TRIM家族蛋白在肿瘤中的研究进展

近年来，三结构域(tripartite motif，TRIM)家族蛋白逐渐成为国内外肿瘤研究领域的热门研究方向。该家族蛋白可调控肿瘤细胞的增殖、转移、凋亡和自噬等多种生物学行为，介导泛素化、染色体异位和转录、p53信号通路和NF-κB信号通路等分子调控机制。本文对TRIM家族蛋白在肿瘤发生发展过程中发挥的功能和参与的分子调控机制进行总结，并对TRIM家族蛋白的研究前景进行展望。     

TRIM44蛋白表达与胃癌预后关系的研究

目的 探讨TRIM44蛋白在胃癌组织中的表达情况以及其对胃癌发生、发展的影响.方法 入组60例确诊并接受根治术的胃癌患者,用免疫组化方法检测60例胃癌组织中TRIM44蛋白的表达情况.结果 TRIM44蛋白在胃癌组织中高表达,表达率为28.3%(17/60),且其表达与2~3个区域淋巴结侵犯、高复发率密切有关(P<0.05);TRIM44蛋白高表达组的预后较低表达组差(P<0.05).结论 TRIM44蛋白在胃癌组织中高表达与肿瘤的淋巴侵犯以及高复发率有关,且TRIM44蛋白高表达的胃癌患者总生存更差.     

TRIM家族蛋白在胰腺癌发生发展中的作用研究进展

胰腺癌是一种具有高度侵袭性且预后极差的消化系统恶性肿瘤，其发病的分子机制及更为有效的治疗手段一直是研 究的热点。三结构域（TRIM）蛋白是具有高度保守的RBCC三段结构域的蛋白家族，其中RING-finger结构域赋予了TRIM蛋白 E3泛素连接酶活性，使其能够介导癌基因和肿瘤抑制因子的泛素化降解，从而在胰腺癌的发生发展中发挥重要作用。TRIM家 族蛋白涉及诸多信号通路，同一个TRIM蛋白分子可能直接或间接参与多个信号通路。单独靶向TRIM家族蛋白（如TRIM2、 TRIM14、TRIM15、TRIM21、TRIM29、TRIM47、TRIM59等），以及靶向TRIM11、TRIM31和TRIM37等与吉西他滨等化疗药物联 合应用有望成为治疗胰腺癌的重要方法和新的策略。TRIM家族蛋白在胰腺癌组织中高表达且与预后密切相关，可能作为早期 诊断和预测胰腺癌预后的生物标志物。研究TRIM家族蛋白在胰腺癌发生发展过程中的分子机制及其作用，有助于为胰腺癌患 者的诊断和治疗提供新思路。     

泛素结合酶10与肿瘤发生发展关系的研究进展

泛素结合酶10(UBCH10)又称泛素偶联酶E2C(UBE2C),是泛素结合酶E2家族的成员,其通过泛素-蛋白酶体途径(UPP)特异性催化细胞周期蛋白A(cyclin A)和细胞周期蛋白B(cyclin B)的泛素化和降解,并与多聚环泛素连接酶E3(APC)共同参与调控纺锤体组装检查点(SAC),是一种重要的细胞周期蛋白。同时,UBCH10具有肿瘤基因的性质,高表达于多种恶性肿瘤,参与其发生与发展。UBCH10所具有的肿瘤基因的性质不仅为肿瘤患者的预后评估提供了新的预测因子,同时也为肿瘤的诊疗提供了潜在的靶点。本文就2010年来UBCH10在肿瘤中的研究进展作一简要综述。     

TRIM59在恶性肿瘤中的研究进展

摘 要：TRIM59（tripartite motif-containing 59）是一个新型的TRIM(tripartite motif)家族成员,与多种肿瘤有关。研究显示TRIM59作为癌基因,在肺癌、胃癌、肝癌、结直肠癌等肿瘤中表达上调;而且,TRIM59可通过多种途径促进肿瘤细胞的增殖和迁移。TRIM59有望成为肿瘤诊断和治疗的新靶点。     

