跳到主要內容

臺灣博碩士論文加值系統

(44.211.26.178) 您好!臺灣時間:2024/06/15 01:56
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:劉恆維
研究生(外文):Heng-Wei Liu
論文名稱:4-AAQB 及garcinol 在膠質母細胞瘤的抗癌效果及相關機制探討
論文名稱(外文):The anti-cancer effects of natural compounds, 4-AAQBand garcinol, in glioblastoma
指導教授:簡銘賢
指導教授(外文):Ming-Hsien Chien
口試委員:楊順發華國泰陳元皓
口試委員(外文):Shun-Fa YangKuo-Tai HuaYuan-Hao Chen
口試日期:2020-07-09
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:123
中文關鍵詞:膠質母細胞瘤牛樟芝山竹
外文關鍵詞:4-AAQBgarcinolglioblastomaGBM
相關次數:
  • 被引用被引用:0
  • 點閱點閱:178
  • 評分評分:
  • 下載下載:22
  • 收藏至我的研究室書目清單書目收藏:0
膠質母細胞瘤 (GBM, World Health Organization grade IV gliomas)是最常見也是預後最差的腦部原發腫瘤,其特色為病程發展快速、容易復發、並且對於化療與放射線治療具有抗藥性,這些特性主是與膠質瘤幹細胞(GBM stem cells)的存在有關。許多的報告指出,植物或草藥的生物活性萃取物可藉由調控癌症幹細胞而具有抗癌的效果,我們團隊在之前的研究中證實牛樟芝生物活性萃取物4-Acetylantroquinonol B (4-AAQB)在卵巢癌中具有抗癌效果,以及山竹生物活性萃取物garcinol在非小細胞肺癌具有抗癌效果。在此研究中,我們想了解此二生物活性萃取物:4-AAQ及garcinol對膠質母細胞瘤的抗癌效果。
首先,我們發現4-AAQB會抑制膠質母細胞瘤細胞株的細胞遷移與侵入,同時下降膠質母細胞瘤細胞株的幹細胞表現,西方墨點法分析中,我們發現4-AAQB明顯調降膠質母細胞瘤細胞株的β-catenin表現並使得catenin/LEF1/Stat3 signaling axis失調,在動物實驗中也證實4-AAQB可以抑制膠質母細胞瘤的生長。第二部分,我們證實garcinol可明顯抑制膠質母細胞瘤細胞株的細胞增生、侵入、與遷移,並且能明顯削弱膠質母細胞瘤細胞株的幹細胞表現,在分析膠質母細胞瘤的轉錄組
(transcriptome)中發現:garcinol對於膠質母細胞瘤的抗癌效果與hsa-miR-181d表現增加有關,同時STAT3/5A與hsa-miR-181d的表現呈現反相關,這個結果進一步藉由動物實驗證實給予garcinol明顯抑制腫瘤的生長。
總結來說,4-AAQB會在膠質母細胞瘤中抑制β-catenin/LEF1/Stat3 signaling進而抑制癌症幹細胞引發的癌化反應。Garcinol則藉由增加hsa-miR-181d/STAT3和hsa-miR-181d/STAT5A在細胞中的比例 (ratio) 達到對膠質母細胞瘤的抗癌效果。此結論顯示4-AAQB與garcinol具有成為膠質母細胞瘤治療藥物之潛力,提供了一個在治療膠質母細胞瘤上可能發展的新方法。
Glioblastoma (GBM), a World Health Organization (WHO) grade IV glioma, is the most common primary brain tumor with the poorest prognosis. GBM is characterized by rapid disease progression, high likelihood to recur, and increased resistance to chemotherapy and radiotherapy, which is attributable to the presence of GBM stem cells (GBM-SCs). Numerous studies have reported that bioactive extracts from plants or herbs possess anticancer effects through the regulation of cancer stem cells (CSCs). In our previous work, we demonstrated the anticancer effects of 4-acetylantroquinonol B (4-AAQB), a bioactive extract from Antrodia camphorata, in aggressive epithelial cancers, and of garcinol, a bioactive extract from Garcinia indica, in non-small cell lung cancer. This study investigated the anticancer effects of the bioactive extracts, 4-AAQB, and garcinol, in GBM.
First, we found that 4-AAQB inhibited invasion and migration of GBM cell lines. Also, 4-AAQB attenuated the stemness phenotype of GBM cells. In Western blot
analysis, 4-AAQB significantly downregulated β-catenin and dysregulated the catenin/LEF1/Stat3 signaling axis in GBM cell lines. In animal study, we proveded that
4-AAQB significantly inhibits tumor growth. Next, we explored that garcinol suppressed GBM cell proliferation, invasion and migration and significantly diminished the ability of GBM-SCs. Furthermore, analysis of the GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d, with the garcinol-mediated anti-GBM effects associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. The results were further verified in vivo using a U87MG mouse xenograft model, whereby the administration of garcinol significantly inhibited tumor growth.
In conclusion, 4-AAQB suppresses the tumor-promoting catenin/LEF1/Stat3 signaling, and inhibited CSCs-induced oncogenic activities in GBM. As for garcinol, it enhanced the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio in GBM cells to establish the anticancer ability in GBM. These results indicate both 4-AAQB and garcinol as potent therapeutic agents for combating aggressive GBM.
致謝 ............................................................................................................................................................. i
Content .................................................................................................................................................... iii
Abbreviations ......................................................................................................................................... vi
摘要 ......................................................................................................................................................... xii
Chapter 1 .................................................................................................................................................. 1
Introduction
1.1 Glioblastoma (GBM) and cancer stem cells (CSCs) ................................................... 1
1.2 4AAQB ..................................................................................................................................... 5
1.3 Garcinol .................................................................................................................................... 5
1.4 Research aims ......................................................................................................................... 6
Chapter 2 .................................................................................................................................................. 8
