p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling

Abstract

Long noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRE-CSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.

Long non-coding RNAs in cutaneous biology and keratinocyte carcinomas

“…p53-regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT) is a recently identified lncRNA with elevated expression in cSCC [129]. PRECSIT is a nuclear-enriched lncRNA downregulated by p53 signaling, and a high level of PRECSIT expression is associated with the absence of functional p53 in cSCC tumor cells in vivo [129].…”

“…p53-regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT) is a recently identified lncRNA with elevated expression in cSCC [129]. PRECSIT is a nuclear-enriched lncRNA downregulated by p53 signaling, and a high level of PRECSIT expression is associated with the absence of functional p53 in cSCC tumor cells in vivo [129]. Depletion of PRECSIT inhibits cSCC cell invasion by downregulating STAT3 expression and activation, and production of matrix metalloproteinases (MMPs), MMP-13, MMP-3, MMP-1, and MMP-10 [129], suggesting a tumor-promoting function for PRECSIT (Fig.…”

“…LINC00319 promotes cSCC cell migration and invasion, and upregulates expression of MMP-2, MMP-9, and markers for epithelial-mesenchymal transition, E-cadherin, and vimentin [130]. PRECSIT regulates the invasion of cSCC cells specifically without affecting cell growth [129], whereas LINC00319 has an anti-apoptotic function and promotes cSCC cell proliferation via miRNA-mediated mechanism [130].…”

The Role of Non-Coding RNAs as Prognostic Factor, Predictor of Drug Response or Resistance and Pharmacological Targets, in the Cutaneous Squamous Cell Carcinoma

“…Bidirectional lncRNAs have transcription start sites at about 1 kb from the promoter region of a protein-coding gene but are transcribed in the opposite direction [ 29 , 121 ]. lncRNAs have tissue-specific expression and are involved in several cell processes by regulating tissue homeostasis, development, repair, or stress response [ 28 ]. Based on their functions, the lncRNAs can be classified into four categories: signal, decoy, guide, and scaffold.…”

“…A growing body of evidence has shown that lncRNAs are involved not only in tissue homeostasis but also in the regulation of tumor initiation, progression, and metastasis with either tumor-promoting or tumor-suppressive functions. Nonetheless, the role of lncRNAs in the cutaneous biology and CSCC tumorigenesis is not yet well known [ 28 , 33 ]. The analysis of the lncRNA landscape reveals their different expression in normal skin and in CSCC samples, in according to the above-mentioned tissues-specific expression of lncRNAs.…”