論文 - 詳細
| RRC ID | 21817 |
|---|---|
| 著者 | Wang C, Zhao R, Huang P, Yang F, Quan Z, Xu N, Xi R. |
| タイトル | APC loss-induced intestinal tumorigenesis in Drosophila: Roles of Ras in Wnt signaling activation and tumor progression. |
| ジャーナル | Dev Biol |
| Abstract |
Adenomatous polyposis coli (APC) and K-ras are the two most frequently mutated genes found in human colorectal cancers. In human colorectal cancers, Wnt signaling activation after the loss of APC is hypothesized to be the key event for adenoma initiation, whereas additional mutations such as Ras activation are required for the progression from adenoma to carcinoma. However, accumulating data have led to conflicting views regarding the precise role of Ras in APC loss-induced tumorigenesis. Here, using Drosophila midgut as a model system, we show that in the absence of Ras, APC mutant epithelial cells cannot initiate hyperplasia, suggesting that Ras plays an essential role in tumor initiation. Conversely, activating Ras by expressing oncogenic Ras or Raf in APC-deficient cells led to a blockage of cell differentiation and to preinvasive tumor outgrowth, characteristics that are shared by advanced colorectal carcinoma in humans. Mechanistically, we find that Ras is not required for Wnt signaling activation after APC loss, although Ras hyperactivation is able to potentiate Wnt signaling by increasing the cytoplasmic and nuclear accumulation of Armadillo/β-catenin via mechanisms independent of JNK/Rac1 or PI3K-Akt signaling, partly owing to the downregulation of DE-cadherin. Together with the data from gene expression analyses, our results indicate that both parallel and cooperative mechanisms of Wnt and Ras signaling are responsible for the initiation and progression of intestinal tumorigenesis after APC loss. |
| 巻・号 | 378(2) |
| ページ | 122-40 |
| 公開日 | 2013-6-15 |
| DOI | 10.1016/j.ydbio.2013.03.020 |
| PII | S0012-1606(13)00163-2 |
| PMID | 23570874 |
| MeSH | Animals Animals, Genetically Modified Armadillo Domain Proteins / genetics Armadillo Domain Proteins / metabolism Cadherins / genetics Cadherins / metabolism Cell Nucleus / metabolism Cell Transformation, Neoplastic / genetics* Cell Transformation, Neoplastic / metabolism Cytoplasm / metabolism Cytoskeletal Proteins / genetics* Cytoskeletal Proteins / metabolism Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster / genetics Drosophila melanogaster / metabolism Gene Expression Profiling Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Humans Intestinal Mucosa / metabolism* Intestinal Neoplasms / genetics Intestinal Neoplasms / metabolism Intestines / pathology Microscopy, Confocal Mutation Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction Transcription Factors / genetics Transcription Factors / metabolism Wnt Proteins / genetics Wnt Proteins / metabolism Wnt Signaling Pathway / genetics beta Catenin / genetics beta Catenin / metabolism ras Proteins / genetics ras Proteins / metabolism |
| IF | 2.896 |
| 引用数 | 31 |
| WOS 分野 | DEVELOPMENTAL BIOLOGY |
| リソース情報 | |
| ショウジョウバエ | 3722R-2 |