Spindly and Bub3 expression in oral cancer: Prognostic and therapeutic implications.

OBJECTIVES: Bub3 and Spindly are essential proteins required for the activation and inactivation of the spindle assembly checkpoint, respectively. Here, we explored the clinicopathological significance and the therapeutic potential of the opposing roles of the two proteins in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Bub3 and Spindly expression was evaluated by immunohistochemistry in 62 tissue microarrays from OSCC and by real-time PCR in OSCC cell lines and in normal human oral keratinocytes. The results were analyzed as to their clinicopathological significance. RNA interference-mediated Spindly or Bub3 inhibition was combined with cisplatin treatment, and the effect on the viability of OSCC cells was assessed. RESULTS: Overexpression of Bub3 and Spindly was detected in OSCC patients. High expression of Spindly, Bub3, or both was an independent prognostic indicator for cancer-specific survival and was associated with increased cellular proliferation. Accordingly, Bub3 and Spindly were upregulated in OSCC cells comparatively to their normal counterpart. Inhibition of Bub3 or Spindly was cytotoxic to OSCC cells and enhanced their chemosensitivity to cisplatin. CONCLUSIONS: The data point out Bub3 and Spindly as potential markers of proliferation and prognosis, and highlight the potential therapeutic benefit of combining their inhibition with cisplatin.

Podoplanin Expression Independently and Jointly with Oral Epithelial Dysplasia Grade Acts as a Potential Biomarker of Malignant Transformation in Oral Leukoplakia.

Our aim was to evaluate the expression of biomarkers, CD44v6, CD147, EGFR, p53, p63, p73, p16, and podoplanin in oral leukoplakias (OL) and to assess their potential for prediction of malignant transformation (MT). We analyzed the expression of CD44v6, CD147, EGFR, p53, p63, p73, p16, and podoplanin by immunohistochemistry in 52 OL, comprised of 41 low-grade (LG) dysplasia and 11 high-grade (HG) cases. Twelve healthy normal tissues (NT) were also included. Univariate and multivariate analysis were performed to evaluate any association with MT. Variable expression among the studied markers was observed, with a significant increase of high expression from NT to LG and HG cases in CD44v6 (p = 0.002), P53 (p = 0.002), P73 (p = 0.043), and podoplanin (p < 0.001). In multivariate analysis, cases with high podoplanin score showed a significant increased risk of MT (HR of 10.148 (95% CI of 1.503−68.532; p = 0.017). Furthermore, podoplanin combined with binary dysplasia grade obtained a HR of 10.238 (95% CI of 2.06−50.889; p = 0.004). To conclude, CD44v6, p53, p73, and podoplanin showed an increasing expression along the natural history of oral carcinogenesis. Podoplanin expression independently or combined with dysplasia grade could be useful predictive markers of MT in OL.

EMMPRIN expression in oral squamous cell carcinomas: correlation with tumor proliferation and patient survival.

The aim of our study was to explore the clinicopathological and prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) expression in oral squamous cell carcinomas (OSCC), and its relation with the proliferative tumor status of OSCC. We examined EMMPRIN and Ki-67 proteins expression by immunohistochemistry in 74 cases with OSCC. Statistical analysis was conducted to examine their clinicopathological and prognostic significance in OSCC. EMMPRIN membrane expression was observed in all cases, with both membrane and cytoplasmic tumor expression in 61 cases (82.4%). EMMPRIN overexpression was observed in 56 cases (75.7%). Moderately or poorly differentiated tumors showed EMMPRIN overexpression more frequently than well-differentiated tumors (P = 0.002). Overexpression of EMMPRIN was correlated with high Ki-67 expression (P = 0.004). In the multivariate analysis, EMMPRIN overexpression reveals an adverse independent prognostic value for cancer-specific survival (CSS) (P = 0.034). Our results reveal that EMMPRIN protein is overexpressed in more than two-thirds of OSCC cases, especially in high proliferative and less differentiated tumors. The independent value of EMMPRIN overexpression in CSS suggests that this protein could be used as an important biological prognostic marker for patients with OSCC. Moreover, the high expression of EMMPRIN makes it a possible therapeutic target in OSCC patients.

Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma.

OBJECTIVES: To evaluate the expression of phosphorylated mammalian target of rapamycin (p-mTOR) and phosphatase and tensin homolog deleted on chromosome TEN (PTEN) in oral squamous cell carcinomas (OSCCs) and relate them with clinicopathologic characteristics and outcome. STUDY DESIGN: We analyzed p-mTOR and PTEN protein expression by immunohistochemistry in 72 OSCCs. Multivariate analysis was conducted to examine their role in survival. RESULTS: p-mTOR expression was observed in 46 (63.9%) cancers and PTEN expression was absent in 22 (30.6%). An adverse independent prognostic value for high p-mTOR expression was found (P = .043) as well as for advanced tumor stage (P = .010) in patients' overall survival (OS). For disease-free survival (DFS), only advanced tumor stage (P = .001) presented an adverse independent prognostic value. CONCLUSIONS: The effect of p-mTOR in OS of OSCC suggests that this marker may serve as a reliable biological marker to identify high-risk subgroups and as a guide to therapy. Furthermore, the high expression of p-mTOR suggests that this protein may be a promising therapeutic target in OSCC.

Usefulness of labial salivary gland biopsy in familial amyloid polyneuropathy Portuguese type.

BACKGROUND: The diagnosis of amyloidosis of all types is definitively made by demonstration of Congo red binding material in the affected tissues. Nerve biopsy was classically used to diagnose amyloid polyneuropathy but less invasive alternative types of biopsies have been proposed including labial salivary gland (LSG) biopsy, a minimally invasive procedure. METHOD: LSG biopsies were done in 87 subjects with molecular diagnosis of TTRVal30Met mutation. The group includes 76 patients in different stages of familial amyloid polyneuropathy and 11 asymptomatic carriers. They were all submitted to a stomatological and a neurological observation to evaluate oral health problems and to determine the neurological stage of the disease. No major oral health problems were found. Mean age of onset of the symptomatic disease was 32.8 years (+/-9.69 SD). CONCLUSIONS: No significant side effects occurred after the surgical procedure, and adequate material for pathological analysis was always obtained. Amyloid deposition was found in 91% of the patients. Patients with negative biopsies (N = 7) were all in the earlier stage of the disease. Two asymptomatic carriers had biopsies with amyloid deposition. We conclude that LSG biopsy is a useful, sensitive and minimal invasive method to detect amyloid deposition.