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Küchler M, Ehmke M, Jaquet K, Wohlmuth P, Feldhege JM, Reese T, Hartmann T, Drexler R, Huber T, Burmester T, Oldhafer KJ. Transcription enhanced associate domain factor 1 (TEAD1) predicts liver regeneration outcome of ALPPS-treated patients. HPB (Oxford) 2025; 27:470-479. [PMID: 39870556 DOI: 10.1016/j.hpb.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 10/01/2024] [Accepted: 12/09/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND The two-stage surgical technique of associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) enables extensive liver resection and promotes future liver remnant regeneration (FLR), in part by inhibiting the Hippo signalling pathway. Its main effector, Yes-associated protein (YAP), has low intrinsic transcriptional activity and requires the transcription enhanced associated domain factor (TEAD) family members as cofactors for target gene transcription. We evaluated the intracellular localization and expression of TEAD1-4, hypothesized to regulate the activity of YAP and, consequently, liver regeneration. METHODS The intracellular localization of TEAD1-4 was characterized in tumor-free liver (TFL) tissue samples from 44 ALPPS patients obtained during the two stages of ALPPS surgery. Expression levels were correlated with clinical and pathological data as well as liver regeneration metrics. RESULTS TEAD family members are simultaneously expressed in individual hepatocytes and show relations with liver regeneration, clinical outcome and outcome parameters when comparing TFL tissue obtained at different stages of ALPPS surgery. Furthermore, differences in TEAD expression and localization within hepatocytes appeared to be independent of global factors. CONCLUSION TEAD1-4 expression correlates with liver regeneration outcomes. Specifically, cytoplasmic and nuclear expression scores of TEAD1 serve as predictive markers for clinical outcomes following ALPPS.
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Affiliation(s)
- Mirco Küchler
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of Cell Biology, Core Lab Facility, Asklepios Hospital St Georg, Hamburg, Germany.
| | - Mareike Ehmke
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of Cell Biology, Core Lab Facility, Asklepios Hospital St Georg, Hamburg, Germany
| | - Kai Jaquet
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of Cell Biology, Core Lab Facility, Asklepios Hospital St Georg, Hamburg, Germany
| | - Peter Wohlmuth
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of Cell Biology, Core Lab Facility, Asklepios Hospital St Georg, Hamburg, Germany
| | - Johannes M Feldhege
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of Cell Biology, Core Lab Facility, Asklepios Hospital St Georg, Hamburg, Germany
| | - Tim Reese
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of HPB Surgery, Department of Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Thilo Hartmann
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of Cell Biology, Core Lab Facility, Asklepios Hospital St Georg, Hamburg, Germany
| | - Richard Drexler
- Division of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tessa Huber
- Department of Gynecology and Obstetrics, University Hospital Zurich, Switzerland
| | - Thorsten Burmester
- Division of Molecular Animal Physiology, Department of Biology, University Hamburg, Germany
| | - Karl J Oldhafer
- Institute for Clinical Research (IKF), Semmelweis University, Campus Hamburg, Germany; Division of HPB Surgery, Department of Surgery, Asklepios Hospital Barmbek, Hamburg, Germany.
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Bhavnagari HM, Shah FD. Decoding gene expression profiles of Hippo signaling pathway components in breast cancer. Mol Biol Rep 2025; 52:216. [PMID: 39928181 DOI: 10.1007/s11033-025-10299-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 01/23/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION The Hippo signaling pathway is an evolutionarily conserved, tumor suppressor, stem cell pathway. This is the very less explored pathway in Breast Cancer. It is a crucial regulator of several biological processes, such as organ size, differentiation, tissue homeostasis, cellular proliferation, and stemness. Interestingly, deregulation of this pathway leads to tumorigenesis. Hence, the present study aims to identify the role of the Hippo signaling pathway in Breast Cancer. MATERIALS AND METHODS The mRNA expression of the Hippo signaling pathway molecules was evaluated in 120 pre-therapeutic patients by quantitative real-time PCR. Statistical analysis was carried out using SPSS 23. The association between the gene expression and clinicopathological parameters was analyzed by the paired sample t-test, and Pearson chi-square test. ROC curve analysis was carried out using Med Cal. A p-value of ≤ 0.05 was considered statistically significant. RESULTS The hippo signaling pathway contains 10 core components i.e.SAV1, MOB1A, MOB1B, MST1, MST2, LATS1, LATS2, YAP, TAZ, and TEAD1 which were downregulated in malignant tissues as compared to adjacent normal tissue in breast cancer. In the correlation of hippo signaling pathway molecules with clinico pathological parameters, only LATS1, MST1, and SAV1 were found to be significantly negatively associated with stages of Breast Cancer. MOB1B was found to be significantly positively correlated with stages of Breast Cancer. ROC curve analysis of YAP, TAZ, LATS2, and TEAD showed significant discrimination between adjacent normal and malignant tissue. CONCLUSION In the current study, all the molecules of the hippo signaling pathway i.e. YAP, TAZ, LATS1, LATS2, MST1, MST2, SAV1, MOB1, MOB1B, TEAD1 were downregulated in BC suggesting the activation of hippo pathway which played a significant role in tumor suppression.
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Affiliation(s)
- Hunayna M Bhavnagari
- Life Science Department, Gujarat University, Ahmedabad, Gujarat, India
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Franky D Shah
- Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India.
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Voutsadakis IA. Gastric Adenocarcinomas with CDX2 Induction Show Higher Frequency of TP53 and KMT2B Mutations and MYC Amplifications but Similar Survival Compared with Cancers with No CDX2 Induction. J Clin Med 2024; 13:7635. [PMID: 39768557 PMCID: PMC11727917 DOI: 10.3390/jcm13247635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/07/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
Background: Gastric cancer is one of the most prevalent gastrointestinal cancers. Mortality is high, and improved treatments are needed. A better understanding of the pathophysiology of the disease and discovery of biomarkers for targeted therapies are paramount for therapeutic progress. CDX2, a transcription factor of hindgut specification, is induced in several gastric cancers, especially with intestinal differentiation, and could be helpful for defining sub-types with particular characteristics. Methods: Gastric cancers with induced CDX2 mRNA expression were identified from the gastric cohort of The Cancer Genome Atlas (TCGA) and were compared with cancers that had no CDX2 mRNA induction. Induced CDX2 mRNA expression was defined as mRNA expression z-score relative to all samples above 0, and non-induced CDX2 mRNA expression was defined as mRNA expression z-score relative to all samples below -1. Results: Patients with gastric cancers with CDX2 mRNA induction were older, had less frequently diffuse histology, and more often had mutations in TP53 and KMT2B and amplifications in MYC. CDX2 induction was correlated with HNF4α induction and was reversely correlated with SOX2. Gastric cancers with CDX2 mRNA induction showed lower PD-L1 expression than cancers with lower CDX2 expression but did not differ in CLDN18 mRNA expression. Progression-free and overall survival of the two groups was also not significantly different. Conclusion: Gastric cancers with CDX2 mRNA induction displayed specific characteristics that differentiate them from cancers with no CDX2 induction and could be of interest for optimizing current and future therapies.
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Affiliation(s)
- Ioannis A. Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, ON P6B 0A8, Canada; or
- Division of Clinical Sciences, Section of Internal Medicine, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada
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Wang S, Shao D, Gao X, Zhao P, Kong F, Deng J, Yang L, Shang W, Sun Y, Fu Z. TEAD transcription factor family emerges as a promising therapeutic target for oral squamous cell carcinoma. Front Immunol 2024; 15:1480701. [PMID: 39430767 PMCID: PMC11486717 DOI: 10.3389/fimmu.2024.1480701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
The treatment of oral squamous cell carcinoma (OSCC) remains a significant difficulty, as there has been no improvement in survival rates over the past fifty years. Hence, exploration and confirmation of new dependable treatment targets and biomarkers is imperative for OSCC therapy. TEAD transcription factors are crucial for integrating and coordinating multiple signaling pathways that are essential for embryonic development, organ formation, and tissue homeostasis. In addition, by attaching to coactivators, TEAD modifies the expression of genes such as Cyr61, Myc, and connective tissue growth factor, hence facilitating tumor progression. Therefore, TEAD is regarded as an effective predictive biomarker due to its significant connection with clinical parameters in several malignant tumors, including OSCC. The efficacy of existing drugs that specifically target TEAD has demonstrated encouraging outcomes, indicating its potential as an optimal target for OSCC treatment. This review provides an overview of current targeted therapy strategies for OSCC by highlighting the transcription mechanism and involvement of TEAD in oncogenic signaling pathways. Finally, the feasibility of utilizing TEAD as an innovative approach to address OSCC and its potential clinical applications were analyzed and discussed.
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Affiliation(s)
- Shuang Wang
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
- Department of Stomatology, Medical College of Qingdao Huanghai University, Qingdao, China
| | - Dan Shao
- Department of Oral and Maxillofacial Surgery, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, China
| | - Xiaoyan Gao
- Department of Quality Inspection, Traditional Chinese Medical Hospital of Huangdao District, Qingdao, China
| | - Peng Zhao
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Fanzhi Kong
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Jiawei Deng
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Lianzhu Yang
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Wei Shang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaping Sun
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, People's Liberation Army of China (PLA), Beijing, China
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Shin E, Kwon Y, Jung E, Kim YJ, Kim C, Hong S, Kim J. TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions. Proc Natl Acad Sci U S A 2024; 121:e2314346121. [PMID: 38315837 PMCID: PMC10873613 DOI: 10.1073/pnas.2314346121] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV- HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV- HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV- HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV- HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV- HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPβ1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV- HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV- HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV- HNSCC.
