Varshney Nidhi, Singh Siddharth, Kandpal Meenakshi, Saini Vaishali, Roberston Erle S, Jha Hem Chandra
Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, MP, India.
Department of Microbiology and the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
BMC Cancer. 2025 Jan 24;25(1):143. doi: 10.1186/s12885-024-13260-z.
Epstein-Barr virus (EBV), an oncogenic gamma-herpesvirus, belongs to group 1 carcinogen and is implicated in various cancers, including gastric cancer. Aurora Kinase A is a major mitotic protein kinase that regulates mitotic progression; overexpression and hyperactivation of AURKA commonly promote genomic instability in many tumours. However, the relationship of functional residues of AURKA and EBV in gastric cancer progression remains unknown. We reveal that AURKA overexpression and EBV infection induce aneuploidy in gastric epithelial cells. The AURKA (S89) N-terminal residue is critical for the centrosome maturation process in EBV-infected gastric epithelial cells. The kinase domain residues T287 and T288 of AURKA are essential for centrosome maturation and bipolar spindle formation in EBV-infected gastric cancer cells. We also show that AURKA 287/288 dm reduces the transcript expression of cell cycle markers involved in mitotic entry in EBV infection. This mutant also enhanced the protein expression of p53 and Rb, which was reduced in EBV infection and decreased the Survivin expression. Further, EBNA1, the latent gene of EBV, stabilises the AURKA in its wild-type form and S89A mutant but unable to stabilise in T287/288A double mutant. These mutants also induce mitotic catastrophe by regulating the apoptosis and autophagy pathway in EBV infection. AURKA287/288 dm also promotes autophagosome formation even in EBV infection. Thus, this study demonstrates that the AURKA kinase domain is essential for its functioning and progression of the oncogenesis of EBV-infected gastric epithelial cells.
爱泼斯坦-巴尔病毒（EBV）是一种致癌性γ疱疹病毒，属于1类致癌物，与包括胃癌在内的多种癌症有关。极光激酶A是一种主要的有丝分裂蛋白激酶，可调节有丝分裂进程；AURKA的过表达和过度激活通常会促进许多肿瘤中的基因组不稳定。然而，AURKA功能残基与EBV在胃癌进展中的关系尚不清楚。我们发现AURKA过表达和EBV感染会诱导胃上皮细胞出现非整倍体。AURKA（S89）N端残基对于EBV感染的胃上皮细胞中的中心体成熟过程至关重要。AURKA的激酶结构域残基T287和T288对于EBV感染的胃癌细胞中的中心体成熟和双极纺锤体形成至关重要。我们还表明，AURKA 287/288缺失突变体降低了EBV感染中参与有丝分裂进入的细胞周期标志物的转录表达。该突变体还增强了p53和Rb的蛋白表达，这在EBV感染中降低，并降低了生存素的表达。此外，EBV的潜伏基因EBNA1以其野生型形式和S89A突变体稳定AURKA，但不能在T287/288A双突变体中稳定。这些突变体还通过调节EBV感染中的凋亡和自噬途径诱导有丝分裂灾难。即使在EBV感染中，AURKA287/288缺失突变体也促进自噬体形成。因此，本研究表明AURKA激酶结构域对于其功能以及EBV感染的胃上皮细胞肿瘤发生的进展至关重要。
