偏肺病毒对副粘病毒细胞融合的新注释

对于副粘病毒科中的大多数病毒而言,细胞融合过程需要病毒的融合蛋白和吸附蛋白共同参与,其中吸附蛋白负责与受体结合,吸附蛋白与融合蛋白的相互作用激活融合蛋白进而激活细胞融合。而偏肺病毒介导的细胞融合则与上述副粘病毒的融合显著不同,所有已报道偏肺病毒介导的细胞融合不需要吸附蛋白的参与,其融合蛋白可单独完成与受体结合和融合。并且近年研究发现有些人偏肺病毒毒株介导的融合需要低pH条件,禽偏肺病毒A型具备极强的融合能力,而禽偏肺病毒B型则较弱。原有的副粘病毒细胞融合理论模型均不能解释上述现象,偏肺病毒介导的这种融合机制目前还不清楚,其研究在近几年日趋成为细胞融合机制研究的热点。近年发现的偏肺病毒介导的融合现象打破了人们对副粘病毒融合的固有理解,拓展了人们对副粘病毒介导的细胞融合的认识。本文旨在对偏肺病毒介导的细胞融合的最新成果和进展加以综述和讨论。     

病毒介导的免疫治疗癌症进展探究

癌症作为近些年来威胁人类健康的疾病,现代医学研究上引起人们的关注,近几年病毒介导在有关癌症的免疫治疗方面发挥着不可忽视的成效。笔者通过对以几个方面病毒介导免疫治疗的讨论,如病毒介导载体类型,对癌细胞的调节,以及对宿主细胞的调节,阐明了病毒介导对癌细胞发展的机制,对病毒介导的癌症治疗和临床研究提供了研究的方向。     

疱疹病毒糖蛋白介导的与宿主细胞膜融合的分子机制

疱疹病毒是一种由双链DNA病毒组成的大家族,包括α-、β-和γ-三个亚科,其糖蛋白gB、gH和gL形成细胞融合的"核心融合机制"。有些疱疹病毒还需要其他糖蛋白(HSV的gD、EBV的gp42和HCMV的gO、UL128-131)的调节作用,促进细胞融合。而糖蛋白gM或gM/gN却对细胞融合具有抑制作用。本文对疱疹病毒糖蛋白介导的细胞融合机制进行阐述,为进一步研究病毒致病机理提供一定的理论依据。     

细胞融合在人类疾病病理与医学应用中的研究进展

细胞融合包括细胞识别和黏附、融合孔开放以及胞质混合等基本步骤，它参与人类的许多生理病理过程。细胞融合为受精卵、胎盘、骨骼肌、破骨细胞等组织细胞正常发育所必需。同时，细胞融合在癌细胞的产生、恶性转移以及病毒入侵等人类重大疾病的发生发展中发挥了重要作用，这严重威胁人类的生命健康。本文围绕细胞融合参与的生理、病理过程，借助相关研究的最新进展，揭示细胞融合在人类疾病病理中的重要作用，进而提出了阻断细胞融合以减缓病毒入侵人体细胞以及肿瘤细胞的产生与扩散的治疗新策略；进一步探讨了细胞融合在干细胞介导的组织再生以及细胞重编程中的潜在作用。这将深化人们对细胞融合在相关疾病病理中作用的认识，并大力推进细胞融合分子的临床应用进程。     

环境致癌物与病毒协同致癌作用的研究进展

癌症是威胁人类健康的重大疾病,其发病与环境、病原体、遗传和生活方式等多种因素有关。环境致癌物是诱发癌症的重要因素之一,如多环芳烃、亚硝胺和霉菌毒素等均为环境中广泛存在的典型致癌物,它们在体内经过代谢活化后导致DNA损伤最终诱发癌症。病毒感染也是人类癌症发病的重要原因,如乙肝病毒(HBV)和丙肝病毒(HCV)能够诱发肝癌;EB病毒(EBV)在鼻咽癌的发生过程中起关键作用;人乳头瘤病毒(HPV)与宫颈癌和食管癌有关。然而,由于癌症发病机制复杂,仅考虑单一因素往往难以进行合理的解释。因此,明确不同致癌因素之间的协同作用对于揭示致癌作用机制具有重要意义。本文综述了近年来有关环境致癌物与病毒协同致癌作用的研究,以期为深入阐明肿瘤发生和发展的作用机制找到新的突破口,进而为相关癌症的防治提供新策略。     

人乳头瘤病毒的致瘤性及机制

高危型人乳头瘤病毒(HPV)可能引发多种癌症,公认的如宫颈癌和宫颈上皮内瘤变.近年来的研究表明,HPV还与头颈部鳞癌、食管癌及乳房癌等的发生密切相关.HPV引起头颈部鳞癌的机制在某种程度上与宫颈癌相似,但又有所不同.因此,阐明HPV的致癌机制对于HPV相关肿瘤的治疗具有重要意义.     

