Role of Wnt/β‐catenin signaling pathway in epithelial‐mesenchymal transition of human prostate cancer induced by hypoxia‐inducible factor‐1α

International Journal of Urology - Tập 14 Số 11 - Trang 1034-1039 - 2007
Yongguang Jiang1, Yong Luo1, Dalin He2, Xiang Li2, Linlin Zhang2, Tao Peng1, Mingchuan Li1, Yun‐Hua Lin1
1Department of Urology, Affiliated Beijing Anzhen Hospital of Capital Medical University, Beijing, and
2Department of Urology, First Hospital of Xi'an Jiaotong University, Xi'an, China

Tóm tắt

Objectives:  Epithelial‐mesenchymal transition (EMT) is an important process in tumor development, and several studies suggest that the Wnt/β‐catenin signal pathway may play an important role in EMT. However, there is no direct evidence showing that the Wnt/β‐catenin pathway actually determines the EMT induced by an exogenous signal. Our previous research has successfully proved that overexpression of hypoxia‐inducible factor‐1α (HIF‐1α) could induce EMT in LNCaP cells, but not in PC‐3. The present study aims to determine whether the signal of HIF‐1α for inducing prostate cancer cells to undergo EMT might possibly pass through the Wnt/β‐catenin pathway.Methods:  Epithelial‐mesenchymal transition associated proteins were detected in several human prostate carcinoma cell lines by Western blot, and then we distinguished the EMT positive cell lines from the EMT negative cell lines. Furthermore, we evaluated the possible correlation between potency of invasiveness and proliferation among these cell lines with different characteristics of EMT using Matrigel transwell and thiazolyl blue tetrazolium bromide (MTT) assays. Finally, the different expression of some critical proteins and genes in Wnt/β‐catenin signaling pathway were analyzed by Western blot and reverse transcription‐polymerase chain reaction (RT‐PCR) in these cells with different characteristics of EMT.Results:  Among several prostate cancer cell lines, PC‐3, LNCaP and PC‐3/HIF‐1α are EMT negative cell lines, whereas LNCaP/HIF‐1α and IA8 have undergone the EMT process. EMT positive cells (LNCaP/HIF‐1α and IA8) exhibit much stronger potency of invasiveness and proliferation than those of PC‐3 and LNCaP, which belong to EMT negative cells. Interestingly, although PC‐3/HIF‐1α had not completed the EMT process, it still displayed stronger potency of invasion and proliferation, resembling EMT positive cells. The protein expression level of total glycogensynthase kinase 3β (GSK‐3β) and phospho‐GSK‐3β in LNCaP/HIF‐1α, IA8 and PC‐3/HIF‐1α cells significantly decreased; however, the relative ratios of p‐GSK3β/t‐GSK3β in LNCaP/HIF‐1α, IA8 and PC‐3/HIF‐1α cells were significantly higher than PC‐3 and LNCaP. Consistently, β‐catenin protein expression increased in LNCaP/HIF‐1α and IA8 cells, but not in PC‐3/HIF‐1α; RT‐PCR confirmed these results, except for the enhanced transcription activity of β‐catenin mRNA in PC‐3/HIF‐1α.Conclusion:  Our data suggests that activation of the Wnt/β‐catenin signaling pathway correlates with the characteristic of EMT and potency of invasiveness and proliferation. This may be the critical factor that directly controls the process of EMT induced by HIF‐1α in prostate cancer cells.

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Tài liệu tham khảo

10.1159/000147748

10.1073/pnas.95.8.4374

10.1083/jcb.148.1.173

10.1128/MCB.19.8.5576

10.1016/S0002-9440(10)65204-2

Krishnamachary B, 2003, Regulation of colon carcinoma cell invasion by hypoxia‐inducible factor 1, Cancer Res., 63, 1138

10.1111/j.1464-410X.2006.06480.x

10.1021/mp034031n

10.1007/BF02911379

10.1002/jcb.20683

Akakura N, 2001, Constitutive expression of hypoxia‐inducible factor‐1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation, Cancer Res., 61, 6548

10.1186/bcr813

10.1111/j.1365-2559.2005.02045.x

10.1073/pnas.96.11.6273

Liotta LA, 1986, Tumor invasion and metastases – role of the extracellularmatrix: rhoads memorial award lecture, Cancer Res., 46, 1

10.3109/10409239709082573

10.1016/j.cell.2004.06.006

10.1016/j.cell.2004.07.011

10.1002/bies.1132

10.1002/ar.10165

10.1016/j.ceb.2003.10.006

Xue C, 2003, The gatekeeper effect of epithelial‐mesenchymal transition regulates the frequency of breast cancer metastasis, Cancer Res., 63, 3386

10.4161/cc.3.12.1280

10.1054/bjoc.2001.2105

10.1159/000084505

10.1172/JCI24399

10.1006/excr.1998.4238

10.1074/jbc.272.40.24735

10.1083/jcb.146.5.967

10.1073/pnas.95.19.11211

10.1093/emboj/16.13.3797

10.1002/(SICI)1096-9896(200001)190:1<15::AID-PATH489>3.0.CO;2-L

10.1091/mbc.11.10.3509

10.1074/jbc.M103167200

10.1073/pnas.150152697

10.1006/cbir.2002.0901

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International Journal of Urology

Tập 14 Số 11

1034-1039

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