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Affiliation(s)
- Eunbie Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Yongsoo Kwon
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Eunji Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Yong Joon Kim
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul03722, South Korea
| | - Changgon Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Semyeong Hong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
| | - Joon Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon34141, Korea
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Thilakasiri P, O'Keefe RN, To SQ, Chisanga D, Eissmann MF, Carli ALE, Duscio B, Baloyan D, Dmello RS, Williams D, Mariadason J, Poh AR, Pal B, Kile BT, Vissers JH, Harvey KF, Buchert M, Shi W, Ernst M, Chand AL. Mechanisms of cellular crosstalk in the gastric tumor microenvironment are mediated by YAP1 and STAT3. Life Sci Alliance 2024; 7:e202302411. [PMID: 37957015 PMCID: PMC10643184 DOI: 10.26508/lsa.202302411] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/16/2023] Open
Abstract
Deregulation of the Hippo pathway is a driver for cancer progression and treatment resistance. In the context of gastric cancer, YAP1 is a biomarker for poor patient prognosis. Although genomic tumor profiling provides information of Hippo pathway activation, the present study demonstrates that inhibition of Yap1 activity has anti-tumor effects in gastric tumors driven by oncogenic mutations and inflammatory cytokines. We show that Yap1 is a key regulator of cell metabolism, proliferation, and immune responses in normal and neoplastic gastric epithelium. We propose that the Hippo pathway is targetable across gastric cancer subtypes and its therapeutic benefits are likely to be mediated by both cancer cell-intrinsic and -extrinsic mechanisms.
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Affiliation(s)
- Pathum Thilakasiri
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Ryan N O'Keefe
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Sarah Q To
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - David Chisanga
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Moritz F Eissmann
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Annalisa LE Carli
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Belinda Duscio
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - David Baloyan
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Rhynelle S Dmello
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - David Williams
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
- Department of Pathology, Austin Health, Heidelberg, Australia
| | - John Mariadason
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Bhupinder Pal
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Benjamin T Kile
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | | | - Kieran F Harvey
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Anatomy and Developmental Biology, and Biomedicine Discovery Institute, Monash University, Clayton, Australia
| | - Michael Buchert
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Wei Shi
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
| | - Ashwini L Chand
- Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, Australia
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Nie X, Zhou Z, Chen Y, Chen S, Chen Y, Lei J, Wu X, He S. VEPH1 suppresses the progression of gastric cancer by regulating the Hippo-YAP signalling pathway. Dig Liver Dis 2024; 56:187-197. [PMID: 37244789 DOI: 10.1016/j.dld.2023.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/13/2023] [Accepted: 05/15/2023] [Indexed: 05/29/2023]
Abstract
BACKGROUND Ventricular zone-expressed PH domain-containing protein homologue 1 (VEPH1) is a recently discovered intracellular adaptor protein that plays an important role in human development. It has been reported that VEPH1 is closely related to the process of cellular malignancy, but its role in gastric cancer has not been elucidated. This study investigated the expression and function of VEPH1 in human gastric cancer (GC). METHODS We performed qRT‒PCR, Western blotting, and immunostaining assays in GC tissue samples to evaluate VEPH1 expression. Functional experiments were used to measure the malignancy of GC cells. A subcutaneous tumorigenesis model and peritoneal graft tumour model were established in BALB/c mice to determine tumour growth and metastasis in vivo. RESULTS VEPH1 expression is decreased in GC and correlates with the overall survival rates of GC patients. VEPH1 inhibits GC cell proliferation, migration, and invasion in vitro and suppresses tumour growth and metastasis in vivo. VEPH1 regulates the function of GC cells by inhibiting the Hippo-YAP signalling pathway, and YAP/TAZ inhibitor-1 treatment reverses the VEPH1 knockdown-mediated increase in the proliferation, migration and invasion of GC cells in vitro. Loss of VEPH1 is associated with increased YAP activity and accelerated epithelial-mesenchymal transition (EMT) in GC. CONCLUSION VEPH1 inhibited GC cell proliferation, migration, and invasion in vitro and in vivo and exerted its antitumour effects by inhibiting the Hippo-YAP signalling pathway and EMT process in GC.
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Affiliation(s)
- Xubiao Nie
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Zhihang Zhou
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Ying Chen
- Department of Medical Examination Center, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Siyuan Chen
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Yongyu Chen
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Jing Lei
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Xiaoling Wu
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China
| | - Song He
- Department of Gastroenterology, Affiliated the Second Affiliated Hospital of Chongqing Medical University, PR. China.
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Wang T, Wang D, Sun Y, Zhuang T, Li X, Yang H, Zang Y, Liu Z, Yang P, Zhang C, Cui J, Fu M, Zhang S, Su P, Li Z, Zhu J, Ding Y. Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer. J Exp Clin Cancer Res 2023; 42:297. [PMID: 37950281 PMCID: PMC10636825 DOI: 10.1186/s13046-023-02870-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 10/18/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed. METHODS We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression. RESULTS In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer. CONCLUSION In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer.
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Affiliation(s)
- Tianshi Wang
- Department of General Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Dehai Wang
- Department of General Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Yanan Sun
- Department of General Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Ting Zhuang
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
- Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Shandong Province, P. R. China
| | - Xin Li
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Huijie Yang
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Yifeng Zang
- Department of General Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Ziping Liu
- Department of General Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Penghe Yang
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Chenmiao Zhang
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Jiayao Cui
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Mingxi Fu
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Shuqing Zhang
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Peng Su
- Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
| | - Zhongbo Li
- Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China.
| | - Jian Zhu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Yinlu Ding
- Department of General Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
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Park MA, Lee YH, Gu MJ. High TEAD4 Expression is Associated With Aggressive Clear Cell Renal Cell Carcinoma, Regardless of YAP1 Expression. Appl Immunohistochem Mol Morphol 2023; 31:649-656. [PMID: 37779294 DOI: 10.1097/pai.0000000000001164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 09/10/2023] [Indexed: 10/03/2023]
Abstract
Yes-associated protein 1 (YAP1) and transcriptional coactivator TEA domain transcription factor 4 (TEAD4) are the main effectors of the Hippo signaling pathway. Deregulation of the Hippo signaling pathway significantly impacts tumorigenesis and tumor progression. We evaluated the mRNA expression level of YAP1 and TEAD4 using the Gene Expression Profiling Interactive Analysis database and investigated the roles of YAP1 and TEAD4 in 349 surgically resected clear cell renal cell carcinoma (CCRCC) samples through immunohistochemical analysis. High YAP1 and TEAD4 expression were observed in 57 (16.3%) and 131 (37.5%) cases, respectively. High YAP1 expression was associated with a low nuclear grade only. High TEAD4 expression was significantly associated with large tumor size, high nuclear grade, lymphovascular invasion, advanced pT classification, advanced clinical stage, sarcomatous differentiation, and metastasis. CCRCC with YAP1-low/TEAD4-high expression was significantly associated with aggressive clinicopathological variables and poor outcomes. For CCRCC, higher tumor stage, sarcomatous differentiation, and metastasis were the independent prognostic factors for overall survival (OS) and disease-free survival (DFS). High TEAD4 expression was significantly associated with short OS and DFS but was not an independent prognostic factor. High TEAD4 and YAP1-low/TEAD4-high expression significantly correlated with adverse clinicopathological factors and worse OS and DFS in patients with CCRCC. YAP1 expression was not significantly associated with clinicopathological factors or patient survival. Therefore, TEAD4 plays a critical role in CCRCC tumor progression independent of YAP1 and may be a potential biomarker and therapeutic target for CCRCC.
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Affiliation(s)
- Min A Park
- Department of Pathology, Yeungnam University College of Medicine, Nam-gu, Daegu, Republic of Korea
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Jung J, Kim JW, Kim G, Kim JY. Low MST1/2 and negative LATS1/2 expressions are associated with poor prognosis of colorectal cancers. Pathol Res Pract 2023; 248:154608. [PMID: 37302275 DOI: 10.1016/j.prp.2023.154608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 05/03/2023] [Accepted: 06/07/2023] [Indexed: 06/13/2023]
Abstract
Mammalian STe20-like protein kinase 1/2 (MST1/2) and large tumor suppressor homolog 1/2 (LATS1/2) are the core components of the tumor-suppressive Hippo pathway. Dysregulation of this pathway is associated with the progression and metastasis of various cancers. However, MST1/2 and LATS1/2 expressions have not been systematically evaluated in colorectal cancers. We evaluated the clinicopathologic correlation and prognostic significance of MST1/2 and LATS1/2 immunohistochemical expressions in 327 colorectal cancer patients. Low MST1/2 expression, identified in 235 (71.9 %) cases, was significantly associated with poor differentiation (P = 0.018) and large size (P < 0.001) of the tumor. Negative LATS1/2 expression, identified in 226 (69.1 %) cases, was significantly correlated with low MST1/2 expression (P = 0.044). Low MST1/2 and negative LATS1/2 expressions were significantly associated with poor overall survivals (P = 0.015 and P = 0.038, respectively). Furthermore, the combined MST1/2lowLATS1/2negative expression group showed significantly worse overall survival than other groups (P = 0.003), and considered as an independent poor prognostic factor for colorectal cancer patients (hazard ratio = 1.720; 95 % confidence interval, 1.143-2.588; P = 0.009). Low MST1/2 and negative LATS1/2 expressions may serve as prognostic indicators in patients with colorectal cancer.
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Affiliation(s)
- Jiyoon Jung
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Jeong Won Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Gilhyang Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Joo Young Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea.
