Dysregulation of PER3 clock gene and its only pseudogene in colorectal cancer and type 2 diabetes





Circadian clock, PER3, PER3P1 pseudogene, Colorectal cancer, Type 2 diabetes


Paper description:

  • The period (PER) family gene PER3P1 is the only known pseudogene of the circadian clock.
  • The expression patterns of PER3P1 in Iranian patients with colorectal cancer (CRC) and type 2 diabetes (T2D) were examined.
  • PER1/2/3 genes and the PER3P1 pseudogene are significantly downregulated in CRC. PER3 and PER3P1 mRNAs are significantly upregulated in T2D.
  • PER3P1 pseudogene and could serve as a potential diagnostic biomarker in CRC and T2D.

Abstract: The period (PER) family genes (PER1, PER2, and PER3) play a fundamental role in regulating the day/night cycle. PER3 has a pseudogene variant, PER3P1 or PER4, whose role and expression pattern is unclear in human health and diseases. This study was performed to evaluate the expression levels of normal PER family members and the PER3P1 pseudogene in colorectal cancer (CRC) and type 2 diabetes (T2D). Blood samples were taken from 50 diabetic patients and analyzed using real-time PCR for quantification of PER3 and PER3P1 expression. Colorectal tumor tissues of 50 individuals were also used to evaluate the expression of PER members. All PER members, including PER3P1, were found to be downregulated in colorectal tumor samples. Blood samples collected from diabetic subjects revealed an opposite expression pattern; both PER3 and its pseudogene were found to be upregulated when compared to the control group. Our results reveal coordination between the expression pattern of PER3P1 and normal PER family genes. Based on our findings and the pathological importance of this pseudogene, it can be suggested that PER3P1 may be one of the key regulators of the molecular clock network and PER family expression. This hypothesis needs to be confirmed by further studies.


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Zhang Y, Zhang W, Liu C. Integration of peripheral circadian clock and energy metabolism in metabolic tissues. J Mol Cell Biol. 2020;12:481-5. https://doi.org/10.1093/jmcb/mjz112

Deng F, Yang K. Current Status of Research on the Period Family of Clock Genes in the Occurrence and Development of Cancer. J Cancer. 2019;10:1117-23. https://doi.org/10.7150/jca.29212

Tsuchiya Y, Umemura Y, Yagita K. Circadian clock and cancer: From a viewpoint of cellular differentiation. Int J Urol. 2020;27:518-24. https://doi.org/10.1111/iju.14231

Pickel L, Sung H-K. Feeding Rhythms and the Circadian Regulation of Metabolism. Front Nutr. 2020;7:39. https://doi.org/10.3389/fnut.2020.00039

Fatima N, Rana S. Metabolic implications of circadian disruption. Pflugers Arch. 2020;472:513-26. https://doi.org/10.1007/s00424-020-02381-6

Sulli G, Lam MTY, Panda S. Interplay between circadian clock and cancer: new frontiers for cancer treatment. Trends Cancer. 2019;5:475-94. https://doi.org/10.1016/j.trecan.2019.07.002

Sancar A, Lindsey-Boltz LA, Gaddameedhi S, Selby CP, Ye R, Chiou Y-Y, Kemp MG, Hu J, Lee JH, Ozturk N. Circadian Clock, Cancer, and Chemotherapy. Biochemistry. 2015;54:110-23. https://doi.org/10.1021/bi5007354

Hsu C-M, Lin S-F, Lu C-T, Lin P-M, Yang M-Y. Altered expression of circadian clock genes in head and neck squamous cell carcinoma. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2012;33:149-55. https://doi.org/10.1007/s13277-011-0258-2

Umemura Y, Yagita K. Development of the Circadian Core Machinery in Mammals. J Mol Biol. 2020;432:3611-7. https://doi.org/10.1016/j.jmb.2019.11.026

Farshadi E, van der Horst GTJ, Chaves I. Molecular Links between the Circadian Clock and the Cell Cycle. J Mol Biol. 2020;432:3515-24. https://doi.org/10.1016/j.jmb.2020.04.003

Arafa K, Emara M. Insights About Circadian Clock and Molecular Pathogenesis in Gliomas. Front Oncol. 2020;10:199. https://doi.org/10.3389/fonc.2020.00199

Sen A, Hoffmann HM. Role of core circadian clock genes in hormone release and target tissue sensitivity in the reproductive axis. Mol Cell Endocrinol. 2020;501:110655. https://doi.org/10.1016/j.mce.2019.110655

Lee Y. Roles of circadian clocks in cancer pathogenesis and treatment. Exp Mol Med. 2021;53:1529-38. https://doi.org/10.1038/s12276-021-00681-0

Najari Hanjani P, Golalipour M. Circadian Oscillation of Natural Antisense Transcripts Related to Human Core Clock Genes. Rep Biochem Mol Biol. 2021;10:471-6. https://doi.org/10.52547/rbmb.10.3.471

Gotter AL, Reppert SM. Analysis of human Per4. Brain Res Mol Brain Res. 2001;92:19-26. https://doi.org/10.1016/S0169-328X(01)00115-2

Tauber E, Last KS, Olive PJW, Kyriacou CP. Clock gene evolution and functional divergence. J Biol Rhythms. 2004;19:445-58. https://doi.org/10.1177/0748730404268775

Clayton JD, Kyriacou CP, Reppert SM. Keeping time with the human genome. Nature. 2001;409:829-31. https://doi.org/10.1038/35057006

Bartha Á, Győrffy B. TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. Int J Mol Sci. 2021;22:2622. https://doi.org/10.3390/ijms22052622

