title: Identification of metastasis-suppressive microRNAs in primary melanoma.
abstract: BACKGROUND
  Surgical management of primary melanoma is curative for most patients with clinically localized disease at diagnosis; however, a substantial number of patients recur and progress to advanced disease. Understanding molecular alterations that influence differential tumor progression of histopathologically similar lesions may lead to improved prognosis and therapies to slow or prevent metastasis.
  
  
  METHODS
  We examined microRNA dysregulation by expression profiling of primary melanoma tumors from 92 patients. We screened candidate microRNAs selected by differential expression between recurrent and nonrecurrent tumors or associated with primary tumor thickness (Student's t test, Benjamini-Hochberg False Discovery Rate [FDR] < 0.05), in in vitro invasion assays. We performed in vivo metastasis assays, matrix remodeling experiments, and molecular studies to identify metastasis-regulating microRNAs and their cellular and molecular mechanisms. All statistical tests were two-sided.
  
  
  RESULTS
  We identified two microRNAs (hsa-miR-382, hsa-miR-516b) whose expression was lower in aggressive vs nonaggressive primary tumors, which suppressed invasion in vitro and metastasis in vivo (mean metastatic foci: control: 37.9, 95% confidence interval [CI] = 25.6 to 50.2; miR-382: 19.5, 95% CI = 12.2 to 26.9, P = .009; miR-516b: 12.5, 95% CI = 7.7 to 17.4, P < .001, Student's t test). Mechanistically, miR-382 overexpression inhibits extracellular matrix degradation by melanoma cells. Moreover, we identified actin regulators CTTN, RAC1, and ARPC2 as direct targets of miR-382. Depletion of CTTN partially recapitulates miR-382 effects on matrix remodeling, invasion, and metastasis. Inhibition of miR-382 in a weakly tumorigenic melanoma cell line increased tumor progression and metastasis in vivo.
  
  
  CONCLUSIONS
  Aberrant expression of specific microRNAs that can functionally impact progression of primary melanoma occurs as an early event of melanomagenesis.
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Doug
authors: D
authors: Hanniford
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Miguel F
authors: MF
authors: Segura
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Judy
authors: J
authors: Zhong
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Elliot
authors: E
authors: Philips
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Xavier
authors: X
authors: Jirau-Serrano
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Farbod
authors: F
authors: Darvishian
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Russell S
authors: RS
authors: Berman
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Richard L
authors: RL
authors: Shapiro
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Anna C
authors: AC
authors: Pavlick
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Brian
authors: B
authors: Brown
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB).
authors: Iman
authors: I
authors: Osman
authors: Department of Pathology (DH, MFS, EP, XJS, FD, EH), Interdisciplinary Melanoma Cooperative Group (DH, MFS, JZ, XJS, FD, RSB, RLS, AP, IO, EH), Department of Environmental Medicine (JZ), Department of Dermatology (AP, IO), Department of Medicine (AP, IO), Department of Urology (IO); Department of Surgery (RSB, RLS), NYU Langone Medical Center, New York, NY; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (BB). eva.hernando-monge@nyumc.org.
authors: Eva
authors: E
authors: Hernando
mesh_terms: D051376:Actin-Related Protein 2-3 Complex; D045744:Cell Line, Tumor; D051356:Cortactin; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000737:chemistry* / Q000473:pathology* / Q000556:secondary; D035683:MicroRNAs / Q000302:isolation & purification*; D012878:Skin Neoplasms / Q000737:chemistry* / Q000473:pathology*; D020830:rac1 GTP-Binding Protein
chemical_list: C000595669:ARPC2 protein, human; D051376:Actin-Related Protein 2-3 Complex; C495868:CTTN protein, human; D051356:Cortactin; C555413:MIRN382 microRNA, human; C557718:MIRN516 microRNA, human; D035683:MicroRNAs; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein