Abstract
Colorectal cancer (CRC) is a heterogeneous disease that is associated with a gradual accumulation of genetic and epigenetic alterations. Among all CRC stages, stage II tumors are highly heterogeneous with a high relapse rate in about 20–25 % of stage II CRC patients following surgery. Thus, a comprehensive analysis of gene signatures to identify aggressive and metastatic phenotypes in stage II CRC is desired for a more accurate disease classification and outcome prediction. By utilizing a Cancer Array, containing 440 oncogenes and tumor suppressors to profile mRNA expression, we identified a larger number of differentially expressed genes in poorly differentiated stage II colorectal adenocarcinoma tissues, compared to their matched normal tissues. Ontology and Ingenuity Pathway Analysis (IPA) indicated that these genes are involved in functional mechanisms associated with several transcription factors. Genomic alterations of these genes were also investigated through The Cancer Genome Atlas (TCGA) database, utilizing 195 published CRC specimens. The percentage of genomic alterations in these genes was ranked based on their mRNA expression, copy number variations and mutations. This data was further combined with published microarray studies from a large set of CRC tumors classified based on prognostic features. This led to the identification of eight candidate genes including RPN2, HMGB1, AARS, IGFBP3, STAT1, HYOU1, NQO1 and PEA15 that were associated with the progressive phenotype. In particular, RPN2 and HMGB1 displayed a higher genomic alteration frequency in CRC, compared to eight other major solid cancers. Immunohistochemistry was performed on additional 78 stage I–IV CRC samples, where RPN2 protein immunostaining exhibited a significant association with stage III/IV tumors, distant metastasis, and poor differentiation, indicating that RPN2 expression is associated with poor prognosis. Further, our study revealed significant transcriptional regulatory mechanisms, networks and gene signatures, underlying CRC malignant progression and phenotype warranting future clinical investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0043-9) contains supplementary material, which is available to authorized users.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide [1]
Utilizing the Ingenuity Pathway Analysis (IPA) tool, we investigated upstream regulatory molecules that are responsible for identified pathways and altered gene expression in stage II CRC
Using IPA analysis, to identify upstream regulators for the differentially expressed genes in stage II CRC samples used in this study, we observed a strong enrichment for tumor suppressor TP53 family members and oncogenic transcription factor (TF) (i.e.NFKB, AP1 and MYC) that either individually or combined regulate gene expression through shared or unique target genes (Fig. 2; Additional file 1: Table S1)
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide [1]. TNM staging is a standard pathologyZhang et al Cell Biosci (2015) 5:53 for improved outcome prediction, such as T4 lesions, poorly differentiated histology or intestinal obstruction [7], the molecular mechanisms underlining the heterogeneous characteristics of stage II CRC are still not well established. Previous publications indicated that clinical outcome prediction and treatment of stage II CRC remains controversial, with a necessity for a better molecular classification utilizing gene signatures and biomarkers, in order to complement TNM staging [8,9,10]. Further discoveries on TP53 and APC have been utilized to predict poor CRC prognosis, with the presence of defective of APC expression or point mutations in TP53 [18]. These gene signatures have not been successfully utilized as biomarkers to classify the heterogeneous stage II CRC for diagnosis and treatment. More comprehensive gene signatures and signaling transduction pathways related to stage II CRC are needed to understand the disease progression and for an improved prognosis, as well as treatment
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