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11
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Liu Y, Zhang B, Zhou Y, Xing Y, Wang Y, Jia Y, Liu D. Targeting Hippo pathway: A novel strategy for Helicobacter pylori-induced gastric cancer treatment. Biomed Pharmacother 2023; 161:114549. [PMID: 36958190 DOI: 10.1016/j.biopha.2023.114549] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 03/25/2023] Open
Abstract
The Hippo pathway plays an important role in cell proliferation, apoptosis, and differentiation; it is a crucial regulatory pathway in organ development and tumor growth. Infection with Helicobacter pylori (H. pylori) increases the risk of developing gastric cancer. In recent years, significant progress has been made in understanding the mechanisms by which H. pylori infection promotes the development and progression of gastric cancer via the Hippo pathway. Exploring the Hippo pathway molecules may yield new diagnostic and therapeutic targets for H. pylori-induced gastric cancer. The current article reviews the composition and regulatory mechanism of the Hippo pathway, as well as the research progress of the Hippo pathway in the occurrence and development of H. pylori-related gastric cancer, in order to provide a broader perspective for the study and prevention of gastric cancer.
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Affiliation(s)
- Yunyun Liu
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China
| | - Bingkai Zhang
- Department of Anorectal Surgery, Qingzhou People's Hospital, Qingzhou, People's Republic of China
| | - Yimin Zhou
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Yuanxin Xing
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China
| | - Yunshan Wang
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China
| | - Yanfei Jia
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan, People's Republic of China; Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, People's Republic of China.
| | - Duanrui Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China; Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
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12
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You Q, Wang F, Du R, Pi J, Wang H, Huo Y, Liu J, Wang C, Yu J, Yang Y, Zhu L. m 6 A Reader YTHDF1-Targeting Engineered Small Extracellular Vesicles for Gastric Cancer Therapy via Epigenetic and Immune Regulation. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2204910. [PMID: 36484103 DOI: 10.1002/adma.202204910] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/02/2022] [Indexed: 06/17/2023]
Abstract
N6 -methyladenosine (m6 A) modulators decide the fate of m6 A-modified transcripts and drive cancer development. RNA interference targeting m6 A modulators promise to be an emerging cancer therapy but is challenging due to its poor tumor targeting and high systematic toxicity. Here engineered small extracellular vesicles (sEVs) with high CD47 expression and cyclic arginine-glycine-aspartic (c(RGDyC)) modification are developed for effective delivery of short interfering RNA against m6 A reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) to treat gastric cancer via epigenetic and immune regulation. This nanosystem efficiently depletes YTHDF1 expression and suppresses gastric cancer progression and metastasis through hampering frizzled7 translation and inactivating Wnt/β-catenin pathway in an m6 A dependent manner. Loss of YTHDF1 mediates overexpression of interferon (IFN)-γ receptor 1 and enhances IFN-γ response, promoting expression of major histocompatibility complex class I on tumor cells to achieve self-presentation of the immunogenic tumor cells to stimulate strong cytotoxic T lymphocytes responses. CD47 expression on the engineered sEVs can competitively bind with signal regulatory protein α to enhance phagocytosis of the tumor cells by tumor-associated macrophages. This versatile nanoplatform provides an efficient and low toxic strategy to inhibit epigenetic regulators and holds great potential in promoting immunotherapy.
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Affiliation(s)
- Qing You
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Fang Wang
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, P. R. China
- The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, 100005, P. R. China
| | - Rong Du
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Jingnan Pi
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, P. R. China
- The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, 100005, P. R. China
| | - Huayi Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- Translational Medicine Center, Chinese Institute for Brain Research (CIBR), Beijing, 102206, P. R. China
| | - Yue Huo
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, P. R. China
- The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, 100005, P. R. China
| | - Jingyi Liu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Chen Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Jia Yu
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, P. R. China
- The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, 100005, P. R. China
| | - Yanlian Yang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Ling Zhu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
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13
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Liu Y, Shi Y, Han R, Liu C, Qin X, Li P, Gu R. Signaling pathways of oxidative stress response: the potential therapeutic targets in gastric cancer. Front Immunol 2023; 14:1139589. [PMID: 37143652 PMCID: PMC10151477 DOI: 10.3389/fimmu.2023.1139589] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 03/20/2023] [Indexed: 05/06/2023] Open
Abstract
Gastric cancer is one of the top causes of cancer-related death globally. Although novel treatment strategies have been developed, attempts to eradicate gastric cancer have been proven insufficient. Oxidative stress is continually produced and continually present in the human body. Increasing evidences show that oxidative stress contributes significantly to the development of gastric cancer, either through initiation, promotion, and progression of cancer cells or causing cell death. As a result, the purpose of this article is to review the role of oxidative stress response and the subsequent signaling pathways as well as potential oxidative stress-related therapeutic targets in gastric cancer. Understanding the pathophysiology of gastric cancer and developing new therapies for gastric cancer depends on more researches focusing on the potential contributors to oxidative stress and gastric carcinogenesis.
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Affiliation(s)
- Yingying Liu
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Yu Shi
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ruiqin Han
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chaoge Liu
- Department of Oromaxillofacial - Head and Neck Surgery, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, China
| | - Xiaogang Qin
- Traditional Chinese Medicine Hospital of Tongzhou District, Nantong, Jiangsu, China
- *Correspondence: Renjun Gu, ; Pengfei Li, ; Xiaogang Qin,
| | - Pengfei Li
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Renjun Gu, ; Pengfei Li, ; Xiaogang Qin,
| | - Renjun Gu
- School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Renjun Gu, ; Pengfei Li, ; Xiaogang Qin,
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14
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Yang J, Song DH, Kim CH, Kim MH, Jo HC, Kim H, Park JE, Baek JC. Expression of the Hippo Pathway Core Components in Endometrial Cancer and Its Association with Clinicopathologic Features. Diagnostics (Basel) 2022; 12:2973. [PMID: 36552980 PMCID: PMC9776728 DOI: 10.3390/diagnostics12122973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The Hippo signaling pathway has a key role in tumorigenesis. This study aimed to evaluate the relationship between the expression of core components of the Hippo signaling pathway and its association with clinicopathological features in endometrial cancer. MATERIALS AND METHODS We retrospectively collected endometrioid endometrial cancer specimens from 60 patients between January 2002 and December 2009 at Gyeongsang National University Hospital. Relevant clinicopathological data were obtained through electronic medical records of patients. The expression patterns of six core components (YAP, p-YAP, LATS1/2, MST1/2, KIBRA, and Merlin) were identified by immunohistochemistry on tissue microarray sections. RESULTS The positive expression ratio was 75.0% for YAP, 73.3% for p-YAP, 26.7% for MST1/2, 16.7% for KIBRA, 15.0% for Merlin, and 15.0% for LATS1/2. YAP expression was negatively correlated with MST 1/2 kinases (p = 0.045) and positively correlated with p-YAP (p = 0.012). Merlin, and MST 1/2 kinases (p = 0.043) showed a positive correlation. A subgroup of patients aged below 60 years (p = 0.004) and with myometrial invasion depth of less than 1/2 (p = 0.041) showed a positive association with YAP expression. p-YAP expression was negatively associated with a subset of patients with primary tumour size ≥4 cm (p = 0.03). Logistic regression analysis showed a significant association between age and YAP expression. The odds ratio of p-YAP expression was significantly lower in the group with tumour size ≥4 cm. CONCLUSION Two prognostic factors, age and tumour size, were significantly associated with the expression of YAP and p-YAP in endometrial cancer. Further research should focus on their expression as a marker for prediction of clinicopathological implications in endometrial cancer.
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Affiliation(s)
- Juseok Yang
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
| | - Dae Hyun Song
- Department of Pathology, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
| | - Cho Hee Kim
- Department of Pathology, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
| | - Min Hye Kim
- Department of Pathology, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Hyen Chul Jo
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
- Institute of Health Science, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Hyoeun Kim
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
| | - Ji Eun Park
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
- Institute of Health Science, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Jong Chul Baek
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
- Institute of Health Science, Gyeongsang National University, Jinju 52727, Republic of Korea
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15
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Seeneevassen L, Dubus P, Gronnier C, Varon C. Hippo in Gastric Cancer: From Signalling to Therapy. Cancers (Basel) 2022; 14:cancers14092282. [PMID: 35565411 PMCID: PMC9105983 DOI: 10.3390/cancers14092282] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/12/2022] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
The Hippo pathway is one of the most important ones in mammals. Its key functions in cell proliferation, tissue growth, repair, and homeostasis make it the most crucial one to be controlled. Many means have been deployed for its regulation, since this pathway is not only composed of core regulatory components, but it also communicates with and regulates various other pathways, making this signalisation even more complex. Its role in cancer has been studied more and more over the past few years, and it presents YAP/TAZ as the major oncogenic actors. In this review, we relate how vital this pathway is for different organs, and how regulatory mechanisms have been bypassed to lead to cancerous states. Most studies present an upregulation status of YAP/TAZ, and urge the need to target them. A focus is made here on gastric carcinogenesis, its main dysregulations, and the major strategies adopted and tested to counteract Hippo pathway disbalance in this disease. Hippo pathway targeting can be achieved by various means, which are described in this review. Many studies have tested different potential molecules, which are detailed hereby. Though not all tested in gastric cancer, they could represent a real interest.
