Dataset Information

Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.

ABSTRACT: Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/beta-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here we demonstrate that Wnt/beta-catenin signaling causes CIN via up-regulation of conductin. Human colon tumor samples with CIN show significantly higher expression of conductin than those without. Conductin is up-regulated during mitosis, localizes along the mitotic spindles of colon cancer cells, and binds to polo-like kinase 1. Ectopic expression of conductin or its up-regulation through small interfering RNA-mediated knock-down of APC leads to CIN in chromosomally stable colon cancer cells. High conductin expression compromises the spindle checkpoint, and this requires localized polo-like kinase 1 activity. Knock-down of conductin by small interfering RNA in colon carcinoma cells or gene ablation in mouse embryo fibroblasts enforces the checkpoint.

SUBMITTER: Hadjihannas MV

PROVIDER: S-EPMC1502302 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.

Hadjihannas Michel V MV Brückner Martina M Jerchow Boris B Birchmeier Walter W Dietmaier Wolfgang W Behrens Jürgen J

Proceedings of the National Academy of Sciences of the United States of America 20060630 28

Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/beta-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here w ...[more]

PMID: 16815967

Similar Datasets

Project description:BackgroundChemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.MethodsWe utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.ResultsHere, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.ConclusionOverall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.

Dataset Information

Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.

Publications

Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets