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. 2015 Nov 3;6(34):35949-63.
doi: 10.18632/oncotarget.5772.

Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression

Dacheng Xie  1 , Jiujie Cui  2 , Tian Xia  2   3 , Zhiliang Jia  2 , Liang Wang  2 , Wenfei Wei  2 , Anna Zhu  2 , Yong Gao  1   2 , Keping Xie  2 , Ming Quan  1   2
Affiliations

Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression

Dacheng Xie et al. Oncotarget. .

Abstract

Transcriptional co-activator with PDZ binding motif (TAZ) is a transducer of the Hippo pathway and promotes cancer development and progression. In the present study, we sought to determine the roles and underlying mechanisms of elevated expression and activation of TAZ in pancreatic cancer development and progression. The mechanistic role of TAZ and Hippo signaling in promotion of pancreatic cancer development and progression was examined using cell culture, molecular biology, and mouse models. The relevance of our experimental and mechanistic findings was validated using human pancreatic tumor specimens. We found that TAZ expression was markedly higher in pancreatic tumors than in normal pancreatic tissue. Further analysis of the correlation of TAZ expression with tissue microarray clinicopathologic parameters revealed that this expression was positively associated with tumor differentiation. Also, TAZ expression was higher in pancreatic cancer cell lines than in pancreatic ductal epithelial cells. TAZ activation in pancreatic cancer cells promoted their proliferation, migration, invasion, and epithelial-mesenchymal transition. Further mechanistic studies demonstrated that aberrant expression and activation of TAZ in pancreatic cancer cells resulted from suppression of the expression of Merlin, a positive regulator upstream of the Hippo pathway, and that the oncogenic function of TAZ in pancreatic cancer cells was mediated by TEA/ATTS domain transcription factors. Therefore, TAZ functioned as an oncogene and promoted pancreatic cancer epithelial-mesenchymal transition and progression. TAZ thus may be a target for effective therapeutic strategies for pancreatic cancer.

Keywords: EMT; TAZ; metastasis; pancreatic cancer; proliferation.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no known conflicts of interest.

Figures

Figure 1
Figure 1. Expression of TAZ in pancreatic tumors and pancreatic cancer cell lines
Pancreatic tumor specimens in a TMA were immunostained for TAZ protein using a specific anti-TAZ antibody. A. Stains of pancreatic tumor specimens showing a. negative TAZ staining, b. weakly positive TAZ staining, c. moderately positive TAZ staining, and d. strongly positive TAZ staining. B. Stains of nonmalignant pancreatic tissue specimens showing negative TAZ staining a., while pancreatic cancer tissue showing positive TAZ staining b.. C. Graph showing that the expression of TAZ was significantly higher in tumor (TT) than in tumor-adjacent normal tissue (TN) specimens and that TAZ expression did not differ significantly between TN and normal tissue (NN) specimens. D. Western blot verifying the expression of TAZ protein in paired normal pancreatic tissue (N) and pancreatic tumor (T) specimens. E. Western blot showing the expression of TAZ protein in pancreatic cancer cell lines.
Figure 2
Figure 2. Effect of altered TAZ expression on pancreatic cancer cell growth in vitro and in vivo
A. Western blots showing altered expression of TAZ and YAP in pancreatic cancer cell lines with stable overexpression of TAZ (BxPC-3 and AsPC-1) or depletion of TAZ (FG and PANC-1). B. and C. A colony formation assay was performed using 24-well plates, and the resulting BxPC-3 and FG cell colonies were counted 14 days after the cells were seeded. (D and E) BxPC-3 cells with TAZ overexpression D. and FG cells with TAZ depletion E. were injected subcutaneously into the right scapular regions of nude mice (n = 5). The resulting tumors were removed from the mice and weighed. The data are presented as the mean ± standard error of the mean from three independent experiments. P values are provided, as comparisons were performed as indicated.
Figure 3
Figure 3. Effect of altered expression of TAZ on pancreatic cancer cell migration and invasion
BxPC-3 cells were transiently transfected with HA-TAZ or a control vector, and FG cells were transfected with Sh-TAZ-1 or a control vector. Cell scratch-wound, transwell migration, and invasion assays were used as described in Materials and Methods. Representative photos of wound healing, migration and invasion are shown. The data are presented as the mean ± standard error of the mean from three independent experiments. P values are provided, as comparisons were performed as indicated.
Figure 4
Figure 4. Influence of TAZ expression on the EMT phenotype of pancreatic cancer cells
AsPC-1 and BxPC-3 cells were transfected with HA-TAZ or a control vector, and FG and PANC-1 cells were transfected with Sh-TAZ-1 or a control vector. A. and B. Immunofluorescent stains showing E-cadherin expression in BxPC-3 and FG cells. DAPI, 4′,6-diamidino-2-phenylindole. C. and D. Western blots showing an abundance of the EMT markers E-cadherin and vimentin in pancreatic cancer cells.
Figure 5
Figure 5. Regulation of the expression, nuclear localization, and transcriptional activity of TAZ by Merlin via the Hippo pathway
A. FG and PANC-1 cells were transfected with a Merlin overexpression vector or control vector. The Western blot shows the expression of Merlin, TAZ, LATS1, phosphorylated LATS1 (phospho-LATS1), MST1, phosphorylated MST1/2 (phospho-MST1/2), and the internal control GAPDH in the cells. B. FG cells were transfected with a Merlin overexpression vector or control vector for 48 h, and cytosolic and nuclear proteins were extracted. The Western blot shows the levels of TAZ expression in the cells. (C and D) The 8×GTIIC-luciferase reporter was co-transfected into BxPC-3 C. and AsPC-1 D. cells with a control vector alone or with pMerlin, HA-TAZ alone or with pMerlin, or 4SA alone or pMerlin for 24 h. The graphs show the resulting promoter activity in the cells as analyzed using a dual luciferase assay.
Figure 6
Figure 6. Mediation of the oncogenic function of TAZ in pancreatic cancer cells by TEAD transcription factors
A. BxPC-3 and AsPC-1 cells were transfected with HA-TAZ, HA-4SA, HA-4SA-S51A, or a control vector. The Western blots show the expression of TAZ and its mutants, TEADs, CTGF, E-cadherin, and vimentin in the cells. B. AsPC-1 cells were transfected with a control vector, HA-TAZ, HA-4SA, or HA-4SA-S51A, and transwell migration and invasion assays were used as described in Materials and Methods. Representative photographs of the cell migration and invasion are shown. C. Graph showing the AsPC-1 cell growth as assessed via cell counting at the indicated time points. The data are presented as the mean ± standard error of the mean from three independent experiments. D. HA-4SA was co-transfected into BxPC-3 and AsPC-1 cells with control vector or shRNAs of TEAD. The Western blots show the expression of TAZ mutants, TEADs, CTGF, E-cadherin and vimentin in the cells.
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