Öz Micro RNAs and voltage-gated potassium channels (VGPCs) both play critical roles in the development of cancer. We aimed to reveal the diversity of miR-126/126*, which effects angiogenesis and vascular development through the inhibition of VGPCs. In this study, potassium channel inhibitors, including tetraethylammonium (5mM), 4-aminopyridine (5mM), margatoxin (1µM) and astemizole (2µM), were applied to MCF-7 and MDA-MB-231 breast cancer cell lines. After totally isolating RNA from the cells, Real-Time Polymerase Chain Reaction was used in order to identify gene expressions. OneWay ANOVA was used for variation analyses, while Tukey HSD and Tamhane were used to assess whether multiple comparisons were statistically significant (P < 0.001). Our results showed an increase in miR-126/126* expressions after the channel inhibition of MCF-7 and MDA-MB-231 cell lines (P < 0.001). miR-126/126* expressions were increased using TEA, 4-AP and astemizole in both cell lines. miR-126/126* expressions were only increased through the use of margatoxin in MCF-7. miR-126/126* may interact with voltage-gated potassium channels. In our study, the inhibition of K channels using K channel blockers resulted in an increase of miR-126/126* expression. Therefore, our data suggested that there could be another perspective between K channels and non-coding RNAs in the development of breast cancer
W. J. Brackenbury, A. M. Chuioni, J. K. J. Diss and M.B.A. Djamgoz. The neonatal splice variant of Navl.5 potentiates in vitro invasive of MDA-MB- 231 human breast cancer cells, Breast cancer research and treatment, 101 (2007) 149-160.
H. O. Ahidouch, A. Ahidouch. K+ Channel Expression in Human Breast Cancer Cells: Involvement in Cell Cycle Regulation and Carcinogenesis, J. Membrane Biol., 221 (2008) 1-6.
M. Abdul, N. Hoosein. Reduced Kv1.3 potassium channel expression in human prostate cancer, J. Membr. Biol., 214 (2006) 99-102.
A. S. Borowiec. IGF-1 Activates HERG K Channels Through an Akt-Dependent Signaling Pathway in Breast Cancer Cells: Role in Cell Proliferation, Journal of Cellular Physiology, (2007) 690-701.
L. Zhang, W. Zou, S. S. Zhou and D. D. Chen. Potassium channels and proliferation and migration of breast cancer cells, Sheng Li Xue Bao, 61 (2009) 15-20.
M. Abdul, A. Santo and N. Hoosein. Activity of potassium channel-blockers in breast cancer, Anticancer Res., 23 (2003) 3347-3351.
L. Y. Jan, Y. N. Jan. Voltage-gated and inwardly rectifying potassium channels, J. Physiol., 505/2 (1997) 267-282.
G. J. Kaczorowski, M. L. Garcia. Pharmacology of voltage-gated and calcium-activated potassium channels, Curr Opin Chem Biol, 3/4 (1999) 448-458. doi: 10.1016/S1367-5931(99)80066-0
J. M. Quayle, M. T. Nelson and N. B. Standen. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle, Physiol Rev, 77/4 (1997) 1165-1232.
S. H. Jang, S. Y. Choi, P. D. Ryu and S. Y. Lee. Anti-proliferative effect of Kv1.3 blockers in A549 human lung adenocarcinoma in vitro and in vivo, Eur J Pharmacol., 651/1-3 (2011) 26-32. doi: 10.1016/j.ejphar.2010.10.066
J. García-Quiroz, J. Camacho. Astemizole: an old anti-histamine as a new promising anti-cancer drug, Anticancer Agents Med Chem. , 11/3 (2011) 307-314.
