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Cancer stem cell generation during epithelial-mesenchymal transition is temporally gated by intrinsic circadian clocks

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Abstract

Epithelial-mesenchymal transition (EMT) is a key event preceding tumor cell metastasis that increases cell invasiveness and cancer stem cell (CSC) populations. Studies suggest that genes used in generating circadian rhythms also serve in regulating EMT. To test the role of circadian clocks in cellular EMT events two cancer cell lines were compared, one that has a well-established circadian clock, C6 from rat glioma, and one that does not, MCF-7 from human breast tumor. MCF-7 tumorsphere cultures were tested for evidence of circadian rhythms because of previously reported circadian rhythm enhancement in C6 tumorspheres shown by elevated rhythm amplitude and increased expression of circadian clock gene Per2. Bioluminescence imaging of Per2 gene expression in MCF-7 tumorspheres revealed a previously unconfirmed circadian clock in this important cancer research model. Inducing CSC generation through EMT in C6 and MCF-7 monolayer cultures revealed circadian oscillations in the size of the post-EMT CSC population, confirming that circadian rhythms are additional processes controlling this stage of cancer progression. EMT was verified by distinct cellular morphological changes and expression of stem cell proteins OCT4, nestin, MSI1, and CD133 along with EMT-related proteins ZEB1, vimentin, and TWIST. Quantifying single-cell events and behaviors through time-lapse imaging indicated the post-EMT population size was determined largely by circadian rhythms in epithelial-like cancer cells undergoing EMT. We then identified a specific phase of the circadian rhythm in Per2 gene activation as a potential target for therapeutic treatments that may suppress EMT, minimize CSCs, and limit metastasis.

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Abbreviations

ANOVA:

Analysis of variance

BLI:

Bioluminescence imaging

CCD:

Charge-coupled device

CSC:

Cancer stem cell

DAPI:

4′,6-Diamidino-2-phenylindole

DMEM:

Dulbecco’s modified eagle medium

E-cell:

Epithelial cancer cell

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

FBS:

Fetal bovine serum

FGF:

Fibroblast growth factor

GFAP:

Glial fibrillary acidic protein

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

ICC:

Immunocytochemistry

JTK:

Jonckheere-Terpstra-Kendall

LED:

Light-emitting diode

LS:

Lomb-Scargle

M-cell:

Mesenchymal cancer cell

MAPK:

Mitogen activated protein kinase

MET:

Mesenchymal-epithelial transition

miRNA:

MicroRNA

MSI1:

Musashi RNA binding protein 1

OCT4:

Octamer-binding transcription factor 4

PBS:

Phosphate-buffered saline

PCNA:

Proliferating cell nuclear antigen

PDGF:

Platelet derived growth factor

PDGFRA:

Platelet derived growth factor receptor alpha

qRT-PCR:

Quantitative real-time polymerase chain reaction

ROI:

Region of interest

SCM:

Stem cell medium

SCN:

Suprachiasmatic nucleus

SD:

Standard deviation

SEM:

Standard error of the mean

SM:

Serum medium

TLI:

Time-lapse imaging

TWIST:

Twist family basic-helix-loop-helix transcription factor

ZEB1:

Zinc finger E-box binding homeobox 1

References

  1. Davis K, Roden LC, Leaner VD, van der Watt PJ (2019) The tumour suppressing role of the circadian clock. IUBMB Life. https://doi.org/10.1002/iub.2005

    Article  PubMed  Google Scholar 

  2. Sancar A, Lindsey-Boltz LA, Gaddameedhi S, Selby CP, Ye R, Chiou YY, Kemp MG, Hu J, Lee JH, Ozturk N (2015) Circadian clock, cancer, and chemotherapy. Biochemistry 54(2):110–123. https://doi.org/10.1021/bi5007354

