|Table of Contents|

IGF-FOXO3a pathway regulates self-renewal of liver cancer stem cells in vitro

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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

Issue:
2017年第16期
Page:
1631-1636
Research Field:
基础医学
Publishing date:

Info

Title:

IGF-FOXO3a pathway regulates self-renewal of liver cancer stem cells in vitro

Author(s):

LI ZhifenSHEN JunjieSHAN JuanjuanCHEN JunQIAN Cheng

College of Life Science, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, 310018; Biological Therapy Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

Keywords:

liver cancer stem cells FOXO3a insulin-like growth factor colony formation ability sphere formation ability

PACS:
R341;R730.23;R735.7
DOI:
-
Abstract:

Objective      To investigate the role of FOXO3a in the regulation of self-renewal capacity in liver cancer stem cells (LCSCs) and study the related mechanisms. Methods     Flow cytometry was used to obtain LCSCs,and then the expression of FOXO3a in the attained cells was detected by real time fluorescent quantitative PCR (qRT-PCR). After the activity of insulin-like growth factor(IGF) was changed with IGF inhibitor or activator, the expression of FOXO3a was measured again with Western blotting and qRT-PCR. The lentiviral vectors expressing or interfering FOXO3a were used to infect the cells, and Western blot analysis was used to detect the efficiencies of overexpression and interference. Cell colony formation assay and sphere formation assay were used to test the self-renewal in the cells infected with the lentivirus that expressing or interfering FOXO3a, and the cells treated with IGF activators meanwhile over-expressing FOXO3a. Results     The expression of FOXO3a was significantly lower in the LCSCs than the liver cancer cells (P<0.01), and it was negatively regulated by IGF. The cell models of stable overexpression or interference of FOXO3a were established successfully. And FOXO3a over-expression resulted in decreases in the colony formation and sphere formation,while FOXO3a interference led to improvement in the formations. Activation of IGF signal, combined with FOXO3a overexpression also induced decreased formations. Conclusion     FOXO3a exerts a negative effect on the self-renewal in LCSCs, and can be negatively regulated by IGF signaling. It mediates the regulation of IGF signaling on the selfrenewal in LCSCs.

References:

[1]TORRE L A, BRAY F, SIEGEL R L,et al.Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108. DOI: 10.3322/caac.21262.
[2]SHAN J, SHEN J, LIU L, et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma[J]. Hepatology, 2012, 56(3): 1004-1014. DOI: 10.1002/hep.25745.
[3]HEDRICK S M, HESS MICHELINI R, DOEDENS A L, et al. FOXO transcription factors throughout T cell biology[J]. NatRev Immunol, 2012, 12(9): 649-661. DOI: 10.1038/nri3278.
[4]WEBB A E, BRUNET A.FOXO transcription factors: key regulators of cellular quality control[J]. Trends BiochemSci, 2014, 39(4): 159-169. DOI: 10.1016/j.tibs.2014.02.003.
[5]WANG Y, ZHOU Y, GRAVES D T.FOXO transcription factors: their clinical significance and regulation[J]. Biomed Res Int, 2014, 2014: 925350. DOI: 10.1155/2014/925350.
[6]NI D, MA X, LI H Z, et al. Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasisfree survival of patients with clear cell renal cell carcinoma[J]. Clin Cancer Res, 2014, 20(7): 1779-1790. DOI: 10.1158/1078-0432.CCR-13-1687.
[7]LIU H, YIN J, WANG H, et al. FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells[J]. Cell Signal, 2015, 27(3): 510-518. DOI: 10.1016/j.cellsig.2015.01.001.
[8]SANTO E E, STROEKEN P, SLUIS P V, et al. FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma[J]. Cancer Res, 2013, 73(7): 2189-2198. DOI: 10.1158/0008-5472.CAN-12-3767.
[9]JIANG Y, ZOU L, LU W Q, et al. Foxo3a expression is a prognostic marker inbreast cancer[J]. PLoS One, 2013, 8(8): e70746. DOI: 10.1371/journal.pone.0070746.
[10]NHO R S, HERGERT P. FoxO3a and disease progression[J]. World J Biol Chem, 2014, 5(3): 346-354. DOI: 10.4331/wjbc.v5.i3.346.
[11]CARBAJO-PESCADOR S, STEINMETZ C, KASHYAP A, et al. Melatonin inducestranscriptional regulation of Bim by FoxO3a in HepG2 cells[J]. Br J Cancer, 2013, 108(2): 442-449. DOI: 10.1038/bjc.2012.563.
[12]LIANG C, CHEN W, ZHI X,et al. Serotonin promotes the proliferation of serumdeprived hepatocellular carcinoma cells via upregulation of FOXO3a[J]. Mol Cancer, 2013, 12(1): 14. DOI: 10.1186/1476-4598-12-14.
[13]WANG J, ZHENG X, ZENG G, et al. Purified vitexin compound 1 inhibits growthand angiogenesis through activation of FOXO3a by inactivation of Akt in hepatocellular carcinoma[J]. Int J Mol Med, 2014, 33(2):441-448. DOI: 10.3892/ijmm.2013.1587.
[14]ZHANG X, RIELLAND M, YALCIN S, et al. Regulation and function of FoxO transcription factors in normal and cancer stem cells: what have we learned?[J]. Curr Drug Targets, 2011,12(9): 1267-1283. DOI: 10.2174/138945011796150325.
[15]FORNER A, LLOVET J M, BRUIX J. Hepatocellular carcinoma[J]. Lancet, 2012, 379(9822): 1245-1255. DOI: 10.1016/S0140-6736(11)61347-0.
[16]LU M, MA J, XUE W, et al. The expression and prognosis of FOXO3a and Skp2 in human hepatocellular carcinoma[J]. Pathol Oncol Res, 2009, 15(4): 679-687. DOI: 10.1007/s12253009-9171-z.
[17]VILCHEZ D, BOYER L, MORANTTE I, et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11[J]. Nature, 2012, 489(7415): 304-308. DOI: 10.1038/nature11468.
[18]SUNAYAMA J, SATO A, MATSUDA K, et al. FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity[J]. Stem Cells, 2011, 29(9): 1327-1337. DOI: 10.1002/stem.696.
[19]EIJKELENBOOM A, BURGERING B M. FOXOs: signalling integrators for homeostasis maintenance[J]. Nat Rev Mol Cell Biol, 2013, 14(2): 83-97. DOI: 10.1038/nrm3507.

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Last Update: 2017-08-23