TAZ expression as a prognostic indicator in colorectal cancer
Authors: Jill M Tham
Xiaoqian Zhang
Cian M McCrudden
Qi Zeng
Yu-Han Huang
WanJin Hong
Shu-Dong Zhang
Hiu-Fung Yuen
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: Hippo pathway; TAZ; YAP; colorectal cancers; prognostic significance
Affiliations: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.

Abstract:  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&lt;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. 

Retracted: No

PubPeer comments:
 Figure 1. * Red boxes: Panels G (Axl expression) and H (CTGF expression) appear to be showing the same data points. However, the Spearmanu2019s rank test values are different.  Could the authors please check? , 
 Figure 2. * Blue boxes: In panel G, the Univariate analysis and Multivariate analysis numbers are identical. Is this a small error or are the values expected to be the same? For all other comparisons in this and other figures the numbers are different. Some values in C and G or D and H are also identical but this appears to be the same analysis.  , 
 Figure 7. * Green boxes: The tumors shown in panels D (HCT116 cells) and E (SW620 cells) appear to look very similar.  , 
 Supplementary Figure 2: * Orange boxes: Two panels displaying survival in two different cohorts appear to look very similar.  ,