Sequential Inductions of the ZEB1 Transcription Factor Caused by Mutation of Rb and Then Ras Proteins Are Required for Tumor Initiation and Progression

Abstract

Background: Ras mutation drives tumor initiation as well as invasion. Results: The ZEB1 transcription factor is sequentially induced with mutation of Rb1 and Ras, and these inductions are required for Ras-mediated tumor initiation and then invasion. Conclusion: ZEB1 plays a critical role in initiation and progression of Ras-mediated tumors. Significance: Induction ZEB1 is important for tumor initiation and invasion in a model of Ras-initiated cancer.

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

“…Mutation of the Rb1 family then provides a permissive environment for Ras mutation, and introduction of mutant Ras into primary fibroblasts lacking Rb1 family members is sufficient for oncogenic transformation 11,37 . Rb1 represses ZEB1, and this repression is dominant over induction by Ras 8,38 . Thus, mutation or inactivation of the Rb1 family, a hallmark of tumours, is also required for Ras induction of ZEB1, and in breast cancer Rb1 hyperphosphorylation coincides with ZEB1 induction 39 .…”

“…4m), demonstrating that the cells are addicted to elevated ZEB1. It is then of note that introduction of mutant Ras into these Rb1 family null primary fibroblasts was sufficient for tumorigenesis when the cells were transplanted into nude mice 8,11 , and knockdown of ZEB1 in these cells to reverse its induction by Ras prevented tumour initiation 8,11 . Thus, ZEB1 induction is required for the tumour-initiating capacity of Ras in these cells.…”

“…Experimentally, overexpression and knockdown of ZEB1 in cancer cell lines has demonstrated its importance for tumour progression when these cells are transplanted into mice 5,6 . In addition, we demonstrated previously that induction of ZEB1 is required for viability and tumorigenity of Rastransformed primary culture cells 8,11 . But, notably, tumours formed with these Ras-transformed primary cells were not metastatic, and the fact that ZEB1 was required for tumorigenicity implied that its induction is somehow critical for Ras-mediated tumour initiation.…”

“…ZEB1 regulates epithelial-mesenchymal balance during development, but its expression is linked to cell proliferation through the Rb1 family and thus it is normally downregulated in most post-mitotic adult tissues [7][8][9][10] . Induction of ZEB1 in tumours drives epithelial-mesenchymal transition (EMT) that is thought to facilitate metastasis in later stage tumours, and accordingly its expression is correlated with poor prognosis [5][6][7][8][9][10] . Experimentally, overexpression and knockdown of ZEB1 in cancer cell lines has demonstrated its importance for tumour progression when these cells are transplanted into mice 5,6 .…”

The role of long noncoding RNAs in cancer metastasis

“…The second is that MIAT operates as a chaperone or scaffold that recruits co-repressor complexes to the promoter of the MIR150 host gene, subsequently reducing the transcriptional output of miR-150. While both scenarios may not be mutually exclusive from one another, these regulatory interactions reinforce the notion that EMT is a highly controlled cellular program responsible for modulating the expression of E-cadherin, which is initiated by several key transcriptional repressors including ZEB1 [176,177] . Interestingly, the resulting consequence of the MIAT-miR-150 interaction is the increased expression of ZEB1 and, in turn, a pro-metastatic phenotype, through the transcriptional upregulation of the MIR29 host gene.…”