Date of Award

10-31-2022

Degree Type

Thesis

Degree Name

MPhil in Biological and Biomedical Sciences

First Advisor

Dr. Muhammad Nouman Mughal

Second Advisor

Dr. Syed Ather Enam

Third Advisor

Dr. Kulsoom Ghias

Department

Biological and Biomedical Sciences

Abstract

Introduction: Gliomas are primary brain tumors originating from glial cells. Glioblastoma being its aggressive type is associated with a poor prognosis. Autophagy is a self-renewing process of the cell having a dual role in gliomagenesis depending on the tumor stage, regulated by autophagy-associated microRNAs. This study aims to investigate the correlation between the autophagy-associated markers ULK-1/2, UVRAG, Beclin-1, mTOR, UVRAG, PI3K, AKT, PTEN and their target microRNAs, namely, miR-126, miR-374, miR-21, miR-7, miR-204 and miR-100.
Methods: A total of 50 fresh tissues with a confirmed diagnosis of glioma were used. Formalin fixed paraffin embedded tissues were used for immunohistochemistry, while fresh tissue samples were used for the extraction of RNA using TRIzol-chloroform method and reverse transcribed cDNA. The cDNA was used to determine the expression of genes and microRNAs using quantitative real-time PCR (qPCR). Mann-Whitney U-test was used to determine the statistical significance.
Results: Results showed that LC3, an important autophagy protein, was highly expressed in all highgrade (HGG) and low-grade (LGG) glioma samples. Whereas low expression of Ki-67 was statistically significant within the patients with improved overall survival. Analysis of autophagy-associated genes namely, LC3, ULK-2 and AKT and autophagy-associated miRNAs namely, miR-126, miR-374 and miR-21 were significantly up-regulated in high-grade gliomas as compared to low-grade gliomas. Analysis of the correlation between autophagy genes and microRNAs showed a positive correlation between (PTEN; miR-7, miR-100, mir-204, mir-374), (ULK-2; miR-7, mir-100, mir-374), (mTOR; mir-100, miR-374), (UVRAG; mir-7, miR100, mir-374), (LC3; 374) in lowgrade gliomas while miR-7 showed a positive correlation with AKT in high-grade gliomas.
Conclusion: A high level of autophagy was identified in glioblastoma as an independent predictor of HGG prognosis and revealed the risk of autophagy and cancer in malignant glioma grade. Most importantly, the present study shows the potential association between autophagy and microRNAs. The classical biomarkers, the differentially expressed autophagy-related genes (ARG), and Autophagy-Related MicroRNAs may be considered therapeutic targets for further exploration.

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1

Last Page

92

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