title: APC loss-induced intestinal tumorigenesis in Drosophila: Roles of Ras in Wnt signaling activation and tumor progression.
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.
authors.affiliation: National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Pin
authors.initials: P
authors.lastname: Huang
authors.forename: Fu
authors.initials: F
authors.lastname: Yang
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Quan
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.forename: Rongwen
authors.initials: R
authors.lastname: Xi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D018613:Microscopy, Confocal; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C118001:APC protein, Drosophila; C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D015820:Cadherins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C501889:shg protein, Drosophila; D049452:Green Fluorescent Proteins; D018631:ras Proteins