TAZ Expression as a Prognostic Indicator in Colorectal Cancer

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<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.

Association between the expression levels of TAZ, AXL and CTGF and clinicopathological parameters in patients with colon cancer

“…R scripting was used to extract the expression values from the probe sets for TAZ, AXL and CTGF, and the clinical data from the data matrixes available at GEO, as previously described (5). All statistical analyses were performed using SPSS software, version 19.0 (IBM SPSS, Armonk, NY, USA).…”

“…However, the identification of further prognostic markers has experienced limited success in recent years (3). Tafazzin (TAZ), also known as WW domain containing transcription regulator 1 (WWTR1), is an important transcription coactivator and a key downstream effector of the mammalian Hippo signaling pathway (4), which participates in the development of colon cancer (5,6).…”

“…The use of the messenger (m)RNA expression levels of TAZ and its downstream factors AXL receptor tyrosine kinase (AXL) and connective tissue growth factor (CTGF) as a three-gene signature for the prognosis of patients with colon cancer has been previously reported in two independent cohort datasets (5). However, these datasets did not contain clinicopathological data of the patients, contrarily to the cohort Gene Expression Omnibus Series (GSE)40967, which has been recently submitted to the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.…”

“…Due to this combination of genetic and clinicopathological data, GSE40967 may be a powerful tool for confirming the prognostic potential of the TAZ-AXL-CTGF mRNA expression signature in colon cancer. In addition, the comprehensive information provided by GSE40967 may enable to determine the association between the aforementioned genetic and clinicopathological characteristics and the prognostic significance of the TAZ-AXL-CTGF signature in patients with colon cancer, which was not possible to test in the previous study by Yuen et al (5).…”

The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation

“…2014; Consistently, a lot of human cancers show overexpression or hyperactivation of nuclear YAP or TAZ or downregulation of Lasts1/2, Mst1/2 or Sav1 function (Dong et al, 2007;Hall et al, 2010;Jiang et al, 2006;Matsuura et al, 2011;Muramatsu et al, 2011;Nallet-Staub et al, 2013;Quan et al, 2014;Seidel et al, 2007;Steinhardt et al, 2008;Su et al, 2012;Takahashi et al, 2005;Wang et al, 2012;Wang et al, 2010;Wierzbicki et al, 2013;Xu et al, 2011;Xu et al, 2009;Yuen et al, 2013;Zender et al, 2006;Zhao et al, 2007;Zhou Z et al, 2011) see also table 4. Moreover, overexpression or hyperactivation of YAP and TAZ have been associated with poor prognosis and shorter survival times for patients in several human cancers (Hall et al, 2010;Liu JH et al, 2013;Muramatsu et al, 2011;Wang et al, 2010;Xu et al, 2009;Zhang et al, 2011).…”