UbcH10与肿瘤关系研究进展

泛素-蛋白酶体系统（UPS）是蛋白质选择性降解的最重要机制之一。蛋白质的泛素化是一个非常复杂而缜密的级联酶促反应过程,参与调节细胞内多种蛋白的表达水平和功能活性。泛素-蛋白酶体系统的异常与恶性肿瘤的发生和进展有着密切的关系。泛素偶联酶UbcH10属于泛素偶联酶E2家族,其与特定的E3酶相互作用引起底物蛋白的降解,是一种参与细胞有丝分裂调控的细胞周期蛋白。UbcH10可激活Cdc20/APC,与细胞周期进展、细胞分裂、染色体分离密切相关。UbcH10表达异常可导致细胞的染色体不稳定,细胞分裂异常。目前已有研究证明UbcH10是一种具有癌基因性质的泛素偶联酶。UbcH10在乳腺癌、结肠癌、胃癌、卵巢癌、肝癌、脑胶质瘤、淋巴瘤等多种肿瘤中高表达并且与肿瘤分期呈正相关,提示不良预后,可能成为新的肿瘤标志物或治疗靶点。本文就近年来关于UbcH10在肿瘤中作用的研究进展加以综述。      

泛素连接酶Pirh2在肿瘤中的研究进展

泛素连接酶Pirh2是体内E3泛素连接酶的一种,可通过泛素一蛋白酶体途径介导p53降解,抑制p53的生物学功能。近来研究表明Pirh2在人体多种肿瘤细胞中呈过度表达,提示其可能参与肿瘤发生和发展过程,将来可能作为肿瘤基因治疗的一个潜在靶点。     

Skp2 的研究进展

  细胞内泛素-蛋白酶体途径通过对泛素化蛋白进行降解，在细胞周期发展、基因转录及信号转导等过程中发挥重要作用。此途径主要包括两步，即蛋白的泛素化，由泛素激活酶(E1)，泛素结合酶(E2)及泛素连接酶(E3)等共同完成；经泛素化的蛋白随后被26S蛋白酶体复合物降解。E3家族成员SCFSkp2泛素连接酶由Skp2与Skp1，Cul1／cdc53及Rbxl结合形成。Skp2属F-盒蛋白家族成员,在泛素化过程中负责对底物蛋白的识别而决定SCF^Skp2复合物作用的特异性。Skp2 通过对多种靶蛋白的泛素化降解而与细胞周期调控及肿瘤的发生、发展和预后密切相关。     

精氨酸甲基转移酶5 在肿瘤发生发展中作用的研究进展

[摘要] 蛋白精氨酸甲基化过程与蛋白的磷酸化、泛素化过程类似,是细胞中常见的翻译后修饰过程。精氨酸甲基转移酶(protein arginine methyltransferase, PRMT)是催化蛋白精氨酸残基氮原子发生甲基化的关键酶。PRMT5 能够催化产生对称性二甲基化精氨酸(symmetrically dimethylated arginine,sDMA),参与调解生命活动。近年来,越来越多的研究表明,PRMT5 与肿瘤的发生发展及肿瘤转移密切相关,并将其作为新靶点进行抗肿瘤药物研究。本文旨在阐述PRMT5 与肿瘤发生发展的相关性和以PRMT5 为靶点的抗肿瘤药物开发及未来的研究发展方向。     

去泛素化酶-USP7通过影响相关癌蛋白参与肿瘤的发生与发展

蛋白质的泛素化程度决定着蛋白质的命运,细胞内存在两类针对蛋白质泛素化修饰的酶,一类是让某个特定蛋白泛素化增强的酶,另一类是让某个特定蛋白去泛素化的酶,这两类酶维持着正常细胞内80％ ～ 90％蛋白的新陈代谢.越来越多的证据支持这两类酶的异常与肿瘤的发生发展有较强的关联.其中USP7,一个去泛素化酶,有大量的文章报道显示它广泛参与影响肿瘤的进程.我们检索了近年来USP7与肿瘤关系的文献,系统回顾了它在肿瘤发生、发展中的作用与机制,并指出研究中存在的问题及将来的发展方向.     

