结肠癌；免疫抑制；UBQLN2；TGF-β," /> 结肠癌；免疫抑制；UBQLN2；TGF-β,"/> Colon cancer,Immunosuppression,UBQLN2,TGF?-β,"/> <em>UBQLN2</em>基因在结肠癌中的表达及其免疫调控作用

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中国癌症防治杂志

中国癌症防治杂志 ›› 2024, Vol. 16 ›› Issue (1): 76-83.doi: 10.3969/j.issn.1674-5671.2024.01.12

• 临床研究 • 上一篇    下一篇

UBQLN2基因在结肠癌中的表达及其免疫调控作用

  

  1. 河北北方学院附属第一医院普通外科；中山大学附属第一医院肝胆外科
  • 出版日期:2024-02-25 发布日期:2024-02-27
  • 通讯作者: 薛军 E-mail：yfyxuejun@163.com
  • 基金资助:
    张家口市2021年市级科技计划项目（2121072D）；国家自然科学基金青年基金项目（82203676）

 Expression of UBQLN2 gene in colon cancer and its immunoregulatory role  

  • Online:2024-02-25 Published:2024-02-27

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摘要： 目的 探讨UBQLN2基因在结肠癌中的表达及其免疫调控功能。方法 收集2021年1月至2023年6月在河北北方学院附属第一医院手术切除的结肠癌及匹配的癌旁组织。采用转录组测序检测UBQLN2表达，qRT⁃PCR检测UBQLN2 mRNA表达水平，免疫组织化学检测UBQLN2蛋白表达水平。分析UBQLN2表达与结肠癌患者临床病理特征及预后的关系。采用多色免疫荧光检测UBQLN2与TGF⁃β的共表达情况，利用单细胞转录组测序和TCGA数据库验证UBQLN2在结肠癌中的表达情况及其与免疫抑制因子、TGF⁃β和结肠癌预后的关系。结果 转录组分析显示，结肠癌组织中UBQLN2基因高表达，其mRNA表达水平高于癌旁组织（P<0.01）。通过TCGA数据库纳入275例结肠癌组织及41例癌旁组织，结肠癌组织中的UBQLN2 mRNA相对表达量也高于癌旁组织 (P<0.001)。免疫组织化学结果显示，UBQLN2蛋白主要在细胞质中表达，且结肠癌组织中UBQLN2蛋白阳性表达强度明显高于癌旁组织。qRT⁃PCR检测结果显示，结肠癌组织中UBQLN2 mRNA表达显著高于癌旁组织(P<0.001)。通路富集分析显示，UBQLN2高表达组肿瘤增殖通路显著上调，免疫激活通路显著下调；而且与UBQLN2低表达组相比，UBQLN2高表达组免疫逃逸评分更高（P<0.05），CD8+T细胞特异性标志物、免疫趋化因子及免疫杀伤因子表达更低（均P<0.05），而免疫耗竭分子表达更高（均P<0.05）。在UBQLN2高表达组中TGF⁃β、IL10和ARG1等免疫抑制细胞因子的表达高于UBQLN2低表达组（均P<0.05），且UBQLN2与TGF⁃β表达呈正相关（r=0.280，P<0.0001），UBQLN2与TGF⁃β在肿瘤中共表达。TGF⁃β和UBQLN2均高表达组较两者均低表达组患者的预后更差（P=0.004）。单细胞转录组测序显示UBQLN2高表达的结肠癌高表达TGF⁃β且微环境呈免疫抑制状态。结论 UBQLN2在结肠癌中高表达且与预后较差相关，UBQLN2高表达的结肠癌可能通过释放TGF⁃β细胞因子抑制CD8+T细胞的杀伤活性，从而实现免疫逃逸。UBQLN2可能是结肠癌的潜在治疗靶点。

