IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

Gao,Yongying; Wu,Yanwei; Zhang,Ningmei; Yuan,Hongmei; Wang,Fei; Xu,Hui; Yu,Jiaxiang; Ma,Jie; Hou,Shaozhang; Cao,Xiangmei

doi:10.3892/mmr.2021.11993

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

Authors:
- Yongying Gao
- Yanwei Wu
- Ningmei Zhang
- Hongmei Yuan
- Fei Wang
- Hui Xu
- Jiaxiang Yu
- Jie Ma
- Shaozhang Hou
- Xiangmei Cao
View Affiliations

Affiliations: Department of Pathology, School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Pathology, Tumor Hospital, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Functional Department, Ningxia Hui Autonomous Region People's Hospital, Yinchuan, Ningxia 750021, P.R. China, Department of Pathology, The First People's Hospital of Yinchuan, Yinchuan, Ningxia 750001, P.R. China
Published online on: March 12, 2021 https://doi.org/10.3892/mmr.2021.11993
Article Number: 354
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Isocitrate dehydrogenase1 (IDH1) mutation is the most important genetic change in glioma. The most common IDH1 mutation results in the amino acid substitution of arginine 132 (Arg/R132), which is located at the active site of the enzyme. IDH1 Arg132His (R132H) mutation can reduce the proliferative rate of glioma cells. Numerous diseases follow circadian rhythms, and there is growing evidence that circadian disruption may be a risk factor for cancer in humans. Dysregulation of the circadian clock serves an important role in the development of malignant tumors, including glioma. Brain‑Muscle Arnt‑Like protein 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are the main biological rhythm genes. The present study aimed to further study whether there is an association between IDH1 R132H mutation and biological rhythm in glioma, and whether this affects the occurrence of glioma. The Cancer Genome Atlas (TCGA) database was used to detect the expression levels of the biological rhythm genes BMAL1 and CLOCK in various types of tumor. Additionally, U87‑MG cells were infected with wild‑type and mutant IDH1 lentiviruses. Colony formation experiments were used to detect cell proliferation in each group, cell cycle distribution was detected by flow cytometry and western blotting was used to detect the expression levels of wild‑type and mutant IDH1, cyclins, biological rhythm genes and Smad signaling pathway‑associated genes in U87‑MG cells. TCGA database results suggested that BMAL1 and CLOCK were abnormally expressed in glioma. Cells were successfully infected with wild‑type and mutant IDH1 lentiviruses. Colony formation assay revealed decreased cell proliferation in the IDH1 R132H mutant group. The cell cycle distribution detected by flow cytometry indicated that IDH1 gene mutation increased the G₁ phase ratio and decreased the S phase ratio in U87‑MG cells. The western blotting results demonstrated that IDH1 R132H mutation decreased the expression levels of the S phase‑associated proteins Cyclin A and CDK2, and increased the expression levels of the G₁ phase‑associated proteins Cyclin D3 and CDK4, but did not significantly change the expression levels of the G₂/M phase‑associated protein Cyclin B1. The expression levels of the positive and negative rhythm regulation genes BMAL1, CLOCK, period (PER s (PER1, 2 and 3) and cryptochrom (CRY)s (CRY1 and 2) were significantly decreased, those of the Smad signaling pathway‑associated genes Smad2, Smad3 and Smad2‑3 were decreased, and those of phosphorylated (p)‑Smad2, p‑Smad3 and Smad4 were increased. Therefore, the present results suggested that the IDH1 R132H mutation may alter the cell cycle and biological rhythm genes in U87‑MG cells through the TGF‑β/Smad signaling pathway.

