Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma
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Mehdi Farshchian1,2, Liisa Nissinen1,2, Elina Siljamäki1,2, Pilvi Riihilä1,2, Minna Piipponen1,2, Atte Kivisaari1,2, Markku Kallajoki3, Reidar Grénman4, Juha Peltonen5, Sirkku Peltonen1, Koen D. Quint6,7, Jan Nico Bouwes Bavinck6 and Veli-Matti Kähäri1,2
1Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland
2MediCity Research Laboratory, University of Turku, Turku, Finland
3Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
4Department of Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Turku, Finland
5Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
6Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
7DDL Diagnostic Laboratory, Rijswijk, The Netherlands
Veli-Matti Kähäri, email: [email protected]
Keywords: skin, cancer, inflammasome, AIM2, keratinocyte
Received: June 29, 2016 Accepted: April 18, 2017 Published: May 02, 2017
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.
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