TRIM5与恶性肿瘤不良预后相关性及其在胰腺癌恶性表型中的作用研究

doi:10.3969/j.issn.1009-976X.2024.05.001

摘要/Abstract

摘要： 目的分析三结构域蛋白家族5（TRIM5）在泛癌中的表达水平及其与预后、临床分期和免疫微环境的关系。方法从TCGA、TARGET 及GTEx数据库获取TRIM5泛癌基因表达谱、体细胞突变数据和临床相关信息。利用R软件包分析TRIM5与肿瘤患者预后、临床病理特征、基因组异质性的关系。通过ESTIMATE和EPIC算法分析TRIM5在泛癌中与免疫细胞浸润、免疫调节基因的关系。进一步对TRIM5相关基因进行GO和KEGG富集分析,并利用体外实验验证TRIM5对胰腺癌增殖和迁移能力的影响。结果 TRIM5在胶质瘤、脑低级别胶质瘤、胰腺癌等多种肿瘤组织中表达上调。TRIM5的异常表达与多种癌症的不良预后有关,如胶质瘤、脑低级别胶质瘤、胰腺癌等。TRIM5促进胶质瘤、脑低级别胶质瘤、胰腺癌恶性进展。TRIM5表达与肿瘤中微卫星不稳定性、同源重组缺陷、肿瘤新抗原和肿瘤突变负荷相关。TRIM5的表达与泛癌中多种免疫细胞浸润呈正相关,如T细胞、巨噬细胞和癌症相关成纤维细胞等。TRIM5与泛癌中免疫调节基因显著相关,其中与免疫检查点基因大多数呈正相关,如PDCD1、CTLA4。基因富集结果显示TRIM5与细胞黏附,癌症相关信号等信号通路密切相关。体外实验结果显示敲低TRIM5基因可显著降低PANC-1细胞增殖、迁移能力。结论 TRIM5在多种肿瘤组织中异常表达,其表达与患者预后、临床病理特征、肿瘤免疫浸润、基因组异质性等密切相关,上述结果提示TRIM5可能是一个新的、有前景的肿瘤治疗靶点和预后生物标志物。

关键词: TRIM5, 预后, 免疫微环境, 胰腺癌

Abstract: Objective To evaluate the expression level of TRIM5 in pan-cancer and its relationship with prognosis, clinical stage, and immune micro-environment. Methods TRIM5 pan-oncogene expression profile, somatic mutation data, and clinically relevant information were obtained from TCGA, TARGET, and GTEx databases. Use R software package to analyze the relationship between TRIM5 and the prognosis, clinical pathological characteristics, and genomic heterogeneity of cancer patients. The relationship between TRIM5 and immune cell infiltration and immune regulatory genes in pan-cancer was analyzed by ESTIMATE and EPIC algorithms. The GO and KEGG enrichment analysis of TRIM5 related genes was further carried out, and the effect of TRIM5 on the proliferation and migration of pancreatic cancer was verified through in vitro experiments. Results TRIM5 was up-regulated in glioma, low-grade glioma, pancreatic cancer and other tumor tissues. The abnormal expression of TRIM5 was associated with poor prognosis in gliomas, low-grade brain gliomas, and pancreatic cancer, etc. TRIM5 promotes malignant progression of glioma, low-grade glioma of brain and pancreatic cancer. TRIM5 expression was associated with microsatellite instability, homologous recombination defects, tumor neoantigens, and tumor mutation burden. The expression of TRIM5 was positively correlated with the infiltration of various immune cells in pan cancer, such as T cells, macrophages, and cancer-related fibroblasts. TRIM5 was significantly correlated with immune regulatory genes in pan cancer, with most of them positively correlated with immune checkpoint genes such as PDCD1 and CTLA4. Gene enrichment results show that TRIM5 was closely related to signaling pathways such as cell adhesion and cancer-related signals. The in vitro experimental results showed that knocking down the TRIM5 gene significantly reduced the proliferation and migration ability of PANC-1 cells. Conclusion TRIM5 is abnormally expressed in various tumor tissues, and its expression is closely related to patient prognosis, clinical pathological characteristics, tumor immune infiltration, immune regulatory genes, genomic heterogeneity, etc. These results suggest that TRIM5 may be a new and promising tumor treatment target and prognostic biomarker.

Key words: TRIM5, prognosis, immune micro-environment, pancreatic cancer

中图分类号:

李伟凡, 黄松音. TRIM5与恶性肿瘤不良预后相关性及其在胰腺癌恶性表型中的作用研究[J]. 岭南现代临床外科, 2024, 24(05): 263-275.

