The Circadian Clock as a Potential Biomarker and Therapeutic Target in
Gastrointestinal Cancers

Sama      Barati; Homina      Saffar; Shima      Mehrabadi; Amir      Avan
Abstract

The circadian clock consists of a hierarchical multi-oscillator network of intracellular and intercellular mechanisms throughout the body that contributes to anticipating metabolic activity and maintaining system homeostasis in response to environmental cues and intrinsic stimuli. Over the past few years, genetic variations of core clock genes have been associated with cancer risk in several epidemiological studies. A growing number of epidemiological research studies have demonstrated a direct correlation between the disturbance of circadian rhythms and the growth of tumors, indicating that shift workers are more susceptible to malignancies of the colon, prostate, ovarian, breast, lung, and liver. One of the most related cancers with circadian rhythm is Gastrointestinal (GI) cancer, which is a leading cause of cancer-related mortality nowadays. The aim of this review was to demonstrate the effect of the clock gene network on the growth of GI cancer, providing molecular targets for GI cancer treatment, possible prognostic biomarkers, and guidance for treatment choices.
[1]
Wang J, Huang Q, Hu X, et al. Disrupting circadian rhythm via the PER1-HK2 axis reverses trastuzumab resistance in gastric cancer. Cancer Res  2022; 82(8): 1503-17.
 [http://dx.doi.org/10.1158/0008-5472.CAN-21-1820] [PMID: 35255118]

[2]
Bechtold DA, Gibbs JE, Loudon ASI. Circadian dysfunction in disease. Trends Pharmacol Sci  2010; 31(5): 191-8.
 [http://dx.doi.org/10.1016/j.tips.2010.01.002] [PMID: 20171747]

[3]
Mehrabadi S, Izadi SF, Pasha S, et al. The potential therapeutic applications of CRISPR/Cas9 in the treatment of gastrointestinal cancers. Curr Mol Med  2024; 24
 [http://dx.doi.org/10.2174/0115665240243076231116080113] [PMID: 38243923]

[4]
Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Lett  2014; 342(1): 9-18.
 [http://dx.doi.org/10.1016/j.canlet.2013.09.040] [PMID: 24099911]

[5]
Sahar S, Corsi SP. Metabolism and cancer: The circadian clock connection. Nat Rev Cancer  2009; 9(12): 886-96.
 [http://dx.doi.org/10.1038/nrc2747] [PMID: 19935677]

[6]
Battaglin F, Chan P, Pan Y, et al. Clocking cancer: The circadian clock as a target in cancer therapy. Oncogene  2021; 40(18): 3187-200.
 [http://dx.doi.org/10.1038/s41388-021-01778-6] [PMID: 33846572]

[7]
Kang Y, Mok S, Zong X, Cao Y. Abstract 3436: Circadian rhythm dysregulation with risk of gastrointestinal cancers: A large-scale prospective analysis. Cancer Res  2024; 84(S6): 3436-6.
 [http://dx.doi.org/10.1158/1538-7445.AM2024-3436]

[8]
Avan A, Mehrabadi S, Velayati M, et al. Growth-hormone-releasing hormone as a prognostic biomarker and therapeutic target in gastrointestinal cancer. Curr Cancer Drug Targets  2023; 23(5): 346-53.
 [http://dx.doi.org/10.2174/1568009623666221228094557] [PMID: 36582060]

[9]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin  2020; 70(1): 7-30.
 [http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]

[10]
Damavandi S, Avan A, Zafari N, et al. Remodeling of the gut microbiota in colorectal cancer and its association with obesity. Curr Pharm Des  2023; 29(4): 256-71.
 [http://dx.doi.org/10.2174/1381612829666230118123018] [PMID: 36654469]

[11]
Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U. Circadian gene expression in individual fibroblasts: Cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell  2004; 119(5): 693-705.
 [http://dx.doi.org/10.1016/j.cell.2004.11.015] [PMID: 15550250]

[12]
Ohdo S. Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption. Adv Drug Deliv Rev  2010; 62(9-10): 859-75.
 [http://dx.doi.org/10.1016/j.addr.2010.01.006] [PMID: 20188774]

[13]
Froy O. Metabolism and circadian rhythms-implications for obesity. Endocr Rev  2010; 31(1): 1-24.
 [http://dx.doi.org/10.1210/er.2009-0014] [PMID: 19854863]

