The Melanoma-Upregulated Long Noncoding RNA SPRY4-IT1 Modulates Apoptosis and Invasion

Abstract

The identification of cancer-associated long noncoding RNAs (lncRNAs) and the investigation of their molecular and biological functions are important to understand the molecular biology of cancer and its progression. Although the functions of lncRNAs and the mechanisms regulating their expression are largely unknown, recent studies are beginning to unravel their importance in human health and disease. Here, we report that a number of lncRNAs are differentially expressed in melanoma cell lines in comparison to melanocytes and keratinocyte controls. One of these lncRNAs, SPRY4-IT1 (GenBank accession ID AK024556), is derived from an intron of the SPRY4 gene and is predicted to contain several long hairpins in its secondary structure. RNA-FISH analysis showed that SPRY4-IT1 is predominantly localized in the cytoplasm of melanoma cells, and SPRY4-IT1 RNAi knockdown results in defects in cell growth, differentiation, and higher rates of apoptosis in melanoma cell lines. Differential expression of both SPRY4 and SPRY4-IT1 was also detected in vivo, in 30 distinct patient samples, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic melanoma. The elevated expression of SPRY4-IT1 in melanoma cells compared to melanocytes, its accumulation in cell cytoplasm, and effects on cell dynamics, including increased rate of wound closure on SPRY4-IT1 overexpression, suggest that the higher expression of SPRY4-IT1 may have an important role in the molecular etiology of human melanoma. Cancer Res; 71(11); 3852-62. Ó2011 AACR.

Epigenetic regulation in human melanoma: past and future

“…83 A corroborating report indicates that SETDB1 is recurrently amplified in melanoma and accelerates tumor development in zebrafish melanoma models harboring the common BRAF V600E mutation. 84 Reports of pro-metastatic activity in multiple pre-clinical model systems, support the hypothesis that this lncRNA is a potential target for melanoma metastasis therapy.…”

“…This lncRNA was identified by Khaitan et al, 84 who compared lncRNAs in melanoma cell lines, melanocytes, and keratinocytes using an lncRNA microarray. 84 SPRY4-IT1 was found to be elevated in the melanoma cell lines.…”

“…Knockdown of this lncRNA caused defects in cell growth and differentiation, and elevated apoptosis rates in melanoma cell lines. 84 Molecular mechanisms by which SPRY4-IT1 affects melanoma progression require further investigation. RNA-FISH analysis showed that this lncRNA is predominantly localized in the cytoplasm of melanoma cells 67 , and an association with polysomes has been demonstrated.…”

“…85 SPRY4 is an inhibitor of the MAPK signaling pathway and may have a tumor suppressor role. 84 SPRY4-IT1 is located within an intron of SPRY4, and these genes have concordant expression profiles 84 , although both of them are transcriptionally and functionally independent. 85 A recent study in non-small cell lung cancer (NSCLC) has found evidence that SPRY4-IT1 controls epithelial-mesenchymal transition (EMT) through regulation of E-cadherin and vimentin expression leading to cell proliferation and metastasis.…”

Aflatoxin B1 Promotes Cell Growth and Invasion in Hepatocellular Carcinoma HepG2 Cells through H19 and E2F1

“…In recent years, the functions of lncRNAs in cancer were broadly investigated. In general, lncRNAs could play an important role in a wide range of biological processes, including proliferation, cell cycle, apoptosis, differentiation and invasion (Calin et al, 2007;Braconi et al, 2011;Khaitan et al, 2011). The list of lncRNA having functions in hepatocellular are H19, HULC, TUC338, MALAT1 and HOTAIR (Gabory et al, 2006;Luo et al, 2006;Panzitt et al, 2007;Braconi et al, 2011;Yang et al, 2011).…”