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GLI3 Knockdown Decreases Stemness, Cell Proliferation and Invasion in Oral Squamous Cell Carcinoma

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GLI3 Knockdown Decreases Stemness, Cell Proliferation and Invasion in Oral Squamous Cell Carcinoma 2458 INTERNATIONAL JOURNAL OF ONCOLOGY 53: 2458-2472, 2018 GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma MARIA FERNANDA SETÚBAL DESTRO RODRIGUES1,2, LUCYENE MIGUITA2, NATHÁLIA PAIVA DE ANDRADE2, DANIELE HEGUEDUSCH2, CAMILA OLIVEIRA RODINI3, RAQUEL AJUB MOYSES4, TATIANA NATASHA TOPORCOV5, RICARDO RIBEIRO GAMA6, ELOIZA ELENA TAJARA7 and FABIO DAUMAS NUNES2 1Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University (UNINOVE), São Paulo 01504000; 2Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000; 3Department of Biological Sciences, Bauru School of Dentistry, Bauru 17012901; 4Department of Head and Neck Surgery, School of Medicine, 5School of Public Health, University of São Paulo, São Paulo 03178200; 6Department of Head and Neck Surgery, Barretos Cancer Hospital, Barretos 014784400; 7Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto 15090000, Brazil Received February 28, 2018; Accepted June 29, 2018 DOI: 10.3892/ijo.2018.4572 Abstract. Oral squamous cell carcinoma (OSCC) is an expression of the Involucrin (IVL) and S100A9 genes. Cellular extremely aggressive disease associated with a poor prognosis. proliferation and invasion were inhibited following GLI3 Previous studies have established that cancer stem cells (CSCs) knockdown. In OSCC samples, a high GLI3 expression was actively participate in OSCC development, progression and associated with tumour size but not with prognosis. On the resistance to conventional treatments. Furthermore, CSCs whole, the findings of this study demonstrate for the first time, frequently exhibit a deregulated expression of normal stem at least to the best of our knowledge, that GLI3 contributes cell signalling pathways, thereby acquiring their distinctive to OSCC stemness and malignant behaviour. These findings abilities, of which self-renewal is an example. In this study, we suggest the potential for the development of novel therapies, examined the effects of GLI3 knockdown in OSCC, as well as either in isolation or in combination with other drugs, based the differentially expressed genes in CSC-like cells (CSCLCs) on CSCs in OSCC. expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. Introduction The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following Head and neck cancer is the seventh most common type of this, we examined the effects of GLI3 knockdown on CD44 cancer worldwide, and oral squamous cell carcinoma (OSCC) and ESA expression, colony and sphere formation capability, accounts for >90% of these cases (1,2). OSCC is usually stem-related gene expression, proliferation and invasion. The aggressive and highly invasive and is associated with a high overexpression of genes related to the Notch, transforming recurrence rate, as well as with metastasis of the lymph growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency nodes (3). As a result, the vast majority of patients with OSCC maintenance pathways was observed in the CD44high cells. have a poor prognosis, and, despite advances in the under- GLI3 knockdown was associated with a significant decrease in standing of the molecular and genetic mechanisms driving different CSCLC fractions, spheres and colonies in addition to OSCC malignancy, the 5-year-survival rate has not shown any the downregulation of the CD44, Octamer-binding transcrip- significant improvement (3,4). tion factor 4 (OCT4; also known as POU5F1) and BMI1 genes. Previous studies have demonstrated that OSCC, similar This downregulation was accompanied by an increase in the to other solid malignant tumours, has a small subpopulation of cells designated as cancer stem cells (CSCs). These cells are characterised by the ability to self-renew indefinitely, in addition to giving rise to transient and differentiated cells which comprise the bulk of the tumour (5-7). CSCs are there- Correspondence to: Professor Fabio Daumas Nunes, Department fore associated with recurrence and therapeutic resistance, of Oral Pathology, School of Dentistry, University of São Paulo, Avenida Professor Lineu Prestes 2227, São Paulo 055080000, Brazil and participate in OSCC metastasis due to their capability to E-mail: [email protected] undergo epithelial to mesenchymal transition (EMT) (8-10). CSCs in OSCC were first identified and isolated by Key words: oral squamous cell carcinoma, cancer stem cell-like Prince et al based on their high expression levels of CD44, cells, stem cell signaling pathways, CD44, GLI3 a cell surface glycoprotein that acts as a receptor for hyal- uronic acid (5). Upon binding