A novel prognostic factor TRIM44 promotes cell proliferation and migration,and inhibits apoptosis in testicular germ cell tumor

Tripartite motif 44 (TRIM44) is one of the TRIM family proteins that are involved in ubiquitination and degradation of target proteins by modulating E3 ubiquitin ligases. TRIM44 overexpression has been observed in various cancers. However, its association with testicular germ cell tumor (TGCT) is unknown. We aimed to investigate the clinical significance of TRIM44 and its function in TGCT. High expression of TRIM44 was significantly associated with α feto‐protein levels, clinical stage, nonseminomatous germ cell tumor (NSGCT), and cancer‐specific survival (P = 0.0009, P = 0.0035, P = 0.0004, and P = 0.0140, respectively). Multivariate analysis showed that positive TRIM44 IR was an independent predictor of cancer‐specific mortality (P = 0.046). Gain‐of‐function study revealed that overexpression of TRIM44 promoted cell proliferation and migration of NTERA2 and NEC8 cells. Knockdown of TRIM44 using siRNA promoted apoptosis and repressed cell proliferation and migration in these cells. Microarray analysis of NTERA2 cells revealed that tumor suppressor genes such as CADM1, CDK19, and PRKACB were upregulated in TRIM44‐knockdown cells compared to control cells. In contrast, oncogenic genes including C3AR1, ST3GAL5, and NT5E were downregulated in those cells. These results suggest that high expression of TRIM44 is associated with poor prognosis and that TRIM44 plays significant role in cell proliferation, migration, and anti‐apoptosis in TGCT.     

TRIM28 haploinsufficiency predisposes to Wilms tumor

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.     

TRIM25: A central factor in breast cancer

TRIM25 is emerging as a central factor in breast cancer due to its regulation and function. In particular, it has been shown that: (1) Estrogens modulate TRIM25 gene expression; (2) TRIM25 has activity as an E3-ligase enzyme for ubiquitin; and (3) TRIM25 is also an E3 ligase for interferon-stimulated gene 15 protein in the ISGylation system. Consequently, the proteome of mammary tissue is affected by TRIM25-associated pathways, involved in tumor development and metastasis. Here, we discuss the findings on the mechanisms involved in regulating TRIM25 expression and its functional relevance in breast cancer progression. These studies suggest that TRIM25 may be a biomarker and a therapeutic target for breast cancer.     

Tripartite Motif-Containing 46 Promotes Viability and Inhibits Apoptosis of Osteosarcoma Cells by Activating NF-kB Signaling Through Ubiquitination of PPARα

Osteosarcoma (OS), the most common bone cancer, causes high morbidity in children and young adults. TRIM46 is a member of the family of tripartite motif (TRIM)-containing proteins that serve as important regulators of tumorigenesis. Here we investigate the possible role of TRIM46 in OS and the underlying molecular mechanism. We report an increase in the expression of TRIM46 in OS and its association with tumor size, Enneking’s stage, and patient prognosis. TRIM46 knockdown inhibits OS cell viability and cell cycle progression and induces apoptosis, while TRIM46 overexpression exerts inverse effects, which are inhibited by peroxisome proliferator-activated receptor alpha (PPAR ) overexpression and the nuclear factor kappa B (NF- B) inhibitor, pyrrolidine dithiocarbamate (PDTC). Furthermore, TRIM46 negatively regulates PPAR expression via ubiquitination-mediated protein degradation and modification. PPAR overexpression also inactivates NF- B signaling and NF- B promoter activity in OS cells overexpressing TRIM46. Moreover, TRIM46 knockdown inhibits tumor growth and induces apoptosis of OS cells in vivo. TRIM46 acts as an oncogene in OS by interacting with and ubiquitinating PPAR , resulting in the activation of NF- B signaling pathway. Thus, TRIM46 may be a potential biomarker of carcinogenesis. Key words: Osteosarcoma (OS); TRIM46; Ubiquitination; NF     