Materials and methods
2.1 Drugs and chemicals............................................................................................................. 8
2.2 Cell lines and culture ............................................................................................................ 9
2.3 Sulfur rhodamine B (SRB) cell viability assay .......................................................... 10
2.4 Western blot analysis ......................................................................................................... 10
2.5 β-catenin siRNA infection ............................................................................................... 12
2.6 Immunohistochemical staining and quantification ................................................... 12
2.7 Immunofluorescence staining ......................................................................................... 14
2.8 Tumorsphere formation assay ......................................................................................... 15
2.9 Colony formation assay .................................................................................................... 15
2.10 Invasion assay ................................................................................................................... 16
2.11. Wound healing migration assay .................................................................................. 16
2.12 Real-time polymerase chain reaction (qRT-PCR) analysis ................................. 17
2.13 PE-Annexin V/7-AAD cell death assay .................................................................... 17
2.14 Mir-181 transfection assay ............................................................................................ 18
2.15 Animal studies ................................................................................................................... 18
2.16 Statistical analysis ............................................................................................................ 20
Chapter 3 ............................................................................................................................................... 21
iv
Results
3.1 4-AAQB study..................................................................................................................... 21
3.1.1. Aberrant expression of β-catenin is characteristic of GBM and
correlates with poor prognosis ..................................................................................... 21
3.1.2. β-catenin facilitates GBM oncogenicity and disease recurrence, as well
as their cancer stem cell-like traits ............................................................................. 22
3.1.3. 4-AAQB disrupts the CSC-associated oncogenic β-catenin/TCF-1/Stat3
signaling axis in GBM cells .......................................................................................... 23
3.1.4. 4-AAQB inhibits the nuclear localization of β-Catenin, Sox2, and Oct4
in GBM cells ...................................................................................................................... 24
3.1.5. 4-AAQB significantly suppresses the viability and oncogenicity of GBM
cells ...................................................................................................................................... 25
3.1.6. 4-AAQB markedly inhibits the stem cell-like phenotype of U87MG and
DBTRG-05MG cells by modulation of β-catenin expression .............................. 26
3.1.7. Compared to oral gavage, intraperitoneal 4-AAQB significantly and
more efficiently suppresses GBM stem cell-induced tumor growth in vivo ..... 27
3.2. Garcinol study .................................................................................................................... 29
3.2.1. STAT3 and STAT5A are highly expressed in primary and recurrent
glioblastoma, and their expression negatively correlates with overall survival
rates ...................................................................................................................................... 29
3.2.2. Garcinol significantly inhibits GBM cell viability and oncogenicity
through induction of STAT3/5A signaling and enhanced apoptosis .................. 30
3.2.3. Garcinol negatively impacts GBM stem cell-like phenotypes ................. 32
3.2.4. Garcinol increases the expression of hsa-miR181d, which has inhibitory
effects on STAT3 and STAT5 activation ..................................................................... 33
3.2.5. Garcinol inhibits tumor growth in GBM mice models through inversely
correlated STAT3/5A and hsa-miR-181d expression ............................................. 36
3.2.6. Garcinol, akin to stattic, a selective inhibitor of STAT3/5A activation,
inhibits the metastatic and cancer stem cell-like phenotypes of primary GBM
culture cells ........................................................................................................................ 37