to its ligand, CD44 can activate RODRIGUES et al: GLI3 IN ORAL SQUAMOUS CELL CARCINOMA 2459 different signalling pathways which regulate a wide variety nuclear form, which inhibits the signalling pathway (27). of cellular processes, including adhesion, proliferation, In adult haematopoiesis, a progressive decrease in the Shh motility, apoptosis, survival and resistance to therapy (11). pathway is associated with increased hematopoietic cellular Subsequently, additional CSC markers were identified and used fate and the transition from an embryonic to a hematopoietic alone or in combination with CD44, including CD133 (12), stem cell. In this context, GLI3 plays a crucial role in medi- epidermal growth factor receptor (EGFR) (13), ESA (14), ating Shh pathway inhibition (28). CD24 (15) and aldehyde dehydrogenase 1 (ALDH1) (16). In cancer, SHH deregulated activation was first described Most importantly, recent studies on CSC plasticity have in nevoid basal cell carcinoma syndrome, where the inherited demonstrated that this subpopulation exists in more than one loss-of-function mutations of the PTCH1 gene was associated phenotype; the association of CD44 with different markers with tumour development (29,30). Abnormal Shh signalling has permitted the identification of distinct subtypes of CSCs. is now associated with the progression and maintenance of Biddle et al (2011) demonstrated that cells expressing high several malignant tumours, e.g., glioblastomas, lung cancer, levels of CD44 (CD44high) cells can be separated, based on prostate cancer and gastric cancer (24,31-34). Additionally, it epithelial-cell adhesion molecule (EpCAM)/ESA levels, into can participate in tumour development via somatic mutations two cellular phenotypes. These phenotypes present significant in upstream pathway proteins (SMO and PTC1), overexpres- differences in proliferation rates, cell motility and morphology sion of GLI transcription factors or in a ligand-dependent in addition to colony- and sphere-forming ability (14). manner (25). CD44high/ESAhigh cells exhibit an epithelial morphology and In different cell types, HH/GLI activation leads to the an increased proliferative ability, while CD44high/ESAlow cells transcription of genes critical to tumour initiation and are migratory and undergo EMT. maintenance. This pathway is associated with an increase Signalling pathways that control stem cell self-renewal and in the quantity of cell cycle proteins which are responsible differentiation are aberrantly activated in CSCs and include for G1/S and G2/M progression, mainly D-type cyclins and the Notch, Sonic Hedgehog (SHH) and Wnt pathways. All anti-apoptotic proteins (35-37). Additionally, it participates these pathways frequently interact with other cellular signal- in the regulation of EMT by inhibiting E-cadherin and ling pathways closely related to tumour development and inducing N-cadherin expression (37,38). Furthermore, GLI2 progression, such as nuclear factor (NF)-κB, mitogen-activated overexpression is associated with a decrease in E-cadherin protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) expression and an increase in SNAIL gene expression, as well and epidermal growth factor (EGF) (17). Thus, the identifica- as with an increase in matrix metalloproteinase (MMP)2 and tion of the crucial pathways necessary for CSC maintenance integrin-beta-1-binding proteins (ICAP-1); all of which favour represents an important therapeutic target with may be used cell invasion and metastasis (39). to block CSC proliferation and self-renewal and, consequently, Some studies have demonstrated that the Shh signalling tumour progression. pathway is upregulated in CSCs. The activation of these In this context, the SHH/Patched/Gli (SHH/PTCH/GLI) pathways in breast CSCs increases GLI expression and leads pathway, involved in the patterning, growth, differentiation to an enhanced SOX2 and OCT4 expression, favouring CSC and survival of normal stem cells also plays an important role maintenance (40). In gastric cancer cell lines and tissues, CSCs in CSCs; it provides proliferative cues that enable the cells identified by the CD44+CD24+ phenotype have demonstrated to accumulate oncogenic mutations that drive self-renewal, an overexpression of the SHH, PTCH1 and GLI3 genes (41). metastasis and therapeutic resistance (17,18). This signalling Zhang et al demonstrated that in liver cancer, CD90+ CSCs pathway initiates with the binding of Hedgehog proteins (Sonic, with GLI1 or GLI3 knockdown, exhibited low proliferation Desert and Indian HH) to the transmembrane receptor, PTCH. rates, and decreased migratory ability and sphere formation This receptor, in the absence of the Hedgehog ligands, inhibits capacity, as well as a decrease in tumour formation in
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