Overexpression of miR‑574‑3p suppresses proliferation and induces apoptosis of chronic myeloid leukemia cells via targeting IL6/JAK/STAT3 pathway

Yang,Haoying; Zhang,Jun; Li,Jiuping; Zhao,Furong; Shen,Yao; Xing,Xuemei

doi:10.3892/etm.2018.6700

Overexpression of miR‑574‑3p suppresses proliferation and induces apoptosis of chronic myeloid leukemia cells via targeting IL6/JAK/STAT3 pathway

Authors:
- Haoying Yang
- Jun Zhang
- Jiuping Li
- Furong Zhao
- Yao Shen
- Xuemei Xing
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Affiliations: Department of Blood Transfusion, San Er Ling Yi Hospital Affiliated to School of Medicine, Xi'an Jiaotong University, Hanzhong, Shanxi 723000, P.R. China, Department of Clinical Laboratory, San Er Ling Yi Hospital Affiliated to School of Medicine, Xi'an Jiaotong University, Hanzhong, Shanxi 723000, P.R. China
Published online on: September 5, 2018 https://doi.org/10.3892/etm.2018.6700
Pages: 4296-4302

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Abstract

The present study aimed to elucidate the potential roles and regulatory mechanism of microRNA (miR)‑574‑3p in the development of chronic myeloid leukemia (CML). The expression of miR‑574‑3p in peripheral blood obtained from patients with CML was examined. Subsequently, miR‑574‑3p was overexpressed and suppressed in CML K562 cells to further investigate the effects of miR‑574‑3p on cell proliferation, and apoptosis. Furthermore, a luciferase reporter assay was performed to investigate whether interleukin‑6 (IL‑6) was a target of miR‑574‑3p. In addition, the regulatory association between miR‑574‑3p and the IL‑6/Janus kinase (JNK)/signal transducer and activator of transcription‑3 (STAT3) signaling pathway was explored. The expression of miR‑574‑3p in the peripheral blood obtained from patients with CML was significantly lower compared with that in healthy controls. Overexpression of miR‑574‑3p significantly inhibited the proliferation and induced the apoptosis of K562 cells, whereas suppression of miR‑574‑3p exhibited opposite effects. In addition, IL‑6 was identified to be a direct target of miR‑574‑3p. Overexpression of IL‑6 significantly promoted the proliferation and inhibited the apoptosis of K562 cells. Furthermore, overexpression of miR‑574‑3p inhibited the activation of the JAK/STAT3 signaling pathway, which was rescued by overexpression of IL‑6. The results of the current study indicate that miR‑574‑3p overexpression may serve an important role in inhibiting proliferation and inducing apoptosis of K562 cells via suppression of IL‑6/JAK/STAT3 signaling pathway activation. miR‑574‑3p may serve as a potential therapeutic target for CML.