人体微生物组的肿瘤诱导作用及机制的研究进展

癌症已经成为威胁人类健康的第一杀手,约20%的癌症病因与微生物存在直接联系。这些微生物除了传统意义上的病原菌、病毒、真菌外,一向和我们和平共处的共生微生物组在细胞癌变的过程中也发挥了重要作用。阐明这些被称为人体第二基因组的口腔、肠道等微生物种群与癌症发生发展的潜在关系及微生物感染、微生物对前致癌物质的激活和对人体细胞信号转导的干扰等肿瘤诱导机制,将可能为癌症的防治提供新的靶点和思路。现就人体微生物组的肿瘤诱导作用及机制的最新进展作一综述。     

人偏肺病毒F蛋白与细胞融合机制研究进展

人偏肺病毒(Human metapneumovirus,hMPV)是一种新发呼吸道病毒。hMPV感染可引起广泛的呼吸道疾病,目前已越来越受到人们的重视。多数副粘病毒与宿主细胞膜的融合过程依赖吸附蛋白和融合蛋白的共同参与。hMPV的特别之处在于其融合蛋白(F)既可以结合受体,又可以介导膜融合。本文从hMPV包膜表面具有双重功能的F蛋白入手,简要介绍F蛋白的结构和生理功能,重点阐述F蛋白介导的细胞融合机制和特性,对近几年来国内外研究进展进行了回顾与展望。     

细胞融合致体细胞重编程机制研究进展

已分化的体细胞能够通过重编程转化回多能干细胞,在细胞移植、疾病细胞模型的制备以及药物筛选等领域具有重要意义。通过干细胞和体细胞的细胞融合,可使体细胞重编程。细胞融合致体细胞重编程速度快、效率高,是一种研究重编程机制的重要手段。对细胞融合致体细胞重编程的机制作一综述。     

人工诱导细胞融合及其机制

近20余年,人工诱导细胞融合技术经历了病毒、化学和电学的不断发展进程,其细胞融合机制已从膜分子水平得到一些新的认识。膜蛋白质分子重新分布是细胞融合的必要前提;膜脂质分子相互作用和重新排列是实现细胞融合的关键。     

Functional modulation of the metastatic suppressor Nm23-H1 by oncogenic viruses

Evidence over the last two decades from a number of disciplines has solidified some fundamental concepts in metastasis, a major contributor to cancer associated deaths. However, significant advances have been made in controlling this critical cellular process by focusing on targeted therapy. A key set of factors associated with this invasive phenotype is the nm23 family of over twenty metastasis-associated genes. Among the eight known isoforms, Nm23-H1 is the most studied potential anti-metastatic factor associated with human cancers. Importantly, a growing body of work has clearly suggested a critical role for Nm23-H1 in limiting tumor cell motility and progression induced by several tumor viruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma associated herpes virus (KSHV) and human papilloma virus (HPV). A more in depth understanding of the interactions between tumor viruses encoded antigens and Nm23-H1 will facilitate the elucidation of underlying mechanism(s) which contribute to virus-associated cancers. Here, we review recent studies to explore the molecular links between human oncogenic viruses and progression of metastasis, in particular the deregulation of Nm23-H1 mediated suppression.     

SARS-CoV-2 cell receptor gene ACE2 -mediated immunomodulation in breast cancer subtypes

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has impacted the world severely. The binding of the SARS-CoV-2 virus to the angiotensin-converting enzyme 2 (ACE2) and its intake by the host cell is a necessary step for infection. ACE2 has garnered widespread therapeutic possibility as it is entry/interactive point for SARS-CoV-2, responsible for coronavirus disease 2019 (COVID-19) pandemic and providing a critical regulator for immune modulation in various disease. Patients with suffering from cancer always being on the verge of being immune compromised therefore gaining knowledge about how SARS-CoV-2 viruses affecting immune cells in human cancers will provides us new opportunities for preventing or treating virus-associated cancers. Despite COVID-19 pandemic got center stage at present time, however very little research being explores, which increase our knowledge in context with how SARS-CoV-2 infection affect cancer a cellular level. Therefore, in light of the ACE-2 as an important contributor of COVID-19 global, we analyzed correlation between ACE2 and tumor immune infiltration (TIL) level and the type markers of immune cells were investigated in breast cancer subtypes by using TIMER database. Our findings shed light on the immunomodulatory role of ACE2 in the luminal A subtype which may play crucial role in imparting therapeutic resistance in this cancer subtype.     