J. Garcia-Quiroz, R. Garcia-Becerra, D. Barrera, N. Santos, E. Avila, D. Ordaz-Rosado et al. Astemizole synergizes calcitriol antiproliferative activity by inhibiting CYP24A1 and upregulating VDR: a novel approach for breast cancer therapy, PLoS ONE, 7/9 (2012) e45063. doi: 10.1371/journal.pone.0045063
M. Conti. Targeting K+ channels for cancer therapy, J. Exp. Ther. Oncol., 4 (2004)161-166.
G. M. Vincent, L. Zhang. The role of genotyping in diagnosing cardiac channelopathies: progress to date, Mol. Diagn., 9 (2005) 105-118.
M. Brevet. Expression of K+ channels in normal and cancerous human breast, Histol. Histopathol., 23 (2008) 965-972.
T. E. DeCoursey, K. G. Chandy, S. Gupta and M. D. Cahalan. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?, Nature, 307 (1984) 465-468.
L. Conforti, M. Petrovic, D. Mohammad, S. Lee, Q. Ma, S. Barone and A. H. Filipovich. Hypoxia regulates expression and activity of Kv1.3 channels in T lymphocytes: a possible role in T cell proliferation, J. Immunol., 170 (2003) 695-702.
N. Gamper, S. Fillon, S. M. Huber, Y. Feng, T. Kobayashi, P. Cohen and F. Lang. IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1, Pflugers Arch., 443 (2002) 625-634. doi: 10.1007/s00424-001-0741-5
G. Kwon, C. A. Marshall, H. Liu, K. L. Pappan, M. S. Remedi and M. L. McDaniel. Glucose-stimulated DNA synthesis through mammalian target of rapamycin (mTOR) is regulated by KATP channels: effects on cell cycle progression in rodent islets, J Biol Chem., 281 (2006) 3261-3267.
H. Malhi, A. N. Irani, P. Rajvanshi, S. O. Suadicani, D. C. Spray, T. V. McDonald and S. Gupta. KATP channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines. Implications for liver growth control and potential therapeutic targeting, J Biol Chem., 275 (2000) 26050-26057. doi: 10.1074/jbc.M001576200
S. Liebau, C. Propper, T. Bockers, F. Lehmann-Horn, A. Storch, S. Grissmer and Wittekindt O. H. Selective blockage of Kv1.3 and Kv3.1 channels increases neural progenitor cell proliferation, J Neurochem., 99 (2006) 426- 437. doi: 10.1111/j.1471-4159.2006.03967.x
A. Ventura, T. Jacks. MicroRNAs and cancer: short RNAs go a long way, Cell, 136 (2009) 586-591. doi: 10.1016/j.cell.2009.02.005
S. M. Elbashir, W. Lendeckel and T. Tuschl. RNA interference is mediated by 21-and 22-nucleotide RNAs, Genes & Development, 15 (2001) 188-200. doi:10.1101/Gad.862301
N. Patel, E. R. Sauter. Body fluid micro(mi)RNAs as biomarkers for human cancer, Journal of Nucleic Acids Investigation, 2 (2011).
S. Y. Chiu, G. F. Wilson. The role of potassium channels in Schwann cell proliferation in Wallerian degeneration of explant rabbit sciatic nerves, J Physiol., 408 (1989) 199-222.
A. S. Borowiec. Regulation of IGF-1-dependent cyclin D1 and E expression by hEag1 channels in MCF-7 cells: the critical role of hEag1 channels in G1 phase progression, Biochim. Biophys. Acta, 1813 (2011) 723-730.
S. Daido, T. Kanzawa, A. Yamamoto, H. Takeuchi, Y. Kondo and S. Kondo. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells, Cancer Res., 64 (2004) 4286-4293. doi: 10.1158/0008-5472.CAN-03-3084
B. Dallaporta, P. Marchetti, M. A. de Pablo, C. Maisse, H. T. Duc, D. Metivier, N. Zamzami, M. Geuskens and G. Kroemer. Plasma membrane potential in thymocyte apoptosis, J Immunol., 162 (1999) 6534-6542.
