beta-catenin

β - catenin
  • 文章类型: Journal Article
    对形态发生原信号水平的精确控制对于正常发育至关重要。一个突出的问题是:什么机制确保适当的形态发生活性和正确的细胞反应?以前的工作已经确定了信号素(SEMA)受体,神经菌毛蛋白(NRP)和神经丛蛋白(PLXNs),作为Hedgehog(HH)信号通路的正调节因子。这里,我们提供了NRP和PLXN拮抗成纤维细胞和上皮细胞中Wnt信号的证据.Further,成纤维细胞中的Nrp1/2缺失导致基线Wnt途径活性升高和对Wnt刺激的最大应答增加。值得注意的是,与HH信号相反,SEMA受体介导的Wnt拮抗作用与初级纤毛无关。机械上,PLXN和NRP在Dishevelled(DVL)的下游起作用,以蛋白酶体依赖性方式使β-catenin(CTNNB1)不稳定。Further,NRP,但不是PLXN,以GSK3b/CK1依赖性方式拮抗Wnt信号,提示这些SEMA受体不同的抑制机制。总的来说,这项研究将SEMA受体鉴定为新型Wnt通路拮抗剂,它们也可能在整合来自多个输入的信号方面发挥更大的作用.
    Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells. Further, Nrp1/2 deletion in fibroblasts results in elevated baseline Wnt pathway activity and increased maximal responses to Wnt stimulation. Notably, and in contrast to HH signaling, SEMA receptor-mediated Wnt antagonism is independent of primary cilia. Mechanistically, PLXNs and NRPs act downstream of Dishevelled (DVL) to destabilize β-catenin (CTNNB1) in a proteosome-dependent manner. Further, NRPs, but not PLXNs, act in a GSK3β/CK1-dependent fashion to antagonize Wnt signaling, suggesting distinct repressive mechanisms for these SEMA receptors. Overall, this study identifies SEMA receptors as novel Wnt pathway antagonists that may also play larger roles integrating signals from multiple inputs.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Case Reports
    纤维瘤是局部侵袭性的,起源于结缔组织的良性肿瘤。尽管确切的病理生理学仍然未知,先前的创伤或手术被认为是重要的促成因素。儿童患者的椎旁硬纤维瘤的发生极为罕见。这里,我们介绍了一例极为罕见的病例,其中一例没有手术史或家族史的儿科患者发生了椎旁硬纤维瘤.一名9岁女性患者出现4个月的进行性背痛,右下肢无力,和麻木。脊柱成像显示左侧硬膜外椎旁肿块压迫了她的胸脊髓并延伸到左胸腔。神经外科和胸外科的多学科方法使病灶完全切除。患者的症状完全缓解,术后影像学无残留肿瘤迹象。病理学显示,硬纤维状肿瘤被β-连环蛋白染色。在她的最后一次随访中,她复发了,她开始接受索拉非尼治疗。纤维瘤是罕见的结缔组织肿瘤,常发生在局部组织创伤后,比如手术引起的。本报告介绍了一例罕见的小儿椎旁硬纤维瘤,该病例发生在无手术史或家族史的患者中。此类肿瘤应进行手术切除以缓解症状和进行组织诊断。由于硬纤维瘤的高复发率,因此对这些患者进行密切的临床和影像学监测至关重要。
    Desmoid tumors are locally aggressive, benign neoplasms originating in connective tissues. Although the exact pathophysiology remains unknown, antecedent trauma or surgery are believed to be important contributing factors. The occurrence of paraspinal desmoid tumor in pediatric patients is extremely uncommon. Here, we present an exceedingly rare case of a pediatric patient with no surgical or family history who developed a paraspinal desmoid tumor. A 9-year-old female patient presented with 4 months of progressive back pain, right lower extremity weakness, and numbness. Spinal imaging revealed a left epidural paraspinal mass compressing her thoracic spinal cord and extending into the left thoracic cavity. A multidisciplinary approach with neurosurgery and thoracic surgery enabled gross total resection of the lesion. The patient had complete resolution of her symptoms with no signs of residual