Department of Bioscience, Manipal University Jaipur, University Jaipur, Dehmi Kalan, Jaipur-Ajmer Expressway, Jaipur, Rajasthan, 303007, India.
Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Bhopal, Saket Nagar, Bhopal 462 020, Madhya Pradesh, India.
Asian Pac J Cancer Prev. 2024 Aug 1;25(8):2929-2944. doi: 10.31557/APJCP.2024.25.8.2929.
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.
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.
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.
了解乳腺癌的异质性，包括非编码 RNA 对 LDHA 表达调控在预后中的作用，目前仍不清楚，这凸显了需要进一步研究其分子作用和诊断方法。
本研究利用各种计算机工具分析组织和癌细胞中 LDHA 的差异。它使用了 TIMER 2.0、UALCAN 和 TISIDB 中的数据来研究乳腺癌患者的基因表达和生存结果。该研究还使用了 Breast Cancer Gene Expression Miner 来研究 LDHA 基因表达与乳腺癌类型之间的关系。其他工具包括 TCGAPortal、TNMplot、ctcRbase、GSCA、Enrichr、TISIDB、Oncomx 和 TANRIC。然后，该研究使用 GSCA 和 TISIDB 存储库探索了肿瘤浸润免疫细胞与 LDHA 形成之间的关系。我们使用 Auto Dock Tools 1.5.6 对 LDHA、醉茄内酯和已知抑制剂 LDH-IN-1 进行配体结合分析。使用 LigPlot+ 和 Pymol 对蛋白-配体复合物进行可视化。
乳腺癌细胞、转移性组织和循环肿瘤细胞中 LDHA 的过表达导致无复发生存、总生存和无远处转移生存时间缩短。在浸润性乳腺癌细胞癌中，我们观察到 LDHA/HIF-1α/TMPO-AS1 过表达，而 miR-383-5p 下调。这种过表达与预后不良相关，可能导致 Act_DC 浸润到肿瘤微环境中。醉茄内酯，即醉茄素 A 和醉茄素 D，与 LDHA 具有高结合亲和力，结合能分别为-9.3kcal/mol 和-10kcal/mol。它们可能是针对 LDHA 的小分子抑制剂设计的有吸引力的选择。
