人巨细胞病毒与肿瘤研究进展

人巨细胞病毒（HCMV）是目前已知最大的β疱疹病毒。HCMV感染具有持续性和潜在性,感染率在全世界范围内都很高,并随着年龄的增长而升高,女性感染率高于男性,其主要的传播途径有垂直传播和性传播等。近年来的研究显示在人类胶质瘤、结直肠癌、乳腺癌和前列腺癌及小细胞型肝癌等多种类型的肿瘤组织中都存在HCMV感染和病毒基因表达,并与肿瘤的恶性程度有相关性,这提示HCMV可能在人类某些类型肿瘤的形成和发展过程中扮演重要角色,有可能成为一种新的人类肿瘤相关病毒。HCMV基因产物可通过多种细胞信号通路抑制细胞凋亡、促进细胞增殖、侵袭、转移和血管生成,并形成独特的免疫逃避机制对抗机体免疫反应。深入研究HCMV与肿瘤的病因学关系及其作用机制,可为肿瘤的临床防治提供新思路。     

人巨细胞病毒调控免疫逃逸相关基因的功能及其机制研究

人巨细胞病毒（HCMV）是一个广泛传播的机会致病原,也是不断利用和操控机体免疫系统致慢性持续性病毒感染的典型代表。在病毒与宿主共同漫长进化过程中,HCMV产生了许多逃避宿主免疫系统识别的机制,其基因组编码了大量产物,通过抑制自然杀伤细胞和树突细胞功能,下调被感染细胞表面主要组织相容性复合体（MHC）Ⅰ类和Ⅱ类分子表达以减少病毒抗原呈递,损伤IgG介导的体液免疫,调节多种趋化因子和细胞因子的作用,从而控制宿主天然免疫应答和适应性免疫应答的核心功能。本文就HCMV的免疫逃避机制进行综述,探讨病毒与宿主相互作用的发生、发展与结局。     

人巨细胞病毒潜伏感染机制的研究进展

人巨细胞病毒(HCMV)的潜伏感染在人群中极为普遍。在儿科学领域,潜伏感染的巨细胞病毒激活后,可能导致死胎、流产、胎儿畸形、生长发育迟缓等一系列严重后果。在病毒潜伏感染过程中,机体会通过免疫反应或诱导宿主细胞凋亡等方式清除病毒。然而,在病毒与宿主共同进化的漫长过程中,病毒会调控自身基因的表达、宿主细胞微环境及免疫杀伤作用,从而达到与长期宿主共存的目的。目前研究揭示,HCMV的潜伏感染可能与病毒立即早期启动子沉默、病毒干扰宿主细胞凋亡、病毒免疫逃逸及非编码RNA调控机制有关。本文将从以上四个方面对HCMV潜伏感染相关机制的研究进展进行总结。     

关于HCMV 潜伏感染与激活感染研究的新进展

人巨细胞病毒(HCMV)是疱疹病毒科中最大的病毒,结构复杂,其感染在人群中非常普遍,近年来免疫妥协(immunocompromised)群体尤其是移植群体中的HCMV潜伏感染和激活感染越来越受到临床重视。本文就HCMV的感染与免疫、HCMV的致病机制、宿主的抗感染与免疫、HCMV的免疫逃逸、HCMV的潜伏与激活及HCMV相关研究的困境与展望近年来此方面研究新进展作一简要综述。     

人巨细胞病毒pp150抗原区的原核表达及初步应用

人巨细胞病毒(human cytomegalovirus,HCMV)感染人体可引起广泛的临床症状,尤其是孕妇和免疫缺陷病人感染HCMV可产生严重的危害[1].传统的减毒活疫苗使用后可能会造成宿主机会性感染或导致肿瘤,因而限制了它的应用.与亚单位疫苗相比,DNA疫苗具有易于构建和制备、稳定性高等特点.多种HCMV病毒蛋白可刺激机体产生相应的抗体,但应选用免疫原性强、特异性好的蛋白抗原基因制备HCMVDNA疫苗.国内外的研究证实[2-5],HCMV的pp150蛋白具有较强的免疫原性.我们用RT-PCR方法扩增了pp150 420～752氨基酸之间多肽片段的编码基因,克隆至原核表达载体,构建了表达pp150抗原决定簇区的工程菌.     