关键词: 结肠癌；免疫抑制；UBQLN2；TGF-β')">">结肠癌；免疫抑制；UBQLN2；TGF-β

Abstract:  Objective To investigate the expression of UBQLN2 gene in colon cancer and its immunoregulatory function. Methods Colon cancer and their matched paracancer tissues surgically removed in the First Affiliated Hospital of Hebei North University from January 2021 to June 2023 were collected. The expression of UBQLN2 was detected by transcriptome sequencing, the expression level of UBQLN2 mRNA was detected by qRT⁃PCR, and the expression of UBQLN2 protein was detected by immunohistochemical. The relationship between the expression of UBQLN2 and the clinical pathological characteristics and prognosis of colon cancer patients was analyzed. Multicolor immunofluorescence was used to detect the co⁃expression of UBQLN2 and TGF⁃β. Single⁃cell transcriptome sequencing and TCGA database were used to verify the expression of UBQLN2 in colon cancer and its relationship with immunosuppressive factors, TGF⁃β and prognosis of colon cancer. Results Transcriptome analysis showed that UBQLN2 gene was significantly overexpressed in colon cancer tissues, and its mRNA expression level was higher than that in cancer⁃adjacent tissues (P<0.01). The relative expressions of UBQLN2 mRNA in 275 colon cancer tissues and 41 paracancer tissues which collected from TCGA database were also significantly higher in colon cancer tissues than that in cancer⁃adjacent tissues (P<0.001). Immunohistochemical results showed that UBQLN2 was mainly expressed in the cytoplasm, and the positive expression intensity of UBQLN2 protein in colon cancer tissues was obviously higher than that in  cancer⁃adjacent tissues. The results of qRT⁃PCR showed that UBQLN2 mRNA expression in colon cancer tissues was significantly higher than that in cancer⁃adjacent tissues (P<0.001). Pathway enrichment analysis showed that the tumor proliferation pathway was significantly up⁃regulated, and the immune activation pathway was significantly down⁃regulated in the UBQLN2 high expression group. Moreover, compared with UBQLN2 low expression group, UBQLN2 high expression group had higher immune escape score (P<0.05), lower expression of CD8+ T cell specific markers, smaller immune recruitment factors and immune killer factors (all P<0.05), and higher expression of immune depletion molecules (all P<0.05). The expressions of TGF⁃β, IL10, ARG1 and other immunosuppressive cytokines in UBQLN2 high expression group were higher than those in UBQLN2 low expression group (all P<0.05), and UBQLN2 was positively correlated with TGF⁃β expression (r=0.280, P<0.0001); UBQLN2 and TGF⁃β were co⁃expressed in tumors. Patients with both high expression of TGF⁃β and UBQLN2 had worse prognosis than those with both low expression (P=0.004). Single⁃cell transcriptome sequencing showed that colon cancer with high expression of UBQLN2 was highly expressed TGF⁃β and the microenvironment was immunosuppressed. Conclusions UBQLN2 is highly expressed in colon cancer and associated with poor prognosis. Colon cancer with high expression of UBQLN2 may inhibit the killing activity of CD8+T cells by releasing TGF⁃β cytokines and realizing immune escape. UBQLN2 may be a potential molecular target for the treatment of colon cancer.

Key words: Colon cancer')">Colon cancer, Immunosuppression, UBQLN2, TGF?-β

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  • 引用本文

    孙光源, 王晓元, 向骁, 任艳丽, 尹洁, 胡智洁, 武雪亮, 薛军. UBQLN2基因在结肠癌中的表达及其免疫调控作用[J]. 中国癌症防治杂志, 2024, 16(1): 76-83.

    SUN Guangyuan, WANG Xiaoyuan, XIANG Xiao, REN Yanli, YIN Jie, HU Zhijie, WU Xueliang, XUE Jun .  Expression of UBQLN2 gene in colon cancer and its immunoregulatory role  [J]. Chinese Journal of Oncology Prevention and Treatment, 2024, 16(1): 76-83.