Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β

Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-β expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-β with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.     

Barth综合征3例临床表现及基因突变分析

目的探讨Barth综合征(BTHS)的临床表现、诊断、治疗及转归。方法回顾性分析2013年6月至2014年10月经基因检测确诊的3例BTHS患儿的临床资料。结果 3例患儿均为男性,其中2例为双胞胎。3例患儿均以心肌病和心功能不全为主要表现,同时合并不同程度的左室心肌疏松,其中2例诊断为左室心肌致密化不全(LVNC);3例患儿均有运动发育迟缓和肌无力表现,生长发育落后;尿液3-甲基戊烯二酸(3-MGCA)水平显著增高,其中1例合并中性粒细胞减少;3例患儿均检测到TAZ基因突变,2例双胞胎患儿检测到1个新的错义突变c.527AG(p.H176R),另外1例患儿检测到1个已知的无义突变c.367CT(p.R123X),突变均来源于患儿母亲。随访过程中2例双胞胎分别于生后7个月和7个半月死亡,另1例目前存活。结论 BTHS是引起儿童心肌病的原因之一,对于合并有肌无力、中性粒细胞减少、3-甲基戊烯二酸尿症等表现的男性心肌病患儿,尤其是合并LVNC时,需要重视BTHS的筛查。     

YAP、TAZ蛋白在口腔鳞状细胞癌中的表达及意义

目的: 探讨YAP、TAZ蛋白在口腔鳞状细胞癌中的表达及意义。方法: 选取2014年2月—2017年3月保存的口腔鳞状细胞癌组织标本113例,选取癌旁组织（距癌组织>2 cm）作为对照,采用免疫组织化学染色法检测YAP和TAZ蛋白的表达,比较其与临床病理特征的关系。采用SPSS 19.0软件包对数据进行统计学分析。结果: 癌组织YAP和TAZ蛋白阳性表达率分别为65.49%和61.95%,显著高于癌旁组织（P<0.05）;中低分化、有淋巴结转移、临床Ⅲ期、肿瘤直径>4 cm的患者,YAP蛋白阳性表达率分别为83.64%、80.33%、82.35%和82.61%,显著高于高分化、无淋巴结转移、临床Ⅰ~Ⅱ期、肿瘤直径≤4 cm的患者（P<0.05）;中低分化、临床Ⅲ期、肿瘤直径>4 cm的患者,TAZ蛋白阳性表达率分别为80.00%、85.29%和82.61%,显著高于高分化、临床Ⅰ~Ⅱ期、肿瘤直径≤4 cm的患者（P<0.05）;YAP蛋白与TAZ蛋白表达呈正相关（r_s=0.571,P<0.05）。结论: YAP和TAZ蛋白在口腔鳞状细胞癌中呈高表达,与肿瘤分化程度、肿瘤直径等临床病理特征有关,提示Hippo信号通路可能参与了口腔鳞状细胞癌的发生与发展。     

CD44v8-10 is a marker for malignant traits and a potential driver of bone metastasis in a subpopulation of prostate cancer cells

Objective:Bone metastasis is a clinically important outcome of prostate carcinoma (PC). We focused on the phenotypic and functional characterization of a particularly aggressive phenotype within the androgen-independent bone metastasis-derived PC3 cell line. These cells, originated from the spontaneous conversion of a CD44-negative subpopulation, stably express the CD44v8-10 isoform (CD44v8-10^pos) and display stem cell-like features and a marked invasive phenotype in vitro that is lost upon CD44v8-10 silencing.Methods:Flow cytometry, enzyme-linked immunoassay, immunofluorescence, and Western blot were used for phenotypic and immunologic characterization. Real-time quantitative polymerase chain reaction and functional assays were used to assess osteomimicry.Results:Analysis of epithelial–mesenchymal transition markers showed that CD44v8-10^pos PC3 cells surprisingly display epithelial phenotype and can undergo osteomimicry, acquiring bone cell phenotypic and behavioral traits. Use of specific siRNA evidenced the ability of CD44v8-10 variant to confer osteomimetic features, hence the potential to form bone-specific metastasis. Moreover, the ability of tumors to activate immunosuppressive mechanisms which counteract effective immune responses is a sign of the aggressiveness of a tumor. Here we report that CD44v8-10^pos cells express programmed death ligand 1, a negative regulator of anticancer immunity, and secrete exceptionally high amounts of interleukin-6, favoring osteoclastogenesis and immunosuppression in bone microenvironment. Notably, we identified a novel pathway activated by CD44v8-10, involving tafazzin (TAZ) and likely the Wnt/TAZ axis, known to play a role in upregulating osteomimetic genes.Conclusions:CD44v8-10 could represent a marker of a more aggressive bone metastatic PC population exerting a driver role in osteomimicry in bone. A novel link between TAZ and CD44v8-10 is also shown.     

Daptomycin resistant Enterococcus faecalis has a mutation in liaX,which encodes a surface protein that inhibits the LiaFSR systems and cell membrane remodeling

The emergence of daptomycin (DAP) resistant Enterococcus species has increased worldwide, but the mechanisms for DAP resistance are not fully understood. We report a case of DAP resistant Enterococcus faecalis, from a clinical sample of a patient with diabetic ulcers, after DAP therapy. Whole-genome sequencing analysis revealed that the isolate had a loss-of-function point mutation within liaX encoding DAP-sensing surface protein, which inhibits the LiaFSR systems and cell membrane remodeling. This is the first case report of a clinical DAP resistant E. faecalis with a mutation in liaX.     

Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis

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