关于HCMV潜伏感染与激活感染研究的新进展

人巨细胞病毒（HCMV）是疱疹病毒科中最大的病毒,结构复杂,其感染在人群中非常普遍,近年来免疫妥协（immunocompmmised）群体尤其是移植群体中的HCMV潜伏感染和激活感染越来越受到临床重视。本文就HCMV的感染与免疫、HCMV的致病机制、宿主的抗感染与免疫、HCMV的免疫逃逸、HCMV的潜伏与激活及HcMV相关研究的困境与展望近年来此方面研究新进辰作一简要综述。     

人巨细胞病毒PP71基因序列分析与表达

人巨细胞病毒(Human cytomegalo virus)在人群中存在非常普遍,大多数呈临床不显性或潜伏感染,孕妇HCMV复发感染或新的感染均可引起新生儿宫内或围产期感染,导致胎儿畸形、智力低下和发育迟缓等.人是HCMV的唯一宿主,病毒可通过人与人间的直接或间接接触传播.近年来对HCMV的致病机理的研究已日趋深入,已有多项研究证实,     

人巨细胞病毒相关肿瘤调节作用的研究新进展

人巨细胞病毒(HCMV)可感染肿瘤细胞,并增加肿瘤恶性程度.最近一些研究者对恶性胶质瘤患者的临床研究发现,HCMV感染的肿瘤细胞数量与肿瘤的恶性程度有关.HCMV通过影响细胞周期进展、阻断受感染细胞凋亡、影响肿瘤细胞恶性行为等发挥肿瘤调节作用.探讨HCMV肿瘤调节作用的具体机制,对将HCMV作为肿瘤治疗的一个靶目标,拓...     

人巨细胞病毒博弈宿主免疫进展

人巨细胞病毒(HCMV)感染在人群中极其普遍,病毒一旦侵入机体,将长期存在于体内,且具有潜伏-活化的生物学特性。在病毒与宿主共同进化的漫长过程中,病毒靶向性的产生了多种免疫逃避机制,通过编码病毒自身免疫调节分子,参与调控机体主要组织相容性复合体、细胞免疫、体液免疫、细胞因子及趋化因子等方面的功能,以躲避宿主的免疫杀伤作用。HCMV的免疫调节基因被认为在病毒的致病机制中扮演重要角色。本文将对近年来有关HCMV的免疫调控机制研究作一综述,从病毒编码的免疫调节分子功能的角度并结合本实验室的相关研究成果,探讨病毒与宿主免疫的相互作用过程,从病毒干预宿主免疫关键分子作用的角度映射机体对抗病毒的免疫机理。     

人巨细胞病毒潜伏-再激活感染的研究进展

人巨细胞病毒(HCMV)感染大多呈亚临床或潜伏状态.当宿主免疫功能减弱时,潜伏的病毒可被激活,出现明显的临床症状,甚至是致死性的.本文概述了HCMV引起潜伏感染的机制、潜伏的组织细胞,以及再激活的诱因,并对今后的研究方向进行了展望.     

High Prevalence of Human Cytomegalovirus Proteins and Nucleic Acids in Primary Breast Cancer and Metastatic Sentinel Lymph Nodes

Background

Breast cancer is a leading cause of death among women worldwide. Increasing evidence implies that human cytomegalovirus (HCMV) infection is associated with several malignancies. We aimed to examine whether HCMV is present in breast cancer and sentinel lymph node (SLN) metastases.

Materials and Methods

Formalin-fixed paraffin-embedded tissue specimens from breast cancer and paired sentinel lymph node (SLN) samples were obtained from patients with (n = 35) and without SLN metastasis (n = 38). HCMV immediate early (IE) and late (LA) proteins were detected using a sensitive immunohistochemistry (IHC) technique and HCMV DNA by real-time PCR.

Results

HCMV IE and LA proteins were abundantly expressed in 100% of breast cancer specimens. In SLN specimens, 94% of samples with metastases (n = 34) were positive for HCMV IE and LA proteins, mostly confined to neoplastic cells while some inflammatory cells were HCMV positive in 60% of lymph nodes without metastases (n = 35). The presence of HCMV DNA was confirmed in 12/12 (100%) of breast cancer and 10/11 (91%) SLN specimens from the metastatic group, but was not detected in 5/5 HCMV-negative, SLN-negative specimens. There was no statistically significant association between HCMV infection grades and progesterone receptor, estrogen receptor alpha and Elston grade status.

Conclusions

The role of HCMV in the pathogenesis of breast cancer is unclear. As HCMV proteins were mainly confined to neoplastic cells in primary breast cancer and SLN samples, our observations raise the question whether HCMV contributes to the tumorigenesis of breast cancer and its metastases.     

Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression

A high frequency of human cytomegalovirus (HCMV) genome and antigens in tumor samples of patients with different malignancies is now well documented, although the causative role for HCMV in the development of the neoplasias remains to be established. HCMV infection can modulate multiple cellular regulatory and signalling pathways in a manner similar to that of oncoproteins of small DNA tumor viruses such as human papilloma virus or adenoviruses. However, in contrast to these DNA tumor viruses, HCMV infection fails to transform susceptible normal human cells. There is now growing evidence that tumor cells with disrupted regulatory and signalling pathways enable HCMV to modulate their properties including stimulation of cell proliferation, survival, invasion, production of angiogenic factors, and immunogenic properties. In contrast to previously suggested "hit and run" transformation we suggest that persistence in tumor cells is essential for HCMV to fully express its oncomodulatory effects. These effects are observed particularly in persistent HCMV infection and are mediated mainly by activity of HCMV regulatory proteins. In persistently HCMV-infected tumor cell lines - a selection of novel, slowly growing virus variants with changes in coding sequences for virus regulatory proteins takes place. As a result, oncomodulatory effects of HCMV infection may lead to a shift to more malignant phenotype of tumor cells contributing to tumor progression.     