Chapter 4 ............................................................................................................................................... 40
Discussion ............................................................................................................................................. 40
v
Chapter 5 ............................................................................................................................................... 49
Conclusion
Chapter 6 ............................................................................................................................................... 50
References
Chapter 7 ............................................................................................................................................... 66
Figures
Figure 1 ......................................................................................................................................... 66
Figure 2 ......................................................................................................................................... 70
Figure 3 ......................................................................................................................................... 74
Figure 4 ......................................................................................................................................... 77
Figure 5 ......................................................................................................................................... 80
Figure 6 ......................................................................................................................................... 83
Figure 7 ......................................................................................................................................... 87
Figure 8 ......................................................................................................................................... 89
Figure 9 ......................................................................................................................................... 94
Figure 10 ................................................................................................................................... 102
Figure 11 ................................................................................................................................... 108
Figure 12 ................................................................................................................................... 113
Figure 13 ................................................................................................................................... 117
Figure 14 ................................................................................................................................... 123
1.Thakkar, J.P.; Dolecek, T.A.; Horbinski, C.; Ostrom, Q.T.; Lightner, D.D.; Barnholtz-Sloan, J.S.; Villano, J.L. Epidemiologic and Molecular Prognostic Review of Glioblastoma. Cancer Epidemiol. Biomarkers Prev. 2014, 23, 1985–1996.
2.Wirsching, H.G.; Galanis, E.; Weller, M. Glioblastoma. Handb. Clin. Neurol. 2016, 134, 381–397.
3.Stupp R, Mason WP, van den Bent MJ, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
4.Roger Stupp, Sophie Taillibert, Andrew Kanner et al, Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With GlioblastomaA Randomized Clinical Trial. JAMA. 2017;318(23):2306-2316. doi:10.1001/jama.2017.18718
5.Galli R, Binda E, Orfanelli U et al.Isolation and characterization of tumorigenic, stem‐like neural precursors from human glioblastoma. Cancer Res 2004;64: 7011–7021.
6.Singh SK, Hawkins C, Clarke ID et al.Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.
7.Clarke MF, Dick JE, Dirks PB et al. Cancer stem cells—Perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006; 66:9339–9344.
8.Colak S., Medema J.P. Cancer stem cells—Important players in tumor therapy resistance. FEBS J. 2014;281:4779–4791. doi: 10.1111/febs.13023.
9.Frank N.Y., Schatton T., Frank M.H. The therapeutic promise of the cancer stem cell concept. J. Clin. Investig. 2010;120:41–50. doi: 10.1172/JCI41004.
10.Jackson M., Hassiotou F., Nowak A. Glioblastoma stem-like cells: At the root of tumor recurrence and a therapeutic target. Carcinogenesis. 2015;36:177–185. doi: 10.1093/carcin/bgu243.
11.Phi L.T.H., Sari I.N., Yang Y.G., Lee S.H., Jun N., Kim K.S., Lee Y.K., Kwon H.Y. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018;2018:1–16. doi: 10.1155/2018/5416923.
12.Toledo-Guzmán M.E., Bigoni-Ordóñez G.D., Hernández M.I., Ortiz-Sánchez E. Cancer stem cell impact on clinical oncology. World J. Stem Cells. 2018;10:183–195. doi: 10.4252/wjsc.v10.i12.183.
13.Vogelstein B., Papadopoulos N., Velculescu V.E., Zhou S., Diaz L.A., Kinzler K.W. Cancer Genome Landscapes. Science. 2013;339:1546–1558. doi: 10.1126/science.1235122.
14.Wang, J.; Ma, Y.; Cooper, M.K. Cancer stem cells in glioma: Challenges and opportunities. Transl. Cancer Res. 
2013, 2, 429–441. 

