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Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma

2017; Impact Journals LLC; Volume: 8; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.17573

1949-2553

Mehdi Farshchian, Liisa Nissinen, Elina Siljamäki, Pilvi Riihilä, Minna Piipponen, Atte Kivisaari, Markku Kallajoki, Reidar Grénman, Juha Peltonen, Sirkku Peltonen, Koen D. Quint, Jan Nico Bouwes Bavinck, Veli‐Matti Kähäri,

Heme Oxygenase-1 and Carbon Monoxide

// Mehdi Farshchian 1, 2 , Liisa Nissinen 1, 2 , Elina Siljamäki 1, 2 , Pilvi Riihilä 1, 2 , Minna Piipponen 1, 2 , Atte Kivisaari 1, 2 , Markku Kallajoki 3 , Reidar Grénman 4 , Juha Peltonen 5 , Sirkku Peltonen 1 , Koen D. Quint 6, 7 , Jan Nico Bouwes Bavinck 6 and Veli-Matti Kähäri 1, 2 1 Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland 2 MediCity Research Laboratory, University of Turku, Turku, Finland 3 Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland 4 Department of Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Turku, Finland 5 Department of Cell Biology and Anatomy, University of Turku, Turku, Finland 6 Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands 7 DDL Diagnostic Laboratory, Rijswijk, The Netherlands Correspondence to: Veli-Matti Kähäri, email: veli-matti.kahari@utu.fi Keywords: skin, cancer, inflammasome, AIM2, keratinocyte Received: June 29, 2016 Accepted: April 18, 2017 Published: May 02, 2017 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.