Keratin 17 Is Induced in Oral Cancer and Facilitates Tumor Growth

Khanom, Rumana; Nguyen, Chi Thi Kim; Kayamori, Kou; Zhao, Xin; Morita, Keiichi; Miki, Yoshio; Katsube, Ken‐ichi; Yamaguchi, Akira; Sakamoto, Kei

doi:10.1371/journal.pone.0161163

“…The coordinated overexpression of KRT17, STAT1, and ICAM1 in OSCC is consistent with findings in previous studies [20,24,29,32,33]. Close correlations between KRT17, STAT1, and ICAM1 expression in epithelial cells have been demonstrated in previous studies.…”

Section: Discussionsupporting

confidence: 92%

“…ICAM1, 23 STAT1, and phosphorylated STAT1 (pSTAT1) expression were also decreased in HSC3/AIRE compared to control cells. The relationship between AIRE and KRT17 was further explored using previously established KRT17-knockout HSC3 cells (HSC3/KRT17 -) [24]. In HSC3/KRT17cells, the expression of AIRE, ICAM1, and STAT1 was remarkably reduced compared to control cells (Fig 5D).…”

Section: Aire Promotes the Expression Of Stat1 Icam1 Cxcl10 Cxcl11mentioning

confidence: 96%

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression

Sakamoto

¹

,

Nguyen

²

,

Sawangarun

³

et al. 2019

Preprint

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Autoimmune regulator (AIRE) is a transcriptional regulator that is primarily expressed in medullary epithelial cells, where it induces tissue-specific antigen expression. Under pathological conditions, AIRE expression is induced in epidermal cells and promotes skin tumor development in association with stress-responsive keratin KRT17. This study aimed to clarify the role of AIRE in the pathogenesis of oral squamous cell carcinoma (OSCC). AIRE expression was evaluated in seven OSCC cell lines and in OSCC tissue specimens. Transient or constitutive expression of AIRE in 293A cells induced KRT17 expression. cDNA microarray analysis of 293A cells stably expressing AIRE revealed that STAT1 and ICAM1 were significantly upregulated by AIRE. Expression of KRT17, STAT1, ICAM1, MMP9, CXCL10, and CXCL11 was elevated in 293A cells stably expressing AIRE, and conversely, was decreased in AIRE-knockout HSC3 OSCC cells when compared to the respective controls. Upregulation of KRT17, STAT1, and ICAM in OSCC cells was confirmed in tissue specimens by immunohistochemistry. We provide evidence that AIRE exerts transcriptional control in cooperation with ETS1. Expression of STAT1, ICAM1, CXCL10, and MMP9 was increased in 293A cells upon Ets1 transfection, and coexpression of AIRE resulted in enhanced expression of STAT1. AIRE coprecipitated with ETS1 in a modified immunoprecipitation assay using formaldehyde crosslinking. Chromatin immunoprecipitation and quantitative PCR analysis revealed that promoter fragments of STAT1, ICAM1, CXCL10, and MMP9 were enriched in the AIRE precipitates. In oral cancer cells, ETS1 was diffusely located in the nucleus and partially overlapped with dot-like AIRE 4 accumulation sites. Nuclear translocation of AIRE was promoted by cotransfection with Ets1. These results indicate that AIRE is induced in OSCC and supports cancer-related gene expression in cooperation with ETS1. This is a novel function of AIRE in extrathymic tissues under the pathological condition.7 keratinocytes [8][9][10][11]. In the mouse epidermis, Aire is induced by inflammatory or tumorigenic stimuli concurrently with Krt17 and stimulates the transcription of several chemokine genes, such as Cxcl10and Cxcl11, and a gene encoding matrix-degrading enzyme, Mmp9, in keratinocytes [6]. The onset of genetically induced skin tumor is delayed in Aire-knockout mice, which mimic the phenotype of Krt17-knockout mice [6]. These results suggest a novel role of AIRE in extrathymic epithelial tissues under pathological conditions; however, the significance of AIRE in other cancers remains to be elucidated.The above findings inspired us to evaluate whether AIRE participates in the pathogenesis of OSCC. To this end, we first assessed the expression of AIRE in OSCC. Then, we explored the role of AIRE in the regulation of KRT17 and other genes associated with OSCC development. Materials and Methods Chemically induced mouse model of tongue and esophageal cancerCD-1 mice were obtained from Sankyo Labo Service Co. (Tokyo, Japan) and were housed in groups ...

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“…Instead, we found evidence of upregulation of STAT1, and ICAM1 by AIRE. The coordinated overexpression of STAT1, and ICAM1 in OSCC is consistent with findings in previous studies [23,28,[31][32][33]. Close correlations between STAT1, and ICAM1 expression in epithelial cells have been demonstrated in previous studies.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, AIRE expression is regulated by KRT17 in cooperation with the ribonucleoprotein hnRNPK [6]. As KRT17 was robustly induced in all the oral cancer tissues examined [31], the induction of AIRE in OSCC may be attributed to KRT17-mediated regulation. Further research is needed to elucidate the details of the mechanism of AIRE induction in cancer cells.…”

Section: Discussionmentioning

confidence: 91%

AIRE is induced in oral squamous cell carcinoma and promotes cancer gene expression

Nguyen

¹

,

Sawangarun

²

,

Mandasari

³

et al. 2020

Self Cite

View full text Add to dashboard Cite

Autoimmune regulator (AIRE) is a transcriptional regulator that is primarily expressed in medullary epithelial cells, where it induces tissue-specific antigen expression. Under pathological conditions, AIRE expression is induced in epidermal cells and promotes skin tumor development. This study aimed to clarify the role of AIRE in the pathogenesis of oral squamous cell carcinoma (OSCC). AIRE expression was evaluated in six OSCC cell lines and in OSCC tissue specimens. Expression of STAT1, ICAM1, CXCL10, CXCL11, and MMP9 was elevated in 293A cells stably expressing AIRE, and conversely, was decreased in AIRE-knockout HSC3 OSCC cells when compared to the respective controls. Upregulation of STAT1, and ICAM in OSCC cells was confirmed in tissue specimens by immunohistochemistry. We provide evidence that AIRE exerts transcriptional control in cooperation with ETS1. Expression of STAT1, ICAM1, CXCL10, CXCL11, and MMP9 was increased in 293A cells upon Ets1 transfection, and coexpression of AIRE further increased the expression of these proteins. AIRE coprecipitated with ETS1 in a modified immunoprecipitation assay using formaldehyde crosslinking. Chromatin immunoprecipitation and quantitative PCR analysis revealed that promoter fragments of STAT1, ICAM1, CXCL10, and MMP9 were enriched in the AIRE precipitates. These results indicate that AIRE is induced in OSCC and supports cancer-related gene expression in cooperation with ETS1. This is a novel function of AIRE in extrathymic tissues under the pathological condition.

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“…Increased K17 expression is also considered as a marker of keratinocyte proliferation [61]. A recent report suggested an important role of K17 in regulation of signaling pathways such as Akt/mTOR in OSCC and Hedgehog (Hh) in basal cell carcinomas (BCC) [60,62]. Altogether, these reports support our in vitro data and suggest a possible role of K17-mediated regulation of 'Cell death and survival' to be involved in decreased tumorigenic potential of A431 cells in the absence of K8.…”

Section: Discussionmentioning

confidence: 99%