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Journal of Gastrointestinal Surgery

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01-03-2013 | 2012 SSAT Plenary Presentation

Circadian Gene Expression and Clinicopathologic Correlates in Pancreatic Cancer

Authors: Daniel Relles, Jocelyn Sendecki, Galina Chipitsyna, Terry Hyslop, Charles J. Yeo, Hwyda A. Arafat

Published in: Journal of Gastrointestinal Surgery | Issue 3/2013

Abstract

Introduction

The circadian rhythm is responsible for physiologic homeostasis, behavior, and components of multiple metabolic processes. Disruption of the circadian rhythm is associated with cancer development, and several circadian clock genes have been implicated in loss of cell cycle control, impaired DNA damage repair, and subsequent tumor formation. Here, we investigated the expression profiles of several circadian clock genes in pancreatic ductal adenocarcinoma (PDA).

Methods

Quantitative real-time polymerase chain reaction was used to examine the circadian clock genes (brain-muscle-like (Bmal)-ARNTL, circadian locomotor output cycles kaput (Clock), cryptochrome 1 (Cry1), cryptochrome 2 (Cry2), casein kinase 1ε (CK1ε), period 1 (Per1), period 2 (Per2), period 3 (Per3), timeless (Tim), and timeless-interacting protein (Tipin)) in PDA, as well as matching adjacent and benign tissue. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan–Meier survival curves were generated based on gene expression.

Results

In the tumor tissue of PDA patients, compared to their matched adjacent tissue, expression levels of all circadian genes were lower, with statistical significance for Per1, Per2, Per3, Cry1, Cry2, Tipin, Tim, CK1ε, Bmal-ARNTL, and Clock (p < 0.025). PDA tumors also expressed significantly lower levels of the circadian genes when compared to benign lesions for Per1, Per2, Per3, Cry2, Tipin, and CK1ε. A significant association between low levels of expression in the tumors and reduced survival was found with Per1, Per2, Per3, Cry2, Tipin, CK1ε, Clock, and Bmal-ARNTL.

Conclusions

Our results reveal for the first time a dysregulated transcription of several circadian genes in PDA. Elevation of the gene levels in the benign and matched adjacent tissues may be indicative of their role during the process of tumorigenesis. The potential of using circadian genes as predictive markers of the outcomes and survival and distinguishing PDA from benign pancreas must be studied in larger populations to validate and demonstrate their eventual clinical utility.

Lowrey PL, Takahashi JS. Genetics of circadian rhythms in mammalian model organisms. Adv Genet 2011;74:175-230.PubMedCrossRef

Costa G, Haus E, Stevens R. Shift work and cancer - considerations on rationale, mechanisms, and epidemiology. Scand J Work Environ Health 2010 Mar;36(2):163-79.PubMedCrossRef

Hansen J. Light at night, shiftwork, and breast cancer risk. J Natl Cancer Inst 2001 Oct 17;93(20):1513-5.PubMedCrossRef

Borgs L, Beukelaers P, Vandenbosch R, Belachew S, Nguyen L, Malgrange B. Cell "circadian" cycle: new role for mammalian core clock genes. Cell Cycle 2009 Mar 15;8(6):832-7.PubMedCrossRef

Sahar S, Sassone-Corsi P. Circadian clock and breast cancer: a molecular link. Cell Cycle 2007 Jun 1;6(11):1329-31.PubMedCrossRef

Uchida Y, Hirayama J, Nishina H. A common origin: signaling similarities in the regulation of the circadian clock and DNA damage responses. Biol Pharm Bull 2010;33(4):535-44.PubMedCrossRef

Lee JH, Sancar A. Regulation of apoptosis by the circadian clock through NF-kappaB signaling. Proc Natl Acad Sci U S A 2011 Jul 19;108(29):12036-41.PubMedCrossRef

Duong HA, Robles MS, Knutti D, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science 2011 Jun 17;332(6036):1436-9.PubMedCrossRef

King DP, Takahashi JS. Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci 2000;23:713-42.PubMedCrossRef

10.

Sladek M, Rybova M, Jindrakova Z, Zemanova Z, Polidarova L, Mrnka L, O'Neill J, Pacha J, Sumova A. Insight into the circadian clock within rat colonic epithelial cells. Gastroenterology 2007 Oct;133(4):1240-9.PubMedCrossRef

11.

Mazzoccoli G, Panza A, Valvano MR, Palumbo O, Carella M, Pazienza V, Biscaglia G, Tavano F, Di Sebastiano P, Andriulli A, et al. Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients. Chronobiol Int 2011 Dec;28(10):841-51.PubMedCrossRef

12.

Oshima T, Takenoshita S, Akaike M, Kunisaki C, Fujii S, Nozaki A, Numata K, Shiozawa M, Rino Y, Tanaka K, et al. Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol Rep 2011 May;25(5):1439-46.PubMedCrossRef

13.

