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1.
Oncogene ; 29(25): 3703-14, 2010 Jun 24.
Article in English | MEDLINE | ID: mdl-20440267

ABSTRACT

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression is deregulated in many cancers. Genetic and biochemical approaches coupled with functional assays in cultured cells were used to explore the consequences of Nrf2 repression. Nrf2 suppression by Keap1-directed ubiquitylation or the expression of independent short hairpin RNA (shRNA)/siRNA sequences enhanced cellular levels of reactive oxygen species, Smad-dependent tumor cell motility and growth in soft agar. Loss of Nrf2 was accompanied by concomitant Smad linker region/C-terminus phosphorylation, induction of the E-cadherin transcriptional repressor Slug and suppression of the cell-cell adhesion protein E-cadherin. Ectopic expression of the wildtype but not dominant-negative Nrf2 suppressed the activity of a synthetic transforming growth factor-beta1-responsive CAGA-directed luciferase reporter. shRNA knock-down of Nrf2 enhanced the activity of the synthetic CAGA reporter, as well as the expression of the endogenous Smad target gene plasminogen activator inhibitor-1. Finally, we found that Nrf2/Smad3/Smad4 formed an immunoprecipitable nuclear complex. Thus, loss of Nrf2 increased R-Smad phosphorylation and R-Smad signaling, supporting the hypothesis that loss of Nrf2 in an oncogenic context-dependent manner can enhance cellular plasticity and motility, in part by using transforming growth factor-beta/Smad signaling.


Subject(s)
Cell Movement , NF-E2-Related Factor 2/deficiency , NF-E2-Related Factor 2/genetics , Neoplasms/genetics , Neoplasms/pathology , Cell Adhesion/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Survival/genetics , Humans , Inverted Repeat Sequences , NF-E2-Related Factor 2/metabolism , Phosphorylation , RNA Interference , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism , Smad Proteins/metabolism , Transcription, Genetic , ras Proteins/metabolism
2.
Br J Cancer ; 99(6): 957-65, 2008 Sep 16.
Article in English | MEDLINE | ID: mdl-18781153

ABSTRACT

Although Smad signalling is known to play a tumour suppressor role, it has been shown to play a prometastatic function also in breast cancer and melanoma metastasis to bone. In contrast, mutation or reduced level of Smad4 in colorectal cancer is directly correlated to poor survival and increased metastasis. However, the functional role of Smad signalling in metastasis of colorectal cancer has not been elucidated. We previously reported that overexpression of Smad7 in colon adenocarcinoma (FET) cells induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Here, we have observed that abrogation of Smad signalling by Smad7 induces liver metastasis in a splenic injection model. Polymerase chain reaction with genomic DNA from liver metastases indicates that cells expressing Smad7 migrated to the liver. Increased expression of TGF-beta type II receptor in liver metastases is associated with phosphorylation and nuclear accumulation of Smad2. Immunohistochemical analyses have suggested poorly differentiated spindle cell morphology and higher cell proliferation in Smad7-induced liver metastases. Interestingly, we have observed increased expression and junctional staining of Claudin-1, Claudin-4 and E-cadherin in liver metastases. Therefore, this report demonstrates, for the first time, that blockade of TGF-beta/Smad pathway in colon cancer cells induces metastasis, thus supporting an important role of Smad signalling in inhibiting colon cancer metastasis.


Subject(s)
Colorectal Neoplasms/pathology , Liver Neoplasms/secondary , Smad7 Protein/physiology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma/secondary , Animals , Biomarkers, Tumor/metabolism , Blotting, Western , Cadherins/metabolism , Cell Proliferation , Claudin-1 , Claudin-4 , Colorectal Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/metabolism , Membrane Proteins/metabolism , Mice , Mice, Nude , Phosphorylation , Polymerase Chain Reaction , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Signal Transduction , Smad2 Protein , Smad3 Protein/metabolism , Transforming Growth Factor beta/metabolism , Tumor Cells, Cultured
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