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Affiliation(s)
- Lornella Seeneevassen
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
| | - Pierre Dubus
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Department of Histology and Pathology, CHU Bordeaux, F-33000 Bordeaux, France
| | - Caroline Gronnier
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Department of Digestive Surgery, Haut-Lévêque Hospital, CHU Bordeaux, F-33000 Bordeaux, France
| | - Christine Varon
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Correspondence:
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16
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Gurer T, Aytekin A, Caki E, Gezici S. miR-485-3p and miR-4728-5p as Tumor Suppressors in Pathogenesis of Colorectal Cancer. Mol Biol 2022. [DOI: 10.1134/s0026893322030062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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17
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Dana D, Das T, Choi A, Bhuiyan AI, Das TK, Talele TT, Pathak SK. Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development. Molecules 2022; 27:347. [PMID: 35056661 PMCID: PMC8779408 DOI: 10.3390/molecules27020347] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/27/2021] [Accepted: 12/30/2021] [Indexed: 11/25/2022] Open
Abstract
Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.
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Affiliation(s)
- Dibyendu Dana
- Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA; (D.D.); (T.D.); (A.C.); (A.I.B.)
- KemPharm Inc., 2200 Kraft Drive, Blacksburg, VA 24060, USA
| | - Tuhin Das
- Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA; (D.D.); (T.D.); (A.C.); (A.I.B.)
| | - Athena Choi
- Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA; (D.D.); (T.D.); (A.C.); (A.I.B.)
- Brooklyn Technical High School, 29 Fort Greene Pl, Brooklyn, NY 11217, USA
| | - Ashif I. Bhuiyan
- Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA; (D.D.); (T.D.); (A.C.); (A.I.B.)
- Chemistry Doctoral Program, The Graduate Center of the City University of New York, 365 5th Ave, New York, NY 10016, USA
| | - Tirtha K. Das
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Mindich Child Health and Development Institute, Department of Pediatrics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Tanaji T. Talele
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA;
| | - Sanjai K. Pathak
- Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA; (D.D.); (T.D.); (A.C.); (A.I.B.)
- Chemistry Doctoral Program, The Graduate Center of the City University of New York, 365 5th Ave, New York, NY 10016, USA
- Biochemistry Doctoral Program, The Graduate Center of the City University of New York, 365 5th Ave, New York, NY 10016, USA
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18
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Li R, Hu Z, Wang Z, Zhu T, Wang G, Gao B, Wang J, Deng X. miR-125a-5p promotes gastric cancer growth and invasion by regulating the Hippo pathway. J Clin Lab Anal 2021; 35:e24078. [PMID: 34708891 PMCID: PMC8649339 DOI: 10.1002/jcla.24078] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/22/2021] [Accepted: 10/16/2021] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE This study was carried out to explore the potential involvement of miR-125a-5p in the oncogenic effects of EphA2, TAZ, and TEAD2 and the activity of the Hippo signaling pathway in gastric cancer progression. METHODS In vitro transfection of miR-125a-5p mimics or inhibitors, qRT-PCR, colony formation assays, and cell invasion assays were used to assess the effect of miR-125a-5p on the growth and invasion in gastric cancer (GC). Male nude mice bearing tumors derived from human GC cells were used for evaluating the effects of miR-125a-5p on tumor growth. Luciferase reporter assay, immunofluorescence, immunohistochemistry, qRT-PCR, and immunoblotting were performed to explore the role of miR-125a-5p in the epithelial-mesenchymal transition (EMT) and association among miR-125a-5p, EphA2, TAZ, and TEAD2 in GC cells. RESULTS MiR-125a-5p enhanced GC cell viability and invasion in vitro, whereas inhibition of miR-125a-5p using a specific inhibitor and antagomir suppressed cancer cell invasion and tumor growth. Moreover, inhibition of miR-125a-5p reversed EMT in vitro. miR-125a-5p upregulated the expression of EphA2, TAZ, and TEAD2, promoted TAZ nuclear translocation, and induced changes in the activity of the Hippo pathway by enhancing the expression of TAZ target genes. Finally, miR-125a-5p was overexpressed in late-stage GCs, and positive correlations were observed with its targets EphA2, TAZ, and TEAD2. CONCLUSION miR-125a-5p can promote GC growth and invasion by upregulating the expression of EphA2, TAZ, and TEAD2.
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Affiliation(s)
- Ruixin Li
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhihao Hu
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhuoyin Wang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Tianyu Zhu
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Guojun Wang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Bulang Gao
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jingtao Wang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xiumei Deng
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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19
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Kim JY, Sung YN, Hong SM. High YAP and TEAD4 immunolabelings are associated with poor prognosis in patients with gallbladder cancer. APMIS 2021; 129:729-742. [PMID: 34779030 DOI: 10.1111/apm.13186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 09/30/2021] [Indexed: 12/30/2022]
Abstract
Yes-associated protein (YAP) and TEA domain-containing sequence-specific transcription factors 4 (TEAD4) are essential components of the Hippo pathway. Abnormal regulation of the Hippo pathway contributes to the progression and metastasis of many cancer types. However, their clinicopathologic and prognostic significances have not been studied in gallbladder cancers. Here, we systematically evaluated the YAP and TEAD4 immunolabelings and their association with clinicopathologic characteristics and survival outcomes using 212 specimens of surgically resected gallbladder cancers. High YAP and TEAD4 immunolabelings were identified in 70 (33%) cases and were associated with infiltrative growth pattern, poor differentiation, perineural invasion, and advanced pT classification and AJCC stage. High YAP immunolabeling was significantly associated with high TEAD4 immunolabeling (p < 0.001). High immunolabeling levels of YAP or TEAD4 alone and the combined YAPhigh TEAD4high group were significantly associated with poor survival in both univariate (p < 0.001) and multivariate analyses (HR = 2.358; 95% CI, 1.369-4.061; p = 0.002). Therefore, the YAP and TEAD4 immunolabelings are associated with aggressive behavior of gallbladder cancers and may be useful as a prognostic indicator in patients with surgically resected gallbladder cancer.
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Affiliation(s)
- Joo Young Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - You-Na Sung
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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The Expression and Prognostic Value of ILK and YAP1 in Glioma. Appl Immunohistochem Mol Morphol 2021; 30:e21-e29. [DOI: 10.1097/pai.0000000000000984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/13/2021] [Indexed: 11/26/2022]
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Hum M, Tan HJ, Yang Y, Srivastava S, Teh M, Lim YP. WBP2 promotes gastric cancer cell migration via novel targeting of LATS2 kinase in the Hippo tumor suppressor pathway. FASEB J 2021; 35:e21290. [PMID: 33475198 DOI: 10.1096/fj.202000393r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 11/04/2020] [Accepted: 12/03/2020] [Indexed: 01/07/2023]
Abstract
Dysregulation of signaling pathways is responsible for many human diseases. The lack of understanding of the molecular etiology of gastric cancer (GC) poses a substantial challenge to the development of effective cancer therapy. To better understand the molecular mechanisms underlying the pathogenesis of GC, which will facilitate the identification and development of effective therapeutic approaches to improve patient outcomes, mass spectrometry-based phosphoproteomics analysis was performed to map the global molecular changes in GC. A total of 530 proteins with altered phosphorylation levels were detected across a panel of 15 normal and GC cell lines. WW domain-binding protein 2 (WBP2) was validated to be upregulated in a subset of GC cell lines. WBP2 is overexpressed in 61% cases of GC compared to non-cancer tissues and high WBP2 expression correlates with poor clinical outcomes. WBP2 was found to be required for GC cell migration but is dispensable for cell growth and proliferation. WBP2 knockdown increased p-LATS2 with a concomitant increase in p-YAP, resulting in the cytoplasmic retention of YAP and ultimately the inhibition of YAP/TEAD activity and downregulation of TEAD target genes--CTGF and CYR61. Importantly, the loss of LATS2 reversed the activation of Hippo pathway caused by WBP2 knockdown, indicating that WBP2 acts through LATS2 to exert its function on the Hippo pathway. Moreover, WBP2 interacted with LATS2 to inhibit its phosphorylation and activity. In conclusion, our study established a pivotal role for WBP2 in the promotion of GC cell migration via a novel mechanism that inactivates the Hippo pathway transducer LATS2.
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Affiliation(s)
- Melissa Hum
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hock Jin Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yixuan Yang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Supriya Srivastava
- Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Ming Teh
- Department of Pathology, National University Health System, Singapore, Singapore
| | - Yoon Pin Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, Singapore, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
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Mohajan S, Jaiswal PK, Vatanmakarian M, Yousefi H, Sankaralingam S, Alahari SK, Koul S, Koul HK. Hippo pathway: Regulation, deregulation and potential therapeutic targets in cancer. Cancer Lett 2021; 507:112-123. [PMID: 33737002 PMCID: PMC10370464 DOI: 10.1016/j.canlet.2021.03.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 01/25/2023]
Abstract
Hippo pathway is a master regulator of development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size control. Hippo pathway relays signals from different extracellular and intracellular events to regulate cell behavior and functions. Hippo pathway is conserved from Protista to eukaryotes. Deregulation of the Hippo pathway is associated with numerous cancers. Alteration of the Hippo pathway results in cell invasion, migration, disease progression, and therapy resistance in cancers. However, the function of the various components of the mammalian Hippo pathway is yet to be elucidated in detail especially concerning tumor biology. In the present review, we focused on the Hippo pathway in different model organisms, its regulation and deregulation, and possible therapeutic targets for cancer treatment.
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Affiliation(s)
- Suman Mohajan
- Department of Biochemistry and Molecular Biology, LSUHSC, Shreveport, USA
| | - Praveen Kumar Jaiswal
- Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, USA; Stanley S. Scott Cancer Center, LSUHSC, New Orleans, USA
| | - Mousa Vatanmakarian
- Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, USA
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, USA
| | | | - Suresh K Alahari
- Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, USA; Stanley S. Scott Cancer Center, LSUHSC, New Orleans, USA
| | - Sweaty Koul
- Stanley S. Scott Cancer Center, LSUHSC, New Orleans, USA
| | - Hari K Koul
- Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, USA; Urology, LSUHSC, School of Medicine, New Orleans, USA; Stanley S. Scott Cancer Center, LSUHSC, New Orleans, USA.
