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Proteins and an inflammatory network expressed in colon tumors.

ABSTRACT: The adenomatous polyposis coli (APC) protein is crucial to homeostasis of normal intestinal epithelia because it suppresses the ?-catenin/TCF pathway. Consequently, loss or mutation of the APC gene causes colorectal tumors in humans and mice. Here, we describe our use of multidimensional protein identification technology (MudPIT) to compare protein expression in colon tumors to that of adjacent healthy colon tissue from Apc(Min/+) mice. Twenty-seven proteins were found to be up-regulated in colon tumors and 25 were down-regulated. As an extension of the proteomic analysis, the differentially expressed proteins were used as "seeds" to search for coexpressed genes. This approach revealed a coexpression network of 45 genes that is up-regulated in colon tumors. Members of the network include the antibacterial peptide cathelicidin (CAMP), Toll-like receptors (TLRs), IL-8, and triggering receptor expressed on myeloid cells 1 (TREM1). The coexpression network is associated with innate immunity and inflammation, and there is significant concordance between its connectivity in humans versus mice (Friedman: p value = 0.0056). This study provides new insights into the proteins and networks that are likely to drive the onset and progression of colon cancer.

SUBMITTER: Zhu W

PROVIDER: S-EPMC3090457 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Proteins and an inflammatory network expressed in colon tumors.

Zhu Wenhong W Fang Changming C Gramatikoff Kosi K Niemeyer Christina C CC Smith Jeffrey W JW

Journal of proteome research 20110412 5

The adenomatous polyposis coli (APC) protein is crucial to homeostasis of normal intestinal epithelia because it suppresses the β-catenin/TCF pathway. Consequently, loss or mutation of the APC gene causes colorectal tumors in humans and mice. Here, we describe our use of multidimensional protein identification technology (MudPIT) to compare protein expression in colon tumors to that of adjacent healthy colon tissue from Apc(Min/+) mice. Twenty-seven proteins were found to be up-regulated in colo ...[more]

PMID: 21366352

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Project description:BACKGROUND: Frameshift mutations in microsatellite instability high (MSI-High) colorectal cancers are a potential source of targetable neo-antigens. Many nonsense transcripts are subject to rapid degradation due to nonsense-mediated decay (NMD), but nonsense transcripts with a cMS in the last exon or near the last exon-exon junction have intrinsic resistance to nonsense-mediated decay (NMD). NMD-resistant transcripts are therefore a likely source of expressed mutant proteins in MSI-High tumours. METHODS: Using antibodies to the conserved N-termini of predicted mutant proteins, we analysed MSI-High colorectal cancer cell lines for examples of naturally expressed mutant proteins arising from frameshift mutations in coding microsatellites (cMS) by immunoprecipitation and Western Blot experiments. Detected mutant protein bands from NMD-resistant transcripts were further validated by gene-specific short-interfering RNA (siRNA) knockdown. A genome-wide search was performed to identify cMS-containing genes likely to generate NMD-resistant transcripts that could encode for antigenic expressed mutant proteins in MSI-High colon cancers. These genes were screened for cMS mutations in the MSI-High colon cancer cell lines. RESULTS: Mutant protein bands of expected molecular weight were detected in mutated MSI-High cell lines for NMD-resistant transcripts (CREBBP, EP300, TTK), but not NMD-sensitive transcripts (BAX, CASP5, MSH3). Expression of the mutant CREBBP and EP300 proteins was confirmed by siRNA knockdown. Five cMS-bearing genes identified from the genome-wide search and without existing mutation data (SFRS12IP1, MED8, ASXL1, FBXL3 and RGS12) were found to be mutated in at least 5 of 11 (45%) of the MSI-High cell lines tested. CONCLUSION: NMD-resistant transcripts can give rise to expressed mutant proteins in MSI-High colon cancer cells. If commonly expressed in primary MSI-High colon cancers, MSI-derived mutant proteins could be useful as cancer specific immunological targets in a vaccine targeting MSI-High colonic tumours.

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Proteins and an inflammatory network expressed in colon tumors.

Publications

Proteins and an inflammatory network expressed in colon tumors.

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