Insights into the structural perturbations of spliced variants of CD44: a modeling and simulation approach

Transient interactions between cancer stem cells and components of the tumor microenvironment initiate various signaling pathways crucial for carcinogenesis. Predominant hyaluronan (HA) receptor, CD44 is structurally and functionally one of the most variable cell surface receptors having the potential to generate a diverse repertory of CD44 isoforms by alternative splicing of variant exons and post-translational modifications. A structurally distinctive variant of CD44, CD44v10, has an inevitable role in malignant progression, invasion, and metastasis. This can be attributed to the binding of HA with CD44v10, which demonstrates a completely different behavioral pattern as compared to the other spliced variants of CD44 molecule. Absence of a comprehensively predicted crystal structure of human CD44s and CD44v10 is an impediment in understanding the resultant structural alterations caused by the binding of HA. Thus, in this study, we aim to predict the CD44s and CD44v10 structures to their closest native confirmation and study the HA binding-induced structural perturbations using homology modeling, molecular docking, and MD simulation approach. The results depicted that modeled 3D structures of CD44s and CD44v10 isoforms were found to be stable throughout MD simulations; however, a substantial decrease was observed in the binding affinity of HA with CD44v10 (?5.355 kcal/mol) as compared to CD44s. Furthermore, loss and gain of several H-bonds and hydrophobic interactions in CD44v10–HA complex during the simulation process not only elucidated the reason for decreased binding affinity for HA but also prompted toward the plausible role of HA-induced structural perturbations in occurrence and progression of carcinogenesis.     

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

Previous studies have demonstrated the in vitro oncogenic role of protein arginine methyltransferase 5 (PRMT5) in gastric cancer cell lines. The in vivo function of PRMT5 in gastric tumorigenesis, however, is still unexplored. Here, we showed that Prmt5 deletion in mouse gastric epithelium resulted in spontaneous tumorigenesis in gastric antrum. All Prmt5-deficient mice displayed intestinal-type gastric cancer within 4 months of age. Of note, 20% (2/10) of Prmt5 mutants finally developed into invasive gastric cancer by 8 months of age. Gastric cancer caused by PRMT5 loss exhibited the increase in Lgr5⁺ stem cells, which are proposed to contribute to both the gastric tumorigenesis and progression in mouse models. Consistent with the notion that Lgr5 is the target of Wnt/β-catenin signaling, whose activation is the most predominant driver for gastric tumorigenesis, Prmt5 mutant gastric cancer showed the activation of Wnt/β-Catenin signaling. Furthermore, in human gastric cancer samples, PRMT5 deletion and downregulation were frequently observed and associated with the poor prognosis. We propose that as opposed to the tumor-promoting role of PRMT5 well-established in the progression of various cancer types, PRMT5 functions as a tumor suppressor in vivo, at least during gastric tumor formation.     

类赖氨酰氧化酶2与肿瘤转移和发生

类赖氨酰氧化酶2（lysyl oxidase—like 2,LOXL2）是赖氨酰氧化酶（1ysyl oxidase,LOX）基因家族的成员之一,其表达产物能促进胶原沉积。LOXL2的过表达能促进纤维化,并与肿瘤侵袭、转移及不良预后有关。目前大部分学者认为LOXL2是一种转移促进基因,也有实验支持其是一种肿瘤抑制基因。研究发现LOXL2可以通过激活Snail／Ecadherin通路或Src／FAK通路促进转移。LOXL2有望作为肿瘤生物标志物,用于预后判断,成为一个新的治疗靶点。     

CRISPR/Cas9 Screening for Identification of Genes Required for the Growth of Ovarian Clear Cell Carcinoma Cells

Epithelial ovarian cancer is classified into four major histological subtypes: serous, clear cell, endometrioid and mucinous. Ovarian clear cell carcinoma (OCCC) responds poorly to conventional chemotherapies and shows poor prognosis. Thus, there is a need to develop new drugs for the treatment of OCCC. In this study, we performed CRISPR/Cas9 screens against OCCC cell lines and identified candidate genes important for their proliferation. We found that quite different genes are required for the growth of ARID1A and PIK3CA mutant and wild-type OCCC cell lines, respectively. Furthermore, we found that the epigenetic regulator KDM2A and the translation regulator PAIP1 may play important roles in the growth of ARID1A and PIK3CA mutant, but not wild-type, OCCC cells. The results of our CRISPR/Cas9 screening may be useful in elucidating the molecular mechanism of OCCC tumorigenesis and in developing OCCC-targeted drugs.     