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Li HL, Li QY, Jin MJ, Lu CF, Mu ZY, Xu WY, Song J, Zhang Y, Zhang SY. A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression. J Cancer Res Clin Oncol 2021; 147:1569-1585. [PMID: 33864521 DOI: 10.1007/s00432-021-03604-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/16/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND The Hippo pathway is widely considered to inhibit cell growth and play an important role in regulating the size of organs. However, recent studies have shown that abnormal regulation of the Hippo pathway can also affect tumor invasion and metastasis. Therefore, finding out how the Hippo pathway promotes tumor development by regulating the expression of target genes provides new ideas for future research on targeted drugs that inhibit tumor progression. METHODS PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched. RESULTS The search strategy identified 1892 hits and 196 publications were finally included in this review. As the core molecule of the Hippo pathway, YAP/TAZ are usually highly expressed in tumors that undergo invasion and migration and are accompanied by abnormally strong nuclear metastasis. Through its interaction with nuclear transcription factors TEADs, it directly or indirectly regulates and the expressions of target genes related to tumor metastasis and invasion. These target genes can induce the formation of invasive pseudopodia in tumor cells, reduce intercellular adhesion, degrade extracellular matrix (ECM), and cause epithelial-mesenchymal transition (EMT), or indirectly promote through other signaling pathways, such as mitogen-activated protein kinases (MAPK), TGF/Smad, etc, which facilitate the invasion and metastasis of tumors. CONCLUSION This article mainly introduces the research progress of YAP/TAZ which are the core molecules of the Hippo pathway regulating related target genes to promote tumor invasion and metastasis. Focus on the target genes that affect tumor invasion and metastasis, providing the possibility for the selection of clinical drug treatment targets, to provide some help for a more in-depth study of tumor invasion and migration mechanism and the development of clinical drugs.
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Affiliation(s)
- Hong-Li Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Qian-Yu Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Min-Jie Jin
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chao-Fan Lu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Zhao-Yang Mu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wei-Yi Xu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China.
| | - Yan Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China. .,Zhengzhou University, Henan Institute of Advanced Technology, Zhengzhou, 450001, China.
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Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair. Cancers (Basel) 2021; 13:cancers13040916. [PMID: 33671606 PMCID: PMC7926742 DOI: 10.3390/cancers13040916] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The p53 family is a complex family of transcription factors with different cellular functions that are involved in several physiological processes. A massive amount of data has been accumulated on their critical role in the tumorigenesis and the aggressiveness of cancers of different origins. If common features are observed, there are numerous specificities that may reflect particularities of the tissues from which the cancers originated. In this regard, gastric cancer tumorigenesis is rather remarkable, as it is induced by bacterial and viral infections, various chemical carcinogens, and familial genetic alterations, which provide an example of the variety of molecular mechanisms responsible for cell transformation and how they impact the p53 family. This review summarizes the knowledge gathered from over 40 years of research on the role of the p53 family in gastric cancer, which still displays one of the most elevated mortality rates amongst all types of cancers. Abstract Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.
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Antitumor Effects of Paeoniflorin on Hippo Signaling Pathway in Gastric Cancer Cells. JOURNAL OF ONCOLOGY 2021; 2021:4724938. [PMID: 33531900 PMCID: PMC7837793 DOI: 10.1155/2021/4724938] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 12/29/2020] [Accepted: 01/02/2021] [Indexed: 12/16/2022]
Abstract
Background Paeoniflorin has been reported to exert antitumor effects on human cancers. However, the role of paeoniflorin in gastric cancer and the underlying molecular mechanism are unelucidated. Therefore, we determined whether paeoniflorin could exhibit anticancer activity in gastric cancer cells. Methods MTT was used to measure the viability of cells after paeoniflorin treatment. FACS was performed to examine cell apoptosis. Wound healing and transwell invasion assays were conducted to examine cell migratory and invasive activities. Western blotting was used to explore the mechanism by which paeoniflorin exerted tumor suppressive effects. Results We found that paeoniflorin suppressed cell growth, enhanced apoptosis, and reduced cell invasion. Notably, we showed that paeoniflorin inhibited the expression of TAZ in gastric cancer cells. The overexpression of TAZ abrogated the antitumor activity of paeoniflorin in gastric cancer cells. In contrast, the downregulation of TAZ promoted the tumor suppressive effects of paeoniflorin treatment. Conclusion Hence, targeting TAZ with paeoniflorin could be a novel approach for the treatment of human gastric cancer.
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Liu X, Fu Q, Bian X, Fu Y, Xin J, Liang N, Li S, Zhao Y, Fang L, Li C, Zhang J, Dionigi G, Sun H. Long Non-Coding RNA MAPK8IP1P2 Inhibits Lymphatic Metastasis of Thyroid Cancer by Activating Hippo Signaling via Sponging miR-146b-3p. Front Oncol 2021; 10:600927. [PMID: 33489905 PMCID: PMC7817949 DOI: 10.3389/fonc.2020.600927] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/09/2020] [Indexed: 12/13/2022] Open
Abstract
The principal issue derived from thyroid cancer is its high propensity to metastasize to the lymph node. Aberrant exprssion of long non-coding RNAs have been extensively reported to be significantly correlated with lymphatic metastasis of thyroid cancer. However, the clinical significance and functional role of lncRNA-MAPK8IP1P2 in lymphatic metastasis of thyroid cancer remain unclear. Here, we reported that MAPK8IP1P2 was downregulated in thyroid cancer tissues with lymphatic metastasis. Upregulating MAPK8IP1P2 inhibited, while silencing MAPK8IP1P2 enhanced anoikis resistance in vitro and lymphatic metastasis of thyroid cancer cells in vivo. Mechanistically, MAPK8IP1P2 activated Hippo signaling by sponging miR-146b-3p to disrupt the inhibitory effect of miR-146b-3p on NF2, RASSF1, and RASSF5 expression, which further inhibited anoikis resistance and lymphatic metastasis in thyroid cancer. Importantly, miR-146b-3p mimics reversed the inhibitory effect of MAPK8IP1P2 overexpression on anoikis resistance of thyroid cancer cells. In conclusion, our findings suggest that MAPK8IP1P2 may serve as a potential biomarker to predict lymphatic metastasis in thyroid cancer, or a potential therapeutic target in lymphatic metastatic thyroid cancer.
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Affiliation(s)
- Xiaoli Liu
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Qingfeng Fu
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Xuehai Bian
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Yantao Fu
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Jingwei Xin
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Nan Liang
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Shijie Li
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Yishen Zhao
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Li Fang
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Changlin Li
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Jiao Zhang
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
| | - Gianlorenzo Dionigi
- Division for Endocrine and Minimally Invasive Surgery, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University Hospital "G. Martino", University of Messina, Messina, Italy
| | - Hui Sun
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China
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Drexler R, Fahy R, Küchler M, Wagner KC, Reese T, Ehmke M, Feyerabend B, Kleine M, Oldhafer KJ. Association of subcellular localization of TEAD transcription factors with outcome and progression in pancreatic ductal adenocarcinoma. Pancreatology 2021; 21:170-179. [PMID: 33317954 DOI: 10.1016/j.pan.2020.12.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive. METHODS A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival. CONCLUSION Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.
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Affiliation(s)
- Richard Drexler
- Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany.
| | - Rebecca Fahy
- Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Mirco Küchler
- Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Kim C Wagner
- Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Tim Reese
- Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Mareike Ehmke
- Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | | | - Moritz Kleine
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Karl J Oldhafer
- Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
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Khanipouyani F, Akrami H, Fattahi MR. Circular RNAs as important players in human gastric cancer. Clin Transl Oncol 2021; 23:10-21. [PMID: 32583185 DOI: 10.1007/s12094-020-02419-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 06/04/2020] [Indexed: 01/17/2023]
Abstract
As one of the most prevalent gastrointestinal diseases, gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. Since GC has no clinical manifestations in the early stage of the disease, most patients are detected in the later phases of disease and have an unfortunately lower chance of recovery. Circular RNAs (circRNAs), a novel category of non-coding RNAs (ncRNAs), are mainly engaged in the regulation of gene expression at the transcriptional and post-transcriptional levels. Numerous evidences have revealed that circRNAs play key roles in GC as they are involved in cell proliferation, growth, and apoptosis via modulating the expression of some target genes, miRNAs, and proteins. Many studies have addressed the impact of circRNA dysregulation on GC initiation, progression, and invasion via binding to miRNAs or RNA binding proteins. Moreover, changes in circRNA expression are associated with pathological and clinical features of GC highlighting their potentials as diagnostic or prognostic biomarkers in GC. In the current study, the recent findings on the significance of circRNAs in the development and progression of GC are reviewed. We focus on the implications of circRNAs as potential diagnostic or prognostic biomarkers in this malignancy.