L. F. Sempere, M. Preis, T. Yezefski, H. Ouyang, A. A. Suriawinata, A. Silahtaroglu, J. R. Conejo-Garcia, S. Kauppinen, W. Wells and M. Korc. Fluorescence-based codetection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumors, Clin Cancer Res., 16 (2010) 4246-4255. doi: 10.1158/1078-0432.CCR-10- 1152
X. Li, Y. Shen, H. Ichikawa, T. Antes and G. S. Goldberg. Regulation of miRNA expression by Src and contact normalization: effects on nonanchored cell growth and migration, Oncogene, 28 (2009) 4272-4283. doi: 10.1038/onc.2009.278
Q. F. Lin, W. D. Mao, Y. Q. Shu, F. Lin, S. P. Liu, H. Shen, W. Gao, S. Q. Li and D. Shen. A cluster of specified microRNAs in peripheral blood as biomarkers for metastatic non-small-cell lung cancer by stem-loop RT- PCR, Journal of Cancer Research and Clinical Oncology, 138 (2012) 85- 93. doi: DOI 10.1007/s00432-011-1068-z
J. Zhang, Y. Y. Du, Y. F. Lin, Y. T. Chen, L. Yang, H. J. Wang and D. Ma. The cell growth suppressor, mir-126, targets IRS-1, Biochem Biophys Res Commun., 377 (2008) 136-140. doi: 10.1016/j.bbrc.2008.09.089
F. Wang, Z. Zheng, J. Guo and X. Ding. Correlation and quantitation of microRNA aberrant expression in tissues and sera from patients with breast tumor, Gynecol Oncol., 119 (2010) 586-593. doi: 10.1016/j.ygyno.2010.07.021
S. S. Li, Y. Wu, X. Jin and C. Jiang. The SUR2B subunit of rat vascular KATP channel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal, Am J Physiol Cell Physiol., 308/2 (2015) 139-145. doi: 10.1152/ajpcell.00311.2014
B. Yang, H. Lin, J. Xiao, Y. Lu, X. Luo, B. Li, Y. Zhang, C. Xu, Y. Bai, H. Wang et al. The Muscle-Specific MicroRNA miR-1 Regulates Cardiac Arrhythmogenic Potential by Targeting GJA1 and KCNJ2, Nature Medicine, 13 (2011) 486-491. doi: 10.1038/nm1569
J. Xiao, X. Luo, H. Lin, Y. Zhang, Y. Lu, N. Wang, Y. Zhang, B. Yang and Z. Wang. MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts, J Biol Chem., 282 (2007) 12363-12367. doi: 10.1074/jbc.C700015200
S. S. Li, Y. J. Ran, D. D. Zhang, S. Z. Li and D. Zhu. MicroRNA-190 regulates hypoxic pulmonary vasoconstriction by targeting a voltage-gated K⁺ channel in arterial smooth muscle cells, J Cell Biochem., 115/6 (2014) 1196-1205. doi: 10.1002/jcb.24771
X. Jia, S. Zheng, X. Xie, Y. Zhang, W. Wang, Z. Wang et al. MicroRNA-1 accelerates the shortening of atrial effective refractory period by regulating KCNE1 and KCNB2 expression: an atrial tachypacing rabbit model, PLoS One., 8/12 (2013). doi: 10.1371/journal.pone.0085639
D. H. Lin, P. Yue, C. Zhang and W. H. Wang. MicroRNA-194 (miR- 194) regulates ROMK channel activity by targeting intersectin 1, Am J Physiol Renal Physiol., 306/1 (2014) 53-60. doi: 10.1152/ajprenal.00349.2013
D. Lin, A. Halilovic, P. Yue, L. Bellner, K. Wang, L. Wang and C. Zhang. Inhibition of miR-205 impairs the wound-healing process in human corneal epithelial cells by targeting KIR4.1 (KCNJ10), Invest Ophthalmol Vis Sci, 54/9 (2013) 6167-6178. doi: 10.1167/iovs.12-11577
N. M. Sosanya, P. P. Huang, L. P. Cacheaux, C. J. Chen, K. Nguyen, N. I. Perrone-Bizzozero, and K. F. Raab-Graham Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1, J Cell Biol., 202/1 (2013) 53-69. doi: 10.1083/jcb.201212089
Q. Ru, X. Tian, M. S. Pi, L. Chen, K. Yue, Q. Xiong et al. Voltage‑gated K+ channel blocker quinidine inhibits proliferation and induces apoptosis by regulating expression of microRNAs in human glioma U87‑MG cells, Int J Oncol., 46/2 (2015) 833-840. doi: 10.3892/ijo.2014.2777
J. Feng, J. Yu, X. Pan, Z. Li, Z. Chen, W. Zhang et al. HERG1 functions as an oncogene in pancreatic cancer and is downregulated by miR-96, Oncotarget, 5/14 (2014) 5832-5844.
