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yap hepatocellular carcinoma

Minjiang Chen, Liming Wu, Jianfei Tu, Zhongwei Zhao, Xiaoxi Fan, Jianting Mao, Qiaoyou Weng, Xulu Wu, Li Huang, Min Xu, Jiansong Ji
BACKGROUND: Resistance to chemotherapeutic treatment is a common phenomenon in cancers, especially in hepatocellular carcinoma (HCC). The Hippo signaling pathway has been demonstrated to play a role in tumor initiation, development, and progression. However, little is known about its roles in the HCC chemoresistance. METHODS: In this study, real-time PCR and western blotting were used to identify the expression profile of key components of Hippo signaling pathway between chemoresistant and chemosensitive HCC cell lines...
August 13, 2018: EBioMedicine
Min Liu, Ke Jiang, Guibin Lin, Peng Liu, Yumei Yan, Tian Ye, Gang Yao, Martin P Barr, Dapeng Liang, Yang Wang, Peng Gong, Songshu Meng, Haozhe Piao
BACKGROUND: Aberrant activation of β-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression. The LIM domain protein Ajuba regulates β-catenin and YAP signaling and is implicated in tumorigenesis. However, roles and mechanism of Ajuba expression in HCC cells remain unclear. The E3 ligase Hakai has been shown to interact with other Ajuba family members and whether Hakai interacts and regulates Ajuba is unknown. METHODS: HCC cell lines stably depleted of Ajuba or Hakai were established using lentiviruses expressing shRNAs against Ajuba or Hakai...
July 24, 2018: Journal of Experimental & Clinical Cancer Research: CR
Xiao-Mei Yang, Xiao-Yan Cao, Ping He, Jun Li, Ming-Xuan Feng, Yan-Li Zhang, Xue-Li Zhang, Ya-Hui Wang, Qin Yang, Lei Zhu, Hui-Zhen Nie, Shu-Heng Jiang, Guang-Ang Tian, Xiao-Xin Zhang, Qiang Liu, Jianguang Ji, Xuefeng Zhu, Qiang Xia, Zhi-Gang Zhang
BACKGROUND & AIMS: Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth. METHODS: Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using Gene Ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that associated with patient survival times...
July 12, 2018: Gastroenterology
Bo Shu, Mimi Zhai, Xiongying Miao, Chao He, Chaolin Deng, Yu Fang, Ming Luo, Luyao Liu, Sushun Liu
YAP-TEAD complex plays an important role in tumorigenesis. 5-HT is proved to upregulate YAP expression by our previous study and VGLL4 is found to compete with YAP for binding to TEAD in several of cancers. Here, we investigated whether 5-HT could affect progression and prognosis of hepatocellular carcinoma (HCC) patients and regulate YAP/VGLL4 balance. We found that 5-HT and YAP/VGLL4 ratio were higher in HCC patients and closely related with progression and poor prognosis. Furthermore, 5-HT level, YAP/VGLL4 ratio and tumor size were proved as independent risk factors of HCC patients in our study...
June 27, 2018: Scientific Reports
Xiaoguang Wang, Bin Wu, Zhengxiang Zhong
Yes-associated protein (YAP) serves an essential role in tumorigenesis. However, the potential role and the molecular mechanism underlying the effect of YAP on hepatocellular carcinoma (HCC) cells have not been elucidated. In the current study, it was revealed that YAP expression was increased significantly in HCC cancer tissues and its overexpression was associated with tumor differentiation. The silencing of YAP by small interferring RNA led to the inhibition of HCC cell growth, which was associated with the promotion of apoptosis...
July 2018: Oncology Letters
Jung-Chien Cheng, Evan Y Wang, Yuyin Yi, Avinash Thakur, Shu-Huei Tsai, Pamela A Hoodless
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway, which ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined...
