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Survivin, an inhibitor of apoptosis protein is a biomarker of significance in prognostication of many malignancies. In the current study we investigated the serum survivin levels in patients with oral submucosal fibrosis (OSMF) and squamous cell carcinoma (OSCC). Serum was isolated from, peripheral blood collected of clinically and histopathologically confirmed OSMF and OSCC patients. Circulating level of survivin was measured in patients and control subjects by ELISA and analyzed further using Kruskal–Wallis test and two-sample Wilcoxon rank-sum (Mann–Whitney) test. Serum Survivin levels were significantly reduced in the OSCC group as compared to the control group. No significant correlation was noted between the serum survivin level and various clinicopathological characteristics of OSCC and OSMF patients. Our study suggests that free, wild form of circulating survivin probably has no role in predicting the prognosis of oral cancer or the malignant transformation potential of oral submucosal fibrosis. [ABSTRACT FROM AUTHOR]

Background. Aberrant nuclear accumulation of proteins influences tumor development and may predict biologic aggressiveness and disease prognosis. This study determined the prognostic significance of pSTAT3 (phosphorylayed signal transducer and activator of transcription 3) in oral squamous cell carcinomas (OSCCs). Methods and Results. Using immunohistochemistry, a significant increase in nuclear accumulation of pSTAT3 was observed in 49 of 90 leukoplakias (54.4%) and 63/94 OSCCs (67%) (ptrend < .001). Increased pSTAT3 was associated with tumor stage (p ¼ .01), nodal metastasis (p ¼ .0018), and tobacco consumption (p ¼ .004). Kaplan–Meier analysis demonstrated that OSCC with increased nuclear pSTAT3 showed significantly reduced disease-free survival (13 months), compared with the patients with no nuclear pSTAT3 expression (64 months, p ¼ .019). Cox regression analysis revealed nuclear pSTAT3 as the most significant predictor of poor prognosis (p ¼ .024, hazard ratio [HR] ¼ 2.7). Conclusions. Increased nuclear accumulation of pSTAT3 occurs in early premalignant stages and is a marker for poor prognosis of OSCC. [ABSTRACT FROM AUTHOR]

J Oral Pathol Med (2010) 39: 477–485 Background: In search of novel molecular markers for oral cancer, we reported increased levels of TC21/R-Ras2 transcripts in oral squamous cell carcinoma by differential display. The aim of this study was to determine the clinical significance of TC21 in oral cancer. Methods: Immunohistochemical analysis of TC21 protein expression was carried out in 120 leukoplakias, 83 OSCCs and 30 non-malignant tissues, confirmed by immunoblotting, and correlated with clinicopathological parameters as well as disease prognosis. Co-immunoprecipitation assays were carried out to identify the interaction partners of TC21 protein in oral cancer cells and tissues. Results: TC21 nuclear expression increased from normal oral tissues to leukoplakia and frank malignancy ( P < 0.001). TC21 overexpression was observed in 74.2% leukoplakia with no dysplasia, 75.9% dysplasias and 79.5% OSCCs in comparison with normal oral tissues. Receiver operating characteristic analysis showed that the area-under-the curve values were 0.895, 0.885, and 0.919, while the positive predictive values were 95.8%, 95.6%, and 97.1%, for nuclear immunostaining for normal versus leukoplakia with no dysplasia, leukoplakic lesions with dysplasia, and OSCCs, respectively. Immunoblotting confirmed overexpression of TC21 in oral lesions. Using co-immunoprecipitation assays, we showed interactions of TC21 with Erk2, PI3-K, 14-3-3ζ and 14-3-3σ proteins in oral cancer cells. Conclusion: Our findings suggested that alteration in TC21 expression is an early event in oral cancer and correlates with poor prognosis of OSCCs. TC21 interactions with Erk2, PI3-K, 14-3-3ζ and 14-3-3σ proteins in oral cancer cells and tissues suggests the involvement of TC21 in signaling pathways in oral cancer. [ABSTRACT FROM AUTHOR]

Background: The functional and clinical significance of 14-3-3 proteins in human cancers remain largely undetermined. Earlier, we have reported differential expression of 14-3-3ζ mRNA in oral squamous cell carcinoma (OSCC) by differential display. Methods: The clinical relevance of 14-3-3ζ protein in oral tumorigenesis was determined by immunohistochemistry in paraffin embedded sections of oral pre-malignant lesions (OPLs), OSCCs and histologically normal oral tissues and corroborated by Western Blotting. Co-immunoprecipitation assays were carried out to determine its association with NFκB, β-catenin and Bcl-2. Results: Intense immunostaining of 14-3-3ζ protein was observed in 61/89 (69%) OPLs and 95/ 120 (79%) OSCCs. Immunohistochemistry showed significant increase in expression of 14-3-3ζ protein from normal mucosa to OPLs to OSCCs (Ptrend < 0.001). Significant increase in expression of 14-3-3ζ protein was observed as early as in hyperplasia (p = 0.009), with further elevation in moderate and severe dysplasia, that was sustained in OSCCs. These findings were validated by Western blotting. Using Co-immunoprecipitation, we demonstrated that 14-3-3ζ protein binds to NFκB, β-catenin and Bcl-2, suggesting its involvement in cellular signaling, leading to proliferation of oral cancer cells. Conclusion: Our findings suggest that over-expression of 14-3-3ζ is an early event in oral tumorigenesis and may have an important role in its development and progression. Thus, 14-3-3ζ may serve as an important molecular target for designing novel therapy for oral cancer. [ABSTRACT FROM AUTHOR]