15.Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007;17:165–72.
16.Ehtesham M, Sarangi A, Valadez JG, et al. Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene. 2007;26:5752–61
17.Lee Y., Lee J.K., Ahn S.H., Lee J., Nam D.H. WNT signaling in glioblastoma and therapeutic opportunities. Lab Investig. 2016;96:137–150. doi: 10.1038/labinvest.2015.140.
18.Liu C., Tu Y., Sun X., Jiang J., Jin X., Bo X., Li Z., Bian A., Wang X., Liu D., et al. Wnt/β-Catenin pathway in human glioma: Expression pattern and clinical/prognostic correlations. Clin. Exp. Med. 2010;11:105–112. doi: 10.1007/s10238-010-0110-9.
19.Lee Y., Kim K.H., Kim D.G., Cho H.J., Kim Y., Rheey J., Shin K., Seo Y.J., Choi Y.S., Lee J.I., et al. FoxM1 Promotes Stemness and Radio-Resistance of Glioblastoma by Regulating the Master Stem Cell Regulator Sox2. PloS ONE. 2015;10:e0137703. doi: 10.1371/journal.pone.0137703.
20.Rheinbay E., Suvà M.L., Gillespie S.M., Wakimoto H., Patel A.P., Shahid M., Oksuz O., Rabkin S.D., Martuza R.L., Rivera M.N., et al. An Aberrant Transcription Factor Network Essential for Wnt Signaling and Stem Cell Maintenance in Glioblastoma. Cell Rep. 2013;3:1567–1579. doi: 10.1016/j.celrep.2013.04.021.
21.Cheng C.C., Shi L.H., Wang X.J., Wang S.X., Wan X.Q., Liu S.R., Wang Y.F., Lu Z., Wang L.H., Ding Y. Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066. Int. J. Oncol. 2018;53:339–348. doi: 10.3892/ijo.2018.4399.
22.Do D.V., Ueda J., Messerschmidt D.M., Lorthongpanich C., Zhou Y., Feng B., Guo G., Lin P.J., Hossain M.Z., Zhang W., et al. A genetic and developmental pathway from STAT3 to the OCT4–NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes Dev. 2013;27:1378–1390. doi: 10.1101/gad.221176.113.
23.Matthews J.R., Sansom O.J., Clarke A.R. Absolute requirement for STAT3 function in small-intestine crypt stem cell survival. Cell Death Differ. 2011;18:1934–1943. doi: 10.1038/cdd.2011.77.
24.Yue P., Turkson J. Targeting STAT3 in cancer: How successful are we? Expert Opin. Investig. Drugs. 2009;18:45–56. doi: 10.1517/13543780802565791.
25.Guryanova O.A., Wu Q., Cheng L., Lathia J.D., Huang Z., Yang J., MacSwords J., Eyler C.E., McLendon R.E., Heddleston J.M., et al. Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell. 2011;19:498–511. doi: 10.1016/j.ccr.2011.03.004.
26.Carro M.S., Lim W.K., Alvarez M.J., Bollo R.J., Zhao X.D., Snyder E.Y., Sulman E.P., Anne S.L., Doetsch F., Colman H., et al. The transcriptional network for mesenchymal transformation of brain tumors. Nature. 2010;463:318–325. doi: 10.1038/nature08712.
