TY - JOUR
T1 - The CASC15 Long Intergenic Noncoding RNA Locus Is Involved in Melanoma Progression and Phenotype Switching
AU - Lessard, Laurent
AU - Liu, Michelle
AU - Marzese, Diego M.
AU - Wang, Hongwei
AU - Chong, Kelly
AU - Kawas, Neal
AU - Donovan, Nicholas C.
AU - Kiyohara, Eiji
AU - Hsu, Sandy
AU - Nelson, Nellie
AU - Izraely, Sivan
AU - Sagi-Assif, Orit
AU - Witz, Isaac P.
AU - Ma, Xiao Jun
AU - Luo, Yuling
AU - Hoon, Dave S.B.
N1 - Funding Information:
This work was supported by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, the Ruth and Martin H. Weil Fund, as well as the award numbers PO1 CA029605 (Project II and Core C) and 1R01CA167967-01A1 from the National Cancer Institute, National Institutes of Health. We are also grateful to members of the Department of Molecular Oncology at John Wayne Cancer Institute for their technical assistance and helpful discussions.
PY - 2015/10/14
Y1 - 2015/10/14
N2 - In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.
AB - In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.
UR - http://www.scopus.com/inward/record.url?scp=84941421410&partnerID=8YFLogxK
U2 - 10.1038/jid.2015.200
DO - 10.1038/jid.2015.200
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AN - SCOPUS:84941421410
SN - 0022-202X
VL - 135
SP - 2464
EP - 2474
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 10
ER -