Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Inflammation is a typical feature in cSCC progression. Analysis of the expression of inflammasome components in cSCC cell lines and normal human epidermal keratinocytes revealed upregulation of the expression of AIM2 mRNA and protein in cSCC cells. Elevated levels of AIM2 mRNA were noted in cSCCs in vivo compared with normal skin. Strong and moderate tumor cell specific expression of AIM2 was detected with immunohistochemistry (IHC) in sporadic human cSCCs in vivo, whereas expression of AIM2 was moderate in cSCC in situ (cSCCIS) and low or absent in actinic keratosis (AK) and normal skin. IHC of cSCCs, cSCCIS and AKs from organ transplant recipients also revealed strong and moderate tumor cell specific expression of AIM2 in cSCCs. Knockdown of AIM2 resulted in reduction in viability of cSCC cells and onset of apoptosis. RNA-seq and pathway analysis after knockdown of AIM2 in cSCC cells revealed downregulation of the biofunction category Cell cycle and upregulation of the biofunction category Cell Death and Survival. Knockdown of AIM2 also resulted in reduction in invasion of cSCC cells and downregulation in production of invasion proteinases MMP1 and MMP13. Knockdown of AIM2 resulted in suppression of growth and vascularization of cSCC xenografts in vivo. These results provide evidence for the role of AIM2 in the progression of cSCC and identify AIM2 inflammasome function as a potential therapeutic target in these invasive and metastatic tumors.
Highlights
Keratinocyte-derived cutaneous squamous cell carcinoma is the most common metastatic skin cancer and its incidence is increasing due to aging of population and increased recreational exposure to the sunlight [1,2,3]
Strong and moderate tumor cell specific expression of absent in melanoma 2 (AIM2) was detected with immunohistochemistry (IHC) in sporadic human Cutaneous squamous cell carcinoma (cSCC) in vivo, whereas expression of AIM2 was moderate in cSCC in situ and low or absent in actinic keratosis (AK) and normal skin
The expression of molecules involved in pathways related to innate immunity (KEGG pathways: Cytosolic DNA-sensing, NOD-like receptor signaling, RIG-I-like receptor signaling) in normal human epidermal keratinocyte (NHEK) and cSCC cells is shown in Supplementary Figure 1
Summary
Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing due to aging of population and increased recreational exposure to the sunlight [1,2,3]. Cumulative lifetime sun exposure is an important risk factor for cSCC and other risk factors include chronic ulcers, chronic inflammation of the skin, and immunosuppression [4, 5]. Changes in www.impactjournals.com/oncotarget the microenvironment of the premalignant skin lesion, such as alteration of the composition of the epidermal basement membrane and dermal extracellular matrix, and accumulation of inflammatory cells and microbial structures, are possible mechanisms for the role of inflammation in progression of AK to cSCC [7]. The HIN-200 domain of AIM2 and IFI16 serves as a sensor for cytoplasmic double stranded DNA and the pyrin domain interacts with ASC for activation of caspase-1 [13, 14]. The role of inflammasome activation in autoinflammatory disorders has recently been emphasized [15]
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