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yap hepatocellular carcinoma

Takahiro Kodama, Jing Yi, Justin Y Newberg, Jean C Tien, Hao Wu, Milton J Finegold, Michiko Kodama, Zhubo Wei, Takeshi Tamura, Tetsuo Takehara, Randy L Johnson, Nancy A Jenkins, Neal G Copeland
Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms that cause NAFLD-HCC remain elusive. To identify molecular drivers of NAFLD-HCC, we performed Sleeping Beauty (SB) transposon mutagenesis screens in liver-specific Pten knockout and in high-fat diet-fed mice, which are murine models of NAFLD-HCC. SB mutagenesis accelerated liver tumor formation in both models and identified 588 and 376 candidate cancer genes (CCGs), respectively; 257 CCGs were common to both screens and were enriched in signaling pathways known to be important for human HCC...
October 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Li-Li Han, Xiao-Ran Yin, Shu-Qun Zhang
Improving the long‑term survival of patients with hepatocellular carcinoma (HCC) remains a challenge due to metastasis and recurrence. In this study, we demonstrate that the overexpression of miR‑103 in HCC cells promotes epithelial‑mesenchymal transition (EMT), and is associated with an enhanced metastasis and poor outcomes, as shown by western blot analysis and immunohistochemistry. Mechanistically, using reporter luciferase assay we reveal that the serine/threonine‑protein kinase, large tumor suppressor kinase 2 (LATS2), a key component of the Hippo signaling pathway, is a direct target of miR‑103 in HCC cells...
October 1, 2018: International Journal of Oncology
Jianchun Li, Honglian Wang, Lu Wang, Ruizhi Tan, Menglian Zhu, Xia Zhong, Yuwei Zhang, Bo Chen, Li Wang
Targeted therapy has a pivotal role for the treatment of liver cancer. The aim of this current study was to examine the effects of decursin on the growth of HepG2 cells and the underlying mechanisms. Our present study showed that treatment of HepG2 cells with decursin significantly inhibited the growth of HepG2 cells by suppressing cell proliferation, cell cycle arresting, and promoting apoptosis in a dose- and time-dependent manner. Most significantly, administration of decursin dramatically impeded in vivo tumor growth in nude mice...
September 24, 2018: Phytotherapy Research: PTR
Yang Cheng, Tianlu Hou, Jian Ping, Tianyang Chen, Baobing Yin
BACKGROUND: In this research, we aimed to investigate the biological functions of LIM domain only 3 (LMO3) in hepatocellular carcinoma (HCC) and uncover the underlying molecular mechanism in it. METHODS: HCC tissue microarray (n = 180) was used to analyze the correlation between LMO3 expression and clinicopathological findings. In vitro transwell matrigel invasion assay and annexin V anoikis assay in HCC cells were conducted to investigate LMO3 related biological functions...
September 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
Fei Gao, Xiaolin Yu, Rongqin Meng, Jisheng Wang, Lin Jia
Background: STARD13 has been revealed to suppress tumor progression. However, the roles in regulating the stemness of hepatocellular carcinoma (HCC) cells are unclear. Methods: Quantitative real-time PCR (qRT-PCR) was used to detect STARD13 expression in HCC tissues and normal adjacent tissues. Kaplan Meier (KM)-plotter analysis was performed to analyze the correlation between STARD13 expression and overall survival of HCC patients. Cell spheroid formation and ALDH1 activity analysis were carried out to detect the effects of STARD13 on the stemness of HCC cells...
2018: OncoTargets and Therapy
Xiaodong Zhang, Yan Li, Yingbo Ma, Liang Yang, Tao Wang, Xin Meng, Zhihong Zong, Xun Sun, Xiangdong Hua, Hangyu Li
BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown. METHODS: We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data...
September 4, 2018: Journal of Experimental & Clinical Cancer Research: CR
Jian Gao, Yingxue Rong, Yuxing Huang, Peng Shi, Xitao Wang, Xuan Meng, Jiahong Dong, Congying Wu
A majority of hepatocellular carcinomas (HCCs) combine with liver cirrhosis. The cirrhotic liver has been implicated in interfering with the effects of HCC-targeted drugs, including sorafenib. Alterations in the tumor microenvironment of the cirrhotic liver include both biochemical and biomechanical factors. In this study, we induced sorafenib resistance in HCC cells. We observed changes in cell morphology, cytoskeletal architecture, and cellular stiffness in these sorafenib-resistant cells, resembling those adapted to stiffer substrates...
August 26, 2018: Journal of Cellular Physiology
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 are associated with patient survival times...
October 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...
October 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
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