Background: Focal adhesion plays an essential role in tumour invasiveness and metastasis. Hippo component YAP has been widely reported to be involved in many aspects of tumour biology. However, its role in focal adhesion regulation in breast cancer remains unexplored. Methods: Tissue microarray was used to evaluate YAP expression in clinical breast cancer specimens by immunohistochemical staining. Cell migration and invasion abilities were measured by Transwell assay. A cell adhesion assay was used to measure the ability of cell adhesion to gelatin. The focal adhesion was visualized through immunofluorescence. Phosphorylated FAK and other proteins were detected by Western blot analysis. Gene expression profiling was used to screen differently expressed genes, and gene ontology enrichment was performed using DAVID software. The gene mRNA levels were measured by quantitative real-time PCR. The activity of the THBS1-promoter was evaluated by dual luciferase assay. Chromatin immunoprecipitation (ChIP) was used to verify whether YAP could bind to the THBS1-promoter region. The prediction of potential protein-interaction was performed with the String program. The ChIP sequence data of TEAD was obtained from the ENCODE database and analysed via the ChIP-seek tool. The gene expression dataset (GSE30480) of purified tumour cells from primary breast tumour tissues and metastatic lymph nodes was used in the gene set enrichment analysis. Prognostic analysis of the TCGA dataset was performed by the SurvExpress program. Gene expression correlation of the TCGA dataset was analysed via R2: Genomics Analysis and Visualization Platform. Results: Our study provides evidence that YAP acts as a promoter of focal adhesion and tumour invasiveness via regulating FAK phosphorylation in breast cancer. Further experiments reveal that YAP could induce FAK phosphorylation through a TEAD-dependent manner. Using gene expression profiling and bioinformatics analysis, we identify the FAK upstream gene, thrombospondin 1, as a direct transcriptional target of YAP-TEAD. Silencing THBS1 could reverse the YAP-induced FAK activation and focal adhesion. Conclusion: Our results unveil a new signal axis, YAP/THBS1/FAK, in the modulation of cell adhesion and invasiveness, and provides new insights into the crosstalk between Hippo signalling and focal adhesion.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Liang Liu1, 2, *, Cong Xu3, *, Jer-Tsong Hsieh4, Jianping Gong1, 2, Daxing Xie1, 2 1Tongji Cancer Research Institute, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, Hubei 430030, China 2Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, Hubei 430030, China 3Department of Gastroenterology, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, Hubei 430030, China 4Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA *These authors contributed equally to this work Correspondence to: Daxing Xie, e-mail: dxxie@tjh.tjmu.edu.cn Jianping Gong, e-mail: jpgong@tjh.tjmu.edu.cn Jer-Tsong Hsieh, e-mail: jt.hsieh@utsouthwestern.edu Keywords: DAB2IP, AIP1, cancer, tumor suppressor Received: July 23, 2015 Accepted: November 15, 2015 Published: December 08, 2015

Metastasis is a critical factor for the high mortality of colorectal cancer (CRC), but its mechanism is not completely understood. Epithelial-mesenchymal transition (EMT) is thought to play a key role in metastasis and also increases the cancer stem cell (CSC) feature that facilitates metastatic colonization. In this study, we investigated the biological roles of DAB2IP regulating EMT and stem cell–like features in human CRC. We demonstrate that DAB2IP suppresses NF-κB-mediated EMT and CSC features in CRC cells. In DAB2IP knockout mice, we discovered the hyperplasia in colonic epithelium which aberrantly represents the mesenchymal feature and NF-κB pathway activation. In clinic CRC tissue, we also reveal that reduced DAB2IP can enrich the CD133⁺ subpopulation. DAB2IP expression was inversely correlated with tumor differentiation and metastasis and patients with lower DAB2IP expression had shorter overall survival time. Taken together, our study demonstrates that DAB2IP inhibits NF-κB-inducing EMT and CSC to suppress the CRC progression and also suggests that DAB2IP is a beneficial prediction factor for CRC patient prognosis.

Gastric cancer is the second leading cause of cancer death worldwide. Here, we propose a novel type of tumor metastasis designated as Metastasis V in gastric cancer. Metastasis V is defined as the appearance of cancer cells in the mesogastrium with perigastric adipose tissue. To detect its incidence and characterize its clinic pathological features, large cross sectional tissue analysis of mesogastrium from 74 patients were used. Metastasis V was detected in 1 of 40 (2.5%) patients with early gastric cancer, 8 of 34 (24%) patients with advanced gastric cancer. The mean distance of Metastasis V from gastric wall was approximately 2.6 cm. Metastasis V was closely associated with tumor invasion depth, along with a number of positive lymph node metastasis. The prognosis of patients with Metastasis V was significantly (P<0.05) worse than those with tumor cell-free mesogastrium. These findings indicate that by using whole-sectional analysis, Metastasis V can be detected in the mesogastrium of gastric cancer patients, and also suggests that it may be a risk factor for patient survival after radical surgery.

Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the underlying mechanism remains to be elucidated. Invadopodia are actin-rich protrusions containing multiple proteases and have been widely reported to promote cell invasiveness by degrading the extracellular matrix. In the present study, we report that YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer cells. We also identify TIAM1, a guanine nucleotide exchange factor, as a target of the YAP1–TEAD4 complex. Our results demonstrate that YAP1 could promote TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression, subsequently increasing RAC1 activity and inducing invadopodia formation. These findings reveal the functional role of Hippo signaling in the regulation of invadopodia and provide potential molecular targets for preventing tumor metastasis in breast cancer.