NEDD化修饰系统及其在肿瘤发展中的作用

目前已经鉴定出17种类泛素蛋白（ubiquitin like proteins,UBLs）,这些蛋白与底物的结合方式与泛素相似．根据进化特征,可将UBLs分为9类,分别为：NEDD8、SUMO、ISG15、FUB1、FAT10、Atg8、Atg12、Urm1和UFM1．NEDD8是目前研究最多的UBLs之一,与泛素的氨基酸序列具有高度相似性．NEDD化修饰是一种动态的可逆蛋白质翻译后修饰方式,可以将NEDD8共价结合到靶蛋白之上,也可以将NEDD8从靶蛋白上去除．NEDD化修饰对蛋白功能具有重要的调节作用,如改变蛋白质的空间构象、阻碍底物与其它蛋白质的相互作用和招募与NEDD8相互作用的蛋白等．最新研究表明,NEDD化与肿瘤的发生发展密切相关,但具体的机制还不清楚．本文将就NEDD化修饰在肿瘤发展过程中的作用机制做一综述．     

病毒疫苗制备用不同核型VERO细胞系在裸鼠体内致癌/致瘤性的系统实验研究

生产疫苗用细胞系可能具有致瘤性,一些常用的细胞系需要检查不同代次有无致癌性。在建立传代细胞种子库与工作库基础上,对研制生产病毒活疫苗所用8株VERO细胞系在219只裸鼠进行了致癌(瘤)实验。本研究结果表明,VERO细胞染色体核型可发生变异,亚四倍体JA株与超二倍体KA株具有强的致癌性,不能用于致弱活病毒疫苗制备,但可替代HeLa细胞系用作恶性肿瘤阳性对照细胞。筛出无致瘤性的YB、dC、M和JB株亚二倍体VERO细胞系,可替代BHK-21细胞用于狂犬病减毒活疫苗制备。VERO细胞系染色体遗传相对稳定。不同代次变化不大。研究发现细胞染色体遗传特征决定致瘤性质并具有种属特异性,不同核型细胞致瘤性不同,细胞染色体数目变异大小和致癌性成正相关,通过体内外交替选育可在裸鼠体内快速选育成功高变异率肿瘤细胞系。高变异率HeLa或VERO细胞系移植于裸鼠可能产生恶性横纹肌样瘤。因此,应当强调疫苗生产用细胞系致瘤性评价的重要性。     

上皮间质转化和细胞衰老在肿瘤发生中的共同调节分子

上皮间质转化(epithelial-mesenchymal transition,EMT)和细胞衰老是与肿瘤发生密切相关的两个重要事件。在肿瘤发展过程中,上皮间质转化是促进迁移和侵袭的重要机制。细胞衰老作为一个重要的细胞自主的肿瘤预防机制,可以抑制细胞转化和肿瘤发生。虽然EMT和细胞衰老发生在肿瘤发展过程中的不同时间段,但众多研究发现,多种介导EMT发生的关键信号通路和转录因子能调节细胞衰老过程;同时,参与细胞衰老的经典信号通路也影响着EMT进程。就联系这两种细胞生物学事件的调控因素作一综述。     

LncRNA ABHD11‐AS1 promotes the development of endometrial carcinoma by targeting cyclin D1

To investigate the expression, role and mechanism of action of long non‐coding RNA (lncRNA) ABHD11‐AS1 in endometrial carcinoma. The expression of lncRNA ABHD11‐AS1 was quantified by qRT‐PCR in human endometrial carcinoma (n = 89) and normal endometrial tissues (n = 27). LncRNA ABHD11‐AS1 was stably overexpressed or knocked‐down in endometrial carcinoma cell lines to examine the cellular phenotype and expression of related molecules. Compared to normal endometrial tissue, lncRNA ABHD11‐AS1 was significantly overexpressed in endometrial carcinoma. Overexpression of lncRNA ABHD11‐AS1 promoted the proliferation, G1‐S progression, invasion and migration of endometrial cancer cells; inhibited apoptosis; up‐regulated cyclin D1, CDK1, CDK2, CDK4, Bcl‐xl and VEGFA; and down‐regulated p16, while ABHD11‐AS1 down‐regulation has the opposite effect. RNA pull down demonstrated that lncRNA ABHD11‐AS1 binds directly to cyclin D1. Knockdown of cyclin D1 can reverse the effect of ABHD11‐AS1. Overexpression of lncRNA ABHD11‐AS1 increased the tumorigenicity and up‐regulated cyclin D1 in an in vivo model of endometrial cancer in nude mice. LncRNA ABHD11‐AS1 functions as an oncogene to promote cell proliferation and invasion in endometrial carcinoma by positively targeting cyclin D1.     

ISL1在肿瘤发生中的作用

胰岛因子1（Islet1,ISL1）,又称胰岛素增强子结合蛋白1,以多效转录因子的身份在多种组织器官的发育及成熟中发挥作用．ISL1在心、胰腺、神经系统等组织器官的胚胎发育过程中发挥重要作用．Isl1基因敲除可导致小鼠心发育不全,4种胰岛内分泌细胞缺失,以及运动神经元分化、迁移障碍等．ISL1具有促进增殖、抑制凋亡的重要功能．近年的研究表明,ISL1在多种肿瘤发生中存在异常高表达．然而,其在肿瘤发生中的具体作用与机制尚未被阐明,有待进一步探索．