A virus causes cancer by inducing massive chromosomal instability through cell fusion

Chromosomal instability (CIN) underlies malignant properties of many solid cancers and their ability to escape therapy, and it might itself cause cancer [1, 2]. CIN is sustained by deficiencies in proteins, such as the tumor suppressor p53 [3-5], that police genome integrity, but the primary cause of CIN in sporadic cancers remains uncertain [6, 7]. The primary suspects are mutations that deregulate telomere maintenance, or mitosis, yet such mutations have not been identified in the majority of sporadic cancers [6]. Alternatively, CIN could be caused by a transient event that destabilizes the genome without permanently affecting mechanisms of mitosis or proliferation [5, 8]. Here, we show that an otherwise harmless virus rapidly causes massive chromosomal instability by fusing cells whose cell cycle is deregulated by oncogenes. This synergy between fusion and oncogenes "randomizes" normal diploid human fibroblasts so extensively that each analyzed cell has a unique karyotype, and some produce aggressive, highly aneuploid, heterogeneous, and transplantable epithelial cancers in mice. Because many viruses are fusogenic, this study suggests that viruses, including those that have not been linked to carcinogenesis, can cause chromosomal instability and, consequently, cancer by fusing cells.     

Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells

E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.     

Consequences of activating the calcium-permeable ion channel TRPV1 in breast cancer cells with regulated TRPV1 expression

Increased expression of specific calcium channels in some cancers and the role of calcium signaling in proliferation and invasion have led to studies assessing calcium channel inhibitors as potential therapies for some cancers. The use of channel activators to promote death of cancer cells has been suggested, but the risk of activators promoting cancer cell proliferation and the importance of the degree of channel over-expression is unclear. We developed an MCF-7 breast cancer cell line with inducible TRPV1 overexpression and assessed the role of TRPV1 levels on cell death mediated by the TRPV1 activator capsaicin and the potential for submaximal activation to promote proliferation. The TRPV1 level was a determinant of cell death induced by capsaicin. A concentration response curve with varying TRPV1 expression levels identified the minimum level of TRPV1 required for capsaicin induced cell death. At no level of TRPV1 over-expression or capsaicin concentration did TRPV1 activation enhance proliferation. Cell death induced by capsaicin was necrotic and associated with up-regulation of c-Fos and RIP3. These studies suggest that activators of specific calcium channels may be an effective way to induce necrosis and that this approach may not always be associated with enhancement of cancer cell proliferation.     

The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway

Escape from cell death is a key event in cancer establishment/progression. While apoptosis is often considered as the main cell death pathway, upon caspase inhibition, cell death is rather delayed than blocked leading to caspase-independent cell death (CICD). Although described for years, CICD’s underlying mechanism remains to be identified. Here, we performed a genome-wide siRNA lethality screening and identified the RING-Type E3 Ubiquitin Transferase (UBR2) as a specific regulator of CICD. Strikingly, UBR2 downregulation sensitized cells towards CICD while its overexpression was protective. We established that UBR2-dependent protection from CICD was mediated by the MAPK/Erk pathway. We then observed that UBR2 is overexpressed in several cancers, especially in breast cancers and contributes to CICD resistance. Therefore, our work defines UBR2 as a novel regulator of CICD, found overexpressed in cancer cells, suggesting that its targeting may represent an innovative way to kill tumor cells.Subject terms: Cancer, Cell death     

Statins,stem cells,and cancer

The statins (3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors) were proven to be effective antilipid agents against cardiovascular disease. Recent reports demonstrate an anticancer effect induced by the statins through inhibition of cell proliferation, induction of apoptosis, or inhibition of angiogenesis. These effects are due to suppression of the mevalonate pathway leading to depletion of various downstream products that play an essential role in cell cycle progression, cell signaling, and membrane integrity. Recent evidence suggests a shared genomic fingerprint between embryonic stem cells, cancer cells, and cancer stem cells. Activation targets of NANOG, OCT4, SOX2, and c‐MYC are more frequently overexpressed in certain tumors. In the absence of bona fide cancer stem cell lines, human embryonic stem cells, which have similar properties to cancer and cancer stem cells, have been an excellent model throwing light on the anticancer affects of various putative anticancer agents. It was shown that key cellular functions in karyotypically abnormal colorectal and ovarian cancer cells and human embryonic stem cells are inhibited by the statins and this is mediated via a suppression of this stemness pathway. The strategy for treatment of cancers may thus be the targeting of a putative cancer stem cell within the tumor with specific agents such as the statins with or without chemotherapy. The statins may thus play a dual prophylactic role as a lipid‐lowering drug for the prevention of heart disease and as an anticancer agent to prevent certain cancers. This review examines the relationship between the statins, stem cells, and certain cancers. J. Cell. Biochem. 106: 975–983, 2009. © 2009 Wiley‐Liss, Inc.     

