TAZ Expression as a Prognostic Indicator in Colorectal Cancer

<div><p>The Hippo pathway restricts the activity of transcriptional coactivators TAZ (<em>WWTR1</em>) 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, <em>AXL</em> and <em>CTGF</em>, 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 <em>AXL</em> and <em>CTGF</em> (<em>p</em><0.05). High level mRNA expression of TAZ, <em>AXL</em> or <em>CTGF</em> 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 (<em>ANTXR1</em>, <em>EFEMP2</em>, <em>SULF1</em>, <em>TAGLN</em>, <em>VCAN</em>, <em>ZEB1</em> and <em>ZEB2</em>) 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 <em>ANO1</em> or <em>SQLE</em> were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that <em>ANO1</em> 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 <em>in vitro</em> and tumor formation <em>in vivo</em>. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.</p>