27.Li G., Wei H., Chen Z., Lv S., Yin C., Wang D. STAT3 silencing with lentivirus inhibits growth and induces apoptosis and differentiation of U251 cells. J. Neuro-Oncology. 2009;91:165–174. doi: 10.1007/s11060-008-9696-0.
28.Cao S., Wang C., Zheng Q., Qiao Y., Xu K., Jiang T., Wu A. STAT5 regulates glioma cell invasion by pathways dependent and independent of STAT5 DNA binding. Neurosci. Lett. 2011;487:228–233. doi: 10.1016/j.neulet.2010.10.028.
29.Latha K., Li M., Chumbalkar V., Gururaj A., Hwang Y., Dakeng S., Furnari F.B. Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. Int. J. Cancer. 2013;132:509–520. doi: 10.1002/ijc.27690.
30.Roos A., Dhruv H.D., Peng S., Inge L.J., Tuncali S., Pineda M., Millard N., Mayo Z., Eschbacher J.M., Loftus J.C., et al. EGFRvIII-Stat5 Signaling Enhances Glioblastoma Cell Migration and Survival. Mol. Cancer Res. 2018;16:1185–1195. doi: 10.1158/1541-7786.MCR-18-0125.
31.Bhaskaran V., Nowicki M.O., Idriss M., Jimenez M.A., Lugli G., Hayes J.L., Mahmoud A.B., Zane R.E., Passaro C., Ligon K.L., et al. The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma. Nat. Commun. 2019;10:442. doi: 10.1038/s41467-019-08390-z.
32.Floyd D., Purow B. Micro-masters of glioblastoma biology and therapy: Increasingly recognized roles for microRNAs. Neuro-Oncology. 2014;16:622–627. doi: 10.1093/neuonc/nou049.
33.Zhang W., Zhang J., Hoadley K., Kushwaha D., Ramakrishnan V., Li S., Kang C., You Y., Jiang C., Song S.W., et al. miR-181d: A predictive glioblastoma biomarker that downregulates MGMT expression. Neuro-Oncology. 2012;14:712–719. doi: 10.1093/neuonc/nos089.
34.Hegi M.E., Diserens A.C., Gorlia T., Hamou M.F., De Tribolet N., Weller M., Kros J.M., Hainfellner J.A., Mason W., Mariani L., et al. MGMTGene Silencing and Benefit from Temozolomide in Glioblastoma. N. Engl. J. Med. 2005;352:997–1003. doi: 10.1056/NEJMoa043331.
35.Bell E.H., Zhang P., Fisher B.J., Macdonald D.R., McElroy J.P., Lesser G.J., Fleming J., Chakraborty A.R., Liu Z., Becker A.P., et al. Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial. JAMA Oncol. 2018;4:1405–1409. doi: 10.1001/jamaoncol.2018.1977.
36.Yang F., Liu X., Liu Y., Liu Y., Zhang C., Wang Z., Jiang T., Wang Y. miR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype through NF-κB pathways in glioblastoma. Cancer Lett. 2017;396:1–9. doi: 10.1016/j.canlet.2017.03.002.
37.José Ignacio Erices, Ángelo Torres, Ignacio Niechi, Isabel Bernales, Claudia Quezada Current natural therapies in the treatment against glioblastoma Phytotherapy Research. 2018;32:2191–2201. doi:10.1002/ptr.6170