    Article  CAS  PubMed  Google Scholar 

  3. Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, Tothova Z, Tejero H, Heckl D, Jaras M, Chen MC, Li H, Tamayo A, Cowley GS, Rozenblatt-Rosen O, Al-Shahrour F, Regev A, Ebert BL (2016) Core circadian clock genes regulate leukemia stem cells in AML. Cell 165(2):303–316. https://doi.org/10.1016/j.cell.2016.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Okazaki F, Matsunaga N, Okazaki H, Azuma H, Hamamura K, Tsuruta A, Tsurudome Y, Ogino T, Hara Y, Suzuki T, Hyodo K, Ishihara H, Kikuchi H, To H, Aramaki H, Koyanagi S, Ohdo S (2016) Circadian clock in a mouse colon tumor regulates intracellular iron levels to promote tumor progression. J Biol Chem 291(13):7017–7028. https://doi.org/10.1074/jbc.M115.713412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Angelousi A, Kassi E, Nasiri-Ansari N, Randeva HS, Kaltsas GA, Chrousos GP (2019) Clock genes and cancer development in particular in endocrine tissues. Endocr Relat Cancer. https://doi.org/10.1530/ERC-19-0094

    Article  PubMed  Google Scholar 

  6. Labrecque N, Cermakian N (2015) Circadian clocks in the immune system. J Biol Rhythms 30(4):277–290. https://doi.org/10.1177/0748730415577723

    Article  CAS  PubMed  Google Scholar 

  7. Wagner PM, Sosa Alderete LG, Gorne LD, Gaveglio V, Salvador G, Pasquare S, Guido ME (2019) Proliferative glioblastoma cancer cells exhibit persisting temporal control of metabolism and display differential temporal drug susceptibility in chemotherapy. Mol Neurobiol 56(2):1276–1292. https://doi.org/10.1007/s12035-018-1152-3

    Article  CAS  PubMed  Google Scholar 

  8. Gutierrez-Monreal MA, Trevino V, Moreno-Cuevas JE, Scott SP (2016) Identification of circadian-related gene expression profiles in entrained breast cancer cell lines. Chronobiol Int 33(4):392–405. https://doi.org/10.3109/07420528.2016.1152976

    Article  CAS  PubMed  Google Scholar 

  9. Slat EA, Sponagel J, Marpegan L, Simon T, Kfoury N, Kim A, Binz A, Herzog ED, Rubin JB (2017) Cell-intrinsic, Bmal1-dependent circadian regulation of temozolomide sensitivity in glioblastoma. J Biol Rhythms 32(2):121–129. https://doi.org/10.1177/0748730417696788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Streuli CH, Meng QJ (2019) Influence of the extracellular matrix on cell-intrinsic circadian clocks. J Cell Sci. https://doi.org/10.1242/jcs.207498

    Article  PubMed  Google Scholar 

  11. Shilts J, Chen G, Hughey JJ (2018) Evidence for widespread dysregulation of circadian clock progression in human cancer. PeerJ 6:e4327. https://doi.org/10.7717/peerj.4327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fan W, Caiyan L, Ling Z, Jiayun Z (2017) Aberrant rhythmic expression of cryptochrome2 regulates the radiosensitivity of rat gliomas. Oncotarget 8(44):77809–77818. https://doi.org/10.18632/oncotarget.20835

    Article  PubMed  PubMed Central  Google Scholar 

  13. Liu Z, Yu K, Zheng J, Lin H, Zhao Q, Zhang X, Feng W, Wang L, Xu J, Xie D, Zuo ZX, Liu ZX, Zheng Q (2019) Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers. Cancer Med. https://doi.org/10.1002/cam4.2035

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sahar S, Sassone-Corsi P (2009) Metabolism and cancer: the circadian clock connection. Nat Rev Cancer 9(12):886–896. https://doi.org/10.1038/nrc2747

    Article  CAS  PubMed  Google Scholar 

  15. Sund M, Kalluri R (2009) Tumor stroma derived biomarkers in cancer. Cancer Metastasis Rev 28(1–2):177–183. https://doi.org/10.1007/s10555-008-9175-2