[14]
Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell  2013; 153(4): 812-27.
 [http://dx.doi.org/10.1016/j.cell.2013.04.020] [PMID: 23663780]

[15]
Qandeel HG, Alonso F, Hernandez DJ, et al. Role of vagal innervation in diurnal rhythm of intestinal peptide transporter 1 (PEPT1). J Gastrointest Surg  2009; 13(11): 1976-85.
 [http://dx.doi.org/10.1007/s11605-009-0984-6] [PMID: 19707837]

[16]
Mollazadeh S, Mehrabadi S, Hassanian SM, et al. Photodynamic therapy as a desirable approach in the treatment of colorectal cancer, with special focus on photodynamic nanotherapeutics in immunotherapy. Curr Med Chem  2024; 31
 [http://dx.doi.org/10.2174/0109298673267788231208073338] [PMID: 38275066]

[17]
Murgo E, Colangelo T, Bellet MM, Malatesta F, Mazzoccoli G. Role of the circadian gas-responsive hemeprotein NPAS2 in physiology and pathology. Biology  2023; 12(10): 1354.
 [http://dx.doi.org/10.3390/biology12101354] [PMID: 37887064]

[18]
Liang Y, Wang S, Huang X, Chai R, Tang Q, Yang R. Dysregulation of circadian clock genes as significant clinic factor in the tumorigenesis of hepatocellular carcinoma. Comput Math Methods Med.   2021; 2021: p. 8238833.

[19]
Shangguan Z, Zhang Q. Period circadian regulator 3 (PER3) enhances sensitivity to radiotherapy in gastric cancer via Wnt/β- catenin pathway. Trop J Pharm Res  2023; 22: 1205-10.

[20]
Qian L, Ding X, Fan X, et al. Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma. Chronobiol Int  2023; 40(6): 744-58.
 [http://dx.doi.org/10.1080/07420528.2023.2205936] [PMID: 37122167]

[21]
Zhang LL, He QK, Lv YN, Zhang ZJ, Xiang YK. Expression pattern and prognostic value of circadian clock genes in pancreatic adenocarcinoma. Chronobiol Int  2021; 38(5): 681-93.
 [http://dx.doi.org/10.1080/07420528.2021.1890760] [PMID: 33691542]

[22]
Hasakova K, Reis R, Vician M, Zeman M, Herichova I. Expression of miR-34a-5p is up-regulated in human colorectal cancer and correlates with survival and clock gene PER2 expression. PLoS One  2019; 14(10): e0224396.
 [http://dx.doi.org/10.1371/journal.pone.0224396] [PMID: 31658284]

[23]
Štorcelová M, Vicián M, Reis R, Zeman M, Herichová I. Expression of cell cycle regulatory factors hus1, gadd45a, rb1, cdkn2a and mre11a correlates with expression of clock gene per2 in human colorectal carcinoma tissue. Mol Biol Rep  2013; 40(11): 6351-61.
 [http://dx.doi.org/10.1007/s11033-013-2749-2] [PMID: 24062075]

[24]
Krugluger W, Brandstaetter A, Kállay E, et al. Regulation of genes of the circadian clock in human colon cancer: Reduced period-1 and dihydropyrimidine dehydrogenase transcription correlates in high-grade tumors. Cancer Res  2007; 67(16): 7917-22.
 [http://dx.doi.org/10.1158/0008-5472.CAN-07-0133] [PMID: 17699798]

[25]
Karantanos T, Theodoropoulos G, Gazouli M, et al. Expression of clock genes in patients with colorectal cancer. Int J Biol Markers  2013; 28(3): 280-5.
 [http://dx.doi.org/10.5301/JBM.5000033] [PMID: 23712462]

[26]
Alexander M, Burch JB, Steck S, et al. Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation. Oncol Rep  2015; 33(2): 935-41.
 [http://dx.doi.org/10.3892/or.2014.3667] [PMID: 25501848]

[27]
Holipah T, Hinoura T, Kozaka N, Kuroda Y. The correlation between PER3 rs2640908 polymorphism and colorectal Cancer in the Japanese population. Appl Cancer Res  2019; 39(1): 3.
 [http://dx.doi.org/10.1186/s41241-019-0072-5]