TRIM44 promotes human esophageal cancer progression via the AKT/mTOR pathway

Aberrant expression of TRIM‐containing protein 44 (TRIM44) acts as a promoter in multiple cancers. Here, we investigated the biological functions and clinical significance of TRIM44 in human esophageal cancer (HEC). TRIM44 expression was significantly higher in HEC tissues than corresponding normal tissues at both the mRNA (2.42 ± 0.52 vs 0.99 ± 0.25) and protein (1.01 ± 0.27 vs 0.30 ± 0.13) levels. Patients with high TRIM44 expression showed poor differentiation (P = 1.39 × 10^?5), advanced TNM stage (P = 3.87 × 10^?4) and, most importantly, significantly poorer prognosis (P = 2.80 × 10^?5). TRIM44 played a crucial role in epithelial mesenchymal transition (EMT). A significant correlation was observed between TRIM44 and Ki67 expression. We demonstrated that TRIM44 markedly enhanced HEC cell proliferation, migration, and invasion. Additionally, TRIM44 was involved in the AKT/mTOR signaling pathway and its downstream targets, such as STAT3 phosphorylation. Thus, elevated TRIM44 expression promotes HEC development by EMT via the AKT/mTOR pathway, and TRIM44 may be a novel prognostic indicator for HEC patients after curative resection.     

Clinical Significance of TRIM44 Expression in Patients with Gastric Cancer

Background: Despite the tremendous efforts in finding a valuable markers for risk stratifying gastric cancer (GC) patients; still, management of this cancer faces multiple obstacles. Given this, we designed a study to explore the possible relationship between the tripartite motif-containing 44 (TRIM44) gene expression, and the outcome of the GC patients. Methods: The real-time quantitative PCR method was used to evaluate the mRNA expression level of TRIM44, and β-catenin in fresh primary tumor and adjacent normal tissues collected from 40 GC patients. The Pearson’s correlation test, Kaplan–Meier method, and Cox proportional-hazards regression were performed to examine the association of TRIM44 expression with some clinicopathological data and the patients’ overall survival (OS). Results: The expression level of both TRIM44 and β-catenin was remarkably higher in GC tissues than in normal tissues (Fold change=1.71, p=0.004). In subgroup analysis based on the TRIM44 expression, pateints with high TRIM44 expression level exhibited poorer overall survival (HR = 1.46, 95% CI: 1.07-1.98, p=0.016). More strikingly, a positive correlation was also found between the expression of TRIM44 and β-catenin in GC, indicating that TRIM44 might exert its oncogenic activities probably through the β-catenin axis. Conclusion: This study highlighted the potent value of TRIM44 as an independent prognostic factor in gastric cancer and shed light on the probable interplay between this tripartite motif-containing protein and β-catenin. However, further investigations, especially with a larger sample size, are required to study the effect of TRIM44 in GC more precisely.     

Prognostic Significance of Tripartite Motif Containing 16 Expression in Patients with Gastric Cancer

Background and Aim: Tripartite Motif Containing 16 (TRIM16) is a member of the TRIM protein family which is known to play a suppressor role in development of numerous tumor types. However, a positive correlation between TRIM16 expression and gastric cancer (GC) progress has created a controversial situation that need to be fully delineated.  The aim of this study was to assess the expression level of TRIM16 mRNA and its relationship with β-catenin, CyclinD, and BCL2 expression in Iranian GC patients and to investigate its possible association with patients’ overall survival.  Materials and Methods: The expression level of TRIM16 of fresh primary tumor and adjacent normal tissues in 40 GC patients was evaluated by real-time quantitative PCR method. Moreover, patients were subdivided into high or low expression subgroups based on the TRIM16 expression levels. The relationship between TRIM16 expression level, β-catenin, Cyclin D, BCL2, some clinicopathological data and prognosis of GC patients was also analyzed. Results: qPCR analysis showed a lower level of TRIM16 in GC tissues (fold change=0.351) in comparison to their matched adjacent noncancerous tissues (p <0.001). Contrary to this, the expression levels of β-catenin, Cyclin D, and BCL2 genes were up-regulated in cancerous samples. This may explain the tumor suppressive function of TRIM16 in GC; as reduction in TRIM16 expression leads to the accumulation of mRNAs from β-catenin, Cyclin D, and BCL2 genes and eventually cancer progression. We did not observe any significant correlation between TRIM16 expression and patients’ overall survival. Univariate Cox regression analysis indicated that anemia, weight loss, bleeding, stomach ache, and smoking are statistically associated with overall survival; while, multivariate analysis did not support any correlation.  Conclusions: In sum, this study suggests a tumor suppressive role for TRIM16 in gastric cancer and proposes it as a potential candidate for GC prognosis.     

