Elevated expression of ANAPC1 in lung squamous cell carcinoma: clinical implications and mechanisms

To investigate the comprehensive expression levels and possible molecular mechanisms of Anaphase Promoting Complex Subunit 1 (ANAPC1) in lung squamous cell carcinoma (LUSC). Data from 2,031 samples were combined to evaluate ANAPC1 mRNA levels, and 118 samples were collected for immunohistochemical (IHC) analysis. High-expression co-expressed genes (HECEGs) associated with ANAPC1 were analyzed for signaling pathways. Clinical significance, immune computations, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) validation of ANAPC1’s role in LUSC were assessed. Molecular docking evaluated binding affinity with potential therapeutics. ANAPC1 mRNA was significantly upregulated in LUSC (SMD = 1.97, 95% CI [1.26–2.67]). Protein-level analysis confirmed this upregulation (<i>p</i> &lt; 0.001). Most HECEGs associated with ANAPC1 were enriched in cell cycle pathways. Higher ANAPC1 expression correlated with poorer survival in LUSC patients (HR = 1.11, 95% CI: 1–1.49). ANAPC1 expression was higher in males and N1-stage vs. females and N0-stage; lower in grade I vs. II/III. Overexpression reduces immune cell infiltration and immunotherapy effectiveness, while knockdown inhibits cell proliferation. Drug sensitivity and docking analyses identified tenovin-1, carboxyatractyloside, and phycocyanobilin as potential antitumor agents targeting ANAPC1. The elevated expression of ANAPC1 might play a role in LUSC advancement and progression through its participation in cell growth-related pathways. This study looks at over 2000 samples and shows that a protein called ANAPC1 is found in higher amounts in lung squamous cell carcinoma (LUSC). The study finds that higher levels of ANAPC1 are associated with poorer survival outcomes and are more commonly observed in males and at later stages of the disease. Lower levels of ANAPC1 might help patients respond better to immunotherapy. The study also shows that removing ANAPC1 slows down cancer cell growth and identifies possible compounds that could target ANAPC1, offering hope for new therapies for LUSC. The High expression of ANAPC1 in lung squamous cell carcinoma (LUSC) has been demonstrated at both the mRNA and protein levels.Most of the highly expressed co-expressed genes (HECEGs) of ANAPC1 are enriched in pathways related to cell growth.Elevated ANAPC1 levels in LUSC are significantly associated with reduced immune cell infiltration.In LUSC patients, higher ANAPC1 expression is associated with poorer prognosis.ANAPC1 expression levels are higher in male patients, those at N1 stage, and those with Pathology grade I, compared to female patients, those at N0 stage, and those with Pathology grades II/III, respectively.Based on in silico analyses, knockdown of ANAPC1 may inhibit the proliferation of LUSC cells. The High expression of ANAPC1 in lung squamous cell carcinoma (LUSC) has been demonstrated at both the mRNA and protein levels. Most of the highly expressed co-expressed genes (HECEGs) of ANAPC1 are enriched in pathways related to cell growth. Elevated ANAPC1 levels in LUSC are significantly associated with reduced immune cell infiltration. In LUSC patients, higher ANAPC1 expression is associated with poorer prognosis. ANAPC1 expression levels are higher in male patients, those at N1 stage, and those with Pathology grade I, compared to female patients, those at N0 stage, and those with Pathology grades II/III, respectively. Based on in silico analyses, knockdown of ANAPC1 may inhibit the proliferation of LUSC cells.

本研究旨在全面探讨后期促进复合物亚基1（Anaphase Promoting Complex Subunit 1, ANAPC1）在肺鳞状细胞癌（Lung Squamous Cell Carcinoma, LUSC）中的表达水平及其潜在分子机制。本研究整合2031例样本的数据以评估ANAPC1的mRNA表达水平，并收集118例样本开展免疫组织化学（Immunohistochemical, IHC）分析。针对与ANAPC1相关的高表达共表达基因（High-expression Co-expressed Genes, HECEGs）进行信号通路富集分析。同时评估ANAPC1在LUSC中的临床意义、免疫浸润分析以及规律成簇间隔短回文重复序列（Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR）验证实验，并通过分子对接技术评估其与潜在治疗药物的结合亲和力。
结果显示，ANAPC1的mRNA在LUSC中显著上调（标准化均数差SMD=1.97，95%置信区间CI：1.26~2.67），蛋白水平分析同样证实了该上调趋势（p<0.001）。大部分与ANAPC1相关的HECEGs富集于细胞周期相关通路。ANAPC1高表达与LUSC患者较差的生存预后显著相关（风险比HR=1.11，95%置信区间CI：1~1.49）。ANAPC1在男性患者、N1期患者中的表达水平显著高于女性患者及N0期患者；在病理I级患者中的表达水平低于II/III级患者。ANAPC1过表达会降低免疫细胞浸润程度及免疫治疗应答效果，而敲低ANAPC1则可抑制肿瘤细胞增殖。药物敏感性及分子对接分析筛选出替诺芬-1（tenovin-1）、羧基苍术苷（carboxyatractyloside）和藻蓝胆素（phycocyanobilin）作为潜在的ANAPC1靶向抗肿瘤药物。
ANAPC1高表达可能通过参与细胞生长相关通路，参与LUSC的发生与疾病进展。本研究纳入超过2000例样本，证实ANAPC1在LUSC组织中呈现高表达状态。研究发现ANAPC1高表达与较差的生存预后相关，且在男性患者及疾病晚期患者中更为常见。ANAPC1低表达的患者可能对免疫治疗具有更好的应答效果。本研究同时证实，敲除ANAPC1可延缓肿瘤细胞增殖，并筛选出潜在的ANAPC1靶向化合物，为LUSC的新型治疗方案提供了研究方向。
本研究已在mRNA及蛋白水平均证实ANAPC1在LUSC中呈现高表达。大部分与ANAPC1相关的HECEGs富集于细胞生长相关通路。ANAPC1在LUSC中的高表达水平与免疫细胞浸润减少显著相关。在LUSC患者中，ANAPC1高表达与较差的预后显著相关。相较于女性患者、N0期患者及病理II/III级患者，ANAPC1在男性患者、N1期患者及病理I级患者中的表达水平更高。基于计算机模拟分析，敲低ANAPC1可抑制LUSC细胞的增殖。