Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications
| Autor: | Vadim Backman, Ashish K. Tiwari, Andrew J. Radosevich, Christopher R. Weber, Navneet Momi, Anuj Chhaparia, Hemant K. Roy, Bilal Latif, Audrey H. Calderwood, Yolanda Stypula-Cyrus, Ramesh K. Wali, Mart Dela Cruz, Luay M. Almassalha |
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| Rok vydání: | 2016 |
| Předmět: |
Adenoma
Male 0301 basic medicine Cancer Research Carcinogenesis Colorectal cancer Adenocarcinoma Biology Bioinformatics medicine.disease_cause White People Article 03 medical and health sciences Biomarkers Tumor medicine Humans Incidence Nuclear Proteins Cancer Middle Aged medicine.disease digestive system diseases Chromatin Black or African American 030104 developmental biology Oncology Colonic Neoplasms Cancer research Immunohistochemistry Biomarker (medicine) Female |
| Zdroj: | Cancer Prevention Research. 9:844-854 |
| ISSN: | 1940-6215 1940-6207 |
| DOI: | 10.1158/1940-6207.capr-16-0054 |
| Popis: | Alterations in high order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer. Cohesins are a family of proteins that modulate high-order chromatin, although the role in colorectal cancer remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in colorectal cancer biology and as a biomarker focusing in particular on the increased incidence/mortality of colorectal cancer among African-Americans. Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; P = 0.001) and adenocarcinomas (75%; P = 0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n = 78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared with those who were neoplasia-free (47%; P = 0.03). From a racial perspective, colorectal cancer tissues from Caucasians had 56% higher SA1 expression than in African-Americans. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared with matched African-American subjects (73%; P = 0.003). However, as a biomarker for colorectal cancer risk, the diagnostic performance as assessed by area under ROC curve was greater in African-Americans (AUROC = 0.724) than in Caucasians (AUROC = 0.585). From a biologic perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility [micrococcal nuclease (MNase)] assays in SA1-knockdown HT29 colorectal cancer cells. The functional consequences were underscored by increased proliferation (WST-1; P = 0.0002, colony formation; P = 0.001) in the SA1-knockdown HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk stratification biomarker giving potential insights into biologic basis of racial disparities in colorectal cancer. Cancer Prev Res; 9(11); 844–54. ©2016 AACR. |
| Databáze: | OpenAIRE |
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