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Title: Biomarker Discovery and Proteomics Profiling of Serum From Oral Squamous Cell Carcinoma (OSCC) Patients
Authors: Usman, Muhammad
Keywords: Chemistry
Issue Date: 2019
Publisher: University of Karachi, Karachi.
Abstract: Oral squamous cell carcinoma is the major type of oral cavity cancer and ranks at top among Pakistani males due to intense use of smokeless tobacco products. Furthermore, highest mortality is also observed among them as evident from recent international reports. Tongue is the most common site of tumor formation followed by buccal mucosa. Pre-cancerous lesions occur during early events of tumor formation and characterized as erythroplakia or leukoplakia based on color appearance. Its advanced form called oral sub-mucous fibrosis (OSF) develops afterwards. Despite intense improvements in treatment modalities, five year survival rate is still lower than 50% merely because of late stage diagnosis. Diagnosis at initial stages may help in prevention of disease. Histopathology is the gold standard method for diagnosis but minor changes can be overlooked; therefore, molecular markers are needed to report such minor changes. Proteomics has incredible role in discovery of various disease biomarkers including cancers. Several OSCC serum/plasma biomarkers have already been reported from different parts of the world using non-invasive or minimally invasive method. Pakistan falls in the high risk zone for OSCC due to frequent consumption of smokeless tobacco products especially among teenagers. Unfortunately, till date, studies on oral cancer from Pakistan are limited with few reports emphasizing proteomics studies. Current study was designed to discover serum biomarker form local population using proteomic approach. Samples were resolved through two dimensional gel electrophoresis and six highly differential spots were identified through mass spectrometric analysis. Among them, three were found to be down-regulated which include keratin type II(KRT1), GIMAP7 and serum albumin whereas HSP90 alpha, haptoglobin and Rabl3 showed up-regulation, Concurrent mRNA expression level of identified proteins was also examined in OSCC tissue through RT-qPCR. Further validation of Rabl3 was achieved using sandwich ELISA which indicated significant increase in OSCC serum. Among identified proteins which were down-regulated, KRT1 is suggested to act as a tumor suppressor. Second interesting protein, GIMAP7 is linked with the cell survival. Serum albumin is likely to be down-regulated since it acts as source of nourishment to fulfill increasing nutrients demand of tumor cells. On the other hand, HSP90 alpha regulates Akt kinase activity hence acts as an oncogene whereas haptoglobin has role in tumor metastasis by inducing change in cellular morphology. Rabl3 is reported to be an oncogene in different cancer including lung and hepatic carcinoma. In oral cancer, we report up-regulation of Rabl3 for the first time. We suggest Rabl3 as a novel candidate non-invasive biomarker because of its role as an oncognenic protein. We also studied the differential expression of key genes involved in oral carcinogenesis. For this purpose, malignant tissue and adjacent healthy tissue samples were used. RTqPCR quantification showed down-expression of tumor suppressor genes i.e., Tp53and CDKN1A with simultaneous over-expression of oncognes including IGF1R, Akt1, MAPK1, SFN and CDK2 Furthermore, in silico analysis of identified proteins along with previously reported serum/plasma protein biomarkers generated fascinating results. Most of the candidates appeared in strong connections inferring their possible integrated roles in carcinogenesis. However, few proteins identified in the current study didn’t show any direct interaction in STRING network which suggest their unique mode of action in oral carcinogenesis. In conclusion, this study provides useful information about differentially expressed proteins and their association in oral carcinogenesis. Our data is an extension of already existing global knowledge about oral cancer. Furthermore, it will help in filling the gap regarding data associated with our particular region. It is expected that such studies would be beneficial in suggesting a unique bio-marker for early diagnosis of oral cancer through non-invasive method.
Gov't Doc #: 20483
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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