38.Chang T.C., Yeh C.T., Adebayo B.O., Lin Y.C., Deng L., Rao Y.K., Huang C.C., Lee W.H., Wu A.T., Hsiao M., et al. 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype. Toxicol. Appl. Pharmacol. 2015;288:258–268. doi: 10.1016/j.taap.2015.07.025.
39.Liu M., Bamodu O.A., Huang W.C., Zucha M.A., Lin Y.K., Wu A.T.H., Huang C.C., Lee W.H., Yuan C.C., Hsiao M., et al. 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway. Toxicol. Appl. Pharmacol. 2017;325:48–60. doi: 10.1016/j.taap.2017.04.003.
40.Chang C.H., Huang T.F., Lin K.T., Hsu C.C., Chang W.L., Wang S.W., Ko F.N., Peng H.C., Chung C.H. 4-Acetylantroquinonol B Suppresses Tumor Growth and Metastasis of Hepatoma Cells via Blockade of Translation-Dependent Signaling Pathway and VEGF Production. J. Agric. Food Chem. 2014;63:208–215. doi: 10.1021/jf504434v.
41.Saadat N., Gupta S.V. Potential Role of Garcinol as an Anticancer Agent. J. Oncol. 2012;2012:647206. doi: 10.1155/2012/647206.
42.Arshad L., Haque M.A., Bukhari S.N.A., Jantan I. An overview of structure–activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents. Futur. Med. Chem. 2017;9:605–626. doi: 10.4155/fmc-2016-0223.
43.Huang W.C., Kuo K.T., Adebayo B.O., Wang C.H., Chen Y.J., Jin K., Yeh C.T. Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. J. Nutr. Biochem. 2018;54:140–150. doi: 10.1016/j.jnutbio.2017.12.008.
44.Hong J., Kwon S.J., Sang S., Ju J., Zhou J.N., Ho C.T., Huang M.T., Yang C.S. Effects of garcinol and its derivatives on intestinal cell growth: Inhibitory effects and autoxidation-dependent growth-stimulatory effects. Free. Radic. Biol. Med. 2007;42:1211–1221. doi: 10.1016/j.freeradbiomed.2007.01.016.
45.Ahmad A., Sarkar S.H., Aboukameel A., Ali S., Biersack B., Seibt S., Li Y., Bao B., Kong D., Banerjee S., et al. Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Carcinogenesis. 2012;33:2450–2456. doi: 10.1093/carcin/bgs290.
46.Ahmad A., Wang Z., Ali R., Maitah M.Y., Kong D., Banerjee S., Padhye S., Sarkar F.H. Apoptosis-inducing effect of garcinol is mediated by NF-κB signaling in breast cancer cells. J. Cell. Biochem. 2010;109:1134–1141. doi: 10.1002/jcb.22492.
47.Vadlakonda L., Pasupuleti M., Pallu R. Role of PI3K-Akt-mTOR and Wnt signaling pathways in transition of G1-S phase of cell cycle in cancer cells. Front. Oncol. 2013;3:e85. doi: 10.3389/fonc.2013.00085.
48.Wei, L.; Su, Y.K.; Lin, C.M.; Chao, T.Y.; Huang, S.P.; Huynh, T.T.; Jan, H.J.; Whang-Peng, J.; Chiou, J.F.; Wu, A.T.; et al. Preclinical investigation of ibrutinib, a Bruton’s kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes. Oncotarget 2016, 7, 69961–69975. 

