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[摘要]
目的:探究含t-复合物1的伴侣蛋白(CCT)的8个亚基在甲状腺癌(TC)组织中的表达及其与TC分期、患者预后、免 疫细胞浸润、免疫检查点表达和化疗药物敏感性的相关性。方法:采用TCGA数据库数据分析CCT各亚基在TC组织和癌旁组 织中的表达;用TCGA数据库数据分析CCT各亚基表达与TC患者预后的关系;用GSEA法分析CCT各亚基的生物学功能;用 TCGA和TIMER2.0数据库数据分析CCT各亚基表达与肿瘤微环境、免疫细胞浸润、化疗药物敏感性、免疫检查点表达的相关性。 结果:数据库数据分析显示,在 TC 组织中 CCT3、CCT7 和 CCT8 mRNA 均呈高表达(P < 0.01 或 P < 0.001),而 CCT1、CCT2、 CCT5和CCT6B mRNA均呈低表达(P < 0.01 或 P < 0.001);CCT3、CCT6B、CCT8 mRNA的表达与T分期有关联(P < 0.05 或 P < 0.01)、CCT6B mRNA 的 表 达 与 淋 巴 结 转 移 有关联(P < 0.01),CCT5 mRNA 的 表 达 与 远 处 转 移 有关联(P < 0.05), CCT6B可能是TC患者OS的独立预后生物标志物;CCT各亚基mRNA表达主要富集于移植物排斥、补体和干扰素-γ等信号通 路;CCT各亚基mRNA低表达组TC组织的基质、免疫和综合评分均显著高于高表达组(P < 0.05或P < 0.01或P < 0.001);CCT各 亚基mRNA表达与TC的基质评分、免疫评分和综合评分均呈负相关(均P < 0.01);CCT各亚基mRNA的表达与CD8+ T细胞和巨 噬细胞浸润均呈正相关(均P < 0.05),多数CCT亚基(CCT6B和CCT7除外)的mRNA表达与中性粒细胞的浸润呈正相关(P < 0.05 或P < 0.01或P < 0.001),而CCT3、4、7、8 mRNA的表达与CD4+ T细胞浸润呈负相关(均P < 0.05);与低表达组比较,大多数CCT 亚基mRNA高表达的TC患者对索拉非尼、乐伐替尼、达拉非尼、曲美替尼、凡德他尼和卡博替尼等化疗药物的 IC50 均明显升高 (P < 0.05或P < 0.01或P < 0.001);TC组织中CCT各亚基mRNA的表达与PD-1、PD-L1、PD-L2、CTLA4、CD80 和 CD86 表达均 有明显关联(P < 0.05或P < 0.01或P < 0.001)。结论: CCT复合物可能通过影响肿瘤微环境促进TC的发生发展,进而影响患 者预后,其可成为难治性TC诊断和免疫治疗的潜在靶点。
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[Abstract]
Objective: To investigate the expression of eight subunits of chaperonin containing t-complex 1 (CCT) in thyroid cancer (TC) tissues and their correlation with TC staging, patient prognosis, immune cell infiltration, immune checkpoint expression, and chemotherapy drug sensitivity. Methods: Data from The Cancer Genome Atlas (TCGA) database were used to analyze the expression of each CCT subunit in TC tissues and para-cancerous tissues as well as their relationship with the prognosis of TC patients. The biological function of each CCT subunit was analyzed by the Gene Set Enrichment Analysis (GSEA). Data from the TCGA and TIMER2.0 databases were used to analyze the correlations between the expression of each CCT subunit and the tumor microenvironment, infiltration of immune cells, chemotherapeutic drug sensitivity, and immune checkpoint expression. Results: Database analysis showed high mRNA expression of CCT3, CCT7, and CCT8 and low mRNA expression of CCT1, CCT2, CCT5, and CCT6B in TC tissues (P < 0.01 or P < 0.001). CCT3, CCT6B, and CCT8 mRNA expression were correlated with T staging (P < 0.05 or P < 0.01); CCT6B mRNA expression was associated with lymph node metastasis (P < 0.01); CCT5 mRNA expression was associated with distant metastasis (P < 0.05); and CCT6B may serve as an independent prognostic biomarker for overall survival (OS) in TC patients. CCT subunit expression was primarily enriched in signaling pathways such as graft rejection, complement, and interferongamma.Low expression groups of CCT subunits demonstrated significantly higher TC stromal score, immune infiltration score and composite score than the high expression groups (P < 0.05 or P < 0.01 or P < 0.001), displaying a negative correlation between the expression of each CCT subunit and TC stromal, immune infiltration and composite scores (all P < 0.01). The mRNA expression of each CCT subunit was positively correlated with CD8+ T cell and macrophage infiltration (all P < 0.05), the mRNA expression of most CCT subunits (except CCT6B and CCT7) was positively correlated with neutrophil infiltration (P < 0.05 or P < 0.01 or P < 0.001), whereas the mRNA expression of CCT3, 4, 7, and 8 was negatively correlated with CD4+ T-cell infiltration (all P < 0.05). Compared to the low-expression group, patients with high mRNA expression of most CCT subunit had significantly higher IC50 for chemotherapeutic agents such as sorafenib, levatinib, darafenib, trametinib, vandetanib, and cabozantinib (all P < 0.05 or P < 0.01 or P < 0.001). CCT subunit expression in TC tissues was significantly correlated with the expression of PD-1, PD-L1, PD-L2, CTLA4, CD80, and CD86 (P < 0.05 or P < 0.01 or P < 0.001). Conclusion: CCT complexes may promote TC development by affecting the tumor microenvironment thus impacting patient prognosis, potentially serving as a target for the diagnosis and immunotherapy of refractory TC.
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