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

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.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…However, as noted above, overexpression of ZEB1 in primary cultures of K-Ras-initiated mouse lung adenocarcinoma caused transition to metastatic disease, implying that a higher threshold of ZEB1 is sufficient to drive transition to metastatic disease, as suggested previously 27,48 . In this regard it is of note that combining K-Ras mutation with tumour-suppressor mutations in p53 or Ink4 leads to metastatic lung adenocarcinoma (reviewed in ref.…”

“…Next we evaluated the linkage between ZEB1 and Pten in primary cultures derived from K-Ras LA1 lung adenocarcinomas 27 . These 393P cells showed induction of ZEB1 mRNA, repression of Pten mRNA and accumulation of Akt-S473, and they formed tumours when transplanted back into mouse lungs, but these tumours were not metastatic ( Fig.…”

“…Accordingly, the cells were no longer tumorigenic, demonstrating that ZEB1 induction is necessary for tumour initiation. If ZEB1 was further overexpressed (393P ZEB1), the cells then gave rise to highly metastatic lung tumours 27 , and knockdown of ZEB1 in these cells likewise caused loss of proliferation and viability (Fig. 4c,d).…”

“…Cells derived from four separate embryos were used with similar results. 393P and 393P ZEB1 mouse lung adenocarcinoma cells were a kind gift from J. Kurie 27 . MEFs and ZEB1 mutant MEFs were isolated as described 10 .…”

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

“…induced invasion (Ahn et al, 2012). Similar to the RhoGTPases themselves, their GAP modulators may regulate multiple processes and are likely influenced by cellular context.…”