View Figures

View References

1	Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, et al: The consensus coding sequences of human breast and colorectal cancers. Science. 314:268–274. 2006. View Article : Google Scholar : PubMed/NCBI
2	Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, et al: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 361:1058–1066. 2009. View Article : Google Scholar : PubMed/NCBI
3	Cardaci S and Ciriolo MR: TCA cycle defects and cancer: When metabolism tunes redox state. Int J Cell Biol. 2012:1618372012. View Article : Google Scholar : PubMed/NCBI
4	Pastore M, Lori G, Gentilini A, Taddei ML, Di Maira G, Campani C, Recalcati S, Invernizzi P, Marra F and Raggi C: Multifaceted aspects of metabolic plasticity in human cholangiocarcinoma: An overview of current perspectives. Cells. 9:5962020. View Article : Google Scholar
5	Bosnyák E, Michelhaugh SK, Klinger NV, Kamson DO, Barger GR, Mittal S and Juhász C: Prognostic molecular and imaging biomarkers in primary glioblastoma. Clin Nucl Med. 42:341–347. 2017. View Article : Google Scholar : PubMed/NCBI
6	Krell D, Assoku M, Galloway M, Mulholland P, Tomlinson I and Bardella C: Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. PLoS One. 6:e198682011. View Article : Google Scholar : PubMed/NCBI
7	Yang H, Ye D, Guan KL and Xiong Y: IDH1 and IDH2 mutations in tumorigenesis: Mechanistic insights and clinical perspectives. Clin Cancer Res. 18:5562–5571. 2012. View Article : Google Scholar : PubMed/NCBI
8	Zhang Y, Lv W, Li Q, Wang Q, Ru Y, Xiong X, Yan F, Pan T, Lin W and Li X: IDH2 compensates for IDH1 mutation to maintain cell survival under hypoxic conditions in IDH1-mutant tumor cells. Mol Med Rep. 20:1893–1900. 2019.PubMed/NCBI
9	Chittaranjan S, Chan S, Yang C, Yang KC, Chen V, Moradian A, Firme M, Song J, Go NE, Blough MD, et al: Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. Oncotarget. 5:7960–7979. 2014. View Article : Google Scholar : PubMed/NCBI
10	Hersh DS, Peng S, Dancy JG, Galisteo R, Eschbacher JM, Castellani RJ, Heath JE, Legesse T, Kim AJ, Woodworth GF, et al: Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas. J Neurooncol. 138:241–250. 2018. View Article : Google Scholar : PubMed/NCBI
11	Sakai Y, Yang C, Kihira S, Tsankova N, Khan F, Hormigo A, Lai A, Cloughesy T and Nael K: MRI radiomic features to predict IDH1 mutation status in gliomas: A machine learning approach using gradient tree boosting. Int J Mol Sci. 21:80042020. View Article : Google Scholar
12	Kim W and Liau LM: IDH mutations in human glioma. Neurosurg Clin N Am. 23:471–480. 2012. View Article : Google Scholar : PubMed/NCBI
13	Ducray F, El Hallani S and Idbaih A: Diagnostic and prognostic markers in gliomas. Curr Opin Oncol. 21:537–542. 2009. View Article : Google Scholar : PubMed/NCBI
14	Bergo E, Lombardi G, Pambuku A, Della Puppa A, Bellu L, D'Avella D and Zagonel V: Cognitive rehabilitation in patients with gliomas and other brain tumors: State of the Art. Biomed Res Int. 2016:30418242016. View Article : Google Scholar : PubMed/NCBI
15	Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, et al: IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 483:474–478. 2012. View Article : Google Scholar : PubMed/NCBI
16	Chen Z, Liu P, Li C, Luo Y, Chen I, Liang W, Chen X, Feng Y, Xia H and Wang F: Deregulated expression of the clock genes in gliomas. Technol Cancer Res Treat. 12:91–97. 2013. View Article : Google Scholar : PubMed/NCBI
17	Luo Y, Wang F, Chen LA, Chen XW, Chen ZJ, Liu PF, li FF, Li CY and Liang W: Deregulated expression of cry1 and cry2 in human gliomas. Asian Pac J Cancer Prev. 13:5725–5728. 2012. View Article : Google Scholar : PubMed/NCBI
18	Chang WH and Lai AG: Timing gone awry: Distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies. J Transl Med. 17:1322019. View Article : Google Scholar : PubMed/NCBI
19	Chan AB, Huber AL and Lamia KA: Cryptochromes modulate E2F family transcription factors. Sci Rep. 10:40772020. View Article : Google Scholar : PubMed/NCBI
20	Young MW and Kay SA: Time zones: A comparative genetics of circadian clocks. Nat Rev Genet. 2:702–715. 2001. View Article : Google Scholar : PubMed/NCBI
