title: Integrated transcriptional profiling and genomic analyses reveal RPN2 and HMGB1 as promising biomarkers in colorectal cancer.
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.
authors.affiliation: School of Public Health, Wuhan University, Wuhan, China ; Clinical Medicine Research Center, The Affiliated Hospital, Inner Mongolia Medical University, Hohhot, China ; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA.
authors.forename: Jialing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Laboratory for Food Safety and Environmental Technology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.affiliation: Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden.
authors.forename: Stephan Stanislaw
authors.initials: SS
authors.lastname: Späth
authors.affiliation: Department of Oncology, The Affiliated Hospital, Inner Mongolia Medical University, Hohhot, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Qun
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA.
authors.forename: Shaleeka
authors.initials: S
authors.lastname: Cornelius
authors.affiliation: Department of Biology, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Daogang
authors.initials: D
authors.lastname: Guan
authors.affiliation: Department of Bioinformatics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Jiaofang
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Respiratory Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA.
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Clinical Medicine Research Center, The Affiliated Hospital, Inner Mongolia Medical University, Hohhot, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Su
authors.affiliation: School of Public Health, Wuhan University, Wuhan, China.
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Bi
keywords: Colorectal cancer; Gene regulation; Gene signature; Genomic alterations; Transcription factor