IQGAP2, A candidate tumour suppressor of prostate tumorigenesis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1822

Article

Xie, Yanyun^1,2,4,5  Yan, Judy^1,2,4  Cutz, Jean-Claude³  Rybak, Adrian P.^1,2,4  He, Lizhi^1,2,4  Wei, Fengxiang^1,2,4,6  Kapoor, Anil^1,4  Schmidt, Valentina A.⁷  Tao, Lijian⁵  Tang, Damu^1,2,4 

[1] St Josephs Hosp, Hamilton Ctr Kidney Res, Hamilton, ON L8N 4A6, Canada

[2] Dept Med, Div Nephrol, Quebec City, PQ, Canada

[3] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada

[4] Father Sean OSullivan Res Inst, Hamilton, ON, Canada

[5] Cent S Univ, Dept Med, Xiangya Hosp, Div Nephrol, Changsha, Hunan, Peoples R China

[6] Inst Women & Childrens Hlth, Genet Lab, Shenzhen, Guangdong, Peoples R China

[7] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA

关键词: IQGAP2;    Tumour suppressor;    EMT;    AKT;    Prostate cancer;   

DOI  :  10.1016/j.bbadis.2012.02.019

来源: Elsevier

【 摘 要 】

Loss of IQGAP2 contributes to the tumorigenesis of hepatocellular carcinoma and gastric cancer. However, whether IQGAP2 also suppresses prostate tumorigenesis remains unclear. We report here that IQGAP2 is a candidate tumour suppressor of prostate cancer (PC). Elevated IQGAP2 was detected in prostatic intraepithelial neoplasia (PIN), early stages of PCs (Gleason score <= 3), and androgen-dependent LNCaP PC cells. However. IQGAP2 was expressed at substantially reduced levels not only in prostate glands and non-tumorigenic BPH-1 prostate epithelial cells but also in advanced (Gleason score 4 or 5) and androgen-independent PCs. Furthermore, xenograft tumours that were derived from stem-like DU145 cells displayed advanced features and lower levels of IQGAP2 in comparison to xenograft tumours that were produced from non stem-like DU145 cells. Collectively, these results suggest that IQGAP2 functions in the surveillance of prostate tumorigenesis. Consistent with this concept, ectopic IQGAP2 reduced the proliferation of DU145, PO, and 293 T cells as well as the invasion ability of DU145 cells. While ectopic IQGAP2 up-regulated E-cadherin in DU145 and PC3 cells, knockdown of IQGAP2 reduced E-cadherin expression. In primary PC and DU145 cells-derived xenograft tumours, the majority of tumours with high levels of IQGAP2 were strongly-positive for E-cadherin. Therefore, IQGAP2 may suppress PC tumorigenesis, at least in part, by up-regulation of E-cadherin. Mechanistically, overexpression of IQGAP2 significantly reduced AKT activation in DU145 cells and inhibition of AKT activation upregulated E-cadherin, suggesting that IQGAP2 increases E-cadherin expression by inhibiting AKT activation. Taken together, we demonstrate here that IQGAP2 is a candidate tumour suppressor of PC. (C) 2012 Elsevier B.V. All rights reserved.

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