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Affiliation(s)
- F Khanipouyani
- Department of Biology, Faculty of Science, Razi University, kermanshah, Iran
| | - H Akrami
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - M R Fattahi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Kim JY, Kim EK, Lee WM, Hong YO, Lee H. VGLL4 with low YAP expression is associated with favorable prognosis in colorectal cancer. APMIS 2020; 128:543-551. [PMID: 32794608 DOI: 10.1111/apm.13070] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 07/27/2020] [Indexed: 02/01/2023]
Abstract
The Hippo pathway is a tumor suppressive pathway regulating Yes-associated protein-TEA domain-containing sequence-specific transcription factor (YAP-TEAD) complex. VGLL (Vestigial-like) proteins are transcriptional cofactors competing with YAP for TEAD binding and interfering oncogenic activity of YAP-TEAD complex. We evaluated the expression of VGLL4, YAP, and TEAD4 and assessed their correlations with clinicopathologic factors and prognostic effects in 295 colorectal cancers. VGLL4 was positive in 164 (55.6%) cases and correlated with small tumor size, low pT classification, and absence of lymph node metastasis. YAP and TEAD4 were highly expressed in 138 (46.8%) cases and 144 (48.8%) cases, respectively, and high expressions were associated with presence of lymphovascular invasion and lymph node metastasis, or distant metastasis. VGLL4 expression was significantly correlated with low YAP expression (p < 0.001) and had significantly better overall survival than negative expression (p < 0.001). High YAP (HR, 2.108; 95% confidence interval, 1.239-3.584; p = 0.006) and TEAD4 (1.724; 1.021-2.912; p = 0.042) expressions were associated with poor overall survivals. The combined VGLL4pos YAPlow expression showed the best overall survival than other groups (p < 0.001). VGLL4 expression (0.381; 0.212-0.683; p = 0.001) and combined VGLL4pos YAPlow expression (0.227; 0.108-0.475; p < 0.001) were independent good prognostic factors in colorectal cancers. The expressions of VGLL4, YAP, and TEAD4 can be used as prognostic markers in colorectal cancer patients.
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Affiliation(s)
- Joo Young Kim
- Department of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
| | - Eun Kyung Kim
- Department of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
| | - Won Mi Lee
- Department of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
| | - Young Ok Hong
- Department of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
| | - Hojung Lee
- Department of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
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Espinosa-Sánchez A, Suárez-Martínez E, Sánchez-Díaz L, Carnero A. Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness. Front Oncol 2020; 10:1533. [PMID: 32984007 PMCID: PMC7479251 DOI: 10.3389/fonc.2020.01533] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/16/2020] [Indexed: 12/11/2022] Open
Abstract
The theory of cancer stem cells (CSCs) proposes that the different cells within a tumor, as well as metastasis deriving from it, are originated from a single subpopulation of cells with self-renewal and differentiation capacities. These cancer stem cells are supposed to be critical for tumor expansion and metastasis, tumor relapse and resistance to conventional therapies, such as chemo- and radiotherapy. The acquisition of these abilities has been attributed to the activation of alternative pathways, for instance, WNT, NOTCH, SHH, PI3K, Hippo, or NF-κB pathways, that regulate detoxification mechanisms; increase the metabolic rate; induce resistance to apoptotic, autophagic, and senescence pathways; promote the overexpression of drug transporter proteins; and activate specific stem cell transcription factors. The elimination of CSCs is an important goal in cancer therapeutic approaches because it could decrease relapses and metastatic dissemination, which are main causes of mortality in oncology patients. In this work, we discuss the role of these signaling pathways in CSCs along with their therapeutic potential.
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Affiliation(s)
- Asunción Espinosa-Sánchez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| | - Elisa Suárez-Martínez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| | - Laura Sánchez-Díaz
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
- CIBER de Cancer, Madrid, Spain
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MAC30 Knockdown Inhibits Proliferation and Enhance Apoptosis of Gastric Cancer by Suppressing Wnt/ β-Cateninsignaling Pathway. Gastroenterol Res Pract 2020; 2020:6358685. [PMID: 32904598 PMCID: PMC7456481 DOI: 10.1155/2020/6358685] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/15/2020] [Indexed: 01/17/2023] Open
Abstract
Gastric cancer is one of the most frequently diagnosed cancer and poses a serious threat to health system in the world. Upregulation of meningioma-associated protein (MAC30) has been found in many solid tumors and can regulate the proliferation, differentiation, and apoptosis of different tumor cells. Quantitative polymerase chain reaction (qPCR) was used to detect the expression of MAC30 in 68 patients with gastric cancer and their adjacent tissues. Lentiviral vector pGCSIL-shMAC30-GFP of the RNA interference (RNAi) of the MAC30 gene was transfected into gastric cancer BGC-823 cell line and the expression of lentivirus label protein GFP was observed via fluorescence microscope, while cell proliferation and apoptosis were determined with flow cytometry and MTT assay, respectively. Also, related protein expressions on Wnt/β-catenin signaling pathway were analyzed by Western blot method. The expression of MAC30 was abnormally elevated in gastric cancer tissues, while interfering of its expression could significantly inhibit the proliferation of gastric cancer BGC-823 cell line. However, the promotion of apoptosis by mitochondrial pathway was mediated by Bax/Bcl-2 upregulation. Present work showed the effect of downregulated MAC30 expression on proliferation and apoptosis of gastric cancer cell through Wnt/β-catenin signaling pathway. Thus, this investigation provides an experimental basis for future development of chemotherapeutic agent on gastric cancer.
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Yang T, Heng C, Zhou Y, Hu Y, Chen S, Wang H, Yang H, Jiang Z, Qian S, Wang Y, Wang J, Zhu X, Du L, Yin X, Lu Q. Targeting mammalian serine/threonine-protein kinase 4 through Yes-associated protein/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis. Metabolism 2020; 108:154258. [PMID: 32376130 DOI: 10.1016/j.metabol.2020.154258] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/13/2020] [Accepted: 04/29/2020] [Indexed: 12/19/2022]
Abstract
RATIONALE Tubulointerstitial fibrosis, which is closely related to functional injury of the kidney, can be observed in advanced stages of diabetic nephropathy (DN). Mammalian serine/threonine-protein kinase 4 (MST1), a core component of the Hippo pathway that is involved in cellular proliferation and differentiation, plays a crucial role in the pathogenesis of multiple metabolic diseases, kidney diseases and cancer. METHODS In type 1 and type 2 diabetic animals, as well as in human proximal tubular epithelial cells (HK-2), activation of MST1 was analyzed by immunohistochemistry and western blotting. In db/db mice, MST1 protein was knocked down or overexpressed by shRNA, and renal function, fibrosis, and downstream signaling were then investigated. RNA silencing and overexpression were performed by using an MST1 or YAP knockdown/expression lentivirus to investigate the regulation of MST1-mediated YAP/TEAD signaling pathways in the fibrosis process in HK-2 cells. Luciferase and coimmunoprecipitation (co-IP) assays were used to identify whether YAP directly regulated TEAD activation by forming a YAP-TEAD heterodimer, which ultimately leads to tubulointerstitial fibrosis. RESULTS MST1 activation was significantly decreased in type 1 and type 2 diabetic nephropathy. Notably, the downregulation of MST1 activation was also observed in HK-2 cells in a glucose- and time-dependent manner. In vivo, downregulation of MST1 was sufficient to promote renal dysfunction and fibrosis in db/m mice, whereas overexpression of MST1 ameliorated diabetic nephropathy-induced renal fibrosis. Further mechanistic study demonstrated that activated YAP induced by MST1 inhibition directly upregulated TEAD activation by binding to TEAD and forming a YAP-TEAD heterodimer, resulting in the promotion of epithelial-mesenchymal transition (EMT) and fibrosis in renal tubular epithelial. CONCLUSIONS MST1 activation represents a potential therapeutic strategy to treat or prevent the progression of diabetic nephropathy-induced renal fibrosis.
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Affiliation(s)
- Tingting Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Cai Heng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Yi Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Yinlu Hu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Shangxiu Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Haiyan Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Hao Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Sitong Qian
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Yinan Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Jianyun Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xia Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Lei Du
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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TAZ Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties. Cells 2020; 9:cells9061462. [PMID: 32545795 PMCID: PMC7348942 DOI: 10.3390/cells9061462] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/01/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZ silencing reduced ZEB1 expression and EMT phenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis.
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Yao Y, Liu Z, Cao Y, Guo H, Jiang B, Deng J, Xiong J. Downregulation of TRIM27 suppresses gastric cancer cell proliferation via inhibition of the Hippo-BIRC5 pathway. Pathol Res Pract 2020; 216:153048. [PMID: 32825933 DOI: 10.1016/j.prp.2020.153048] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 05/18/2020] [Accepted: 06/05/2020] [Indexed: 11/26/2022]
Abstract
Although tripartite motif containing 27 (TRIM27) protein has been implicated in the progression of many cancer types, its role in gastric cancer (GC) remains poorly understood. Given that TRIM27 may be associated with the baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) gene, which is downstream of the Hippo pathway, we clarified their relationship in GC progression. In vitro cultures of 7 GC cell lines, 92 GC patient tumor samples and 46 normal clinical samples were used to examine the influence of changes in TRIM27 expression, which was assessed by quantitative PCR, immunohistochemistry, western blot analysis, and cell viability assays. We found that TRIM27 overexpression was correlated with tumor size, depth of invasion, and poor GC prognosis, while TRIM27 small interfering RNA knockdown inhibited cell proliferation and colony formation, induced apoptosis, and increased sensitivity towards 5-fluorouracil treatment in MGC-803 and HGC-27 GC cell lines. Notably, TRIM27 downregulation resulted in BIRC5 suppression via large tumor suppressor kinase 2 (LATS2) upregulation and subsequent Yes-associated protein 1 (YAP1) inhibition in MGC-803 and HGC-27 GC cell lines. In conclusion, our findings revealed the positive correlation between TRIM27 and GC progression through mediation of the Hippo-BIRC5 axis in GC.