June 14, 2018: Molecular Cancer Research: MCR
Qingping Guo, Jiale Wang, Zeyu Cao, Yongchang Tang, Chao Feng, Feizhou Huang
Despite advances in surgery and chemotherapy, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor. In the present study, the role of S100A1 in the progression of HCC was investigated. Immunohistochemical staining was used to measure the expression of S100A1 in HCC tissues. S100A1 was knocked down by siRNA. A battery of experiments was used to evaluate the biology functions of S100A1. It was found that S100A1 was upregulated in HCC tissues, and its upregulation was associated with a large tumor size, low differentiation and shorter survival time...
August 2018: International Journal of Oncology
Min-Kyung Kim, Jee Young Park, Yu Na Kang
Yes-associated protein (YAP) is a nuclear effector of the cell-density sensing Hippo pathway and interacts with Src homology phosphotyrosine phosphatase 2 (SHP2), which controls cell proliferation and survival. The tumor promoting/suppressing activities of YAP and SHP2 during liver tumorigenesis remain controversial. This study aimed to investigate the tumorigenic roles of YAP and SHP2 in hepatocellular carcinogenesis. Cell density associated subcellular distributions of YAP and SHP2 in normal human hepatocytes (THLE-2) and hepatocellular carcinoma (HCC) cells (SK-Hep1, SNU-182) were investigated by Western blotting and cell block immunohistochemistry...
July 2018: Pathology, Research and Practice
Hong Zhu, Dan-Dan Wang, Tao Yuan, Fang-Jie Yan, Chen-Ming Zeng, Xiao-Yang Dai, Zi-Bo Chen, Ying Chen, Tianyi Zhou, Guang-Han Fan, Meidan Ying, Ji Cao, Peihua Luo, Xi-Jie Liu, Yuandong Hu, Yong Peng, Qiaojun He, Bo Yang
Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling...
July 15, 2018: Cancer Research
Zhenhai Fan, Hongwei Xia, Huanji Xu, Ji Ma, Sheng Zhou, Wanting Hou, Qiulin Tang, Qiyong Gong, Yongzhan Nie, Feng Bi
High expression levels of CD44 and YAP have been identified as poor prognostic factors in hepatocellular carcinoma (HCC). However, the mechanistic relationship between CD44 and YAP during HCC tumorigenesis remains largely unknown. To investigate the mutual regulation between standard CD44 (CD44S) and YAP1 in HCC cell lines and tissue samples, CD44S and YAP1 expression in 40 pairs of tumor samples and matched distal normal tissues from HCC patients was examined by immunohistochemical staining. High expression of either CD44S or YAP1 was associated with a younger age and worse pathology grade...
July 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yuhua Xue, Wendy M Mars, William Bowen, Aatur D Singhi, John Stoops, George K Michalopoulos
Glypican (GPC)-3 is overexpressed in hepatocellular carcinomas (HCCs). GPC3 binds to CD81. Forced expression of CD81 in a GPC3-expressing HCC cell line caused activation of Hippo, a decrease in ezrin phosphorylation, and a decrease in yes-associated protein (YAP). CD81 is also associated with hepatitis C virus (HCV) entry into hepatocytes. Activation of CD81 by agonistic antibody causes activation of tyrosine-protein kinase SYK (SYK) and phosphorylation of ezrin, a regulator of the Hippo pathway. In cultures of normal hepatocytes, CD81 agonistic antibody led to enhanced phosphorylation of ezrin and an increase in nuclear YAP...
June 2018: American Journal of Pathology
Weicheng Zhang, Jingyuan Shen, Fengming Gu, Ying Zhang, Wenjuan Wu, Jiachun Weng, Yuexia Liao, Zijing Deng, Qing Yuan, Lu Zheng, Yu Zhang, Weigan Shen
Accumulating evidence implicates monopolar spindle-one-binder protein (MOB)2 as an inhibitor of nuclear-Dbf2-related kinase (NDR) by competing with MOB1 for interaction with NDR1/2. NDR/large tumor suppressor (LATS) kinases may function similarly to yes-associated protein (YAP) kinases and be considered as members of the Hippo core cassette. MOB2 appears to serve roles in cell survival, cell cycle progression, responses to DNA damage and cell motility. However, the underlying mechanisms involved remain unclarified...
