ABSTRACT
@#[摘 要] 肾癌是泌尿系统最常见的肿瘤之一，早期临床表现不典型，经手术治疗后仍有部分发生复发和转移，病死率高。因此，肾癌的早期诊断和晚期治疗成为亟待解决的两大问题。以YAP/TAZ为核心的Hippo通路在肾癌的发生发展中发挥着重要作用，YAP/TAZ通过直接调控肾癌细胞的转录活性、内源性竞争RNA（ceRNA）机制、促进血管形成、增强肾细胞铁死亡敏感性以及作为肾癌细胞中其他信号通路的转导枢纽等多种机制，促进肾癌细胞的侵袭、转移和耐药；除此之外，YAP/TAZ在多种罕见的肾癌组织学亚型中起到指导分型和预测预后的作用。对于YAP/TAZ在肾癌中的作用及其机制的认识可为临床肾癌的早期诊断和晚期治疗提供理论参考依据。
ABSTRACT
Objective:Cholangiocarcinoma (CCA) is a malignant tumor derived from bile duct epithelial cells with extremely poor prognosis. The Hippo-Yes-associated protein (YAP)/transcription activator with PDZ binding motif (TAZ) signaling plays a critical role in cancer stem cell biology. Previous studies have shown that the positive expression of YAP/TAZ in CCA predicts larger tumor size and unfavorable clinical outcomes. We aim to evaluate the prognostic value of YAP/TAZ detection in CCA patients.Methods:CCA patients who underwent radical resection were retrospectively analyzed at our institution from January 2011 to June 2016. Postoperative pathological specimens were scored by YAP/TAZ immunohistochemical staining. The prognostic value of YAP/TAZ was analyzed by multivariate Cox-proportional hazards model.Results:A total of 91 CCA patients were enrolled. During a median follow-up time of 11.0 months, 69.2% patients relapsed and 45.1% died. The median OS and DFS were 10.7 months and 8.8 months respectively. The YAP/TAZ dual positive patients owned a worse TNM stage ( P=0.015), poorer tissue differentiation ( P=0.007), and a higher CA199 than those in negative patients. Multivariate Cox analysis identified that YAP/TAZ dual positivity as a significant factor predicted poorer OS ( P=0.010) and DFS ( P=0.028) in CCA patients after radical resection. In subgroup analysis, YAP/TAZ combination also significantly predicted OS ( P=0.044) and DFS ( P=0.043) in CCA patients with positive lymphatic metastasis and/or surgical margin who required adjuvant therapy. Conclusions:YAP/TAZ positivity is an independent predictive factor for survival in CCA patients after radical resectiony.
ABSTRACT
BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.
Subject(s)
Humans , Female , Genes, Tumor Suppressor , RNA-Binding Proteins/genetics , Nuclear Matrix-Associated Proteins/genetics , Triple Negative Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Cell Movement , Apoptosis , Cell Line, Tumor , Cell Proliferation , Epithelial-Mesenchymal TransitionABSTRACT
Liver fibrosis is a tissue repair compensatory response to liver injury caused by various chronic factors, ultimately leading to liver cirrhosis, liver failure and even hepatocellular carcinoma. Abnormal activation of hepatic stellate cells is the cellular basis of liver fibrosis development. Pepstatin Pr, the derivative of pepstatin A, was isolated from Streptomyces sp. CPCC 202950. Our purpose was to investigate the anti-fibrotic activity of pepstatin Pr and explore its molecular mechanism. Hepatic stellate cell LX-2 was stimulated by TGFβ1 and sub- sequently treated with pepstatin Pr. Its cytotoxicity was detected by sulforhodamine B (SRB) assay. The expression of COL1A1, α-SMA and cathepsin D, signaling proteins TGFβ, Smad and YAP/TAZ were detected by Western blot or real-time PCR. The results showed that pepstatin Pr was not cytotoxic to LX-2 cells. And pepstatin Pr significantly reduced the mRNA and protein expression of COL1A1 and α-SMA, which are important liver fibrosis markers. Pepstatin Pr also repressed the protein expression level of cathepsin D, TGFβ1, YAP/TAZ, the phospholation level of Smad2, and YAP nuclear translocation. In conclusion, pepstatin Pr exhibits anti-fibrotic effects in TGFβ1-stimulaed LX-2 cells by mediating YAP-TGFβ-Smad pathway.
ABSTRACT
Hepatic fibrosis is a repair response to liver injury,and hepatic stellate cell activation is the center of hepatic fibrosis,which involves Hippo,Notch,Wnt/β-catenin,and TGF-β/Smad signaling pathways.YAP/TAZ is an important nucleus factor for Hippo tumor suppressor pathway and its activity is the key to the growth of whole organs,cell proliferation,and specific amplification of progenitor cells in the process of tissue renewal and regeneration.As the hub of signaling pathways,such as Hippo,Notch,Wnt/β-catenin,TGF-β/Smad signaling,YAP/TAZ regulates the genesis and development of liver fibrosis.
ABSTRACT
The Hippo-YAP/TAZ signaling pathway is an evolutionarily conserved pathway, which has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, and tumorigenesis. Recent research findings show that the Hippo-YAP/TAZ signaling pathway is closely associated with the development and progression of primary liver cancer, and inhibition of the activity of this pathway may be a new method for the treatment of liver cancer. This article reviews the research advances in the role of the Hippo-YAP/TAZ signaling pathway in primary liver cancer.