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Affiliation(s)
- Yangyang Yao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Zhen Liu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yuan Cao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Hui Guo
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Bailing Jiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Jun Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
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Association of Genetic Polymorphisms in FOXA1 with the Progression of Genetic Susceptibility to Gastric Cancer. Gastroenterol Res Pract 2020; 2020:3075837. [PMID: 32411194 PMCID: PMC7204115 DOI: 10.1155/2020/3075837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/15/2019] [Accepted: 12/24/2019] [Indexed: 12/13/2022] Open
Abstract
Objective To investigate the relationship between polymorphism of FOXA1 gene rs12894364 and rs7144658 and susceptibility to gastric cancer. Methods A case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele was tested through a snapshot method. Results There was no significant difference in the frequency distribution of genotype between the case group and control group (P > 0.05). Stratified analyses showed the SNPs were not correlated with the susceptibility of GC according to different age, gender, cigarette smoking, and alcohol drinking status. Conclusion There is no significant correlation between the polymorphisms of FOXA1 gene rs12894364 and rs7144658 and the risk of gastric cancer.
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Moloudizargari M, Asghari MH, Nabavi SF, Gulei D, Berindan-Neagoe I, Bishayee A, Nabavi SM. Targeting Hippo signaling pathway by phytochemicals in cancer therapy. Semin Cancer Biol 2020; 80:183-194. [PMID: 32428716 DOI: 10.1016/j.semcancer.2020.05.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022]
Abstract
The current era of cancer research has been continuously advancing upon identifying novel aspects of tumorigenesis and the principal mechanisms behind the unleashed proliferation, invasion, drug resistance and immortality of cancer cells in hopes of exploiting these findings to achieve a more effective treatment for cancer. In pursuit of this goal, the identification of the first components of an extremely important regulatory pathway in Drosophila melanogaster that largely determines cell fate during the developmental stages, ended up in the discovery of the highly sophisticated Hippo signaling cascade. Soon after, it was revealed that deregulation of the components of this pathway either via mutations or through epigenetic alterations can be observed in a vast variety of tumors and these alterations greatly contribute to the neoplastic transformation of cells, their survival, growth and resistance to therapy. As more hidden aspects of this pathway such as its widespread entanglement with other major cellular signaling pathways are continuously being uncovered, many researchers have sought over the past decade to find ways of therapeutic interventions targeting the major components of the Hippo cascade. To date, various approaches such as the use of exogenous targeting miRNAs and different molecular inhibitors have been recruited herein, among which naturally occurring compounds have shown a great promise. On such a basis, in the present work we review the current understanding of Hippo pathway and the most recent evidence on targeting its components using natural plant-derived phytochemicals.
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Affiliation(s)
- Milad Moloudizargari
- Department of Immunology, School of Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Mohammad Hossein Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol 4717647745, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 4717647745, Iran.
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran
| | - Diana Gulei
- MedFuture - Research Center for Advanced Medicine, Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400337, Romania
| | - Ioana Berindan-Neagoe
- MedFuture - Research Center for Advanced Medicine, Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400337, Romania; Department of Functional Genomics and Experimental Pathology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca 400337, Romania
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran.
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Ouyang T, Meng W, Li M, Hong T, Zhang N. Recent Advances of the Hippo/YAP Signaling Pathway in Brain Development and Glioma. Cell Mol Neurobiol 2020; 40:495-510. [PMID: 31768921 PMCID: PMC11448948 DOI: 10.1007/s10571-019-00762-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/16/2019] [Indexed: 12/13/2022]
Abstract
The Hippo signaling pathway is highly conserved from Drosophila melanogaster to mammals and plays a crucial role in organ size control, tissue regeneration, and tumor suppression. The Yes-associated protein (YAP) is an important transcriptional co-activator that is negatively regulated by the Hippo signaling pathway. The Hippo signaling pathway is also regulated by various upstream regulators, such as cell polarity, adhesion proteins, and other signaling pathways (the Wnt/β-catenin, Notch, and MAPK pathways). Recently, accumulated evidence suggests that the Hippo/YAP signaling pathway plays important roles in central nervous system development and brain tumor, including glioma. In this review, we summarize the results of recent studies on the physiological effect of the Hippo/YAP signaling pathway in neural stem cells, neural progenitor cells, and glial cells. In particular, we also focus on the expression of MST1/2, LATS1/2, and the downstream effector YAP, in glioma, and offer a review of the latest research of the Hippo/YAP signaling pathway in glioma pathogenesis. Finally, we also present future research directions and potential therapeutic strategies for targeting the Hippo/YAP signaling in glioma.
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Affiliation(s)
- Taohui Ouyang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Jiangxi Province, China
| | - Wei Meng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Jiangxi Province, China
| | - Meihua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Jiangxi Province, China
| | - Tao Hong
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Jiangxi Province, China
| | - Na Zhang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Jiangxi Province, No.17, Yongwai Street, Nanchang, 336000, China.
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Li R, Jiang J, Shi H, Qian H, Zhang X, Xu W. CircRNA: a rising star in gastric cancer. Cell Mol Life Sci 2020; 77:1661-1680. [PMID: 31659415 PMCID: PMC11104848 DOI: 10.1007/s00018-019-03345-5] [Citation(s) in RCA: 275] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/08/2019] [Accepted: 10/14/2019] [Indexed: 01/17/2023]
Abstract
In recent years, a large number of circRNAs have been identified in mammalian cells with high-throughput sequencing technologies and bioinformatics. The aberrant expression of circRNAs has been reported in many human diseases including gastric cancer (GC). The number of GC-related circRNAs with validated biological functions and mechanisms of action is growing. CircRNAs are critically involved in GC cell proliferation, apoptosis, migration, and invasion. CircRNAs have been shown to function as regulators of parental gene transcription and alternative splicing and miRNA sponges. Moreover, circRNAs have been suggested to interact with proteins to regulate their expression level and activities. Several circRNAs have been identified to encode functional proteins. Due to their great abundance, high stability, tissue- and developmental-stage-specific expression patterns, and wide distribution in various body fluids and exosomes, circRNAs exhibit a great potential to be utilized as biomarkers for GC. Herein, we briefly summarize their biogenesis, properties and biological functions and discuss about the current research progress of circRNAs in GC with a focus on the potential application for GC diagnosis and therapy.
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Affiliation(s)
- Rong Li
- Aoyang Institute of Cancer, Jiangsu University, 279 Jingang Road, Suzhou, 215600, Jiangsu, China
- Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Jiangsu University, 279 Jingang Road, Suzhou, 215600, Jiangsu, China
| | - Hui Shi
- Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Hui Qian
- Aoyang Institute of Cancer, Jiangsu University, 279 Jingang Road, Suzhou, 215600, Jiangsu, China
- Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Xu Zhang
- Aoyang Institute of Cancer, Jiangsu University, 279 Jingang Road, Suzhou, 215600, Jiangsu, China.
- Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
| | - Wenrong Xu
- Aoyang Institute of Cancer, Jiangsu University, 279 Jingang Road, Suzhou, 215600, Jiangsu, China.
- Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
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Joo JS, Cho SY, Rou WS, Kim JS, Kang SH, Lee ES, Moon HS, Kim SH, Sung JK, Kwon IS, Eun HS, Lee BS. TEAD2 as a novel prognostic factor for hepatocellular carcinoma. Oncol Rep 2020; 43:1785-1796. [PMID: 32323824 PMCID: PMC7160555 DOI: 10.3892/or.2020.7578] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 02/14/2020] [Indexed: 12/26/2022] Open
Abstract
TEA Domain Transcription Factors (TEADs) are important in development and serve essential roles in tumorigenesis; however, the role of TEAD2 expression in hepatocellular carcinoma (HCC) has not been widely examined. The present study was conducted to investigate the expression status of TEAD2 in HCC and to evaluate whether the expression of TEAD2 is associated with the prognosis of patients with HCC. mRNA expression data was retrieved for Hippo pathway genes of 50 normal control and 377 HCC samples from The Cancer Genome Atlas data portal. Gene set enrichment, GeneNeighbors, ClassNeighbors and survival analyses were then performed based on the gene expression levels. The mRNA expression of TEAD2 and VGLL4 was significantly higher in HCC compared with the normal control samples, and the mRNA expression of TEAD2 was higher in advanced stages than in early stages. Specifically, survival analysis revealed that higher mRNA expression of TEAD2 was significantly associated with a less favorable overall survival rate (P=0.0067) and there was a trend towards significance between higher mRNA expression of VGLL4 and poor overall survival rate (P=0.051). According to the gene set enrichment analysis, patients with higher mRNA expression of TEAD2 and VGLL4 had strongly enhanced epithelial-mesenchymal transition and angiogenesis, which are associated with tumor progression. In conclusion, increased mRNA expression of TEAD2 is associated with a poor prognosis in patients with HCC. TEAD2 may serve as a prognostic factor for HCC and a novel therapeutic target.
