The Role of p53 in Progression of Cutaneous Squamous Cell Carcinoma

Abstract

Skin cancers are the most common types of cancer worldwide, and their incidence is increasing. Melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC) are the three major types of skin cancer. Melanoma originates from melanocytes, whereas BCC and cSCC originate from epidermal keratinocytes and are therefore called keratinocyte carcinomas. Chronic exposure to ultraviolet radiation (UVR) is a common risk factor for skin cancers, but they differ with respect to oncogenic mutational profiles and alterations in cellular signaling pathways. cSCC is the most common metastatic skin cancer, and it is associated with poor prognosis in the advanced stage. An important early event in cSCC development is mutation of the TP53 gene and inactivation of the tumor suppressor function of the tumor protein 53 gene (TP53) in epidermal keratinocytes, which then leads to accumulation of additional oncogenic mutations. Additional genomic and proteomic alterations are required for the progression of premalignant lesion, actinic keratosis, to invasive and metastatic cSCC. Recently, the role of p53 in the invasion of cSCC has also been elucidated. In this review, the role of p53 in the progression of cSCC and as potential new therapeutic target for cSCC will be discussed.

Keywords: cancer; p53; skin; squamous cell carcinoma.

Figure 1

Molecular features involved in the development of actinic keratosis, cutaneous squamous cell carcinoma in situ (cSCCIS), and invasive cSCC. BM, basement membrane; TGFBR, transforming growth factor-β receptor; EGFR, epidermal growth factor receptor; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α.

Figure 2

Genetic alterations involved in cSCC progression. Mutational inhibition of wild-type function (in blue) of TP53, CDKN2A, or NOTCH1/2 predisposes cells to genomic instability and uncontrolled growth as the expression of their downstream targets, cell cycle regulators p21, p14, and p16 is abrogated. Notch is also transcriptionally regulated by p53. Notch intracellular domain (NICD) is cleaved upon ligand binding and transported to the nucleus to regulate gene transcription in co-operation with other factors. Mutational activation (in red) of EGFR or HRAS induces cell proliferation and survival via MAPK and PI3K signaling.

Figure 3

Mutations in TP53 gene in cSCC in cBioPortal database [102,103]. (A) Left: TP53 alteration frequency in three independent cSCC cohorts comprising a total of 125 samples (1 = MD Anderson [39], 2 = DFCI [38], 3 = UCSF excluding cSCCs with hereditary disorders). Right: Mutation plot showing p53 mutation type and count in cSCCs. (B) The number and position of mutations in the TP53 gene. The green bar indicates p53 transactivating domain, the red bar the DNA-binding domain, and the blue bar the p53 tetramerization motif. The circles are colored with respect to the corresponding mutation types (green = missense, black = truncating, orange = inframe deletion or insertion). The hotspot mutation R248W/Q/L is highlighted in the plot.

Figure 4

Mutant p53 gain-of-function mechanisms. (A) A missense mutation in the TP53 DNA-binding domain (e.g., in amino acid residue 248) can disturb p53 protein binding to gene regulatory areas and prevent transcription of the p53 wild-type target genes. (B) Gain-of-function p53 mutants can influence several cellular processes to facilitate cancer progression. (C) The mutant p53 (p53*) cannot recognize the p53 DNA response elements, but it can bind to various transcription factors (in orange) and recruit them to gene promoters to activate transcription. (D) In some instances, mutant p53 may decoy transcription factors (in red) from their target sites and inhibit transcription. (E) Mutant p53 can upregulate expression of chromatin remodeling proteins, such as MLL1, MLL2, MLL4, and MOZ, or bind to and recruit chromatin modifying proteins (in purple, e.g., MLL4 or the SWI/SNF complex) to alter the epigenetic state of the chromatin and make it accessible for gene transcription. (F) Mutant p53 may inhibit the wild-type p53, or other p53 family members p63 or p73 (in green) in a dominant-negative manner, where it complexes with the wild-type p53/p63/p73 to block its function and target gene expression.

Figure 5

PRECSIT is a p53-regulated lncRNA with a tumorigenic role in cutaneous squamous cell carcinoma (cSCC). Proposed molecular model for the mechanistic role of PRECSIT in cSCC; low level of PRECSIT expression is maintained in normal epidermal keratinocytes by p53. The red cross indicates blockage of the downstream signaling. In cSCC cells, mutational inactivation of p53, which leads to loss of p53 expression, results in upregulation and accumulation of PRECSIT in the nucleus. Elevated PRECSIT expression contributes to STAT3 activation and up-regulation of matrix metalloproteinases collagenase-1 (MMP-1), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), and stromelysin-2 (MMP-10). MMP-3 and MMP-10 are capable of degrading several extracellular matrix (ECM) components, including basement membrane type IV collagen, fibronectin, and laminin. They also activate latent collagenases MMP-1 and MMP-13, capable of cleaving fibrillar collagens type I and III in the dermal ECM. The proteolytic remodeling of ECM and the basement membrane by MMPs is essential for cSCC cell invasion and tumor cell implantation.