Inhibition of miR-19a-3p Increases Bortezomib-Induced Apoptosis in Myeloma Cell Lines by Targeting SOCS3
Inhibition of miR-19a-3p Increases Bortezomib-Induced Apoptosis in Myeloma Cell Lines by Targeting SOCS3
OBJECTIVE Apoptosis is considered the main factor inducing by bortezomib in myeloma cells. Although bortezomib (BTZ) is a crucial drug for the treatment of MM, chemoresistance is a major problem. OncomiR19a plays an oncogenic role in many types of cancer such as MM; however, the function of miR-19a in the pathogenesis of MM and drug resistance has not been identified well. The present research aims at investigating the inhibition of miR-19a by antagomir to conclude BTZ responsiveness and suggests that miR-19a may be a biomarker for the prognosis of the patient. METHODS In the present research, the viability and apoptosis of myeloma cells were analyzed by colorimetric MTT and Annexin-PI flow cytometric assays. QRT-PCR was implemented to evaluate the expression level of miR-19a, its targets SOCS3 and STAT3, at the mRNA level. RESULTS Following treating transfected cells with bortezomib we found out that miR-19a was downregulated, and the rate of apoptosis of myeloma cells after bortezomib treatment considerably increased. It indicated that mRNA of SOCS3 increased and STAT3 decreased. CONCLUSION The research results indicate that oncomiR-19a as a biomarker may induce better responsiveness to bortezomib in myeloma cell lines through its targets SOCS3, STAT3, and may provide new therapeutic targets in the future for myeloma. The research results indicate that oncomiR-19a as a biomarker may induce better responsiveness to bortezomib in myeloma cell lines through its targets SOCS3, STAT3 and may provide new therapeutic targets in the future for myeloma
___
- 1. Caracciolo D, Montesano M, Altomare E, Scionti F, Di Martino MT, Tagliaferri P, et al. The potential role of miRNAs in multiple myeloma therapy. Expert Rev Hematol 2018;11(10):793–803.
- 2. Szymczyk A, Macheta A, Podhorecka M. Abnormal microRNA expression in the course of hematological malignancies. Cancer Manag Res 2018;10:4267–77.
- 3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394–424.
- 4. Zhang X, Chen Y, Zhao P, Zang L, Zhang Z, Wang X. MicroRNA-19a functions as an oncogene by regulating PTEN/AKT/pAKT pathway in myeloma. Leukemia & lymphoma 2017;58(4):932–40.
- 5. Yin Z, Yang J, Ning R, Liu Y, Feng M, Gu C, et al. Signal pathways, diseases, and functions associated with the miR‐19a/92a cluster and the use of berberine to modulate the expression of this cluster in multiple myeloma cells. J Biochem Mol Toxicol 2018;32(6):e22057
- 6. Peng J, Thakur A, Zhang S, Dong Y, Wang X, Yuan R, et al. Expressions of miR-181a and miR-20a in RPMI8226 cell line and their potential as biomarkers for multiple myeloma. Tumor Biol 2015;36(11):8545– 52.
- 7. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348(26):2609–17.
- 8. Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat 2015;18:18–35.
- 9. Lv H, Wu X, Ma G, Sun L, Meng J, Song X, et al. An integrated bioinformatical analysis of miR-19a target genes in multiple myeloma. Exp Ther Med 2017;14(5):4711–20.
- 10.Wang Y, Zhao S, Zhu L, Zhang Q, Ren Y. MiR-19a negatively regulated the expression of PTEN and promoted the growth of ovarian cancer cells. Gene 2018;670:166–73.
- 11.Zhu B, Ju S, Chu H, Shen X, Zhang Y, Luo X, et al. The potential function of microRNAs as biomarkers and therapeutic targets in multiple myeloma. Oncol Lett 2018;15(5):6094–106.
- 12.Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016 Jan 28;1:15004.
- 13.Loffler D, Brocke-Heidrich K, Pfeifer G, Stocsits C, Hackermuller J, Kretzschmar A K, et al. Interleukin-6 dependent survival of multiple myeloma cells involves the STAT3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 2007;110(4):1330–33.
- 14.Pichiorri F, Suh S S, Ladetto M, Kuehl M, Palumbo T, Drandi D, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 2008;105(35):12885–90.
- 15.Federico C, Sacco A, Belotti A, Ribolla R, Cancelli V, Giacomini A, et al. Circulating microRNAs and their role in multiple myeloma. Non-coding RNA 2019;5(2):37.
- 16.Collins AS, McCoy CE, Lloyd AT, O’Farrelly C, Stevenson N J. miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signaling. PLoS One 2013;8(7):e69090.
- 17.Mahony R, Ahmed S, Diskin C, Stevenson N J. SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use? Cell Mol Life Sci 2016;73(17):3323–36.
- 18.He G, Karin M. NF-kappaB, and STAT3 - key players in liver inflammation and cancer. Cell Res 2011;21(1):159–68.
- 19.Bromberg J. Stat proteins and oncogenesis. J Clin Invest 2002;109(9):1139–42.
- 20.Selvi N, Kaymaz BT, Gunduz C, Aktan C, Kiper H D, Sahin F, et al. Bortezomib induces apoptosis by interacting with the JAK/STAT pathway in K562 leukemic cells. Tumour Biol 2014;35(8):7861–70.
- 21.Rastgoo N, Abdi J, Hou J, Chang H. Role of epigenetics-microRNA axis in drug resistance of multiple myeloma. J Hematol Oncol 2017;10(1):121.