21	Lowrey PL and Takahashi JS: Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation. Ann Rev Genet. 34:533–562. 2000. View Article : Google Scholar : PubMed/NCBI
22	Dunlap JC: Molecular bases for circadian clocks. Cell. 96:271–290. 1999. View Article : Google Scholar : PubMed/NCBI
23	Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH and Reppert SM: mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell. 98:193–205. 1999. View Article : Google Scholar : PubMed/NCBI
24	van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, et al: Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature. 398:627–630. 1999. View Article : Google Scholar : PubMed/NCBI
25	Vitaterna MH, Selby CP, Todo T, Niwa H, Thompson C, Fruechte EM, Hitomi K, Thresher RJ, Ishikawa T, Miyazaki J, et al: Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc Natl Acad Sci USA. 96:12114–12119. 1999. View Article : Google Scholar : PubMed/NCBI
26	Dibner C, Schibler U and Albrecht U: The mammalian circadian timing system: Organization and coordination of central and peripheral clocks. Ann Rev Physiol. 72:517–549. 2010. View Article : Google Scholar
27	Harmer SL, Panda S and Kay SA: Molecular bases of circadian rhythms. Ann Rev Cell Dev Biol. 17:215–253. 2001. View Article : Google Scholar
28	Oster H: The genetic basis of circadian behavior. Genes Brain Behav. 5 (Suppl 2):S73–S79. 2006. View Article : Google Scholar
29	Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schütz G and Schibler U: Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science. 289:2344–2347. 2000. View Article : Google Scholar : PubMed/NCBI
30	Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F and Schibler U: Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14:2950–2961. 2000. View Article : Google Scholar : PubMed/NCBI
31	Yagita K, Tamanini F, van Der Horst GT and Okamura H: Molecular mechanisms of the biological clock in cultured fibroblasts. Science. 292:278–281. 2001. View Article : Google Scholar : PubMed/NCBI
32	Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, van der Horst GT, Hastings MH and Reppert SM: Interacting molecular loops in the mammalian circadian clock. Science. 288:1013–1019. 2000. View Article : Google Scholar : PubMed/NCBI
33	Mazzoccoli G, Vinciguerra M, Papa G and Piepoli A: Circadian clock circuitry in colorectal cancer. World J Gastroenterol. 20:4197–4207. 2014. View Article : Google Scholar : PubMed/NCBI
34	Blakeman V, Williams JL, Meng QJ and Streuli CH: Circadian clocks and breast cancer. Br Cancer Res. 18:892016. View Article : Google Scholar
35	Cao Q, Gery S, Dashti A, Yin D, Zhou Y, Gu J and Koeffler HP: A role for the clock gene per1 in prostate cancer. Cancer Res. 69:7619–7625. 2009. View Article : Google Scholar : PubMed/NCBI
36	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. 29:1201–1209. 2009.PubMed/NCBI
37	Zhang S, Zhang J, Deng Z, Liu H, Mao W, Jiang F, Xia Z and Li JD: Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells. Oncotarget. 7:66087–66099. 2016. View Article : Google Scholar : PubMed/NCBI
38	Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L, Bhutkar A, Bartlebaugh J, Vander Heiden MG and Jacks T: Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 24:324–331. 2016. View Article : Google Scholar : PubMed/NCBI
39	Yang MY, Lin PM, Hsiao HH, Hsu JF, Lin HY, Hsu CM, Chen IY, Su SW, Liu YC and Lin SF: Up-regulation of PER3 expression is correlated with better clinical outcome in acute leukemia. Anticancer Res. 35:6615–6622. 2015.PubMed/NCBI
40	Farshadi E, van der Horst GTJ and Chaves I: Molecular links between the circadian clock and the cell cycle. J Mol Biol. 432:3515–3524. 2020. View Article : Google Scholar : PubMed/NCBI
41	Scheving LE, Tsai TH and Scheving LA: Chronobiology of the intestinal tract of the mouse. Am J Anatomy. 168:433–465. 1983. View Article : Google Scholar
42	Farshadi E, Yan J, Leclere P, Goldbeter A, Chaves I and van der Horst GTJ: The positive circadian regulators CLOCK and BMAL1 control G₂/M cell cycle transition through Cyclin B1. Cell Cycle. 18:16–33. 2019. View Article : Google Scholar : PubMed/NCBI
43	Shan DZ, Zhang C and Cao XM: Preparation and expression of isocitrate dehydrogenase 1 and mutant recombinant lentivirus. Chin J Neuroanatomy. 36:200–206. 2020.