49.Ye, S.; Zhang, D.; Cheng, F.; Wilson, D.; Mackay, J.; He, K.; Ban, Q.; Lv, F.; Huang, S.; Liu, D.; et al. Wnt/β-catenin and LIF–Stat3 signaling pathways converge on Sp5 to promote mouse embryonic stem cell self-renewal. Development 2016, 129, 269–276. 

50.Hao, J.; Li, T.-G.; Qi, X.; Zhao, D.-F.; Zhao, G.-Q. WNT/β-catenin pathway up-regulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells. Development. Biol. 2006, 290, 81–91. 

51.Fragoso, M.A.; Patel, A.K.; Nakamura, R.E.I.; Yi, H.; Surapaneni, K.; Hackam, A.S. The Wnt/β-Catenin Pathway Cross-Talks with STAT3 Signaling to Regulate Survival of Retinal Pigment Epithelium Cells. PLoS ONE 2012, 7, e46892. 

52.Raggioli, A.; Junghans, D.; Rudloff, S.; Kemler, R. β-Catenin Is Vital for the Integrity of Mouse Embryonic Stem Cells. PLoS ONE 2014, 9, e86691. 

53.Murayama, H.; Masaki, H.; Sato, H.; Hayama, T.; Yamaguchi, T.; Nakauchi, H. Successful Reprogramming of Epiblast Stem Cells by Blocking Nuclear Localization of β-Catenin. Stem Cell Rep. 2015, 4, 103–113. 

54.Bradshaw, A.; Wickremsekera, A.; Tan, S.T.; Peng, L.; Davis, P.F.; Itinteang, T. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme. Front. Surg. 2016, 3, e21 

55.Iacopino, F.; Angelucci, C.; Piacentini, R.; Biamonte, F.; Mangiola, A.; Maira, G.; Grassi, C.; Sica, G. Isolation of Cancer Stem Cells from Three Human Glioblastoma Cell Lines: Characterization of Two Selected Clones. PLoS ONE 2014, 9, e105166. 

56.Beier, D.; Schulz, J.B.; Beier, C.P. Chemoresistance of glioblastoma cancer stem cells—much more complex than expected. Mol. Cancer 2011, 10, e128. 

57.Omuro, A.; DeAngelis, L.M. Glioblastoma and other malignant gliomas: A clinical review. JAMA 2013, 310, 1842–1850. 

58.Lathia, J.D.; Mack, S.C.; Mulkearns-Hubert, E.E.; Valentim, C.L.; Rich, J.N. Cancer stem cells in glioblastoma. Genes Dev. 2015, 29, 1203–1217. 

59.Liu, X.; Wang, L.; Zhao, S.; Ji, X.; Luo, Y.; Ling, F. β-Catenin overexpression in malignant glioma and its role in proliferation and apoptosis in glioblastma cells. Med. Oncol. 2010, 28, 608–614.
60.Rossi, M.; Magnoni, L.; Miracco, C.; Mori, E.; Tosi, P.; Pirtoli, L.; Tini, P.; Oliveri, G.; Cosci, E.; Bakker, A. β-catenin and Gli1 are prognostic markers in glioblastoma. Cancer Biol. Ther. 2011, 11, 753–761.
61.Grossmann, T.N.; Yeh, J.T.-H.; Bowman, B.R.; Chu, Q.; Moellering, R.E.; Verdine, G.L. Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin. Proc. Natl. Acad. Sci. USA 2012, 109, 17942–17947. 

62.Hwang, S.Y.; Deng, X.; Byun, S.; Lee, C.; Lee, S.J.; Suh, H.; Zhang, J.; Kang, Q.; Zhang, T.; Westover, K.D.; et al. Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling. Cell Rep. 2016, 16, 28–36. 

63.Nager, M.; Bhardwaj, D.; Cantí, C.; Medina, L.; Nogués, P.; Herreros, J. β-Catenin Signalling in Glioblastoma Multiforme and Glioma-Initiating Cells. Chemother. Res. Practice 2012, 2012, 1–7. 

64.Rajendran, V.; Jain, M.V. In Vitro Tumorigenic Assay: Colony Forming Assay for Cancer Stem Cells. Cancer Stem Cells 2017, 1692, 89–95. 

65.Dietrich, J.; Diamond, E.L.; Kesari, S. Glioma stem cell signaling: Therapeutic opportunities and challenges. Exp. Rev. Anticancer Ther. 2010, 10, 709–722. 

66.Agoram, B.M. Use of pharmacokinetic/pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics. Br. J. Clin. Pharmacol. 2009, 67, 153–160. 

