Article

ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression.

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
The Journal of clinical investigation (Impact Factor: 13.77). 08/2012; 122(9):3170-83. DOI: 10.1172/JCI63608
Source: PubMed

ABSTRACT Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient's likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.

2 Followers
 · 
200 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) is a genetically heterogeneous disease that develops and progresses through several distinct pathways characterized by genomic instability. In recent years, it has emerged that inherent plasticity in some populations of CRC cells can contribute to heterogeneity in differentiation state, metastatic potential, therapeutic response, and disease relapse. Such plasticity is thought to arise through interactions between aberrant signaling events, including persistent activation of the APC/β-catenin and KRAS/BRAF/ERK pathways, and the tumor microenvironment. Here, we highlight key concepts and evidence relating to the role of epithelial-mesenchymal plasticity as a driver of CRC progression and stratification of the disease into distinct molecular and clinicopathological subsets.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53's tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.
    Clinical and Experimental Gastroenterology 01/2014; 7:395-413. DOI:10.2147/CEG.S43738

Full-text (2 Sources)

Download
115 Downloads
Available from
Jun 1, 2014