TAZ expression as a prognostic indicator in colorectal cancer.
TAZ expression as a prognostic indicator in colorectal cancer.
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DOI：
10.1371/journal.pone.0054211
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hong W
中科院分区：
文献类型：
--
作者：
Yuen HF;McCrudden CM;Huang YH;Tham JM;Zhang X;Zeng Q;Zhang SD;Hong W
Hippo通路限制转录辅激活因子TAZ（WWTR 1）和雅普的活性。据报道，TAZ和雅普在多种癌症中过表达，然而，它们在结直肠癌中的预后意义尚未研究。TAZ和雅普及其下游转录靶标AXL和CTGF的表达水平从Gene Expression Omnibus数据库中可获得的两个独立的结肠癌患者数据集中提取，共计522名患者。TAZ、雅普mRNA表达与AXL、CTGF mRNA表达呈正相关（p<0.05）。TAZ、AXL或CTGF的高水平mRNA表达与较短的生存期显著相关。重要的是，共过表达所有3种基因的患者的生存时间显著缩短，这3种基因的组合表达是生存的独立预测因子。通过Java应用程序MyStats鉴定TAZ-AXL-CTGF过表达的下游靶基因。有趣的是，与结肠癌进展相关的基因（ANTXR 1，EFEMP 2，SULF 1，TAGLN，VCAN，ZEB 1和ZEB 2）在共过表达TAZ-AXL-CTGF的患者中上调。然后将该TAZ-AXL-CTGF基因表达特征（GES）应用于连接图，以鉴定可能用于逆转该GES的小分子。在通过连接图鉴定的前20种小分子中，阿米洛利（一种保钾利尿剂）和维甲酸（全反式维甲酸）在抑制结肠癌细胞生长方面显示出治疗前景。使用MyStats，我们发现ANO 1或SQLE的低水平表达与共过表达TAZ-AXL-CTGF的患者的预后更好相关，并且ANO 1与TAZ-AXL-CTGF一起是生存的独立预测因子。最后，我们证实TAZ调节Axl，并且在体外克隆形成和非粘附生长以及体内肿瘤形成中起重要作用。这些数据表明，TAZ可能是治疗结肠癌的治疗靶点。
The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic,) and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.
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影响因子：
8
作者：
Ehsanian, R.;Brown, M.;Lu, H.;Yang, X. P.;Pattatheyil, A.;Yan, B.;Duggal, P.;Chuang, R.;Doondeea, J.;Feller, S.;Sudol, M.;Chen, Z.;Van Waes, C.
通讯作者：
Van Waes, C.
影响因子：
9.7
作者：
HOOSEIN, NM;BRATTAIN, DE;BRATTAIN, MG
通讯作者：
BRATTAIN, MG
影响因子：
56.9
作者：
Hong, JH;Hwang, ES;Yaffe, MB
通讯作者：
Yaffe, MB
影响因子：
16
作者：
Basu, S;Totty, NF;Downward, J
通讯作者：
Downward, J
影响因子：
8.4
作者：
de Cristofaro, Tiziana;Di Palma, Tina;Zannini, Mariastella
通讯作者：
Zannini, Mariastella