LI Wei-fan, HUANG Song-yin. Pan-cancer analysis of tripartite motif 5 and its validation in promoting malignant phenotypes of pancreatic cancer[J]. Lingnan Modern Clinics In Surgery, 2024, 24(05): 263-275.

参考文献

[1] Bray F, Laversanne M, Sung H, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2] Gonçalves-Carneiro D, Takata MA, Ong H, et al.Origin and evolution of the zinc finger antiviral protein[J]. PLoS Pathog, 2021, 17(4): e1009545.
[3] Yaparla A, Reeves P, Grayfer L.Myelopoiesis of the Amphibian Xenopus laevis Is Segregated to the Bone Marrow, Away From Their Hematopoietic Peripheral Liver[J]. Front Immunol, 2019, 10: 3015.
[4] Zhan W, Zhang S.TRIM proteins in lung cancer: Mechanisms, biomarkers and therapeutic targets[J]. Life Sci, 2021, 268: 118985.
[5] Zhao G, Liu C, Wen X, et al.The translational values of TRIM family in pan-cancers: From functions and mechanisms to clinics[J]. Pharmacol Ther, 2021, 227: 107881.
[6] Hatakeyama S.TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis[J]. Trends Biochem Sci, 2017, 42(4): 297-311.
[7] Kawai T, Akira S.Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins[J]. EMBO Mol Med, 2011, 3(9): 513-527.
[8] Zhou Z, Ji Z, Wang Y, et al.TRIM59 is up-regulated in gastric tumors, promoting ubiquitination and degradation of p53[J]. Gastroenterology, 2014, 147(5): 1043-1054.
[9] An X, Ji B, Sun D.TRIM34 localizes to the mitochondria and mediates apoptosis through the mitochondrial pathway in HEK293T cells[J]. Heliyon, 2020, 6(1): e03115.
[10] Chiramel AI, Meyerson NR, McNally KL, et al. TRIM5α Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation[J]. Cell Rep, 2019, 27(11): 3269-3283.e3266.
[11] Mandell MA, Jain A, Arko-Mensah J, et al.TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition[J]. Dev Cell, 2014, 30(4): 394-409.
[12] 陈悦,李琴,张洁,等. TRIM5高表达与胶质瘤患者不良预后和免疫浸润的相关性研究[J]. 生物医学工程学杂志, 2020, 37(3): 469-479.
[13] Liu H, Tang Y, Zhang J, et al.TRIM5 as a promising diagnostic biomarker of hepatocellular carcinoma: integrated analysis and experimental validation[J]. Funct Integr Genomics, 2024, 24(2): 63.
[14] Tymon-Rosario JR, Manara P, Manavella DD, et al.Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a poly (adenosine diphosphate[ADP]- ribose) polymerase (PARP) inhibitor[J]. Gynecol Oncol, 2022, 166(1): 117-125.
[15] de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth[J]. Cancer Cell, 2023, 41(3): 374-403.
[16] Cords L, Engler S, Haberecker M, et al. Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer[J]. Cancer Cell, 2024, 42(3): 396-412. e395.
[17] Luo H, Xia X, Huang LB, et al.Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment[J]. Nat Commun, 2022, 13(1): 6619.
[18] Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts[J]. Nat Rev Clin Oncol, 2021, 18(12): 792-804.
[19] 李旭, 黄尚科, 王玉珍, 等. 乳腺癌组织肿瘤相关巨噬细胞与肿瘤浸润转移的临床及病理关系[J]. 中华临床医师杂志(电子版), 2017, 11(18): 2217-2222.
[20] Wang J, Li S, Lan Y, et al.Glioma-associated macrophages: unraveling their dual role in the microenvironment and therapeutic implications[J]. Current Medicine, 2024, 3(1): 4.
[21] 戈文珂,吴卫兵. 肿瘤微环境中肿瘤相关巨噬细胞极化的影响因素及其意义[J]. 中国肺癌杂志, 2023, 26(3): 228-237.
[22] Shao Y, Han S, Hou Z, et al.Tumor-associated macrophages within the immunological milieu: An emerging focal point for therapeutic intervention[J]. Heliyon, 2024, 10(17): e36839.
[23] Goenka A, Khan F, Verma B, et al.Tumor microenvironment signaling and therapeutics in cancer progression[J]. Cancer Commun (Lond), 2023, 43(5): 525-561.
[24] Korman AJ, Garrett-Thomson SC, Lonberg N.The foundations of immune checkpoint blockade and the ipilimumab approval decennial[J]. Nat Rev Drug Discov, 2022, 21(7): 509-528.

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