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428. https://doi.org/10.1172/JCI39104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14(10):611–629. https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lee JK, Joo KM, Lee J, Yoon Y, Nam DH (2014) Targeting the epithelial to mesenchymal transition in glioblastoma: the emerging role of MET signaling. OncoTargets Ther 7:1933–1944. https://doi.org/10.2147/OTT.S36582

    Article  CAS  Google Scholar 

  19. Kahlert UD, Nikkhah G, Maciaczyk J (2013) Epithelial-to-mesenchymal(-like) transition as a relevant molecular event in malignant gliomas. Cancer Lett 331(2):131–138. https://doi.org/10.1016/j.canlet.2012.12.010

    Article  CAS  PubMed  Google Scholar 

  20. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751. https://doi.org/10.1038/onc.2010.215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527(7579):525–530. https://doi.org/10.1038/nature16064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aiello NM, Brabletz T, Kang Y, Nieto MA, Weinberg RA, Stanger BZ (2017) Upholding a role for EMT in pancreatic cancer metastasis. Nature 547(7661):E7–E8. https://doi.org/10.1038/nature22963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ballesta A, Innominato PF, Dallmann R, Rand DA, Levi FA (2017) Systems chronotherapeutics. Pharmacol Rev 69(2):161–199. https://doi.org/10.1124/pr.116.013441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. De A, Beligala DH, Birkholz TM, Geusz ME (2019) Anticancer properties of curcumin and interactions with the circadian timing system. Integr Cancer Ther 18:1534735419889154. https://doi.org/10.1177/1534735419889154

    Article  CAS  PubMed Central  Google Scholar 

  25. Tamai TK, Nakane Y, Ota W, Kobayashi A, Ishiguro M, Kadofusa N, Ikegami K, Yagita K, Shigeyoshi Y, Sudo M, Nishiwaki-Ohkawa T, Sato A, Yoshimura T (2018) Identification of circadian clock modulators from existing drugs. EMBO Mol Med. https://doi.org/10.15252/emmm.201708724

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sulli G, Manoogian ENC, Taub PR, Panda S (2018) Training the circadian clock, clocking the drugs, and drugging the clock to prevent, manage, and treat chronic diseases. Trends Pharmacol Sci 39(9):812–827. https://doi.org/10.1016/j.tips.2018.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sharma VP, Anderson NT, Geusz ME (2014) Circadian properties of cancer stem cells in glioma cell cultures and tumorspheres. Cancer Lett 345(1):65–74. https://doi.org/10.1016/j.canlet.2013.11.009

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X, Nie D, Chakrabarty S (2010) Growth factors in tumor microenvironment. Front Biosci (Landmark Ed) 15:151–165

    Article  CAS  Google Scholar 

  29. Ananthasubramaniam B, Herzog ED, Herzel H (2014) Timing of neuropeptide coupling determines synchrony and entrainment in the mammalian circadian clock. PLoS Comput Biol 10(4):e1003565. https://doi.org/10.1371/journal.pcbi.1003565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Beligala DH, De A, Geusz ME (2018) A meta-analysis characterizing stem-like gene expression in the suprachiasmatic nucleus and its circadian clock. Biomed Res Int 2018:3610603. https://doi.org/10.1155/2018/3610603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Beligala DH, De A, Malik A, Silver R, Rimu K, LeSauter J, McQuillen HJ, Geusz ME (2019) Musashi-2 and related stem cell proteins in the mouse suprachiasmatic nucleus and their potential role in circadian rhythms. Int J Dev Neurosci 75:44–58. https://doi.org/10.1016/j.ijdevneu.2019.04.007