TRIM59调控波形蛋白促进人肝细胞肝癌细胞的增殖与迁移

目的:探讨三结构域蛋白59（tripartite-motif protein 59,TRIM59)对于人肝细胞肝癌(hepatocellular carcinoma，HCC)细胞增殖与迁移的影响以及波形蛋白（vimentin,VIM）作为其中潜在调控靶点的相关性研究。方法:通过细胞培养和细胞转染得到所需要的人HCC细胞，采用定量实时聚合酶链反应(qRT-PCR)方法检测其中TRIM59 mRNA的表达水平并通过蛋白印迹法（Western blot）检测TRIM59蛋白质的表达水平；采用慢病毒介导的基因沉默效应与TRIM59过表达质粒进行转染介导的基因过表达效应调控TRIM59 基因的表达，通过集落形成试验检测TRIM59处于不同表达水平时的肝癌细胞系的增殖能力差别；通过细胞划痕试验检测TRIM59 基因处于不同表达水平时HCC细胞的迁移能力差异；并通过考马斯亮蓝法（Bradford法）检测TRIM59基因处于不同表达水平时，VIM的表达情况，通过统计学方法研究TRIM59及VIM表达的相关性。结果:通过定量qRT-PCR与Western blot检测，在所选取的HCC细胞系中，TRIM59 mRNA及TRIM59蛋白质的表达量均高于普通肝细胞（P均<0.01）。细胞集落形成实验显示，在所选的肝癌细胞中，TRIM59的表达与HCC的细胞集落形成数量呈正相关（P均<0.01）。细胞划痕试验显示,TRIM59的表达与HCC的细胞迁移能力呈正相关（P均<0.05）。Bradford法检测显示,在所选取的HCC细胞系中，TRIM59蛋白质的表达与VIM的表达呈正相关（P均<0.01）。结论:TRIM59 促进人HCC细胞的增殖与迁移，可能是通过调控VIM表达而完成，可为HCC的靶向治疗提供新的靶点。     

TRIM28转录激活RMI2对肝癌SK-Hep-1细胞恶性生物学行为的影响

目的:探究RecQ介导的基因组不稳定性(因子)-2 (RMI2)对肝癌(HCC)SK-Hep-1细胞恶性表型的影响。方法:GEPIA数据库检测RMI2、三结构域蛋白28(TRIM28)在HCC组织中的表达,并预测HCC分期、HCC患者总体生存率和无病生存率,以及RMI2与TRIM28表达在HCC组织中的相关性;实时定量PCR(RT-qPCR)和免疫印迹法(Western blot)检测RMI2和TRIM28表达。基于HumanTFDB网站预测RMI2启动子与TRIM28结合位点;荧光素酶报告实验和染色质免疫沉淀法(ChIP)验证RMI2与TRIM28两者的结合关系。采用MTT和EdU染色检测细胞增殖;流式细胞术和TUNEL实验分别检测细胞周期和凋亡;Western blot分析增殖和凋亡相关蛋白表达。结果:HCC组织和细胞系中RMI2和TRIM28表达水平较正常组织和肝上皮细胞增加(P<0.001),且与预后不良相关。敲低RMI2后SK-Hep-1细胞增殖能力降低(P<0.001),导致G0/G1期细胞阻滞(P<0.001),细胞凋亡率增加(P<0.001)。HCC组织中RMI2和TRIM28的表达呈正相关,TRIM28可结合RMI2启动子从而上调其表达(P<0.001)。TRIM28过表达可逆转RMI2敲低对SK-Hep-1细胞增殖、细胞周期及凋亡的影响(P<0.05)。结论:RMI2受TRIM28转录激活从而调控SK-Hep-1细胞恶性表型。