tumor on postoperative imaging. Pathology revealed a desmoid tumor that avidly stained for beta-catenin. On her last follow-up, she developed a recurrence, to which she was started on sorafenib therapy. Desmoid tumors are rare connective tissue neoplasms that often occur after local tissue trauma, such as that caused by surgery. This report presents a rare case of a pediatric paraspinal desmoid tumor that occurred in a patient with no surgical or family history. Such tumors should undergo surgical resection for symptomatic relief and tissue diagnosis. Close clinical and radiographic surveillance are essential in these patients due to the high recurrence rates of desmoid tumor.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    β-catenin基因突变导致肝癌细胞释放更少的外泌体,从而减少浸润肿瘤的免疫细胞的数量。
    Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    谷氨酰胺代谢的重编程是更普遍的癌症中的关键事件,尤其是肝细胞癌(HCC)。谷氨酰胺消耗通过三羧酸循环的回补为肿瘤提供ATP和代谢物,而谷氨酰胺合成酶的过表达可以提高谷氨酰胺的产量。在HCC中,谷氨酰胺产生的增加是由编码β-连环蛋白的CTNNB1基因中的激活突变驱动的。谷氨酰胺合成或利用增加会影响肿瘤表观遗传学,氧化应激,自噬,免疫和相关途径,例如mTOR(哺乳动物雷帕霉素靶)途径。在这次审查中,我们将讨论强调谷氨酰胺过度生产的促肿瘤或肿瘤抑制作用的研究。很明显,需要更全面的研究作为开发针对谷氨酰胺代谢途径的合适疗法的基础,取决于预测的促或抗肿瘤作用的异常谷氨酰胺代谢在不同的遗传环境。
    The reprogramming of glutamine metabolism is a key event in cancer more generally and in hepatocellular carcinoma (HCC) in particular. Glutamine consumption supplies tumours with ATP and metabolites through anaplerosis of the tricarboxylic acid cycle, while glutamine production can be enhanced by the overexpression of glutamine synthetase. In HCC, increased glutamine production is driven by activating mutations in the CTNNB1 gene encoding β-catenin. Increased glutamine synthesis or utilisation impacts tumour epigenetics, oxidative stress, autophagy, immunity and associated pathways, such as the mTOR (mammalian target of rapamycin) pathway. In this review, we will discuss studies which emphasise the pro-tumoral or tumour-suppressive effect of glutamine overproduction. It is clear that more comprehensive studies are needed as a foundation from which to develop suitable therapies targeting glutamine metabolic pathways, depending on the predicted pro- or anti-tumour role of dysregulated glutamine metabolism in distinct genetic contexts.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Case Reports
    大多数纤维瘤样型纤维瘤病(DTF)病例表现出APC或CTNNB1突变。我们报告了一例肠系膜DTF,其中未发现APC或CTNNB1突变,但在RAD51C中发现了一个不确定意义的种系变异体(VUS)和在MYST3中发现了一个亚克隆突变.在这种情况下,这些遗传变化在DTF中是否重要,或遗传常规DTF细胞是否以低于检测的密度存在未知;在野生型APC/CTNNB1病例的进一步研究中看到结果将是令人感兴趣的。
