Abstract
Transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. However, the expression profiles of TAZ/YAP differ depending on the cancer cell type, suggesting that these proteins have different roles during cancer progression, yet no studies have examined the biologic significance of the balance between TAZ and YAP expression levels. Here we examined the functional roles of TAZ/YAP in hepatocellular carcinoma progression. We found that TAZ, but not YAP, was predominantly expressed in HCC. TAZ knockdown under normal conditions attenuated cell growth in HCC cells; however, TAZ knockdown combined with 5-fluorouracil treatment significantly increased chemoresistance compared with control cells. Notably, TAZ knockdown induced compensatory YAP expression and was accompanied by upregulation of CD90, a HCC-specific cancer stem cell marker. Continuous treatment with 5-fluorouracil also induced YAP expression and promoted tumor formation in vivo. Conversely, double knockdown of TAZ/YAP reduced chemoresistance and tumorigenicity. Moreover, YAP knockdown aggravated HCC cell growth to a greater degree than TAZ knockdown, and YAP overexpression was strongly associated with poor prognoses in patients with HCC. Collectively, these studies demonstrate that TAZ and YAP exhibit different functional roles in cancer progression, and a shift to predominant YAP expression upon TAZ depletion conferred cancer stem cell-like properties including chemoresistance and tumorigenicity in HCC. Therefore, targeting of both TAZ/YAP will be required for a complete antitumor response in HCC.
Highlights
Contact inhibition of proliferation is crucial for well-controlled organogenesis, and disruption of this process results in sustained cell proliferation, which is a hallmark of solid tumors
In contrast to other gastrointestinal cancer cells, transcriptional coactivator with PDZ-binding motif (TAZ) was expressed at higher levels than yes-associated protein (YAP) in all seven hepatocellular carcinoma (HCC) cell lines and human HCC samples (Fig. 1D), indicating that TAZ was a predominant profile while YAP was a minor protein in these cells under normal culture conditions
TAZ and YAP have often been described to equivalent factors downstream of the Hippo pathway, TAZ initially exhibited higher expression than YAP in HCC, and TAZ overexpression at the mRNA level was a prognostic factor predicting poor outcomes in the current study
Summary
Contact inhibition of proliferation is crucial for well-controlled organogenesis, and disruption of this process results in sustained cell proliferation, which is a hallmark of solid tumors. Threonine kinase (MST) 1/2 in mice, induce the hyperactivation of Hippo downstream effectors, such as transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP), and result in liver outgrowth and the development of hepatocellular carcinoma Several studies have demonstrated the overexpression of TAZ or YAP in human cancers, including HCC [9,10,11,12,13,14,15,16,17]. TAZ and YAP are equivalently placed as downstream effectors in the Hippo pathway, it is unclear whether they have similar or different functional roles in cancer progression
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