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1	Aquino SS, Gonçalves RP and Silva LB: The pharmacotherapeutic follow-up of patients with chronic myeloid leukemia (CML) on imatinib mesylate therapy. Rev Bras Hematol Hemoter. 31:137–142. 2009. View Article : Google Scholar
2	Marzag H: Développement de nouvelles réactions éco-compatibles: Application à la synthèse de molécules bioactives. 2013.
3	Jabbour E and Kantarjian H: Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol. 89:547–556. 2014. View Article : Google Scholar : PubMed/NCBI
4	Holyoake TL, Jiang X, Drummond MW, Eaves AC and Eaves CJ: Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia. 16:549–558. 2002. View Article : Google Scholar : PubMed/NCBI
5	Chu Y, Zhu H, Lv L, Zhou Y and Huo J: MiRNAs in oesophageal squamous cancer. Neth J Med. 71:69–75. 2013.PubMed/NCBI
6	Mo MH, Chen L, Fu Y, Wang W and Fu SW: Cell-free circulating miRNA biomarkers in cancer. J Cancer. 3:432–448. 2012. View Article : Google Scholar : PubMed/NCBI
7	Reddy KB: MicroRNA (miRNA) in cancer. Cancer Cell Int. 15:382015. View Article : Google Scholar : PubMed/NCBI
8	Arya D, Sachithanandan SP, Ross C, Palakodeti D, Li S and Krishna S: MiRNA182 regulates percentage of myeloid and erythroid cells in chronic myeloid leukemia. Cell Death Dis. 8:e25472017. View Article : Google Scholar : PubMed/NCBI
9	Xishan Z, Ziying L, Jing D and Gang L: MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia. Sci Rep. 5:124602015. View Article : Google Scholar : PubMed/NCBI
10	Liu Y, Song Y, Ma W, Zheng W and Yin H: Decreased microRNA-30a levels are associated with enhanced ABL1 and BCR-ABL1 expression in chronic myeloid leukemia. Leuk Res. 37:349–356. 2013. View Article : Google Scholar : PubMed/NCBI
11	Yu Y, Yang L, Zhao M, Zhu S, Kang R, Vernon P, Tang D and Cao L: Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells. Leukemia. 26:1752–1760. 2012. View Article : Google Scholar : PubMed/NCBI
12	Li Y, Zhao L, Li N, Miao Y, Zhou H and Jia L: miR-9 regulates the multidrug resistance of chronic myelogenous leukemia by targeting ABCB1. Oncol Rep. 37:2193–2200. 2017. View Article : Google Scholar : PubMed/NCBI
13	Tatarano S, Chiyomaru T, Kawakami K, Enokida H, Yoshino H, Hidaka H, Nohata N, Yamasaki T, Gotanda T, Tachiwada T, et al: Novel oncogenic function of mesoderm development candidate 1 and its regulation by MiR-574-3p in bladder cancer cell lines. Int J Oncol. 40:951–959. 2012. View Article : Google Scholar : PubMed/NCBI
14	Krishnan P, Ghosh S, Wang B, Li D, Narasimhan A, Berendt R, Graham K, Mackey JR, Kovalchuk O and Damaraju S: Next generation sequencing profiling identifies miR-574-3p and miR-660-5p as potential novel prognostic markers for breast cancer. BMC Genomics. 16:7352015. View Article : Google Scholar : PubMed/NCBI
15	Ujihira T, Ikeda K, Suzuki T, Yamaga R, Sato W, Horie-Inoue K, Shigekawa T, Osaki A, Saeki T, Okamoto K, et al: MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast cancer. Sci Rep. 5:76412015. View Article : Google Scholar : PubMed/NCBI
16	Su Y, Ni Z, Wang G, Cui J, Wei C, Wang J, Yang Q, Xu Y and Li F: Aberrant expression of microRNAs in gastric cancer and biological significance of miR-574-3p. Int Immunopharmacol. 13:468–475. 2012. View Article : Google Scholar : PubMed/NCBI
17	Ma L, Zhu Z, Jiang L, Sun X, Lu X, Zhou M, Qian S and Jianyong L: Matrine suppresses cell growth of human chronic myeloid leukemia cells via its inhibition of the interleukin-6/Janus activated kinase/signal transducer and activator of transcription 3 signaling cohort. Leuk Lymphoma. 56:2923–2930. 2015. View Article : Google Scholar : PubMed/NCBI
18	Xu H, Liu X, Zhou J, Chen X and Zhao J: miR-574-3p acts as a tumor promoter in osteosarcoma by targeting SMAD4 signaling pathway. Oncol Lett. 12:5247–5253. 2016. View Article : Google Scholar : PubMed/NCBI
19	Okumura T, Kojima H, Miwa T, Sekine S, Hashimoto I, Hojo S, Nagata T and Shimada Y: The expression of microRNA 574-3p as a predictor of postoperative outcome in patients with esophageal squamous cell carcinoma. World J Surg Oncol. 14:2282016. View Article : Google Scholar : PubMed/NCBI
20	Yamasaki T, Kim EJ, Cerutti H and Ohama T: Argonaute3 is a key player in miRNA-mediated target cleavage and translational repression in Chlamydomonas. Plant J. 85:258–268. 2016. View Article : Google Scholar : PubMed/NCBI
21	Hong DS, Angelo LS and Kurzrock R: Interleukin-6 and its receptor in cancer: Implications for translational therapeutics. Cancer. 110:1911–1928. 2007. View Article : Google Scholar : PubMed/NCBI
22	Maeda K, Baba Y, Nagai Y, Miyazaki K, Malykhin A, Nakamura K, Kincade PW, Sakaguchi N and Coggeshall KM: IL-6 blocks a discrete early step in lymphopoiesis. Blood. 106:879–885. 2005. View Article : Google Scholar : PubMed/NCBI
23	Reynaud D, Pietras E, Barry-Holson K, Mir A, Binnewies M, Jeanne M, Sala-Torra O, Radich JP and Passegué E: IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell. 20:661–673. 2011. View Article : Google Scholar : PubMed/NCBI
24	Ciarcia R, Vitiello MT, Galdiero M, Pacilio C, Iovane V, d'Angelo D, Pagnini D, Caparrotti G, Conti D, Tomei V, et al: Imatinib treatment inhibit IL-6, IL-8, NF-KB and AP-1 production and modulate intracellular calcium in CML patients. J Cell Physiol. 227:2798–2803. 2012. View Article : Google Scholar : PubMed/NCBI
25	Kumar H, Tichkule S, Raj U, Gupta S, Srivastava S and Varadwaj PK: Effect of STAT3 inhibitor in chronic myeloid leukemia associated signaling pathway: A mathematical modeling, simulation and systems biology study. 3 Biotech. 6:402016. View Article : Google Scholar : PubMed/NCBI
26	Baśkiewicz-Masiuk M and Machaliński B: The role of the STAT5 proteins in the proliferation and apoptosis of the CML and AML cells. Eur J Haematol. 72:420–429. 2004. View Article : Google Scholar : PubMed/NCBI
27	Jung JH, Kwon TR, Jeong SJ, Kim EO, Sohn EJ, Yun M and Kim SH: Apoptosis induced by tanshinone IIA and cryptotanshinone is mediated by distinct JAK/STAT3/5 and SHP1/2 signaling in chronic myeloid leukemia K562 cells. Evid Based Complement Alternat Med. 2013:8056392013. View Article : Google Scholar : PubMed/NCBI
28	Kaymaz BT, Cetintaş VB, Aktan C and Kosova B: MicroRNA-520a-5p displays a therapeutic effect upon chronic myelogenous leukemia cells by targeting STAT3 and enhances the anticarcinogenic role of capsaicin. Tumor Biol. 35:8733–8742. 2014. View Article : Google Scholar
29	Selvi N, Kaymaz BT, Gündüz C, Aktan Ç, Kiper HD, Şahin F, Cömert M, Selvi AF, Kosova B and Saydam G: Bortezomib induces apoptosis by interacting with JAK/STAT pathway in K562 leukemic cells. Tumor Biol. 35:7861–7870. 2014. View Article : Google Scholar
30	Cai H, Qin X and Yang C: Dehydrocostus lactone suppresses proliferation of human chronic myeloid leukemia cells through Bcr/Abl-JAK/STAT signaling pathways. J Cell Biochem. 118:3381–3390. 2017. View Article : Google Scholar : PubMed/NCBI