Hsu CM, Lin SF, Lu CT, Lin PM, Yang MY. Altered expression of circadian clock genes in head and neck squamous cell carcinoma. Tumour Biol 2012 Feb;33(1):149-55.PubMedCrossRef

14.

Yang X, Wood PA, Oh EY, Du-Quiton J, Ansell CM, Hrushesky WJ. Down regulation of circadian clock gene period 2 accelerates breast cancer growth by altering its daily growth rhythm. Breast Cancer Res Treat 2009 Sep;117(2):423-31.PubMedCrossRef

15.

Wang Y, Hua L, Lu C, Chen Z. Expression of circadian clock gene human Period2 (hPer2) in human colorectal carcinoma. World J Surg Oncol 2011 Dec 13;9:166.PubMedCrossRef

16.

Oda A, Katayose Y, Yabuuchi S, Yamamoto K, Mizuma M, Shirasou S, Onogawa T, Ohtsuka H, Yoshida H, Hayashi H, et al. Clock gene mouse period2 overexpression inhibits growth of human pancreatic cancer cells and has synergistic effect with cisplatin. Anticancer Res 2009 Apr;29(4):1201-9.PubMed

17.

Muhlbauer E, Wolgast S, Finckh U, Peschke D, Peschke E. Indication of circadian oscillations in the rat pancreas. FEBS Lett 2004 Apr 23;564(1-2):91-6.PubMedCrossRef

18.

Sadacca LA, Lamia KA, deLemos AS, Blum B, Weitz CJ. An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia 2011 Jan;54(1):120-4.PubMedCrossRef

19.

Zeng ZL, Wu MW, Sun J, Sun YL, Cai YC, Huang YJ, Xian LJ. Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity. J Biochem 2010 Sep;148(3):319-26.PubMedCrossRef

20.

Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV, Takahashi JS, Antoch MP. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/Bmal1 transactivation complex. Proc Natl Acad Sci U S A 2005 Mar 1;102(9):3407-12.PubMedCrossRef

21.

Yang X, Wood PA, Ansell CM, Quiton DF, Oh EY, Du-Quiton J, Hrushesky WJ. The circadian clock gene Per1 suppresses cancer cell proliferation and tumor growth at specific times of day. Chronobiol Int 2009 Oct;26(7):1323-39.PubMedCrossRef

22.

Gu X, Xing L, Shi G, Liu Z, Wang X, Qu Z, Wu X, Dong Z, Gao X, Liu G, et al. The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis. Cell Death Differ 2011 Aug 5.

23.

Antoch MP, Kondratov RV, Takahashi JS. Circadian clock genes as modulators of sensitivity to genotoxic stress. Cell Cycle 2005 Jul;4(7):901-7.PubMedCrossRef

24.

Xiang S, Coffelt SB, Mao L, Yuan L, Cheng Q, Hill SM. Period-2: a tumor suppressor gene in breast cancer. J Circadian Rhythms 2008 Mar 11;6:4.PubMedCrossRef

25.

Lin YM, Chang JH, Yeh KT, Yang MY, Liu TC, Lin SF, Su WW, Chang JG. Disturbance of circadian gene expression in hepatocellular carcinoma. Mol Carcinog 2008 Dec;47(12):925-33.PubMedCrossRef

26.

Yeh KT, Yang MY, Liu TC, Chen JC, Chan WL, Lin SF, Chang JG. Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol 2005 May;206(1):111-20.PubMedCrossRef

27.

Sato F, Nagata C, Liu Y, Suzuki T, Kondo J, Morohashi S, Imaizumi T, Kato Y, Kijima H. PERIOD1 is an anti-apoptotic factor in human pancreatic and hepatic cancer cells. J Biochem 2009 Dec;146(6):833-8.PubMedCrossRef

28.

Gery S, Komatsu N, Baldjyan L, Yu A, Koo D, Koeffler HP. The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol Cell 2006 May 5;22(3):375-82.PubMedCrossRef

29.

Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 2005 Jul;26(7):1241-6.PubMedCrossRef

30.

Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A. Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol 2005 Apr;25(8):3109-16.PubMedCrossRef

31.

Brockschmidt C, Hirner H, Huber N, Eismann T, Hillenbrand A, Giamas G, Radunsky B, Ammerpohl O, Bohm B, Henne-Bruns D, et al. Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo. Gut 2008 Jun;57(6):799-806.PubMedCrossRef

32.

Yang WS, Stockwell BR. Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest. Genome Biol 2008;9(6):R92.PubMedCrossRef

Title: Circadian Gene Expression and Clinicopathologic Correlates in Pancreatic Cancer
Authors: Daniel Relles
Jocelyn Sendecki
Galina Chipitsyna
Terry Hyslop
Charles J. Yeo
Hwyda A. Arafat
Publication date: 01-03-2013
Publisher: Springer-Verlag
Published in: Journal of Gastrointestinal Surgery / Issue 3/2013
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI: https://doi.org/10.1007/s11605-012-2112-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Circadian Gene Expression and Clinicopathologic Correlates in Pancreatic Cancer

Abstract

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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