Oral Submucous Fibrosis (OSMF) is a chronic debilitating disease more frequently found in the South East Asian population. This disease poses a public health priority, as it is grouped under oral potentially malignant disorders, with malignant transformation rates of around 7 to 13%. Hence, early identification of high-risk OSMF patients is of the utmost importance to prevent malignant transformation. Proteomic expression profiling is a promising method for identifying differentially expressed proteins for disease prognosis and risk stratification in OSMF. In this study, overexpressed proteins in OSMF, OSMF transformed into oral squamous cell carcinoma (OSCC) and normal tissues were evaluated by proteomic analysis using two-dimensional electrophoresis (2DE) and mass spectrometry, which revealed 23 upregulated proteins. Validation was done using immunohistochemistry for three secretory proteins, namely 14-3-3ε (n = 130), carbonic anhydrase 1 (CA 1) (n = 125) and heat shock protein 70 (HSP 70) (n = 117), which showed significant overexpression in OSMF, OSCC compared to normal. The present study is the first of its kind in India to the best of our knowledge, assessing the altered expression of proteins in OSMF and OSMF which has undergone malignant transformation, obtaining a better knowledge of the molecular pathways involved in the disease progression. The current study shows that the biomarkers studied can be potentially useful for risk stratification of OSMF to OSCC serving as novel targets for therapeutic intervention. Clinical validation of the targets can further pave way for precision medicine to improve the quality of life in OSMF patients.
Oral Submucous Fibrosis (OSMF) is a chronic debilitating disease more frequently encountered in the South-East Asian population. This disease represents a public health priority as it is grouped within oral potentially malignant disorders, with malignant transformation rates of around 7–19%. Hence, early identification of high-risk OSMF patients is of the utmost importance to prevent malignant transformation. Among various biomarkers, EGFR overexpression has an unfavorable clinical outcome, poor prognosis, and low survival rates in Oral Squamous Cell Carcinoma (OSCC). The current study aimed to evaluate the expression of EGFR in saliva and exfoliated buccal cells of OSMF. Immunoexpression of EGFR was observed in healthy controls (n = 11), OSCC (n = 106), and OPMD with dysplasia (n = 56), which showed significant expression with increasing grades of dysplasia and OSCC. EGFR expression was evaluated in saliva and exfoliated buccal cells of healthy controls (n = 15), OSMF (n = 24), and OSCC (n = 10) patients using ELISA, which revealed significant expression in OSMF and OSCC. Validation studies were also performed using real-time PCR (RT-PCR) to compare gene expression in healthy controls (n = 9), OSMF (n = 9), and OSCC (n = 25), which showed significant 18-fold upregulation in OSCC and three-fold upregulation in OSMF when compared to healthy controls. Hence, saliva and exfoliated buccal cells could be considered as potential non-invasive diagnostic samples for the evaluation of high-risk patients of OSMF using EGFR as a biomarker.
Oral submucous fibrosis (OSMF) is highly prevalent in South East Asia with higher rates of malignant transformation in Indian subcontinent. Numerous biomarkers are now being studied to predict disease prognosis and detect malignant alterations at an early stage. Patients with clinically and biopsy-proven oral submucous fibrosis and oral squamous cell carcinoma were included in the study as the experimental group, while patients without a tobacco or betel nut habit who had their third molars surgically removed were included as the healthy control group. For the immunohistochemistry (IHC) investigation, 5-μm slices from formalin-fixed, paraffin-embedded tissue blocks (FFPE) were obtained. Fresh tissues (n = 45) from all three groups were collected and gene expression was studied using relative quantitation-based qPCR. The protein expression of octamer-binding transcription factor 3/4 (OCT 3/4) and sex-determining region Y-box 2 (SOX 2) was evaluated in the experimental group and compared with healthy controls. The IHC results showed a significant correlation with the expression of OCT 3/4 (p value = 0.000; χ2 = 20.244) and SOX 2 (p value = 0.006; χ2 = 10.101) among OSCC and OSMF patients in comparison to healthy controls. Both OCT 3/4 and SOX 2 showed overexpression of four-fold and three-fold in OSMF when compared to OSCC and healthy controls, respectively. This study shows the significant importance of cancer stem cell markers OCT 3/4 and SOX 2 to assess the disease prognosis in OSMF.
Survival rate of patients with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. Deregulated cell signaling pathways such as BRAF/MAPK/ERK pathway and AMPK pathway along with suppression of iodine metabolising genes including NIS and TSHR are seen in ATC. In ATC, BRAFV600E mutation is the major mutation occurring in ATC that constitutively activate MAPK/ERK signaling and result in the transformation of normal cells in to undifferentiated cancer cells. Although Vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study on ATC has showed resistance to Vemurafenib. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer. Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR in our study and demonstrated that combination of Vemurufenib with metformin has synergistic anti-cancer effects and provide the evidence that the combination of drugs suppressed the progression of ATC cells growth by inducing significant apoptosis through downregulation of ERK signaling, upregulation of AMPK pathway and by reversing epithelial-mesenchymal transition (EMT) markers - E-cadherin and Vimentin expression. Our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. cAMP signaling has been studied in ATC for the first time through our study wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment. To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.
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