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

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.

SUBMITTER: Farshchian M

PROVIDER: S-EPMC5542230 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Farshchian Mehdi M Nissinen Liisa L Siljamäki Elina E Riihilä Pilvi P Piipponen Minna M Kivisaari Atte A Kallajoki Markku M Grénman Reidar R Peltonen Juha J Peltonen Sirkku S Quint Koen D KD Bavinck Jan Nico Bouwes JNB Kähäri Veli-Matti VM

Oncotarget 20170701 28

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 immuno ...[more]

PMID: 28526809

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Project description:Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65- to 100-fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B-induced epidermal hyperplasia and hyperproliferation in SKH-1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell-specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan-FGFR inhibitor; AZD4547 significantly decreased cSCC cell-cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR-mediated effects. To further bolster the in vitro studies, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle-only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.

Project description:Background Circular RNAs (circRNAs) were reported to play an important role in regulating tumor pathogenesis. The molecular mechanism of circRNAs in cervical squamous cell carcinoma (CSCC) remains poorly understood. We aimed to identify the circRNAs differentially expressed, and to investigate the role of a novel circRNA, hsa_circ_0065898, in regulating proliferation, migration, and invasion in CSCC. Methods The online Kaplan-Meier Plotter was used to analyze the relationship between miRNA expression and overall survival. Bioinformatics tools, such as R, Cytoscape, and Perl, were used to analyze the Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction (PPI) network, and regulatory network. The expression level of hsa_circ_0065898 in CSCC cell lines was evaluated using quantitative polymerase chain reaction in vitro. The cell counting kit-8 (CCK-8) and transwell assays were used to assess cell proliferation, migration, and invasion. Results circRNA expression data (GSE102686) was downloaded from the Gene Expression Omnibus database, and this included data from 5 CSCC patients and 5 normal tissues. 13 differentially expressed circRNAs were identified, which included 9 upregulated circRNAs and 4 downregulated circRNAs. GO enrichment analysis showed that the target genes of miRNAs associated with hsa_circ_0065898 were enriched in ubiquitin-protein transferase activity, ubiquitin-like protein transferase activity, core promoter sequence-specific DNA binding, mRNA 3’-UTR AU-rich region binding, core promoter binding, and so on. KEGG showed that the Hippo and p53 signaling pathways played significant role in the pathway network. Hsa_circ_0065898 was significantly overexpressed in the CSCC cell lines. Hsa_circ_0065898 facilitated cell proliferation, migration, and invasion in CSCC. Conclusions This study identified differentially expressed circRNAs and constructed the regulatory network of hsa_circ_0065898 targeting microRNAs and mRNAs. We demonstrated that hsa_circ_0065898 promoted CSCC cell proliferation, migration, and invasion. Hence, hsa_circ_0065898 might be useful as a biomarker for CSCC diagnosis and targeted therapy.

Dataset Information

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

Publications

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

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