    Most cases of desmoid-type fibromatosis (DTF) exhibit a mutation in APC or CTNNB1. We report a case of mesenteric DTF in which no mutation in APC or CTNNB1 was found, but a germline variant of uncertain significance (VUS) in RAD51C and a subclonal mutation in MYST3 were identified. Whether these genetic changes are important in DTF in this case, or whether genetically conventional DTF cells were present at a density below detection is unknown; it will be of interest to see results in further studies of wild-type APC/CTNNB1 cases.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Preprint
    背景:以铂为基础的化疗方案是卵巢癌(OC)治疗的支柱,但化疗耐药的出现带来了重大的临床挑战.卵巢癌干细胞(OCSCs)在初级治疗结束时的持久性有助于疾病复发。这里,我们假设细胞外基质在化疗期间保护CSC,并通过激活整合素连接激酶(ILK)支持其致瘤功能,耐药的关键酶。方法使用整合的蛋白质组学和基因表达分析研究TCGA数据集和OC模型,并检查ILK与化学耐药途径和临床结局的相关性。典型的Wnt通路成分,促生存信号,使用OC模型检查干性。为了研究ILK在OCSC表型中的作用,在体外和体内OC模型中使用了ILK与卡铂的新型药理学抑制剂。结果响应纤维连接蛋白(FN)分泌增加和整合素β1聚集,异常ILK激活支持OCSC表型,有助于OC球状体增殖并降低对铂治疗的反应。在肿瘤中检测到ILK与Wnt受体卷曲7(Fzd7)形成的复合物,并显示出与转移进展的强相关性。此外,TCGA数据集证实,高级别浆液性卵巢肿瘤中ILK和Fzd7的联合表达与化疗反应降低和患者预后不良相关。机械上,ILK与Fzd7的相互作用增加了对Wnt配体的反应,从而放大干性相关的Wnt/β-连环蛋白信号传导。值得注意的是,临床前研究表明,新的ILK抑制剂化合物22(cpd-22)单独破坏了ILK与Fzd7和CSC增殖的相互作用。此外,当与卡铂合用时,这种破坏导致持续的AKT抑制,OCSCs的凋亡损伤和小鼠致瘤性降低。结论这种“外向内”的信号机制可能是可操作的,ILK-Fzd7的联合靶向可能代表了根除OCSCs和改善患者预后的新治疗策略。
    UNASSIGNED: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance.
    UNASSIGNED: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models.
    UNASSIGNED: In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice.
    UNASSIGNED: This \"outside-in\" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    目的:研究多叶黄素I(PPI)联合肿瘤坏死因子相关凋亡诱导配体(TRAIL)通过下调Wnt/β-catenin信号通路对骨肉瘤细胞生长的协同作用。
    方法:细胞活力,使用细胞计数试剂盒-8和流式细胞术检测细胞凋亡和细胞周期分布。用倒置相差显微镜观察癌细胞的形态。通过xCELLigence实时细胞分析DP系统和transwell测定法检查了迁移和侵袭能力。聚(二磷酸腺苷-核糖)聚合酶的表达,C-Myc,细胞周期蛋白B1,细胞周期蛋白依赖性激酶1,N-钙粘蛋白,Vimentin,活性-β-连环蛋白,β-连环蛋白,通过蛋白质印迹法测定P-糖原合酶激酶3β(GSK-3β)和GSK-3β。
    结果:PPI致敏TRAIL诱导的活力下降,移民和入侵,以及MG-63和U-2OS骨肉瘤细胞凋亡和细胞周期阻滞的增加。PPI与TRAIL在抑制骨肉瘤细胞生长方面的协同作用至少部分是通过Wnt/β-catenin信号通路的失活实现的。
    结论:PPI和TRAIL联合治疗骨肉瘤可能是一种新的治疗策略。
    OBJECTIVE: To investigate the synergistic effects of polyphyllin I (PPI) combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the growth of osteosarcoma cells through downregulating the Wnt/β-catenin signaling pathway.
    METHODS: Cell viability, apoptosis and cell cycle distribution were examined using cell counting kit-8 and flow cytometry assays. The morphology of cancer cells was observed with inverted phase contrast microscope. The migration and invasion abilities were examined by xCELLigence real time cell analysis DP system and transwell assays. The expressions of poly (adenosine diphosphate-ribose) polymerase, C-Myc, Cyclin B1, cyclin-dependent kinases 1, N-cadherin, Vimentin, Active-β-catenin, β-catenin, p-glycogen synthase kinase 3β (GSK-3β) and GSK-3β were determined by Western blotting assay.