Identification of novel variants of metadherin in breast cancer

Metadherin (MTDH, also known as AEG-1, and Lyric) has been demonstrated to play a potential role in several significant aspects of tumor progression. It has been reported that overexpression of MTDH is associated with progression of disease and poorer prognosis in breast cancer. However, there are no studies to date assessing variants of the MTDH gene and their potential relationship with breast cancer susceptibility. Thus, we investigated all variants of the MTDH gene and explored the association of the variants with breast cancer development. Our cohort consisted of full-length gene sequencing of 108 breast cancer cases and 100 healthy controls; variants were detected in 11 breast cancer cases and 13 controls. Among the variants detected, 9 novel variants were discovered and 2 were found to be associated with the susceptibility of breast cancer. However, additional studies need to be conducted in larger sample sizes to validate these findings and to further investigate whether these variants are prognostic in breast cancer patients.     

Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU)

Emerging evidence has declared that Proteasome 26S subunit ATPase 2 (PSMC2) is involved in tumor progression. However, its role in breast cancer has not been investigated. Therefore, we sought to establish a correlation between breast cancer and PSMC2. PSMC2 expression in tissues was detected by immunohistochemistry. Loss-of-function study was used to evaluate the effects of PSMC2 knockdown in cell proliferation, apoptosis and migration. A gene microarray was performed to explore the potential downstream of PSMC2 with the help of Ingenuity Pathway Analysis (IPA). The effects of the PSMC2/PLAU axis on breast cancer were examined in vitro. Compared to para-cancer tissues, PSMC2 level was considerably elevated in breast cancer, which was significantly correlated with tumor grade. Knockdown of PSMC2 suppressed breast cancer progression in vitro and in vivo. The mechanistic research revealed that PSMC2 promotes the development and progression of human breast cancer through interacting with PLAU. Outcomes of our study showed that overexpression of PSMC2 provide tumorigenic and metastatic advantages in breast cancer, which may involve the regulation of PLAU. This study not only reveals a critical mechanism of breast cancer development, but also provides a promising therapeutic target for breast cancer treatment.Subject terms: Cancer, Breast cancer     

Human cytomegalovirus UL76 induces chromosome aberrations

Background  

Human cytomegalovirus (HCMV) is known to induce chromosome aberrations in infected cells, which can lead to congenital abnormalities in infected fetuses. HCMV UL76 belongs to a conserved protein family from herpesviruses. Some reported roles among UL76 family members include involvement in virulence determination, lytic replication, reactivation of latent virus, modulation of gene expression, induction of apoptosis, and perturbation of cell cycle progression, as well as potential nuclease activity. Previously, we have shown that stable expression of UL76 inhibits HCMV replication in glioblastoma cells.     

Downregulation and antiproliferative role of FHL3 in breast cancer

Four and a half LIM domain (FHL) protein 3 is a member of the FHL protein family that plays roles in the regulation of signal transduction, cell adhesion, survival, and mobility. FHL3 has been implicated in the development and progression of liver cancer. However, the biological function of FHL3 in other cancers remains unclear. Here, we show that FHL3 is downregulated in breast cancer patients. Using small interfering RNA (siRNA) knockdown and/or overexpression experiments, we demonstrated that FHL3 suppressed anchorage-dependent and -independent growth of human breast cancer cells. The antiproliferative effects of FHL3 on breast cancer cell growth were associated with both the G1 and the G2/M cell cycle arrest, which was accompanied by a marked inhibition of the G1-phase marker cyclin D1 and the G2/M-phase marker cyclin B1 as well as the induction of the cyclin dependent kinase inhibitor p21 (WAF1/CIP1), a negative regulator of cell cycle progression at G1 and G2. These results suggest that FHL3 may play a role in the development and progression of breast cancer, and thereby may be a potential target for human breast cancer gene therapy.     

Proteomic analysis of serum associated fucosylated glycoproteins in the development of primary hepatocellular carcinoma

Changes in N-linked glycosylation are known to occur during the development of cancer. For example, increased branching of oligosaccharides has been associated with metastasis and has been correlated to tumor progression in human cancers of the breast, colon and melanomas. Increases in core fucosylation have also been associated with the development of hepatocellular carcinoma (HCC). Chronic infection with the hepatitis B virus is associated with more than 55% of all cases of hepatocellular carcinoma. We show here that increased levels of core fucosylation can be observed via glycan analysis of total serum and are associated with the development of HCC. In a blinded study, the serum glycoproteins derived from people diagnosed with HBV induced liver cancer were found to possess a dramatically higher level of fucosylation. This change occurs on both immunoglobulin molecules and on other serum glycoproteins. Targeted glycoproteomic analysis was used to identify those glycoproteins that are hyperfucosylated in cancer. In total, 19 proteins were found to be hyperfucosylated in cancer. The potential of these proteins as biomarkers of cancer is discussed.