[28]
Cao M, Wang Y, Xiao Y, et al. Activation of the clock gene TIMELESS by H3k27 acetylation promotes colorectal cancer tumorigenesis by binding to Myosin-9. J Exp Clin Cancer Res  2021; 40(1): 162.
 [http://dx.doi.org/10.1186/s13046-021-01936-4] [PMID: 33971927]

[29]
Colangelo T, Carbone A, Mazzarelli F, et al. Loss of circadian gene Timeless induces EMT and tumor progression in colorectal cancer via Zeb1-dependent mechanism. Cell Death Differ  2022; 29(8): 1552-68.
 [http://dx.doi.org/10.1038/s41418-022-00935-y] [PMID: 35034102]

[30]
Stokes K, Nunes M, Trombley C, Flôres DE, Wu G, Taleb Z. The circadian clock gene, bmal1, regulates intestinal stem cell signaling and represses tumor initiation. Cell Mol Gastroenterol Hepatol  2021; 12(5): 1847-1872.e0.
 [http://dx.doi.org/10.1016/j.jcmgh.2021.08.001]

[31]
Sahar N, Qadir J, Riaz SK, Sultan A, Arif A, Malik MFA. Dysregulation of core circadian genes, BMAL1 and CLOCK, in colorectal cancer. Biol Rhythm Res  2022; 53(9): 1400-13.
 [http://dx.doi.org/10.1080/09291016.2021.1940623]

[32]
Cheng LT, Tan GYT, Chang FP, et al. Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt cells. Sci Rep  2023; 13(1): 17597.
 [http://dx.doi.org/10.1038/s41598-023-44997-5] [PMID: 37845346]

[33]
Huisman SA, Ahmadi AR, IJzermans JNM, Verhoef C, van der Horst GTJ, de Bruin RWF. Disruption of clock gene expression in human colorectal liver metastases. Tumour Biol  2016; 37(10): 13973-81.
 [http://dx.doi.org/10.1007/s13277-016-5231-7] [PMID: 27492458]

[34]
Hasakova K, Vician M, Reis R, Zeman M, Herichova I. The expression of clock genes cry1 and cry2 in human colorectal cancer and tumor adjacent tissues correlates differently dependent on tumor location. Neoplasma  2018; 65(6): 986-92.
 [http://dx.doi.org/10.4149/neo_2018_180122N47] [PMID: 29940771]

[35]
He Y, Chen Y, Dai X, Huang S. Dysregulation of circadian clock genes associated with tumor immunity and prognosis in patients with colon cancer. Comput Math Methods Med  2022; 2022: 4957996.

[36]
He A, Huang Z, Zhang R, et al. Circadian clock genes are correlated with prognosis and immune cell infiltration in colon adenocarcinoma. Comput Math Methods Med  2022; 2022: 1709918.
 [http://dx.doi.org/10.1155/2022/4957996] [PMID: 35116071]

[37]
Hu ML, Yeh KT, Lin PM, et al. Deregulated expression of circadian clock genes in gastric cancer. BMC Gastroenterol  2014; 14(1): 67.
 [http://dx.doi.org/10.1186/1471-230X-14-67] [PMID: 24708606]

[38]
Karantanos T, Theodoropoulos G, Pektasides D, Gazouli M. Clock genes: Their role in colorectal cancer. World J Gastroenterol  2014; 20(8): 1986-92.
 [http://dx.doi.org/10.3748/wjg.v20.i8.1986] [PMID: 24587674]

[39]
Papantoniou K, Vinyals CG, Espinosa A, et al. Sleep duration and napping in relation to colorectal and gastric cancer in the MCC-Spain study. Sci Rep  2021; 11(1): 11822.
 [http://dx.doi.org/10.1038/s41598-021-91275-3] [PMID: 34083698]

[40]
Zhao H, Zeng Z-L, Yang J, et al. Prognostic relevance of Period1 (Per1) and Period2 (Per2) expression in human gastric cancer. Int J Clin Exp Pathol  2014; 7(2): 619-30.
 [PMID: 24551282]

[41]
Tian Y, Xie Y, Bai F, Zhang D. Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling. Molecul Cancer Therap  2022; 14: 2154-64.
 [http://dx.doi.org/10.21203/rs.3.rs-2142367/v1]

