Ets family proteins regulate the EMT transcription factors Snail and ZEB in cancer cells.

The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. Snail and ZEB1/2 (ZEB1 and ZEB2), known as EMT transcription factors, are key regulators of this transition. ZEB1/2 are positively correlated with EMT phenotypes and the aggressiveness of cancers. On the contrary, Snail is also correlated with the aggressiveness of cancers, but is not correlated with the expression of EMT marker proteins. Snail is induced by transforming growth factor-ß (TGF-ß), a well-known inducer of EMT, in various cancer cells. Interestingly, Snail induction by TGF-ß is markedly enhanced by active Ras signals. Thus, cancer cells harboring an active Ras mutation exhibit a drastic induction of Snail by TGF-ß alone. Here, we found that members of the E26 transformation-specific (Ets) transcription factor family, Ets1 and Ets2, contribute to the upregulation of both Snail and ZEB1/2. Snail induction by TGF-ß and active Ras is dramatically inhibited using siRNAs against both Ets1 and Ets2 together, but not on their own; in addition, siRNAs against both Ets1 and Ets2 also downregulate the constitutive expression of Snail and ZEB1/2 in cancer cells. Examination of several alternatively spliced variants of Ets1 revealed that p54-Ets1, which includes exon VII, but not p42-Ets1, which excludes exon VII, regulates the expression of the EMT transcription factors, suggesting that Ets1 is a crucial molecule for regulating Snail and ZEB1/2, and thus cancer progression is mediated through post-translational modification of the exon VII domain.

Assessment of lateral pterygoid muscle and temporomandibular joint disc after Le Fort I osteotomy with and without intentional pterygoid plate fracture and sagittal split ramus osteotomy in class II and class III patients.

The aim of the study was to examine lateral pterygoid muscle (LPM) and temporomandibular joint (TMJ) disc before and after Le Fort I osteotomy with and without intentional pterygoid plate fracture and sagittal split ramus osteotomy (SSRO) in class II and class III patients. Le Fort I osteotomy and SSRO were performed in class II and class III patients. LPM measurements using oblique sagittal computed tomography (CT) images and TMJ disc position using magnetic resonance imaging (MRI) were examined. Statistical comparisons were performed for the LPM and TMJ between class II and class III patients and between those with and without intentional pterygoid plate fracture in Le Fort I osteotomy. The subjects comprised 60 female patients (120 sides), with 30 diagnosed as class II and 30 as class III. Preoperatively, the width of the condylar attachment, width at eminence, length of the LPM, angle of the LPM, and square of the LPM were significantly smaller in the class II group than in the class III group (p < 0.05). After 1 year, the width of the condylar attachment, width at eminence, and angle of the LPM remained significantly smaller in the class II group than in the class III group (p < 0.0001). TMJ disc position was significantly related to the width of the condylar attachment of the LPM, both pre- and postoperatively (p < 0.0001). However, postoperative disc position did not change in all patients. Next, the class II patients (60 sides) were divided into two groups who underwent Le Fort I osteotomy with or without intentional pterygoid plate fracture. Changes in all measurements of the LPM showed no significant differences between these two groups. Our study suggested that TMJ disc position classification could be associated with the width of condylar attachment of the LPM before and after surgery, while the surgical procedure, including Le Fort I osteotomy with intentional pterygoid plate fracture, might not affect postoperative LMP or disc position in class II patients.

Evaluation of condylar surface CT values related to condylar height reduction after orthognathic surgery.

This study was performed to evaluate the relationship between condylar height reduction and changes in condylar surface computed tomography (CT) values in jaw deformity patients following orthognathic surgery. Mandibular advancement by sagittal split ramus osteotomy (SSRO) with Le Fort I osteotomy was performed in class II patients, and mandibular setback by SSRO with Le Fort I osteotomy was performed in class III patients. The maximum CT values (pixel values) at five points on the condylar surface and the condylar height, ramus height, condylar square, ramus angle, and gonial angle in the sagittal plane were measured preoperatively and 1 year postoperatively. Disc position was classified as anterior disc displacement (ADD) or other types by using magnetic resonance imaging (MRI). Ninety-two condyles of 46 female patients were prepared for this study. Their temporomandibular joints (TMJs) were divided into two groups based on class (46 joints in class II and 46 joints in class III) and two groups based on the findings (25 joints with ADD and 67 joints with other findings). ADD with and without reduction was observed in two joints in the class III group and in 23 joints in the class II group. The distribution of ADD incidence had not changed 1 year after surgery. Condylar height decreased 1 year after surgery in both class II patients (mandibular advancement) (p < 0.0001) and class III patients (mandibular setback) (p = 0.0306). Similarly, condylar height decreased 1 year after surgery both in patients who showed ADD (p = 0.0087) and those with other types (p = 0.0023). Significant postoperative increases at all angle sites on the condylar surface were found in the class II (p < 0.05) and ADD (p < 0.05) groups. This study showed that an enhanced condylar surface CT value might be one sign of condylar height reduction related to sequential condylar resorption, in combination with ADD.

Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells.

The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. ZEB1/2 are EMT transcription factors that are positively correlated with EMT phenotypes and breast cancer aggressiveness. ZEB1/2 regulate the alternative splicing and hence isoform switching of fibroblast growth factor receptors (FGFRs) by repressing the epithelial splicing regulatory proteins, ESRP1 and ESRP2. Here, we show that the mesenchymal-like phenotypes of oral squamous cell carcinoma (OSCC) cells are dependent on autocrine FGF-FGFR signaling. Mesenchymal-like OSCC cells express low levels of ESRP1/2 and high levels of ZEB1/2, resulting in constitutive expression of the IIIc-isoform of FGFR, FGFR(IIIc). By contrast, epithelial-like OSCC cells showed opposite expression profiles for these proteins and constitutive expression of the IIIb-isoform of FGFR2, FGFR2(IIIb). Importantly, ERK1/2 was constitutively phosphorylated through FGFR1(IIIc), which was activated by factors secreted autonomously by mesenchymal-like OSCC cells and involved in sustained high-level expression of ZEB1. Antagonizing FGFR1 with either inhibitors or siRNAs considerably repressed ZEB1 expression and restored epithelial-like traits. Therefore, autocrine FGF-FGFR(IIIc) signaling appears to be responsible for sustaining ZEB1/2 at high levels and the EMT phenotype in OSCC cells.