    RESULTS: PPI sensitized TRAIL-induced decrease of viability, migration and invasion, as well as increase of apoptosis and cell cycle arrest of MG-63 and U-2 OS osteosarcoma cells. The synergistic effect of PPI with TRAIL in inhibiting the growth of osteosarcoma cells was at least partially realized through the inactivation of Wnt/β-catenin signaling pathway.
    CONCLUSIONS: The combination of PPI and TRAIL is potentially a novel treatment strategy of osteosarcoma.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Case Reports
    多灶性纤维瘤病(DTF)非常罕见,通常是区域性的。我们报告了三例最初似乎是多灶性的病例,但是随后的详细成像显示,在两个病例中,没有怀疑地追踪神经。这种神经扩散让人想起神经肌肉性脉络膜瘤(NMC),一种罕见的发育损伤,其中成熟的骨骼肌细胞,或者很少有平滑肌细胞,浸润并扩大周围神经。NMC经常与DTF相关联。这两种情况表明,DTF沿神经扩散,并表现为明显的多灶性病变,但实际上是连续的。第三个病例被认为代表真正的多灶性肿瘤发展,可能是由于胸部手术时的肿瘤种植。讨论了DTF与NMC的关系。
    Multifocal desmoid-type fibromatosis (DTF) is very rare and usually regional. We report three cases that initially appeared to be multifocal, but subsequent detailed imaging revealed unsuspected tracking along nerves in two cases. This neural spread is reminiscent of neuromuscular choristoma (NMC), a rare developmental lesion in which mature skeletal muscle cells, or rarely smooth muscle cells, infiltrate and enlarge peripheral nerves. NMC is frequently associated with DTF. These two cases suggest that DTF spread along nerves and appeared as distinct multifocal lesions while actually being contiguous. The third case was felt to represent true multifocal tumor development, possibly due to tumor seeding at the time of chest surgery. The relationship of DTF to NMC is discussed.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    暂无摘要。
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    成釉细胞癌是一种罕见的恶性肿瘤,具有特征性的组织病理学特征,与良性牙源性病变相比,旨在采取积极的手术方法。它影响所有年龄段的人,主要在后下颌骨,没有种族或性别的偏好。从头癌症是其主要类型之一,而第二种类型被定义为良性成釉细胞瘤的恶性改变。分子生物学的快速发展导致成釉细胞瘤含有超过60%的BRAF-V600E基因突变。除了常规成釉细胞癌,在文献中也描述了罕见的组织学变异,包括透明和梭形细胞。这些变体对它是去分化还是独特的实体提出了诊断挑战。数据的缺乏使人们相信这些组织学变化与高级肿瘤和更具侵略性的结果有关。因此,本报告旨在分析一系列诊断为具有梭形和透明细胞类型的头颈部常规成釉细胞癌的患者,并对文献进行简要评估。
    Ameloblastic carcinoma is a rare malignant neoplasm with characteristic histopathological features that are directed towards an aggressive surgical approach than benign odontogenic lesions. It affects people of all ages, mostly in the posterior mandible, without a preference for race or gender. De novo cancer is one of its primary types, while the second type is defined as a malignant change from an antecedent case of benign ameloblastoma. The rapid progression of molecular biology led to the revelation that ameloblastoma contains a BRAF-V600E genetic mutation over 60%. Besides conventional ameloblastic carcinomas, rare histologic variants have also been described in the literature, including clear and spindle cells. These variants pose diagnostic challenges as to whether it is a dedifferentiation or a distinct entity. The dearth of data lends credence to the notion that these histologic variations are related to high-grade neoplasms and more aggressive outcomes. As a result, the current report intends to analyze a series of patients diagnosed with conventional ameloblastic carcinoma of the head and neck region with spindle and clear cell types along with a brief assessment of the literature.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

公众号