Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Although some of the early events involved in this pathology have been identified, the subsequent steps leading to tumor development are poorly defined. Researchers from Universite Cote d Azur demonstrate here that the development of mouse tumors induced by the concomitant application of a carcinogen and a tumor promoter (7,12 dimethylbenz[a]anthracene [DMBA] and 12-O-tetradecanoylphorbol-13-acetate [TPA], respectively) is associated with the upregulation of a previously uncharacterized long noncoding RNA (lncRNA), termed AK144841. They found that AK144841 expression was absent from normal skin and was specifically stimulated in tumors and highly tumorigenic cells. They also found that AK144841 exists in two variants, one consisting of a large 2-kb transcript composed of four exons and one of a 1.8-kb transcript lacking the second exon. Gain- and loss-of-function studies indicated that AK144841 mainly inhibited gene expression, specifically downregulating the expression of genes of the late-cornified-envelope-1 (Lce1) family involved in epidermal terminal differentiation and of anticancer genes such as Cgref1, Brsk1, Basp1, Dusp5, Btg2, Anpep, Dhrs9, Stfa2, Tpm1, SerpinB2, Cpa4, Crct1, Cryab, Il24, Csf2, and Rgs16. Interestingly, the lack of the second exon significantly decreased AK144841’s inhibitory effect on gene expression. The researchers also noted that high AK144841 expression correlated with a low expression of the aforementioned genes and with the tumorigenic potential of cell lines. These findings suggest that AK144841 could contribute to the dedifferentiation program of tumor-forming keratinocytes and to molecular cascades leading to tumor development.
Effects of AK144841 silencing on the mSCC-38 cell transcriptome
MSCC-38 cells were transfected with 2 distinct siRNAs directed against AK144841 (Si1AK-Si2AK) and a control siRNA (SiC). The gene expression profiles were determined at 48 h post-transfection using a pan genomic microarrays (GE 8x60K microarrays from Agilent). The Graph shows the heatmap representing the normalized log2 intensity of the 129 genes whose expression is statistically modulated by AK144841 siRNA in the different experimental conditions. Threshold values used to select the 129 of up-and down-regulated genes represented on the heat map are average expression > 7.0; absolute log FC > 0.6; adjusted pvalue < 0.05. NT (1-4) = 4 samples of non-transfected mSCC-38. SiC (1-3) = 3 samples of mSCC-38 transfected with a non-relevant siRNA (SiC). Si1AK (1-4) = 4 samples of mSCC-38 transfected with Si1AK, a first AK144841-specific siRNA. Si2AK (1-3) = 3 samples of mSCC-38 transfected with Si2AK a second AK144841 siRNA