X. Wu, D. Zhong, Q. Gao, W. Zhai, Z. Ding and J. Wu. MicroRNA-34a inhibits human osteosarcoma proliferation by downregulating ether à go-go 1 expression, Int J Med Sci., 10/6 (2013) 676-682. doi: 10.7150/ijms.5528.
H. Lin, Z. Li, C. Chen, X. Luo, J. Xiao, D. Dong, D. et al. Transcriptional and post-transcriptional mechanisms for oncogenic overexpression of ether à go-go K+ channel, PLoS One, 6/5 (2011) doi: 10.1371/journal.pone.0020362
Y. Bai, H. Liao, T. Liu, X. Zeng, F. Xiao, L. Luo et al.. MiR-296-3p regulates cell growth and multi-drug resistance of human glioblastoma by targeting ether-à-go-go (EAG1), Eur J Cancer., 49/3 (2013) 710-724. doi: 10.1016/j.ejca.2012.08.020.
W. Meng, L. Jiang, L. Lu, H. Hu, H. Yu, D. Ding et al. Anti-miR-155 oligonucleotide enhances chemosensitivity of U251 cell to taxol by inducing apoptosis, Cell Biol Int., 36/7 (2012) 653-659. doi: 10.1042/CBI20100918
J. Y. Wang, J. Wang, V. A. Golovina, L. Li, O. Platoshyn and J. X. Yuan. Role of K(+) channel expression in polyamine-dependent intestinal epithelial cell migration, Am J Physiol Cell Physiol., 278 (2000) 303-314.
X. Wang, A. Y. Xiao, T. Ichinose and S. P. Yu. Effects of tetraethylammonium analogs on apoptosis and membrane currents in cultured cortical neurons, J Pharmacol Exp Ther., 295 (2000) 524-530.
S. P. Yu. Regulation and critical role of potassium homeostasis in apoptosis, Prog Neurobiol., 70 (2003) 363-386.
M. J. Morton, S. Chipperfield, A. Abohamed, A. Sivaprasadarao and M. Hunter. Na(+)-induced inward rectification in the two-pore domain K(+) channel, TASK-2, Am J Physiol Renal Physiol, 288 (2005) 162-169. doi: 10.1152/ajprenal.00248.2004
J. Liu, S. Feng, L. Zhang, Z. Wu, Q. Chen, W. Cheng, S. Q. Wang and W. Zou. Expression and properties of potassium channels in human mammary epithelial cell line MCF10A and its possible role in proliferation, Sheng Li Xue Bao, 62 (2010) 203-209.
D. Ekhterae, O. Platoshyn, S. Krick, Y. Yu, S. S. McDaniel and J. X. Yuan. Bcl-2 decreases voltage-gated K+ channel activity and enhances survival in vascular smooth muscle cells, Am J Physiol Cell Physiol., 281 (2001) 157- 165.
N. Ferrara. VEGF: an update on biological and therapeutic aspects, Curr Opin Biotechnol., 11 (2000) 617-624.