[42]
Zheng Z X, Cai X, Bi J T, Liu Y Q. The expression and prognostic significance of circadian gene NR1D1/2 in patients with gastric cancer. Res Sq 2023.
 [http://dx.doi.org/10.21203/rs.3.rs-2560341/v1]

[43]
Cao X, Kang W, Xia T, Yuan S, Guo C, Wang W. High expression of the circadian clock gene NPAS2 is associated with progression and poor prognosis of gastric cancer: A single-center study. World J Gastroenterol  2023; 29(23): 3645-57.
 [http://dx.doi.org/10.21203/rs.3.rs-2483331/v1]

[44]
He Q, Guo P, Lin Y, Zhang Z, Lv Y, Xiang Y. Genomics and prognosis analysis of circadian clock genes in hepatocellular carcinoma. Res Sq 2020.
 [http://dx.doi.org/10.21203/rs.3.rs-35099/v1]

[45]
Lin YM, Chang JH, Yeh KT, Yang MY, Liu TC, Lin SF. Disturbance of circadian gene expression in hepatocellular carcinoma. Mol Carcinog  2008; 47(12): 925-33.
 [http://dx.doi.org/10.1002/mc.20446]

[46]
Zhu M, Zhang J, Bian S, et al. Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β- catenin pathway via stabilizing dishevelled segment polarity protein 3.  Biol Proced Online  2022; 24(1): 21.
 [http://dx.doi.org/10.1186/s12575-022-00183-x] [PMID: 36460966]

[47]
Tavano F, Pazienza V, Fontana A, et al. SIRT1 and circadian gene expression in pancreatic ductal adenocarcinoma: Effect of starvation. Chronobiol Int  2015; 32(4): 497-512.
 [http://dx.doi.org/10.3109/07420528.2014.1003351] [PMID: 25798752]

[48]
Wong VCL, Ko JMY, Qi RZ, et al. Abrogated expression of DEC1 during oesophageal squamous cell carcinoma progression is age- and family history-related and significantly associated with lymph node metastasis. Br J Cancer  2011; 104(5): 841-9.
 [http://dx.doi.org/10.1038/bjc.2011.25] [PMID: 21326238]

[49]
Cheng J, Chen F, Cheng Y. Construction and evaluation of a risk score model for lymph node metastasis-associated circadian clock genes in esophageal squamous carcinoma. Cells  2022; 11(21): 3432.
 [http://dx.doi.org/10.3390/cells11213432] [PMID: 36359828]

[50]
Fuhr L, El-Athman R, Scrima R, et al. The circadian clock regulates metabolic phenotype rewiring via HKDC1 and modulates tumor progression and drug response in colorectal cancer. EBioMedicine  2018; 33: 105-21.
 [http://dx.doi.org/10.1016/j.ebiom.2018.07.002] [PMID: 30005951]

[51]
Brandi G, Calabrese C, Pantaleo MA, et al. Circadian variations of rectal cell proliferation in patients affected by advanced colorectal cancer. Cancer Lett  2004; 208(2): 193-6.
 [http://dx.doi.org/10.1016/j.canlet.2003.11.015] [PMID: 15142678]

[52]
Dulong S, Huang Q, Innominato PF, et al. Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer. Sci Rep  2021; 11(1): 24015.
 [http://dx.doi.org/10.1038/s41598-021-03247-2] [PMID: 34907230]

[53]
Parascandolo A, Bonavita R, Astaburuaga R, et al. Effect of naive and cancer-educated fibroblasts on colon cancer cell circadian growth rhythm. Cell Death Dis  2020; 11(4): 289.
 [http://dx.doi.org/10.1038/s41419-020-2468-2] [PMID: 32341349]

[54]
Abolmaali K, Balakrishnan A, Stearns AT, et al. Circadian variation in intestinal dihydropyrimidine dehydrogenase (DPD) expression: A potential mechanism for benefits of 5FU chrono-chemotherapy. Surgery  2009; 146(2): 269-73.
 [http://dx.doi.org/10.1016/j.surg.2009.05.005] [PMID: 19628084]

[55]
Lévi F, Focan C, Karaboué A, et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev  2007; 59(9-10): 1015-35.
 [http://dx.doi.org/10.1016/j.addr.2006.11.001] [PMID: 17692427]

[56]
BH JG, Shankar SJ, Munisamy M, RS A, Sagar VS. Development of pH-dependent chronomodulated delivery systems of 5-fluorouracil and oxaliplatin to treat colon cancer. Int J App Pharm  2020; 12: 118-30.

