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https://www.readbyqxmd.com/read/29449645/egfr-pi3k-pdk1-pathway-regulates-yap-signaling-in-hepatocellular-carcinoma-the-mechanism-and-its-implications-in-targeted-therapy
#1
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
https://www.readbyqxmd.com/read/29440237/tension-dependent-regulation-of-mammalian-hippo-signaling-through-limd1
#2
Consuelo Ibar, Elmira Kirichenko, Benjamin Keepers, Edward Enners, Katelyn Fleisch, Kenneth D Irvine
Hippo signaling is regulated by biochemical and biomechanical cues that influence the cytoskeleton, but the mechanisms that mediate this have remained unclear. We show that all three mammalian Ajuba family proteins - AJUBA, LIMD1, and WTIP - exhibit tension-dependent localization to adherens junctions, and that both Lats family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization. This localization of Ajuba and Lats family proteins is also influenced by cell density, and by Rho activation...
February 13, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29440144/spon2-promotes-m1-like-macrophage-recruitment-and-inhibits-hepatocellular-carcinoma-metastasis-by-distinct-integrin-rho-gtpase-hippo-pathways
#3
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...
February 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29438698/programming-of-schwann-cells-by-lats1-2-taz-yap-signaling-drives-malignant-peripheral-nerve-sheath-tumorigenesis
#4
Lai Man Natalie Wu, Yaqi Deng, Jincheng Wang, Chuntao Zhao, Jiajia Wang, Rohit Rao, Lingli Xu, Wenhao Zhou, Kwangmin Choi, Tilat A Rizvi, Marc Remke, Joshua B Rubin, Randy L Johnson, Thomas J Carroll, Anat O Stemmer-Rachamimov, Jianqiang Wu, Yi Zheng, Mei Xin, Nancy Ratner, Q Richard Lu
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29438691/hippo-stampede-in-nerve-sheath-tumors
#5
M Laura Feltri, Yannick Poitelon
Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29437787/reg%C3%AE-controls-hippo-signaling-and-reciprocal-nf-%C3%AE%C2%BAb-yap-regulation-to-promote-colon-cancer
#6
Xiaotao Li, Qingwei Wang, Xiao Gao, Tong Yu, Lei Yuan, Jie Dai, Weicang Wang, Geng Chen, Chan Jiao, Wang Zhou, Quan Huang, Long Cui, Pei Zhang, Robb E Moses, Jianhua Yang, Fengyuan Chen, Junjiang Fu, Jianru Xiao, Lei Li, Yongyan Dang
PURPOSE: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We have previously demonstrated a regulatory circuit between the proteasome activator REGγ and NF-kappaB (NF-κB) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic CRC. How the inflammatory microenvironment affects the Hippo pathway during CRC development is largely unknown. EXPERIMENTAL DESIGN: Here, we used REGγ deficient colon cancer cell lines, REGγ knockout mice and human CRC samples to identify the novel molecular mechanism by which REGγ functions as an oncoprotein in the development of colorectal cancer...
February 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29436693/yap-regulates-gastric-cancer-survival-and-migration-via-sirt1-mfn2-mitophagy
#7
Hongzhu Yan, Chengmin Qiu, Weiwei Sun, Minmin Gu, Feng Xiao, Jue Zou, Li Zhang
Gastric cancer is the fifth most common cancer worldwide and Hippo-Yap is the novel signaling pathway which plays an important role in gastric cancer tumor development and progression. However, little insight is available to date regarding the specific role of Yes-associated protein (Yap) in gastric cancer. In the present study, we identified the mechanism through which Yap sustains gastric cancer viability and migration. Yap was greatly upregulated in gastric cancer cells and its expression promoted cellular migration and survival...