Zheng H, Zhang G, Zhang L, Wang Q, Li H, Han Y, Xie L, Yan Z, Li Y, An Y, Dong H, Zhu W, Guo X. Comprehensive Review of Web Servers and Bioinformatics Tools for Cancer Prognosis Analysis. Front Oncol. 2020;10:68. https://doi.org/10.3389/fonc.2020.00068

Zhu C, Menyhart O, Győrffy B, He X. The prognostic association of SPAG5 gene expression in breast cancer patients with systematic therapy. BMC Cancer. 2019;19:1046. https://doi.org/10.1186/s12885-019-6260-6

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98-102. https://doi.org/10.1093/nar/gkx247

Zou KH, O'Malley AJ, Mauri L. Receiver-operating characteristic analysis for evaluating diagnostic tests and predictive models. Circulation. 2007;115:654-7. https://doi.org/10.1161/CIRCULATIONAHA.105.594929

Yang S, Berdine G. The receiver operating characteristic (ROC) curve. Southwest Respir Crit Care Chron. 2017;5:34-6. https://doi.org/10.12746/swrccc.v5i19.391

Wang X, Yan D, Teng M, Fan J, Zhou C, Li D, Qiu G, Sun X, Li T, Xing T, Tang H, Peng X, Peng Z. Reduced expression of PER3 is associated with incidence and development of colon cancer. Ann Surg Oncol. 2012;19:3081-8. https://doi.org/10.1245/s10434-012-2279-5

Rahman S, Wittine K, Sedić M, Markova-Car EP. Small Molecules Targeting Biological Clock; A Novel Perspective for Anti-Cancer Drugs. Molecules. 2020;25(2):4937. https://doi.org/10.3390/molecules25214937

Blakeman V, Williams JL, Meng Q-J, Streuli CH. Circadian clocks and breast cancer. Breast Cancer Res BCR. 2016;18:89. https://doi.org/10.1186/s13058-016-0743-z

Rahman S, Kraljević Pavelić S, Markova-Car E. Circadian (De)regulation in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci. Multidisciplinary Digital Publishing Institute; 2019;20:2662. https://doi.org/10.3390/ijms20112662

Yue C, Ren Y, Ge H, Yan L, Xu Y, Wang G, Wu J. Pseudogene DUXAP10 can be used as a diagnostic and prognostic biomarker in human cancers. J Cell Physiol. 2019;234:23685-94. https://doi.org/10.1002/jcp.28937

Poliseno L, Marranci A, Pandolfi PP. Pseudogenes in Human Cancer. Front Med. 2015;2:68. https://doi.org/10.3389/fmed.2015.00068

Dai C, Sheng X, Wang J, Dai Y, Kuang Y, Xu Z, Guo Y. Prognostic Value of PTENP1 Expression in Patients with Cancer: a Systematic Review and Meta-Analysis. Clin Lab. 2022;68(1):210328. https://doi.org/10.7754/Clin.Lab.2021.210328

Deng F, Yang K, Zheng G. Period Family of Clock Genes as Novel Predictors of Survival in Human Cancer: A Systematic Review and Meta-Analysis. Dis Markers. Hindawi; 2020;2020:e6486238. https://doi.org/10.1155/2020/6486238

de Assis LVM, Oster H. The circadian clock and metabolic homeostasis: entangled networks. Cell Mol Life Sci CMLS. 2021;78:4563-87. https://doi.org/10.1007/s00018-021-03800-2

Escobar C, Salgado-Delgado R, Gonzalez-Guerra E, Tapia Osorio A, Angeles-Castellanos M, Buijs RM. Circadian Disruption Leads to Loss of Homeostasis and Disease. Sleep Disord. 2011;2011:964510. https://doi.org/10.1155/2011/964510

Sokolosky ML, Wargovich MJ. Homeostatic Imbalance and Colon Cancer: The Dynamic Epigenetic Interplay of Inflammation, Environmental Toxins, and Chemopreventive Plant Compounds. Front Oncol. 2012;2:57. https://doi.org/10.3389/fonc.2012.00057

Kotas ME, Medzhitov R. Homeostasis, Inflammation, and Disease Susceptibility. Cell. 2015;160:816-27. https://doi.org/10.1016/j.cell.2015.02.010

Johnsson P, Lipovich L, Grandér D, Morris KV. Evolutionary conservation of long noncoding RNAs; sequence, structure, function. Biochim Biophys Acta. NIH Public Access; 2014;1840:1063. https://doi.org/10.1016/j.bbagen.2013.10.035

Qu Z, Adelson DL. Evolutionary conservation and functional roles of ncRNA. Front Genet. 2012;3:205. https://doi.org/10.3389/fgene.2012.00205

Lou W, Ding B, Fu P. Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer. Front Cell Dev Biol. 2020;8:85. https://doi.org/10.3389/fcell.2020.00085

Moreno-García L, López-Royo T, Calvo AC, Toivonen JM, de la Torre M, Moreno-Martínez L, Molina N, Aparicio P, Zaragoza P, Manzano R, Osta R. Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases. Int J Mol Sci. 2020;21:9582. https://doi.org/10.3390/ijms21249582

An Y, Furber KL, Ji S. Pseudogenes regulate parental gene expression via ceRNA network. J Cell Mol Med. 2017;21:185-92. https://doi.org/10.1111/jcmm.12952




How to Cite

Najari-Hanjani P, Najafi R, Akbar S. Dysregulation of PER3 clock gene and its only pseudogene in colorectal cancer and type 2 diabetes. Arch Biol Sci [Internet]. 2022Jun.27 [cited 2023May31];74(2):111-8. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/7526