    Article  CAS  PubMed  Google Scholar 

  32. Noguchi T, Wang LL, Welsh DK (2013) Fibroblast PER2 circadian rhythmicity depends on cell density. J Biol Rhythms 28(3):183–192. https://doi.org/10.1177/0748730413487494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li X, Wang S, Yang S, Ying J, Yu H, Yang C, Liu Y, Wang Y, Cheng S, Xiao J, Guo H, Jiang Z, Wang Z (2018) Circadian locomotor output cycles kaput affects the proliferation and migration of breast cancer cells by regulating the expression of E-cadherin via IQ motif containing GTPase activating protein 1. Oncol Lett 15(5):7097–7103. https://doi.org/10.3892/ol.2018.8226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Feillet C, van der Horst GT, Levi F, Rand DA, Delaunay F (2015) Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth. Frontiers Neurol 6:96. https://doi.org/10.3389/fneur.2015.00096

    Article  Google Scholar 

  35. Ishiwata T (2016) Cancer stem cells and epithelial-mesenchymal transition: novel therapeutic targets for cancer. Pathol Int 66(11):601–608. https://doi.org/10.1111/pin.12447

    Article  CAS  PubMed  Google Scholar 

  36. Fujioka A, Takashima N, Shigeyoshi Y (2006) Circadian rhythm generation in a glioma cell line. Biochem Biophys Res Commun 346(1):169–174

    Article  CAS  PubMed  Google Scholar 

  37. Sarma A, Sharma VP, Sarkar AB, Sekar MC, Samuel K, Geusz ME (2016) The circadian clock modulates anti-cancer properties of curcumin. BMC Cancer 16(1):759. https://doi.org/10.1186/s12885-016-2789-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lellupitiyage Don SS, Lin HH, Furtado JJ, Qraitem M, Taylor SR, Farkas ME (2019) Circadian oscillations persist in low malignancy breast cancer cells. Cell Cycle 18(19):2447–2453. https://doi.org/10.1080/15384101.2019.1648957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang Y, Giacchetti S, Parouchev A, Hadadi E, Li X, Dallmann R, Xandri-Monje H, Portier L, Adam R, Levi F, Dulong S, Chang Y (2018) Dosing time dependent in vitro pharmacodynamics of Everolimus despite a defective circadian clock. Cell Cycle 17(1):33–42. https://doi.org/10.1080/15384101.2017.1387695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xiang S, Mao L, Duplessis T, Yuan L, Dauchy R, Dauchy E, Blask DE, Frasch T, Hill SM (2012) Oscillation of clock and clock controlled genes induced by serum shock in human breast epithelial and breast cancer cells: regulation by melatonin. Breast Cancer (Auckl) 6:137–150. https://doi.org/10.4137/BCBCR.S9673

    Article  CAS  Google Scholar 

  41. Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U (2000) Resetting of circadian time peripheral tissues by glucocorticoid signaling. Science 289(5488):2344–2347

    Article  CAS  PubMed  Google Scholar 

  42. Heng BC, Jiang S, Yi B, Gong T, Lim LW, Zhang C (2019) Small molecules enhance neurogenic differentiation of dental-derived adult stem cells. Arch Oral Biol 102:26–38. https://doi.org/10.1016/j.archoralbio.2019.03.024

    Article  CAS  PubMed  Google Scholar 

  43. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9(5):391–403. https://doi.org/10.1016/j.ccr.2006.03.030

    Article  CAS  PubMed  Google Scholar 

  44. Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P, Postigo A (2010) ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 29(24):3490–3500. https://doi.org/10.1038/onc.2010.102

    Article  CAS  PubMed  Google Scholar 

  45. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, Brunton VG, Morton J, Sansom O, Schuler J, Stemmler MP, Herzberger C, Hopt U, Keck T, Brabletz S, Brabletz T, (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11(12):1487–1495. https://doi.org/10.1038/ncb1998

    Article  CAS  PubMed  Google Scholar 

  46. Rushing EJ, Sandberg GD, Horkayne-Szakaly I (2010) High-grade astrocytomas show increased Nestin and Wilms's tumor gene (WT1) protein expression. Int J Surg Pathol 18(4):255–259. https://doi.org/10.1177/1066896909338596