February 7, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29435056/furin-inhibitor-d6r-suppresses-epithelial-mesenchymal-transition-in-sw1990-and-patu8988-cells-via-the-hippo-yap-signaling-pathway
#8
Meng Zhou, Youli Zhang, Hong Wei, Junbo He, Dawei Wang, Baoding Chen, Jian Zeng, Aihua Gong, Min Xu
Hexa-D-arginine (D6R), an inhibitor of furin, has potential therapeutic applications in different types of human tumor. However, the function of D6R in targeting pancreatic cancer cells remains to be elucidated. In the present study, the proliferation, invasion and migration abilities of SW1990 and PaTu8988 cells were examined using a Cell Counting Kit-8, and Transwell and wound healing assays. Subsequently, the expression of proteins associated with epithelial-mesenchymal transition (EMT) and the Hippo-yes-associated protein (YAP) pathway were detected using western blot analysis...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29429151/the-role-of-hippo-pathway-in-cancer-stem-cell-biology
#9
Jae Hyung Park, Ji Eun Shin, Hyun Woo Park
The biological significance and deregulation of the Hippo pathway during organ growth and tumorigenesis have received a surge of interest in the past decade. The Hippo pathway core kinases, MST1/2 and LATS1/2, are tumor suppressors that inhibit the oncogenic nuclear function of YAP/TAZ and TEAD. In addition to earlier studies that highlight the role of Hippo pathway in organ size control, cell proliferation, and tumor development, recent evidence demonstrates its critical role in cancer stem cell biology, including EMT, drug resistance, and self-renewal...
February 5, 2018: Molecules and Cells
https://www.readbyqxmd.com/read/29416763/dysregulation-of-yap-by-the-hippo-pathway-is-involved-in-intervertebral-disc-degeneration-cell-contact-inhibition-and-cell-senescence
#10
Cong Zhang, Feng Wang, Zhiyang Xie, Lu Chen, Arjun Sinkemani, Haomin Yu, Kun Wang, Lu Mao, Xiaotao Wu
The Hippo pathway plays important roles in wound healing, tissue repair and regeneration, and in the treatment of degenerative diseases, by regulating cell proliferation and apoptosis in mammals. Intervertebral disc degeneration (IDD) is one of the major causes of low back pain, a widespread issue associated with a heavy economic burden. However, the mechanism underlying how the Hippo pathway regulates IDD is not well understood. Here, we demonstrate that the Hippo pathway is involved in natural IDD. Activation and dephosphorylation of yes-associated protein (YAP) were observed in younger rat discs, and decreased gradually with age...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29415512/linking-extracellular-matrix-agrin-to-the-hippo-pathway-in-liver-cancer-and-beyond
#11
REVIEW
Sayan Chakraborty, Wanjin Hong
In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co-activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer...
February 6, 2018: Cancers
https://www.readbyqxmd.com/read/29410983/nanotopography-regulates-motor-neuron-differentiation-of-human-pluripotent-stem-cells
#12
Weiqiang Chen, Shuo Han, Weiyi Qian, Shinuo Weng, Haiou Yang, Yubing Sun, Luis G Villa-Diaz, Paul H Krebsbach, Jianping Fu
The regulation of human pluripotent stem cell (hPSC) behaviors has been mainly studied through exploration of biochemical factors. However, the current directed differentiation protocols for hPSCs that completely rely on biochemical factors remain suboptimal. It has recently become evident that coexisting biophysical signals in the stem cell microenvironment, including nanotopographic cues, can provide potent regulatory signals to mediate adult stem cell behaviors, including self-renewal and differentiation...
February 7, 2018: Nanoscale
https://www.readbyqxmd.com/read/29402328/expression-of-the-hippo-transducer-taz-in-association-with-wnt-pathway-mutations-impacts-survival-outcomes-in-advanced-gastric-cancer-patients-treated-with-first-line-chemotherapy
#13
Elisa Melucci, Beatrice Casini, Livia Ronchetti, Laura Pizzuti, Francesca Sperati, Matteo Pallocca, Francesca De Nicola, Frauke Goeman, Enzo Gallo, Carla Azzurra Amoreo, Domenico Sergi, Irene Terrenato, Patrizia Vici, Luigi Di Lauro, Maria Grazia Diodoro, Edoardo Pescarmona, Maddalena Barba, Marco Mazzotta, Marcella Mottolese, Maurizio Fanciulli, Gennaro Ciliberto, Ruggero De Maria, Simonetta Buglioni, Marcello Maugeri-Saccà
BACKGROUND: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. METHODS: In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice...
