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.

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    • "We and others showed that ectopic expression of miR-34 suppresses invasion and migration, which are processes required for metastasis, of colorectal, breast, liver, osteosarcoma, and lung cancer cells (Kim et al., 2011b; Mudduluru et al., 2011; Siemens et al., 2011; Dang et al., 2013; Yang et al., 2013b; Zhao et al., 2013b). The direct targets that mediate the suppression of cancer cell migration and invasion by miR-34 include the EMT-TF SNAIL (Kim et al., 2011b; Siemens et al., 2011), the RAS-oncogene homolog RRAS (Kaller et al., 2011), c-kit (Siemens et al., 2013a), Axl (Mackiewicz et al., 2011; Mudduluru et al., 2011), Arhgap1 (Ahn et al., 2012), PDGFR-a/b (Garofalo et al., 2013), Fra-1 (Wu et al., 2012; Yang et al., 2013b), and c-Met (Li et al., 2009a; Yan et al., 2012; Dang et al., 2013; Siemens et al., 2013b). Interestingly, c-Met is also directly repressed by p53 via the inhibition of SP1 binding to its promoter (Hwang et al., 2011). "
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