Department of Endoscope, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China.
Department of Gastroenterology, Aviation General Hospital, Chaoyang District, Beijing 100012, China.
Int J Biol Macromol. 2024 Nov;279(Pt 3):135394. doi: 10.1016/j.ijbiomac.2024.135394. Epub 2024 Sep 6.
The onset and progression of colorectal cancer is intricately linked to a multitude of factors. Among these, immune cells present within the tumor microenvironment play a pivotal role, particularly natural killer (NK) cells, which are essential for mediating anti-tumor immunity. This study aims to elucidate the mechanism by which the VWA2 protein facilitates the invasion and migration of colorectal cancer cells through the inhibition of NK cell activation. Understanding this molecular mechanism is crucial for deciphering the underlying processes involved in colorectal cancer. To achieve the study's objectives, various methodologies were employed, including cell culture techniques, transgenic technology, and assessments of NK cell functionality. The "limma" bioinformatics tool was utilised to identify differentially expressed genes (DEGs) between samples of colon cancer or polyps and normal tissue through transcriptome sequencing. Subsequent Wien analysis was conducted to pinpoint overlapping genes of interest. The impact of VWA2 on both the invasion and migration of colorectal cancer cell lines was assessed through experiments designed for the overexpression and knockout of VWA2.In addition, flow cytometry was employed to evaluate the activation status of NK cells, enabling an analysis of how VWA2 modulates relevant signaling pathways. The findings revealed that overexpression of VWA2 led to a marked inhibition of NK cell activation, which corresponded with reduced cytotoxic activity against tumor cells. Further examination indicated that VWA2 significantly amplified the migration and invasion capabilities of colorectal cancer cells by upregulating immunosuppressive factors while simultaneously downregulating pro-inflammatory factors. Conversely, the reduction of VWA2 expression was shown to markedly enhance NK cell functionality and decrease the invasive potential of colorectal cancer cells. Thus, the evidence suggests that the VWA2 protein actively promotes the migration and invasion of colorectal cancer cells primarily by suppressing NK cell activation, highlighting its potential role as a significant contributor to tumor progression in colorectal cancer.
结直肠癌的发生和发展与众多因素密切相关。在这些因素中，肿瘤微环境中的免疫细胞起着关键作用，尤其是自然杀伤 (NK) 细胞，它们对于介导抗肿瘤免疫至关重要。本研究旨在阐明 VWA2 蛋白通过抑制 NK 细胞激活促进结直肠癌细胞侵袭和迁移的机制。了解这种分子机制对于解析结直肠癌中涉及的潜在过程至关重要。为了实现研究目标，采用了多种方法，包括细胞培养技术、转基因技术和 NK 细胞功能评估。利用“limma”生物信息学工具，通过转录组测序，在结肠癌或息肉和正常组织的样本之间鉴定差异表达基因 (DEGs)。随后进行 Wien 分析，以确定感兴趣的重叠基因。通过设计用于 VWA2 过表达和敲除的实验，评估 VWA2 对结直肠癌细胞系侵袭和迁移的影响。此外，通过流式细胞术评估 NK 细胞的激活状态，分析 VWA2 如何调节相关信号通路。研究结果表明，VWA2 的过表达导致 NK 细胞激活明显抑制，这与对肿瘤细胞的细胞毒性活性降低相对应。进一步的研究表明，VWA2 通过上调免疫抑制因子和下调促炎因子，显著增强结直肠癌细胞的迁移和侵袭能力。相反，降低 VWA2 表达可显著增强 NK 细胞功能，并降低结直肠癌细胞的侵袭潜力。因此，有证据表明，VWA2 蛋白通过抑制 NK 细胞激活，积极促进结直肠癌细胞的迁移和侵袭，突出了其作为结直肠癌肿瘤进展的重要贡献者的潜在作用。