    Article  CAS  PubMed  Google Scholar 

  47. Lewis-Tuffin LJ, Rodriguez F, Giannini C, Scheithauer B, Necela BM, Sarkaria JN, Anastasiadis PZ (2010) Misregulated E-cadherin expression associated with an aggressive brain tumor phenotype. PLoS One 5(10):e13665. https://doi.org/10.1371/journal.pone.0013665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang XY, Penalva LO, Yuan H, Linnoila RI, Lu J, Okano H, Glazer RI (2010) Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol Cancer 9:221. https://doi.org/10.1186/1476-4598-9-221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ling GQ, Chen DB, Wang BQ, Zhang LS (2012) Expression of the pluripotency markers Oct3/4, Nanog and Sox2 in human breast cancer cell lines. Oncol Lett 4(6):1264–1268. https://doi.org/10.3892/ol.2012.916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rossetti S, Esposito J, Corlazzoli F, Gregorski A, Sacchi N (2012) Entrainment of breast (cancer) epithelial cells detects distinct circadian oscillation patterns for clock and hormone receptor genes. Cell Cycle 11(2):350–360. https://doi.org/10.4161/cc.11.2.18792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chacolla-Huaringa R, Moreno-Cuevas J, Trevino V, Scott SP (2017) Entrainment of breast cell lines results in rhythmic fluctuations of MicroRNAs. Int J Mol Sci. https://doi.org/10.3390/ijms18071499

    Article  PubMed  PubMed Central  Google Scholar 

  52. Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98(24):1777–1785. https://doi.org/10.1093/jnci/djj495

    Article  PubMed  Google Scholar 

  53. Takahashi JS (2016) Molecular architecture of the circadian clock in mammals. In: Sassone-Corsi P, Christen Y (eds) A time for metabolism and hormones. Springer, Cham. https://doi.org/10.1007/978-3-319-27069-2_2

    Chapter  Google Scholar 

  54. Proctor E, Waghray M, Lee CJ, Heidt DG, Yalamanchili M, Li C, Bednar F, Simeone DM (2013) Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. PLoS One 8(2):e55820. https://doi.org/10.1371/journal.pone.0055820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yin J, Zheng G, Jia X, Zhang Z, Zhang W, Song Y, Xiong Y, He Z (2013) A Bmi1-miRNAs cross-talk modulates chemotherapy response to 5-fluorouracil in breast cancer cells. PLoS One 8(9):e73268. https://doi.org/10.1371/journal.pone.0073268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB (2014) A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A 111(45):16219–16224. https://doi.org/10.1073/pnas.1408886111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jager R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM (2014) Comparative absorption of curcumin formulations. Nutr J 13:11. https://doi.org/10.1186/1475-2891-13-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Enright JT (1980) Temporal precision in circadian systems: a reliable neuronal clock from unreliable components? Science 209(4464):1542–1545

    Article  CAS  PubMed  Google Scholar 

  59. Ghosh P, Singh UN (1997) Intercellular communication in rapidly proliferating and differentiated C6 glioma cells in culture. Cell Biol Int 21(9):551–557. https://doi.org/10.1006/cbir.1997.0193

    Article  CAS  PubMed  Google Scholar 

  60. Welsh DK, Yoo SH, Liu AC, Takahashi JS, Kay SA (2004) Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol 14(24):2289–2295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Patke A, Young MW, Axelrod S (2020) Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol 21(2):67–84. https://doi.org/10.1038/s41580-019-0179-2

    Article  CAS  PubMed  Google Scholar 

  62. Balsalobre A, Marcacci L, Schibler U (2000) Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr Biol 10(20):1291–1294. https://doi.org/10.1016/s0960-9822(00)00758-2

    Article  CAS  PubMed  Google Scholar 

  63. Akashi M, Nishida E (2000) Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev 14(6):645–649

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Mogi A, Yomoda R, Kimura S, Tsushima C, Takouda J, Sawauchi M, Maekawa T, Ohta H, Nishino S, Kurita M, Mano N, Osumi N, Moriya T (2018) Entrainment of the Circadian Clock in Neural Stem Cells by Epidermal growth factor is closely associated with ERK1/2-mediated induction of multiple clock-related genes. Neuroscience 379:45–66. https://doi.org/10.1016/j.neuroscience.2018.02.045

