Document Type : Research Articles
Authors
1
Department of Bioscience, Manipal University Jaipur, University Jaipur, Dehmi Kalan, Jaipur-Ajmer Expressway, Jaipur, Rajasthan, 303007, India.
2
Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Bhopal, Saket Nagar, Bhopal 462 020, Madhya Pradesh, India.
Abstract
Background: Understanding the heterogeneous nature of breast cancer, including the role of LDHA expression regulation via non-coding RNAs in prognosis, is still unknown, highlighting the need for more research into its molecular roles and diagnostic approaches. Methods: The study utilized various computer tools to analyze the differences between LDHA in tissues and cancer cells. It used data from TIMER 2.0, UALCAN, and TISIDB to study gene expression and survival outcomes in breast cancer patients. The study also used the Breast Cancer Gene Expression Miner to examine the relationship between LDHA gene expression and breast cancer type. Other tools included TCGAPortal, TNMplot, ctcRbase, GSCA, Enrichr, TISIDB, Oncomx, and TANRIC. The study then explored the relationship between tumor-infiltrating immune cells and LDHA formation using the GSCA and TISIDB repositories. We used Auto Dock Tools 1.5.6 to perform ligand binding analysis for LDHA, withanolides, and the known inhibitor LDH-IN-1. LigPlot+ and Pymol were used for visualization of protein-ligand complexes. Results: LDHA overexpression in breast cancer cells, metastatic tissue, and circulating tumor cells leads to shortened recurrence-free survival, overall survival, and distant metastasis-free survival. In invasive breast cell carcinoma, we observed that LDHA/HIF-1α /TMPO-AS1 are overexpressed while miR-383-5p is downregulated. This overexpression is associated with poor prognosis and may lead to Act_DC infiltration into the tumor microenvironment. Withanolides, viz., Withaferine A and Withanolide D, have shown high binding affinity with LDHA, with binding energies of -9.3kcal/mol and -10kcal/mol respectively. These could be attractive choices for small-molecule inhibitor design against LDHA.
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