February 5, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29400695/claudin-18-mediated-yap-activity-regulates-lung-stem-and-progenitor-cell-homeostasis-and-tumorigenesis
#14
Beiyun Zhou, Per Flodby, Jiao Luo, Dan R Castillo, Yixin Liu, Fa-Xing Yu, Alicia McConnell, Bino Varghese, Guanglei Li, Nyam-Osor Chimge, Mitsuhiro Sunohara, Michael N Koss, Wafaa Elatre, Peter Conti, Janice M Liebler, Chenchen Yang, Crystal N Marconett, Ite A Laird-Offringa, Parviz Minoo, Kunliang Guan, Barry R Stripp, Edward D Crandall, Zea Borok
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400692/hippo-mediated-suppression-of-irs2-akt-signaling-prevents-hepatic-steatosis-and-liver-cancer
#15
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...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29397869/the-history-and-regulatory-mechanism-of-the-hippo-pathway
#16
Wantae Kim, Eek-Hoon Jho
How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer...
February 5, 2018: BMB Reports
https://www.readbyqxmd.com/read/29393412/wwc3-inhibits-intimal-proliferation-following-vascular-injury-via-the-hippo-signaling-pathway
#17
Beijia Chen, Guinan Liu
The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on vascular smooth muscle cells (VSMCs) following injury were investigated, in addition to the associated mechanisms underlying this process. Platelet‑derived growth factor BB (PDGF‑BB) was used as a cell injury factor, and rats with balloon injuries were used as a model of carotid intimal injury. Furthermore, the expression levels of WWC3 in VSMCs and arteries post‑injury were investigated, in addition to the effect of WWC3 on the proliferation and migration of VSMCs...
January 25, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29387948/expression-of-hippo-signaling-pathway-and-aurora-kinase-genes-in-chronic-myeloid-leukemia
#18
Ana Paula Zambuzi Cardoso Marsola, Belinda Pinto Simões, Leonardo Carvalho Palma, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Fabíola Attié de Castro
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR-ABL1 oncogene, which encodes the Bcr-Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI...
January 31, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29383103/yap-regulates-pd-l1-expression-in-human-nsclc-cells
#19
Jinbai Miao, Ping-Chih Hsu, Yi-Lin Yang, Zhidong Xu, Yuyuan Dai, Yucheng Wang, Geraldine Chan, Zhen Huang, Bin Hu, Hui Li, David M Jablons, Liang You
Programmed death-ligand 1 (PD-L1) is a membrane protein on tumor cells that binds to the PD-1 receptor expressed on immune cells, leading to the immune escape of tumor cells. Yes-associated protein (YAP) is a main effector of the Hippo/YAP signaling pathway, which plays important roles in cancer development. Here we show that YAP regulates PD-L1 expression in human non-small cell lung cancer (NSCLC) cells. First, we investigated YAP and PD-L1 expression at the protein level in 142 NSCLC samples and 15 normal lung samples...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29382819/rassf1a-uncouples-wnt-from-hippo-signalling-and-promotes-yap-mediated-differentiation-via-p73
#20
Angelos Papaspyropoulos, Leanne Bradley, Asmita Thapa, Chuen Yan Leung, Konstantinos Toskas, Delia Koennig, Dafni-Eleftheria Pefani, Cinzia Raso, Claudia Grou, Garth Hamilton, Nikola Vlahov, Anna Grawenda, Syed Haider, Jagat Chauhan, Ludovico Buti, Alexander Kanapin, Xin Lu, Francesca Buffa, Grigory Dianov, Alex von Kriegsheim, David Matallanas, Anastasia Samsonova, Magdalena Zernicka-Goetz, Eric O'Neill
Transition from pluripotency to differentiation is a pivotal yet poorly understood developmental step. Here, we show that the tumour suppressor RASSF1A is a key player driving the early specification of cell fate. RASSF1A acts as a natural barrier to stem cell self-renewal and iPS cell generation, by switching YAP from an integral component in the β-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the Rassf1A promoter maintains stemness by allowing a quaternary association of YAP-TEAD and β-catenin-TCF3 complexes on the Oct4 distal enhancer...
January 30, 2018: Nature Communications
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