Overexpression of microRNA-612 Restrains the Growth, Invasion, and Tumorigenesis of Melanoma Cells by Targeting Espin

다국어 초록 (Multilingual Abstract)

microRNA (miR)-612 shows anticancer activity in several types of cancers, yet its function in melanoma is still unclear. This study was undertaken to investigate the expression of miR-612 and its biological relevance in melanoma cell growth, invasion, and tumorigenesis. The expression and prognostic significance of miR-612 in melanoma were examined. The effects of miR-612 overexpression on cell proliferation, colony formation, tumorigenesis, and invasion were determined. Rescue experiments were conducted to identify the functional target gene(s) of miR-612. miR-612 was significantly downregulated in melanoma tissues compared to adjacent normal tissues. Low miR-612 expression was significantly associated with melanoma thickness, lymph node metastasis, and shorter overall, and disease-free survival of patients. Overexpression of miR-612 significantly decreased cell proliferation, colony formation, and invasion of SK-MEL-28 and A375 melanoma cells. In vivo tumorigenic studies confirmed that miR-612 overexpression retarded the growth of A375 xenograft tumors, which was coupled with a decline in the percentage of Ki-67-positive proliferating cells. Mechanistically, miR-612 targeted Espin in melanoma cells. Overexpression of Espin counteracted the suppressive effects of miR-612 on melanoma cell proliferation, invasion, and tumorigenesis. A significant inverse correlation (r = -0.376, P = 0.018) was observed between miR-612 and Espin protein expression in melanoma tissues. In addition, overexpression of miR-612 and knockdown of Espin significantly increased the sensitivity of melanoma cells to doxorubicin. Collectively, miR-612 suppresses the aggressive phenotype of melanoma cells through downregulation of Espin. Delivery of miR-612 may represent a novel therapeutic strategy against melanoma.

참고문헌 (Reference)

1 Tao, Z.H., "miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma" 210 : 789-803, 2013

2 Liu, Y., "miR-612 suppresses stem cell-like property of hepatocellular carcinoma cells by modulating Sp1/Nanog signaling" 7 : e2377-, 2016

3 Sheng, L., "miR-612 negatively regulates colorectal cancer growth and metastasis by targeting AKT2" 6 : e1808-, 2015

4 Wang, L., "Whirlin interacts with espin and modulates its actin-regulatory function: an insight into the mechanism of Usher syndrome type II" 21 : 692-710, 2012

5 Zheng, L., "The deaf jerker mouse has a mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and lacks espins" 102 : 377-385, 2000

6 van Akkooi, A.C., "Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma" 35 : e505-e514, 2016

7 Mao, Y., "RNA sequencing analyses reveal novel differentially expressed genes and pathways in pancreatic cancer" 8 : 42537-42547, 2017

8 Waters, A.M., "Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma" 14 : 1559-1569, 2015

9 Pal, H.C., "Phytochemicals for the Management of Melanoma" 16 : 953-979, 2016

10 Xu, D., "MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1" 9 : 7047-7057, 2016

11 Li, B., "MicroRNA-613 targets FMNL2 and suppresses progression of colorectal cancer" 8 : 5475-5484, 2016

12 Shu, X., "MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity" 116 : 77-84, 2017

13 Cheerla, N., "MicroRNA based Pan-Cancer diagnosis and treatment recommendation" 18 : 32-, 2017

14 Tang, J., "MiR-612 suppresses the stemness of liver cancer via Wnt/${\beta}$-catenin signaling" 447 : 210-215, 2014

15 Tas, F., "Metastatic behavior in melanoma: timing, pattern, survival, and influencing factors" 2012 : 647684-, 2012

16 Kircher, D.A., "Melanoma Brain Metastasis: Mechanisms, Models, and Medicine" 17 (17): E1468-, 2016

17 Taura, A., "Hair cell stereociliary bundle regeneration by espin gene transduction after aminoglycoside damage and hair cell induction by Notch inhibition" 23 : 415-423, 2016

18 Fahrioglu, U., "Ferulic acid decreases cell viability and colony formation while inhibiting migration of MIA PaCa-2 human pancreatic cancer cells in vitro" 576 : 476-482, 2016

19 Sekerkova, G., "Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli" 63 : 2329-2341, 2006

20 Donaudy, F., "Espin gene (ESPN) mutations associated with autosomal dominant hearing loss cause defects in microvillar elongation or organisation" 43 : 157-161, 2006

21 Zhang, K., "Circulating miRNA profile in esophageal adenocarcinoma" 6 : 2713-2721, 2016

22 Komina, A., "Antiproliferative and Pro-Apoptotic Effects of MiR-4286 Inhibition in Melanoma Cells" 11 : e0168229-, 2016

23 Deacu, E., "Activin type II receptor restoration in ACVR2-deficient colon cancer cells induces transforming growth factor-beta response pathway genes" 64 : 7690-7696, 2004

24 Yanagishita, T., "Actin-binding protein, Espin: a novel metastatic regulator for melanoma" 12 : 440-446, 2014

25 Alaoui-Jamali, M.A., "A novel experimental heme oxygenase-1-targeted therapy for hormonerefractory prostate cancer" 69 : 8017-8024, 2009