Wajiha Amin1, Syed Hani Abidi2, Sufiyan Sufiyan1, Sahar Ilyas3, Sana Naeem3, Siraj Uddin1, Syed Ather Enam1,3, Nouman Mughal3,4
1Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan;
2Department of Biomedical Sciences, Nazarbayev School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan;
3Centre of Oncological Research in Surgery, Aga Khan University Hospital, Karachi, Pakistan;
4Department of Biological and Biomedical Sciences, Aga Khan University Hospital, Karachi, Pakistan
Correspondence to: Syed Ather Enam, MD, PhD, FRCSI, FRCSC, FRCSG, FACS. Professor of Neurosurgery, Director, Center of Oncological Research in Surgery, Scientific Director, Juma Research Laboratories, Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan; Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan. Email: ather.enam@aku.edu; Nouman Mughal, PhD. Assistant Professor, Department of Biological and Biomedical Sciences, Aga Khan University Hospital, Karachi, Pakistan; Center of Oncological Research in Surgery, Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan. Email: muhammad.nouman@aku.edu.
Background: Autophagy is a self-renewing process of the cell having a dual role in gliomagenesis depending on the tumor stage. Several microRNAs play a key role in the regulation of autophagy and the outcome of cancer. We investigated the potential relevance of autophagy in gliomagenesis and survival by exploring the association of the basal gene expression of autophagy-associated markers LC3, ULK1/2, UVRAG, Beclin1, mTOR, UVRAG, PI3K, AKT, PTEN and their target microRNAs miR-126, miR-374, miR-21, miR-7, miR-204 and miR-100 in low- and high-grades of gliomas.
Methods: A total of 50 fresh glioma tissues 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 polymerase chain reaction (qPCR). Mann-Whitney U-test was used to determine the statistical significance.
Results: In high-grade glioma, increased expression of AKT and miR-21, coupled with reduced ULK2 and LC3 expression was distinctly observed. While correlation analysis identified a strong positive correlation between ULK2 and UVRAG, PTEN, miR-7, and miR-100 and a moderate positive correlation emerged between ULK2 and mTOR, miR-7, miR-30, miR-100, miR-204, and miR-374, also between miR-21 and miR-126 in low-grade glioma. Similarly, a positive correlation appeared between ULK2 and AKT, LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7 and miR-374. AKT positively correlated with LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7, miR-30, miR-204, miR-374, miR-126 and miR-21 weakly correlated with AKT and miR-30 in high-grade glioma. The low ULK2, UVRAG, and miR-374 expression group exhibited significantly poor overall survival in glioma, while miR-21 over-expression indicated a poor prognosis in glioma patients.
Conclusions: This study provides comprehensive insights into the molecular landscape of gliomas, highlighting the dysregulation of autophagy genes ULK2, and UVRAG and the associated miR-21, miR-126 and miR-374 as potential prognostic biomarkers and emphasizing their unique significance in shaping survival outcomes in gliomas patients.
Keywords: Glioma; autophagy; miRNAs (miRs); prognostic markers; overall survival (OS)