    Article  CAS  PubMed  Google Scholar 

  65. Smart CE, Morrison BJ, Saunus JM, Vargas AC, Keith P, Reid L, Wockner L, Askarian-Amiri M, Sarkar D, Simpson PT, Clarke C, Schmidt CW, Reynolds BA, Lakhani SR, Lopez JA (2013) In vitro analysis of breast cancer cell line tumourspheres and primary human breast epithelia mammospheres demonstrates inter- and intrasphere heterogeneity. PLoS One 8(6):e64388. https://doi.org/10.1371/journal.pone.0064388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nagel R, Clijsters L, Agami R (2009) The miRNA-192/194 cluster regulates the Period gene family and the circadian clock. Febs J 276(19):5447–5455. https://doi.org/10.1111/j.1742-4658.2009.07229.x

    Article  CAS  PubMed  Google Scholar 

  67. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68(19):7846–7854. https://doi.org/10.1158/0008-5472.CAN-08-1942

    Article  CAS  PubMed  Google Scholar 

  68. Pichiorri F, Suh SS, Rocci A, De Luca L, Taccioli C, Santhanam R, Zhou W, Benson DM Jr, Hofmainster C, Alder H, Garofalo M, Di Leva G, Volinia S, Lin HJ, Perrotti D, Kuehl M, Aqeilan RI, Palumbo A, Croce CM (2010) Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 18(4):367–381. https://doi.org/10.1016/j.ccr.2010.09.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kato M, Arce L, Wang M, Putta S, Lanting L, Natarajan R (2011) A microRNA circuit mediates transforming growth factor-beta1 autoregulation in renal glomerular mesangial cells. Kidney Int 80(4):358–368. https://doi.org/10.1038/ki.2011.43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Obrietan K, Impey S, Storm DR (1998) Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat Neurosci 1(8):693–700

    Article  CAS  PubMed  Google Scholar 

  71. Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG (2005) Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26(7):1241–1246. https://doi.org/10.1093/carcin/bgi075

    Article  CAS  PubMed  Google Scholar 

  72. Hao H, Schwaber J (2006) Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. Brain Res 1088(1):45–48. https://doi.org/10.1016/j.brainres.2006.02.100

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Prof. Kathryn M. Eisenmann of The University of Toledo, OH for graciously providing the MCF-7 cell line. We also thank Profs. William Maltese and Amit K. Tiwari of The University of Toledo for valuable advice, Profs. Hitoshi Okamura and Kazuhiro Yagita of Kyota University, Japan for the Per2::Per2:luc construct, and Prof. Vipa Phuntumart of Bowling Green State University, OH for assistance with PCR. We are grateful to BGSU students Ben Fry, Sanjhi D. Gandhi, Jordan C. Hennemyre, and Bomani Ngozi for assistance with data analysis.

Author information

Author notes

  1. Arpan De

    Present address: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

  2. Dilshan H. Beligala

    Present address: Department of Molecular Biology and Biotechnology, Faculty of Science, University of Peradeniya, Peradeniya, 20400, Sri Lanka

  3. Vishal P. Sharma

    Present address: Celsee, Inc., Ann Arbor, MI, 48108, USA

Authors and Affiliations

  1. Department of Biological Sciences, Bowling Green State University, 217 Life Science Bldg., Bowling Green, OH, 43403, USA

    Arpan De, Dilshan H. Beligala, Vishal P. Sharma, Christian A. Burgos, Angelia M. Lee & Michael E. Geusz

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De, A., Beligala, D.H., Sharma, V.P. et al. Cancer stem cell generation during epithelial-mesenchymal transition is temporally gated by intrinsic circadian clocks. Clin Exp Metastasis 37, 617–635 (2020). https://doi.org/10.1007/s10585-020-10051-1

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