Calcineurin phosphatase activity regulates Varicella-Zoster Virus induced cell-cell fusion

Cell-cell fusion (abbreviated as cell fusion) is a characteristic pathology of medically important viruses, including varicella-zoster virus (VZV), the causative agent of chickenpox and shingles. Cell fusion is mediated by a complex of VZV glycoproteins, gB and gH-gL, and must be tightly regulated to enable skin pathogenesis based on studies with gB and gH hyperfusogenic VZV mutants. Although the function of gB and gH-gL in the regulation of cell fusion has been explored, whether host factors are directly involved in this regulation process is unknown. Here, we discovered host factors that modulated VZV gB/gH-gL mediated cell fusion via high-throughput screening of bioactive compounds with known cellular targets. Two structurally related non-antibiotic macrolides, tacrolimus and pimecrolimus, both significantly increased VZV gB/gH-gL mediated cell fusion. These compounds form a drug-protein complex with FKBP1A, which binds to calcineurin and specifically inhibits calcineurin phosphatase activity. Inhibition of calcineurin phosphatase activity also enhanced both herpes simplex virus-1 fusion complex and syncytin-1 mediated cell fusion, indicating a broad role of calcineurin in modulating this process. To characterize the role of calcineurin phosphatase activity in VZV gB/gH-gL mediated fusion, a series of biochemical, biological and infectivity assays was performed. Pimecrolimus-induced, enhanced cell fusion was significantly reduced by shRNA knockdown of FKBP1A, further supporting the role of calcineurin phosphatase activity in fusion regulation. Importantly, inhibition of calcineurin phosphatase activity during VZV infection caused exaggerated syncytia formation and suppressed virus propagation, which was consistent with the previously reported phenotypes of gB and gH hyperfusogenic VZV mutants. Seven host cell proteins that remained uniquely phosphorylated when calcineurin phosphatase activity was inhibited were identified as potential downstream factors involved in fusion regulation. These findings demonstrate that calcineurin is a critical host cell factor pivotal in the regulation of VZV induced cell fusion, which is essential for VZV pathogenesis.     

Coxsackievirus and adenovirus receptor expression in non-malignant lung tissues and clinical lung cancers

Adenoviral vector mediated gene delivery has been applied in clinical trials and mechanistic studies to explore new treatment approaches for lung cancers. The expression of coxsackievirus adenovirus receptor (CAR), the primary receptor for the most commonly used adenovirus serotype 5 (Ad5)-based vectors, predominantly determines the permissiveness of lung cancer cells. CAR expression is also suggested to modulate tumor cell proliferation capacity. Here, we studied CAR expression in archival lung cancer specimens by using well-characterized CAR 72 antibodies. High levels of CAR expression were observed in most of the 32 cases of squamous cell carcinoma lung cancers and in all the five cases of small cell lung cancers investigated. In contrast, high levels of CAR expression were detected only in 6 of 22 adenocarcinoma lung cancers. The relative levels of CAR expression did not correlate with the pathologic grade in lung cancers, and was thus inconsistent with a role of modulating cancer cell proliferation. Of note, CAR expression was not detected in non-malignant alveolar cells. Our data suggest a preferred utility of Ad5 vector mediated gene delivery to squamous cell carcinoma lung cancers, small cell lung cancers, but not to the majority of adenocarcinoma lung cancers.     

Telomere shortening and cell fates in mouse models of neoplasia.

Cell division in the absence of telomerase leads to telomere shortening that can activate checkpoint responses and impair chromosomal stability. The absence of telomerase in primary human cells and its near universal reactivation in human cancers has highlighted the importance of telomere shortening and telomerase reactivation during tumor development. Data from telomerase-deficient mouse models of cancer have indicated that telomere shortening can exert profoundly different influences on cell fates in developing cancers, limiting tumorigenesis by enhancing cell death or facilitating carcinogenesis by compromising chromosomal stability. These alternate fates depend on the integrity of the p53 pathway and on cell type.