title: Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer.
abstract: Metastatic recurrence is the leading cause of cancer-related deaths in patients with colorectal carcinoma. To capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression datasets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biologic process. In silico analysis of one metastasis-related coexpression module predicted nuclear factor of activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and downregulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells, whereas inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes upregulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Tripathi
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Natasha G
authors.initials: NG
authors.lastname: Deane
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Hanbing
authors.initials: H
authors.lastname: An
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Shinji
authors.initials: S
authors.lastname: Mima
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Sekhar
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Advanced Computing Center for Research & Education, Vanderbilt University, Nashville, Tennessee.
authors.forename: Zhiao
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Naresh
authors.initials: N
authors.lastname: Prodduturi
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ciombor
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. dan.beauchamp@vanderbilt.edu bing.zhang@vanderbilt.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cell and Development Biology, Vanderbilt University Medical Center, Nashville, Tennessee. dan.beauchamp@vanderbilt.edu bing.zhang@vanderbilt.edu.
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Beauchamp
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014157:Transcription Factors / Q000235:genetics
chemical_list: D050778:NFATC Transcription Factors; D014157:Transcription Factors