[57]
Dulong S, Ballesta A, Okyar A, Lévi F. Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling. Mol Cancer Ther  2015; 14(9): 2154-64.
 [http://dx.doi.org/10.1158/1535-7163.MCT-15-0129] [PMID: 26141947]

[58]
Innominato PF, Ballesta A, Huang Q, et al. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Med  2020; 9(12): 4148-59.
 [http://dx.doi.org/10.1002/cam4.3056] [PMID: 32319740]

[59]
Hesse J, Martinelli J, Aboumanify O, Ballesta A, Relógio A. A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer. Comput Struct Biotechnol J  2021; 19: 5170-83.
 [http://dx.doi.org/10.1016/j.csbj.2021.08.051] [PMID: 34630937]

[60]
Basti A, Malhan D, Dumbani M, Dahlmann M, Stein U, Relógio A. Core-clock genes regulate proliferation and invasion via a reciprocal interplay with MACC1 in colorectal cancer cells. Cancers  2022; 14(14): 3458.
 [http://dx.doi.org/10.3390/cancers14143458] [PMID: 35884519]

[61]
Wei W, Zhao W, Zhang Y. CBX4 provides an alternate mode of colon cancer development via potential influences on circadian rhythm and immune infiltration. Front Cell Dev Biol  2021; 9: 669254.
 [http://dx.doi.org/10.3389/fcell.2021.669254] [PMID: 34222240]

[62]
Yu F, Zhang T, Zhou C, et al. The circadian clock gene Bmal1 controls intestinal exporter MRP2 and drug disposition. Theranostics  2019; 9(10): 2754-67.
 [http://dx.doi.org/10.7150/thno.33395] [PMID: 31244920]

[63]
Fuhr L, Basti A, Brás TS, Duarte MF, Relógio A. Antiproliferative effects of cynara cardunculus in colorectal cancer cells are modulated by the circadian clock. Int J Mol Sci  2022; 23(16): 9130.
 [http://dx.doi.org/10.3390/ijms23169130] [PMID: 36012399]

[64]
Moreno-SanJuan S, Puentes-Pardo JD, Casado J, et al. Agomelatine, a melatonin-derived drug, as a new strategy for the treatment of colorectal cancer. Antioxidants  2023; 12(4): 926.
 [http://dx.doi.org/10.3390/antiox12040926] [PMID: 37107301]

[65]
Lévi F, Karaboué A, Gorden L, et al. Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): Safety, efficacy and improved secondary surgical resectability. Cancer Chemother Pharmacol  2011; 67(2): 339-48.
 [http://dx.doi.org/10.1007/s00280-010-1327-8] [PMID: 20401611]

[66]
Okazaki F, Matsunaga N, Hamamura K, et al. Administering xCT inhibitors based on circadian clock improves antitumor effects. Cancer Res  2017; 77(23): 6603-13.
 [http://dx.doi.org/10.1158/0008-5472.CAN-17-0720] [PMID: 29038345]

[67]
Zeng Z, Luo H, Yang J, et al. Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectal cancer. Clin Cancer Res  2014; 20(4): 1042-52.
 [http://dx.doi.org/10.1158/1078-0432.CCR-13-0171] [PMID: 24277452]

[68]
Fang L, Yang Z, Zhou J, et al. Circadian clock gene CRY2 degradation is involved in chemoresistance of colorectal cancer. Mol Cancer Ther  2015; 14(6): 1476-87.
 [http://dx.doi.org/10.1158/1535-7163.MCT-15-0030] [PMID: 25855785]

[69]
Li XM, Djafari MA, Dumitru M, et al. A circadian clock transcription model for the personalization of cancer chronotherapy. Cancer Res  2013; 73(24): 7176-88.
 [http://dx.doi.org/10.1158/0008-5472.CAN-13-1528] [PMID: 24154875]
Cite As
Current Pharmaceutical Design

The Circadian Clock as a Potential Biomarker and Therapeutic Target in Gastrointestinal Cancers

Abstract