44	Yu H, Yuan Y, Shen H and Cheng T: Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood. 107:1200–1206. 2006. View Article : Google Scholar : PubMed/NCBI
45	Yuan Y, Shen H, Franklin DS, Scadden DT and Cheng T: In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G₁-phase inhibitor, p18INK4C. Nat Cell Biol. 6:436–442. 2004. View Article : Google Scholar : PubMed/NCBI
46	Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI
47	Mandal AS, Biswas N, Karim KM, Guha A, Chatterjee S, Behera M and Kuotsu K: Drug delivery system based on chronobiology-A review. J Control Release. 147:314–325. 2010. View Article : Google Scholar : PubMed/NCBI
48	Zhao Q, Zheng G, Yang K, Ao YR, Su XL, Li Y and Lv XQ: The clock gene PER1 plays an important role in regulating the clock gene network in human oral squamous cell carcinoma cells. Oncotarget. 7:70290–70302. 2016. View Article : Google Scholar : PubMed/NCBI
49	Qu M, Duffy T, Hirota T and Kay SA: Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. Proc Natl Acad Sci USA. 115:E12305–E12312. 2018. View Article : Google Scholar : PubMed/NCBI
50	Shafi AA and Knudsen KE: Cancer and the circadian clock. Cancer Res. 79:3806–3814. 2019. View Article : Google Scholar : PubMed/NCBI
51	Hou X, Zhang J, Wang Y, Xiong W and Mi J: TGFBR-IDH1-Cav1 axis promotes TGF-beta signalling in cancer-associated fibroblast. Oncotarget. 8:83962–83974. 2017. View Article : Google Scholar : PubMed/NCBI
52	Lopez M, Meier D, Muller A, Franken P, Fujita J and Fontana A: Tumor necrosis factor and transforming growth factor beta regulate clock genes by controlling the expression of the cold inducible RNA-binding protein (CIRBP). J Biol Chem. 289:2736–2744. 2014. View Article : Google Scholar : PubMed/NCBI
53	Sato F, Sato H, Jin D, Bhawal UK, Wu Y, Noshiro M, Kawamoto T, Fujimoto K, Seino H, Morohashi S, et al: Smad3 and Snail show circadian expression in human gingival fibroblasts, human mesenchymal stem cell, and in mouse liver. Biochem Biophys Res Commun. 419:441–446. 2012. View Article : Google Scholar : PubMed/NCBI
54	Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, Manova-Todorova K, Blasberg R, Gerald WL and Massagué J: Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA. 102:13909–13914. 2005. View Article : Google Scholar : PubMed/NCBI
55	Dou C, Lee J, Liu B, Liu F, Massague J, Xuan S and Lai E: BF-1 interferes with transforming growth factor beta signaling by associating with Smad partners. Mol Cell Biol. 20:6201–6211. 2000. View Article : Google Scholar : PubMed/NCBI
56	Parisot S, Wells W III, Chemouny S, Duffau H and Paragios N: Concurrent tumor segmentation and registration with uncertainty-based sparse non-uniform graphs. Med Image Anal. 18:647–659. 2014. View Article : Google Scholar : PubMed/NCBI
57	de Robles P, Fiest KM, Frolkis AD, Pringsheim T, Atta C, St Germaine-Smith C, Day L, Lam D and Jette N: The worldwide incidence and prevalence of primary brain tumors: A systematic review and meta-analysis. Neurooncology. 17:776–783. 2015.