67.Turner, P.V.; Brabb, T.; Pekow, C.; Vasbinder, M.A. Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider. J. Am. Assoc. Lab. Anim. Sci. 2011, 50, 600–613. 

68.Mohanty, S.K.; Yagiz, K.; Pradhan, D.; Luthringer, D.J.; Amin, M.B.; Alkan, S.; Cinar, B. STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer. Oncotarget 2017, 8, 85997–86010. 

69.Ghanem, S.; Friedbichler, K.; Boudot, C.; Bourgeais, J.; Gouilleux-Gruart, V.; Régnier, A.; Herault, O.; Moriggl, R.; Gouilleux, F. STAT5A/5B-specific expansion and transformation of hematopoietic stem cells. Blood Cancer J. 2017, 7, e514. 

70.Gleixner, K.V.; Schneeweiss, M.A.; Herrmann, H.; Blatt, K.; Berger, D.; Eisenwort, G.; Greiner, G.; Byrgazov, K.; Hoermann, G.; Konopleva, M.; et al. Combined Targeting of STAT3 and STAT5: A Novel Approach to Overome Drug Resistance in Ph+ Cml. Blood 2016, 128, 4241. 

71.Yuan, J.; Zhang, F.; Niu, R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci. Rep. 2015, 5, 17663. 

72.Kwon, S.J.; Kwon, O.S.; Kim, K.T.; Go, Y.H.; Yu, S.I.; Lee, B.H.; Miyoshi, H.; Oh, E.; Cho, S.J.; Cha, H.J. Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii. Mol. Cancer 2017, 16, 140. 

73.Shi, M.; Ji, H.; Jiang, H.; Li, D.; Chen, G.; Wang, Z. MicroRNA-181d is a tumor suppressor in human esophageal squamous cell carcinoma inversely regulating Derlin-1. Oncol. Rep. 2016, 36, 2041–2048. 

74.Wang, X.F.; Shi, Z.M.; Wang, X.R.; Cao, L.; Wang, Y.Y.; Zhang, J.X.; Yin, Y.; Luo, H.; Kang, C.S.; Liu, N.; et al. MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2. J. Cancer Res. Clin. Oncol. 2012, 138, 573–584. 

75.Luo, N.; Balko, J.M. Role of JAK-STAT Pathway in Cancer Signaling. In Predictive Biomarkers in Oncology; Badve, S., Kumar, G., Eds.; Springer: Cham, Switzerland, 2019; pp. 311–319. 

76.Zhuang, G.; Wu, X.; Jiang, Z.; Kasman, I.; Yao, J.; Guan, Y.; Oeh, J.; Modrusan, Z.; Bais, C.; Sampath, D.; et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 2012, 31, 3513–3523. 

77.Lam, D.; Barré, B.; Guette, C.; Coqueret, O. Circulating miRNAs as new activators of the JAK-STAT3 pathway. JAK STAT 2013, 2, e22996. 

78.Liu, X.; Gao, X.; Zhang, W.; Zhu, T.; Bi, W.; Zhang, Y. MicroRNA-204 deregulation in lung adenocarcinoma controls the biological behaviors of endothelial cells potentially by modulating Janus kinase 2-signal transducer and activator of transcription 3 pathway. IUBMB Life 2017, 70, 81–91. 

79.Ho, K.H.; Chen, P.H.; Hsi, E.; Shih, C.M.; Chang, W.C.; Cheng, C.H.; Lin, C.W.; Chen, K.C. Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA/mRNA regulatory network analysis. Sci. Rep. 2017, 7, 732. 

80.Kim, J.E.; Patel, M.; Ruzevick, J.; Jackson, C.M.; Lim, M. STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications. Cancers 2014, 6, 376–395. 

81.Ramalingam, D.; Ziegelbauer, J.M. Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses. Sci. Rep. 2017, 7, 40813. 

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