miR-30a Inhibits Melanoma Tumor Metastasis by Targeting the E-cadherin and Zinc Finger E-box Binding Homeobox 2


1 Applied Physiology Research Center, Cardiovascular Research Institute, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Epithelial–mesenchymal transition (EMT) is actively involved in tumor invasion. The main hallmark of EMT is downregulation of the adherens junction protein E-cadherin due to transcriptional repression. Candidate E-cadherin transcription repressors are members of ZEB family, ZEB2 belong to the ZEB family transcription factor that is pivotal for embryonic development and tumor progression. ZEB2 (zinc finger E-box binding homeobox 2) is most widely known as an inducer of EMT. Growing evidence have shown the involvement of microRNAs in cancer progression. In this study, we demonstrate that miR-30a is a potent suppressor of melanoma metastasis to the lung. Materials and Methods: In this study, miR-30a has been transfected into B16-F10 melanoma cells, and then cells were injected intravenously into C57BL/6 mice. Then, the mice were sacrificed and nodules in the lungs were enumerated. Results: Ectopic expression of miR-30a in melanoma cell line resulted in the suppression of pulmonary metastasis. We also found that transfected miR-30a into melanoma cells could increase E-cadherin and decrease ZEB2 expression. Conclusions: Our findings showed that increased expression of miR-30a in melanoma inhibited metastasis in vivo by targeting ZEB2 and E-cadherin.


Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003;112:1776-84.  Back to cited text no. 1
Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740-6.  Back to cited text no. 2
ElMoneim HM, Zaghloul NM. Expression of E-cadherin, N-cadherin and snail and their correlation with clinicopathological variants: An immunohistochemical study of 132 invasive ductal breast carcinomas in egypt. Clinics (Sao Paulo) 2011;66:1765-71.  Back to cited text no. 3
Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, et al. Vimentin regulates EMT induction by slug and oncogenic H-ras and migration by governing axl expression in breast cancer. Oncogene 2011;30:1436-48.  Back to cited text no. 4
Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000;2:76-83.  Back to cited text no. 5
Peinado H, Olmeda D, Cano A. Snail, zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer 2007;7:415-28.  Back to cited text no. 6
Baraniskin A, Birkenkamp-Demtroder K, Maghnouj A, Zöllner H, Munding J, Klein-Scory S, et al. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL. Carcinogenesis 2012;33:732-9.  Back to cited text no. 7
Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 2001;7:1267-78.  Back to cited text no. 8
Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res 2005;33:6566-78.  Back to cited text no. 9
Chen CZ. MicroRNAs as oncogenes and tumor suppressors. N Engl J Med 2005;353:1768-71.  Back to cited text no. 10
Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 2008;283:14910-4.  Back to cited text no. 11
Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 2008;22:894-907.  Back to cited text no. 12
Völler D, Ott C, Bosserhoff A. MicroRNAs in malignant melanoma. Clin Biochem 2013;46:909-17.  Back to cited text no. 13
Kao CJ, Martiniez A, Shi XB, Yang J, Evans CP, Dobi A, et al. MiR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT. Oncogene 2014;33:2495-503.  Back to cited text no. 14
Kumarswamy R, Mudduluru G, Ceppi P, Muppala S, Kozlowski M, Niklinski J, et al. MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting snai1 and is downregulated in non-small cell lung cancer. Int J Cancer 2012;130:2044-53.  Back to cited text no. 15
He R, Yang L, Lin X, Chen X, Lin X, Wei F, et al. MiR-30a-5p suppresses cell growth and enhances apoptosis of hepatocellular carcinoma cells via targeting AEG-1. Int J Clin Exp Pathol 2015;8:15632-41.  Back to cited text no. 16
Zhang J, Zhang H, Liu J, Tu X, Zang Y, Zhu J, et al. MiR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting snail1. Biochem Biophys Res Commun 2012;417:1100-5.  Back to cited text no. 17
Mueller DW, Rehli M, Bosserhoff AK. MiRNA expression profiling in melanocytes and melanoma cell lines reveals miRNAs associated with formation and progression of malignant melanoma. J Invest Dermatol 2009;129:1740-51.  Back to cited text no. 18
Di Gennaro A, Damiano A, Brisotto G, Armellin M, Perin T, Zucchetto A, et al. A p53/miR-30a/ZEB2 axis controls triple negative breast cancer aggressiveness. Cell Death & Differentiation, 2018: p. 1.  Back to cited text no. 19
Van de Putte T, Maruhashi M, Francis A, Nelles L, Kondoh H, Huylebroeck D, et al. Mice lacking ZFHX1B, the gene that codes for smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of hirschsprung disease-mental retardation syndrome. Am J Hum Genet 2003;72:465-70.  Back to cited text no. 20
Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E, et al. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet 2002;32:153-9.  Back to cited text no. 21
Jechlinger M, Grunert S, Tamir IH, Janda E, Lüdemann S, Waerner T, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene 2003;22:7155-69.  Back to cited text no. 22
Yang SJ, Yang SY, Wang DD, Chen X, Shen HY, Zhang XH, et al. The miR-30 family: Versatile players in breast cancer. Tumour Biol 2017;39:1010428317692204.  Back to cited text no. 23
Chang CW, Yu JC, Hsieh YH, Yao CC, Chao JI, Chen PM, et al. MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting slug in breast cancer. Oncotarget 2016;7:16462-78.  Back to cited text no. 24
Liu Z, Tu K, Liu Q. Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma. FEBS Lett 2014;588:3089-97.  Back to cited text no. 25
Yu Y, Yang L, Zhao M, Zhu S, Kang R, Vernon P, et al. Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells. Leukemia 2012;26:1752-60.  Back to cited text no. 26
Zhang N, Wang X, Huo Q, Sun M, Cai C, Liu Z, et al. MicroRNA-30a suppresses breast tumor growth and metastasis by targeting metadherin. Oncogene 2014;33:3119-28.  Back to cited text no. 27
Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T, et al. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS One 2008;3:e2141.  Back to cited text no. 28
Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T, et al. MicroRNA expression profiling in prostate cancer. Cancer Res 2007;67:6130-5.  Back to cited text no. 29
Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008;299:425-36.  Back to cited text no. 30
Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A, et al. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 2007;26:7590-5.  Back to cited text no. 31
Yan LX, Huang XF, Shao Q, Huang MY, Deng L, Wu QL, et al. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 2008;14:2348-60.  Back to cited text no. 32
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006;9:189-98.  Back to cited text no. 33
Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 2008;111:3183-9.  Back to cited text no. 34