Circadian Dysregulation in Colorectal Cancer: Decreased Nuclear Translocation of Cryptochrome 2.
Mark A Valasek, Russell N Van Gelder, Suzanne M Dintzis. University of Washington Medical Center, Seattle
Background: There is growing evidence that circadian rhythms impact development and response to treatment of cancer. Mice lacking critical circadian 'clock genes' have increased rates of tumor development. Cryptochromes are a family of transcriptional repressors which are critical to the core circadian clock mechanism in mammals. Loss of cryptochromes in mice suppresses cancer development in p53 knockout mice. Recent data demonstrate that cryptochrome expression level is a prognostic marker for B-cell lymphoma. The role of cryptochrome expression in solid tumors has not been evaluated to date. In this study, we analyzed the expression of Cryptochrome 2 (Cry 2) by immunohistochemistry in colorectal carcinoma and pre-malignant lesions.
Design: Using human tissue microarrays containing 204 sections, including non-neoplastic, adenomatous and carcinomatous colon and metastatic disease, we determined nuclear expression of p53 and Cry2 by immunohistochemistry. Nuclear expression levels were quantified using the Allred scoring method applied to appropriate cell populations. Microarrays were scored by two independent readers. Significant differences between groups were determined by ANOVA with post-hoc testing.
Results: Nuclear Cry2 staining levels showed significant variation across classes of colon tissue, ranging from near 100% expression in benign colon to 41% expression among lymph node colorectal metastases. Nuclear Cry2 was significantly downregulated when comparing normal tissues with large tubulovillous or villous adenomas, adenocarcinoma at T1-T2 stage, or T3 stage (decreased 39-56%). Cry2 staining was generally inverse to p53 staining except in large adenomas.
Conclusions: Cry2 nuclear expression is decreased in colorectal cancers and large adenomas. This finding suggests that the circadian clock is progressively dysregulated in pre-malignant and malignant lesions of the colon. Further studies will determine if Cryptochrome expression has prognostic significance in colorectal carcinoma.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 224, Wednesday Morning