58	Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, et al: Glioma Groups Based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 372:2499–2508. 2015. View Article : Google Scholar : PubMed/NCBI
59	Miller JJ, Shih HA, Andronesi OC and Cahill DP: Isocitrate dehydrogenase-mutant glioma: Evolving clinical and therapeutic implications. Cancer. 123:4535–4546. 2017. View Article : Google Scholar : PubMed/NCBI
60	Ferreira MSV, Sørensen MD, Pusch S, Beier D, Bouillon AS, Kristensen BW, Brümmendorf TH, Beier CP and Beier F: Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation. J Neurooncol. 147:1–14. 2020. View Article : Google Scholar : PubMed/NCBI
61	Karpel-Massler G, Nguyen TTT, Shang E and Siegelin MD: Novel IDH1-targeted glioma therapies. CNS Drugs. 33:1155–1166. 2019. View Article : Google Scholar : PubMed/NCBI
62	Salavaty A, Mohammadi N, Shahmoradi M and Naderi Soorki M: Bioinformatic analysis of circadian expression of oncogenes and tumor suppressor genes. Bioinform Biol Insights. 11:11779322177469912017. View Article : Google Scholar : PubMed/NCBI
63	Jiang W, Zhao S, Jiang X, Zhang E, Hu G, Hu B, Zheng P, Xiao J, Lu Z, Lu Y, et al: The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett. 371:314–325. 2016. View Article : Google Scholar : PubMed/NCBI
64	Lin F, Chen Y, Li X, Zhao Q and Tan Z: Over-expression of circadian clock gene Bmal1 affects proliferation and the canonical Wnt pathway in NIH-3T3 cells. Cell Biochem Funct. 31:166–172. 2013. View Article : Google Scholar : PubMed/NCBI
65	Jung CH, Kim EM, Park JK, Hwang SG, Moon SK, Kim WJ and Um HD: Bmal1 suppresses cancer cell invasion by blocking the phosphoinositide 3-kinase-Akt-MMP-2 signaling pathway. Oncol Rep. 29:2109–2113. 2013. View Article : Google Scholar : PubMed/NCBI
66	Guan F, Kang Z, Wang L, Wang K, Mao BB, Peng WC, Zhang BL, Lin ZY, Zhang JT and Hu ZQ: Retinol dehydrogenase 10 promotes metastasis of glioma cells via the transforming growth factor-β/SMAD signaling pathway. Chin Med J (Engl). 132:2430–2437. 2019. View Article : Google Scholar : PubMed/NCBI
67	Derynck R and Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI
68	Frei K, Gramatzki D, Tritschler I, Schroeder JJ, Espinoza L, Rushing EJ and Weller M: Transforming growth factor-β pathway activity in glioblastoma. Oncotarget. 6:5963–5977. 2015. View Article : Google Scholar : PubMed/NCBI
69	Huse K, Bakkebø M, Wälchli S, Oksvold MP, Hilden VI, Forfang L, Bredahl ML, Liestøl K, Alizadeh AA, Smeland EB and Myklebust JH: Role of Smad proteins in resistance to BMP-induced growth inhibition in B-cell lymphoma. PLoS One. 7:e461172012. View Article : Google Scholar : PubMed/NCBI
70	Sadeghi Y, Tabatabaei Irani P, Rafiee L, Tajadini M, Amouheidari A and Javanmard SH: Evaluation of rs1982073 polymorphism of transforming growth factor-β1 in glioblastoma. J Res Med Sci. 24:402019. View Article : Google Scholar : PubMed/NCBI
71	Dong C, Gongora R, Sosulski ML, Luo F and Sanchez CG: Regulation of transforming growth factor-beta1 (TGF-β1)-induced pro-fibrotic activities by circadian clock gene BMAL1. Respir Res. 17:42016. View Article : Google Scholar : PubMed/NCBI
72	Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, Tothova Z, Tejero H, Heckl D, Järås M, et al: Core circadian clock genes regulate leukemia stem cells in AML. Cell. 165:303–316. 2016. View Article : Google Scholar : PubMed/NCBI
73	Li A, Lin X, Tan X, Yin B, Han W, Zhao J, Yuan J, Qiang B and Peng X: Circadian gene Clock contributes to cell proliferation and migration of glioma and is directly regulated by tumor-suppressive miR-124. FEBS Lett. 587:2455–2460. 2013. View Article : Google Scholar : PubMed/NCBI
74	Dong Z, Zhang G, Qu M, Gimple RC, Wu Q, Qiu Z, Prager BC, Wang X, Kim LJY, Morton AR, et al: Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 9:1556–1573. 2019. View Article : Google Scholar : PubMed/NCBI
75	Liu WS, Chan SH, Chang HT, Li GC, Tu YT, Tseng HH, Fu TY, Chang HY, Liou HH, Ger LP and Tsai KW: Isocitrate dehydrogenase 1-snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability. Breast Cancer Res. 20:252018. View Article : Google Scholar : PubMed/NCBI
76	Xia HC, Niu ZF, Ma H, Cao SZ, Hao SC, Liu ZT and Wang F: Deregulated expression of the Per1 and Per2 in human gliomas. Can J Neurol Sci. 37:365–370. 2010. View Article : Google Scholar : PubMed/NCBI