April 2018: Oncology Letters
Jingxiao Wang, Mingjie Dong, Zhong Xu, Xinhua Song, Shanshan Zhang, Yu Qiao, Li Che, John Gordan, Kaiwen Hu, Yan Liu, Diego F Calvisi, Xin Chen
Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes...
June 2018: Oncogene
Shirley Abitbol, Rajae Dahmani, Cédric Coulouarn, Bruno Ragazzon, Bernhard Mlecnik, Nadia Senni, Mathilde Savall, Pascale Bossard, Pierre Sohier, Valerie Drouet, Emilie Tournier, Florent Dumont, Romain Sanson, Julien Calderaro, Jessica Zucman-Rossi, Mireille Vasseur-Cognet, Pierre-Alexandre Just, Benoît Terris, Christine Perret, Hélène Gilgenkrantz
BACKGROUND & AIMS: The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/β-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/β-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations...
June 2018: Journal of Hepatology
Guanglin Xu, Ying Wang, Weijie Li, Yuanyuan Cao, Jinling Xu, Ziwei Hu, Yaping Hao, Li Hu, Yawen Sun
COX-2 and YAP are shown to be highly associated with hepatocellular carcinoma (HCC) and frequently upregulated during tumor formation. However, despite their importance, whether there is a mutual interaction between COX-2 and YAP and how they regulate each other are not clear. In this paper, we showed that COX-2 overexpression in HCC cell lines resulted in increased levels of YAP mRNA, protein, and its target genes. COX-2 promoted proliferation of HCC cell lines, and knockdown of YAP antagonized this effect...
April 2018: Neoplasia: An International Journal for Oncology Research
Sumera Rizvi, Samantha R Fischbach, Steven F Bronk, Petra Hirsova, Anuradha Krishnan, Renumathy Dhanasekaran, James B Smadbeck, Rory L Smoot, George Vasmatzis, Gregory J Gores
Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively...
January 19, 2018: Oncotarget
Hongwei Xia, Xinyu Dai, Huangfei Yu, Sheng Zhou, Zhenghai Fan, Guoqing Wei, Qiulin Tang, Qiyong Gong, Feng Bi
The epidermal growth factor receptor (EGFR) pathway and Hippo signaling play an important role in the carcinogenesis of hepatocellular carcinoma (HCC). However, the crosstalk between these two pathways and its implications in targeted therapy remains unclear. We found that the activated EGFR signaling could bypass RhoA to promote the expression of YAP(Yes-associated protein), the core effector of the Hippo signaling, and its downstream target Cyr61. Further studies indicated that EGFR signaling mainly acted through the PI3K-PDK1 (Phosphoinositide 3-kinase-Phosphoinositide-dependent kinase-1) pathway to activate YAP, but not the AKT and MAPK pathways...
February 15, 2018: Cell Death & Disease
Yan-Li Zhang, Qing Li, Xiao-Mei Yang, Fang Fang, Jun Li, Ya-Hui Wang, Qin Yang, Lei Zhu, Hui-Zhen Nie, Xue-Li Zhang, Ming-Xuan Feng, Shu-Heng Jiang, Guang-Ang Tian, Li-Peng Hu, Ho-Young Lee, Su-Jae Lee, Qiang Xia, Zhi-Gang Zhang
Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis...
May 1, 2018: Cancer Research
Sun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-Min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, Dae-Sik Lim
Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice...
March 1, 2018: Journal of Clinical Investigation
Shanshan Zhang, Jingxiao Wang, Haichuan Wang, Lingling Fan, Biao Fan, Billy Zeng, Junyan Tao, Xiaolei Li, Li Che, Antonio Cigliano, Silvia Ribback, Frank Dombrowski, Bin Chen, Wenming Cong, Lixin Wei, Diego F Calvisi, Xin Chen
Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated...
April 2018: American Journal of Pathology
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