Objective: TheMEMD gene was reported to be overexpressed in human esophageal squamous cell carcinoma (ESCC), using differential display. The aim of this study was to determine the clinical significance of MEMD/ALCAM in esophageal tumorigenesis. Methods: Analysis of MEMD/ALCAM expression in esophageal tissues was carried out at protein and RNA level using immunohistochemistry and semiquantitative RT-PCR, respectively. Results: Increased MEMD/ALCAM expression was observed in 42/65 (65%) ESCCs (p = 0.000, odds ratio, OR = 3.665) and in 17/25 (68%) dysplasias (p = 0.000, OR = 4.248) compared to paired distant histologically normal esophageal tissues. Increased MEMD mRNAlevels were observed in ESCCs and dysplasias showing overexpression of MEMD/ALCAM protein. Interestingly, increased membranous MEMD/ALCAM expression was observed in dysplasias in comparison with ESCCs (p = 0.002, OR = 3.177). MEMD/ALCAM overexpression in ESCCs was associated with late clinical stage (p = 0.002, OR = 3.619), enhanced tumor invasiveness (p = 0.002, OR = 3.619), and nodal metastasis (p = 0.000, OR = 4.206). Conclusion: To our knowledge, this is the first report showing MEMD expression at pre-malignant stage (dysplasia), suggesting that MEMD/ALCAM expression is an early event in the development of esophageal cancer. Furthermore, in ESCCs its correlation with late clinical stage, enhanced tumor invasiveness and nodal metastasis suggests an association with aggressive tumor behavior. Our data suggest that MEMD/ALCAM may serve as a potential marker for early diagnosis, tumor invasion and nodal metastasis in ESCCs. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes. Phosphorylated S6 (p-S6), a downstream effector of EGFR and cyclin D1-CDK4/6 signalling, showed a progressive increase from normal oral tissues to leukoplakia and frank malignancy, and associated with poor outcome of the patients. This increased p-S6 expression was drastically reduced after combination treatment with afatinib and palbociclib in the cell lines and mouse models, suggesting its utiliy as a prognostic marker in HNSCC. Combination treatment also reduced the cell growth and induced cell senescence via increasing reactive oxygen species with concurrent ablation of glycolytic and tricarboxylic acid cycle intermediates. Finally, our findings in sub-cutaneous and genetically engineered mouse model (K14-CreERtam;LSL-KrasG12D/+;Trp53R172H/+) studies showed a significant reduction in the tumor growth and delayed tumor progression after combination treatment. This study collectively demonstrates that dual targeting may be a critical therapeutic strategy in blocking tumor progression via inducing metabolic alteration and warrants clinical evaluation. [ABSTRACT FROM AUTHOR]

Abstract: Early metastasis and a poor five-year survival make lung cancer the leading cause of cancer related deaths worldwide. The clinical profile of lung cancer patients in India differs from the West as they present earlier, with squamous cell carcinoma being the commonest histological type. We compared gene expression profiles in primary lung squamous cell carcinoma (LSCC) and matched normal lung tissues in Asian Indians. Using suppression subtractive hybridization, two subtracted cDNA libraries containing differentially expressed genes in the tumors were constructed. Differential expression was confirmed by reverse Northern blot analysis. DNA of confirmed clones was sequenced and subjected to GenBank Blast searches. RNA expression levels were then analyzed by Northern blotting and validated by semiquantitative RT-PCR (in 10 cases of NSCLC). Seventeen differentially expressed gene cDNA fragments of LSCC were analyzed. The differentially expressed genes included those associated with cellular metabolism, cell-cycle, -structure, -adhesion, transcription, proliferation, apoptosis and signal transduction. The study provided first evidence that KIAA0767, a Death Inducing Protein, a novel p53 independent target of E2F1, and Geminin, an inhibitor of DNA replication are differentially expressed in LSCC. Identification of the differentially expressed genes in lung cancer in this study may serve as better molecular markers for early diagnosis and identifying novel intervention sites for anticancer therapy. [Copyright &y& Elsevier]