway in pancreatic cancer cells. Int J Oncol. 43:1066–1072. 2013.PubMed/NCBI
19	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
20	Wu D, Niu X, Pan H, Zhang Z, Zhou Y, Qu P and Zhou J: MicroRNA-497 targets hepatoma-derived growth factor and suppresses human prostate cancer cell motility. Mol Med Rep. 13:2287–2292. 2016.PubMed/NCBI
21	Sun B, Yang M, Li M and Wang F: The microRNA-217 functions as a tumor suppressor and is frequently downregulated in human osteosarcoma. Biomed Pharmacother. 71:58–63. 2015. View Article : Google Scholar : PubMed/NCBI
22	Wei R, Deng Z and Su J: miR-217 targeting Wnt5a in osteosarcoma functions as a potential tumor suppressor. Biomed Pharmacother. 72:158–164. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang H, Dong X, Gu X, Qin R, Jia H and Gao J: The MicroRNA-217 functions as a potential tumor suppressor in gastric cancer by targeting GPC5. PLoS One. 10:e01254742015. View Article : Google Scholar : PubMed/NCBI
24	Wang B, Shen ZL, Jiang KW, Zhao G, Wang CY, Yan YC, Yang Y, Zhang JZ, Shen C, Gao ZD, et al: MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism. BMC Cancer. 15:4372015. View Article : Google Scholar : PubMed/NCBI
25	Guo J, Feng Z, Huang Z, Wang H and Lu W: MicroRNA-217 functions as a tumour suppressor gene and correlates with cell resistance to cisplatin in lung cancer. Mol Cells. 37:664–671. 2014. View Article : Google Scholar : PubMed/NCBI
26	Su J, Wang Q, Liu Y and Zhong M: miR-217 inhibits invasion of hepatocellular carcinoma cells through direct suppression of E2F3. Mol Cell Biochem. 392:289–296. 2014. View Article : Google Scholar : PubMed/NCBI
27	Li H, Zhao J, Zhang JW, Huang QY, Huang JZ, Chi LS, Tang HJ, Liu GQ, Zhu DJ and Ma WM: MicroRNA-217, down-regulated in clear cell renal cell carcinoma and associated with lower survival, suppresses cell proliferation and migration. Neoplasma. 60:511–515. 2013. View Article : Google Scholar : PubMed/NCBI
28	Vychytilova-Faltejskova P, Kiss I, Klusova S, Hlavsa J, Prochazka V, Kala Z, Mazanec J, Hausnerova J, Kren L, Hermanova M, et al: MiR-21, miR-34a, miR-198 and miR-217 as diagnostic and prognostic biomarkers for chronic pancreatitis and pancreatic ductal adenocarcinoma. Diagn Pathol. 10:382015. View Article : Google Scholar : PubMed/NCBI
29	Zhang Q, Yuan Y, Cui J, Xiao T and Jiang D: MiR-217 promotes tumor proliferation in breast cancer via targeting DACH1. J Cancer. 6:184–191. 2015. View Article : Google Scholar : PubMed/NCBI
30	Shen L, Wang P, Yang J and Li X: MicroRNA-217 regulates WASF3 expression and suppresses tumor growth and metastasis in osteosarcoma. PLoS One. 9:e1091382014. View Article : Google Scholar : PubMed/NCBI
31	Zuber J, Tchernitsa OI, Hinzmann B, Schmitz AC, Grips M, Hellriegel M, Sers C, Rosenthal A and Schäfer R: A genome-wide survey of RAS transformation targets. Nat Genet. 24:144–152. 2000. View Article : Google Scholar : PubMed/NCBI
32	Crespo P and León J: Ras proteins in the control of the cell cycle and cell differentiation. Cell Mol Life Sci. 57:1613–1636. 2000. View Article : Google Scholar : PubMed/NCBI
33	Wu Y, Zhuang Y, Han M, Xu T and Deng K: Ras promotes cell survival by antagonizing both JNK and Hid signals in the Drosophila eye. BMC Dev Biol. 9:532009. View Article : Google Scholar : PubMed/NCBI
34	Lagadinou ED, Ziros PG, Tsopra OA, Dimas K, Kokkinou D, Thanopoulou E, Karakantza M, Pantazis P, Spyridonidis A and Zoumbos NC: c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia. Leukemia. 22:1899–1908. 2008. View Article : Google Scholar : PubMed/NCBI
35	Kweon SH, Song JH and Kim TS: Resveratrol-mediated reversal of doxorubicin resistance in acute myeloid leukemia cells via downregulation of MRP1 expression. Biochem Biophys Res Commun. 395:104–110. 2010. View Article : Google Scholar : PubMed/NCBI
36	Tao J, Lu Q, Wu D, Li P, Xu B, Qing W, Wang M, Zhang Z and Zhang W: ΜicroRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol Rep. 25:1721–1729. 2011.PubMed/NCBI