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Affiliation(s)
- Jong Seok Joo
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Sang Yeon Cho
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Woo Sun Rou
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Ju Seok Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Sun Hyung Kang
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Eaum Seok Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Hee Seok Moon
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Seok Hyun Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Jae Kyu Sung
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - In Sun Kwon
- Clinical Trial Center, Chungnam National University Hospital, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Hyuk Soo Eun
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Jung‑gu, Daejeon 35015, Republic of Korea
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Luo SY, Kwok HH, Yang PC, Ip MSM, Minna JD, Lam DCL. Expression of large tumour suppressor (LATS) kinases modulates chemotherapy response in advanced non-small cell lung cancer. Transl Lung Cancer Res 2020; 9:294-305. [PMID: 32420069 PMCID: PMC7225163 DOI: 10.21037/tlcr.2020.03.26] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Background The Hippo signalling pathway plays an important role in regulating organ size and cell proliferation. Down-regulation of large tumour suppressor (LATS) protein homologs LATS1 or LATS2 has been found in lung cancer. LATS1 and LATS2 are the core components of the Hippo signalling pathway. LATS1 and LATS2 share some conserved structural features and exhibit redundant biological functions. The aim of this study was to dissect the interaction between these two homologs. Methods In lung adenocarcinoma (AD) cells, protein expression of LATS1 and LATS2 were determined by western blotting; cell viability and apoptosis were measured by MTT and annexin V staining after treatment with cisplatin; subcellular distributions of LATS proteins were determined by immunofluorescence microscopy; LATS2 expression was modulated by shRNA-mediated knockdown or ectopic expression in cancer cell lines. Results Manipulation of the expression of these two LATS kinases influenced cisplatin response in advanced lung AD cell lines. High LATS2-to-LATS1 ratio in H2023 cells was associated with cisplatin resistance, while low LATS2-to-LATS1 ratio in CL1-0 and CL83 cells was associated with sensitivity to cisplatin. Manipulating the LATS2-to-LATS1 ratio by LATS2 over-expression in CL1-0 and CL83 rendered them resistant to cisplatin treatment, whereas LATS2 knockdown in H2023 alleviated the LATS2-to-LATS1 ratio and sensitized cancer cells to cisplatin exposure. Conclusions Our data suggested that the ratio of expression of LATS kinases played a role in the modulation of cisplatin sensitivity in advanced lung AD, and targeting of LATS proteins as a novel therapeutic strategy for lung AD deserves further investigation.
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Affiliation(s)
- Susan Yang Luo
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Hoi-Hin Kwok
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Pan-Chyr Yang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei
| | - Mary Sau-Man Ip
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - John Dorrance Minna
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - David Chi-Leung Lam
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
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Liu Q, Xia H, Zhou S, Tang Q, Zhou J, Ren M, Bi F. Simvastatin Inhibits the Malignant Behaviors of Gastric Cancer Cells by Simultaneously Suppressing YAP and β-Catenin Signaling. Onco Targets Ther 2020; 13:2057-2066. [PMID: 32210573 PMCID: PMC7074824 DOI: 10.2147/ott.s237693] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 02/25/2020] [Indexed: 02/05/2023] Open
Abstract
Background Statins, which are used to lower blood cholesterol levels by inhibiting HMG-CoA reductase, have shown anticancer effects in many cancer cells. However, the role of statins in gastric cancer remains unclear. This study aims to investigate whether the statins could antagonize progression of gastric cancer cells and tried to find the molecule mechanism. Methods Effects of simvastatin on the morphology, proliferation, migration, apoptosis, and invasion of gastric cancer cells were detected and compared. Western blotting, cell viability assay, fluorescence, and transfection were employed to study the molecule mechanism of the effects and the interaction between YAP and β-catenin signaling. Results Simvastatin could inhibit proliferation, migration and invasion, and promote the apoptosis in gastric cancer cells. Mechanistic studies showed that simvastatin treatment could inhibit the expression of β-catenin and the activity of YAP and the downstream targets of YAP and β-catenin in gastric cancer cells. Moreover, we found that YAP and β-catenin could form a positive feedback loop in gastric cancer cells. Further investigation revealed that simvastatin mainly acted through by inhibiting the activity of RhoA to inhibit YAP and β-catenin, and the geranylgeranyl pyrophosphate pathway mediated this regulation. Conclusion Statins represent a promising therapeutic option for gastric cancer by simultaneously targeting YAP and β-catenin signaling.
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Affiliation(s)
- Qing Liu
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.,Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Hongwei Xia
- Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Sheng Zhou
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.,Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Qiulin Tang
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.,Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Jitao Zhou
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Min Ren
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Feng Bi
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.,Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
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Dong G, Qiu F, Liu C, Wu H, Liu Y. [High expression of DNMT3B promotes proliferation and invasion of hepatocellular carcinoma cells via Hippo signaling pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 39:1443-1452. [PMID: 31907153 DOI: 10.12122/j.issn.1673-4254.2019.12.08] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To explore the role of DNMT3B in regulating the proliferation and invasion of hepatocellular carcinoma (HCC) cells. METHODS We collected the tumor tissues and adjacent tissues from a total of 175 patients with HCC diagnosed in the Second Affiliated Hospital of Chongqing Medical University between May, 2008 and May, 2013 to prepare the tissue microarrays. The association of the expression of DNMT3B with the prognosis and the tumor-free survival and tumor-specific survival rates of the patients was analyzed. Univariate and multivariate Cox regression analyses were used to analyze the effect of DNMT3B expression on the prognosis of HCC. We used RNA interference technique to knock down the expression of DNMT3B in Huh-7 hepatoma cells and observed the changes in cell proliferation using CCK-8 assay and EDU staining and in cell migration and invasion ability using Transwell assay. RESULTS The positive rates of DNMT3B was significantly higher in HCC tissues than in paired adjacent tissues (67.4% vs 41.1%, P=0.015). A high DNMT3B expression in HCC was significantly associated with the tumor size (P=0.001), vascular invasion (P=0.004), and intrahepatic metastasis (P=0.018). The patients with high DNMT3B expressions had significantly lower tumor-free and tumor-specific survival rates than those with low DNMT3B expressions (P < 0.005). In Huh-7 cells, silencing DNMT3B significantly inhibited the cell proliferation and inhibited cell migration and invasion. Western blotting showed that silencing DNMT3B obviously increased LATS1 expression, decreased the expression of YAP1, and activated Hippo signaling pathway. Methylation-specific PCR showed that the methylation level of LATS1 was decreased in the cells with DNMT3B silencing. CONCLUSIONS The expression level of DNMT3B is significantly higher HCC tissues than in the adjacent tissues, and the high expression of DNMT3B is closely related to the low survival rate of the patients. Silencing DNMT3B inhibits the proliferation, migration and invasion of HCC cells. DNMT3B promotes the progression of HCC primarily by enhancing the expression of YAP1 through methylation of LATS1 and inhibition of its expression, which inhibits the anti-cancer effect of Hippo signaling pathway.
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Affiliation(s)
- Gaohong Dong
- Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, China
| | - Fuliang Qiu
- Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, China
| | - Changan Liu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Hao Wu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Yan Liu
- Department of Gastroenterology, Fifth People's Hospital of Chengdu, Chengdu 611130, China
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Rojas A, Araya P, Gonzalez I, Morales E. Gastric Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1226:23-35. [PMID: 32030673 DOI: 10.1007/978-3-030-36214-0_2] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A compelling body of evidence has demonstrated that gastric cancer has a very particular tumor microenvironment, a signature very suitable to promote tumor progression and metastasis. Recent investigations have provided new insights into the multiple molecular mechanisms, defined by genetic and epigenetic mechanisms, supporting a very active cross talk between the components of the tumor microenvironment and thus defining the fate of tumor progression. In this review, we intend to highlight the role of very active contributors at gastric cancer TME, particularly cancer-associated fibroblasts, bone marrow-derived cells, tumor-associated macrophages, and tumor-infiltrating neutrophils, all of them surrounded by an overtime changing extracellular matrix. In addition, the very active cross talk between the components of the tumor microenvironment, defined by genetic and epigenetic mechanisms, thus defining the fate of tumor progression, is also reviewed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile.
| | - Paulina Araya
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Ileana Gonzalez
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile
| | - Erik Morales
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile
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Zinatizadeh MR, Miri SR, Zarandi PK, Chalbatani GM, Rapôso C, Mirzaei HR, Akbari ME, Mahmoodzadeh H. The Hippo Tumor Suppressor Pathway (YAP/TAZ/TEAD/MST/LATS) and EGFR-RAS-RAF-MEK in cancer metastasis. Genes Dis 2019; 8:48-60. [PMID: 33569513 PMCID: PMC7859453 DOI: 10.1016/j.gendis.2019.11.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/24/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023] Open
Abstract
Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth. This pathway is activated in response to cell cycle arrest signals (cell polarity, transduction, and DNA damage) and limited by growth factors or mitogens associated with EGF and LPA. The major pathway consists of the central kinase of Ste20 MAPK (Saccharomyces cerevisiae), Hpo (Drosophila melanogaster) or MST kinases (mammalian) that activates the mammalian AGC kinase dmWts or LATS effector (MST and LATS). YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation (TEA domain family, TEAD1-4), stem cells (Oct4 mononuclear factor and SMAD-related TGFβ effector), differentiation (RUNX1), and Cell cycle/apoptosis control (p53, p63, and p73 family members). This is due to the diverse roles of YAP and may limit tumor progression and establishment. TEAD also coordinates various signal transduction pathways such as Hippo, WNT, TGFβ and EGFR, and effects on lack of regulation of TEAD cancerous genes, such as KRAS, BRAF, LKB1, NF2 and MYC, which play essential roles in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. However, RAS signaling is a pivotal factor in the inactivation of Hippo, which controls EGFR-RAS-RAF-MEK-ERK-mediated interaction of Hippo signaling. Thus, the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.
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Affiliation(s)
- Mohammad Reza Zinatizadeh
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
- Corresponding author. Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Seyed Rouhollah Miri
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
| | - Peyman Kheirandish Zarandi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
| | - Ghanbar Mahmoodi Chalbatani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Catarina Rapôso
- Faculty of Pharmaceutical Sciences State University of Campinas – UNICAMP Campinas, SP, Brazil
| | - Hamid Reza Mirzaei
- Cancer Research Center, Shohadae Tajrish Hospital, Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Habibollah Mahmoodzadeh
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran
- Corresponding author. Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran.
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Song W, Zhang J, Zhang J, Sun M, Xia Q. Overexpression of lncRNA PIK3CD-AS1 promotes expression of LATS1 by competitive binding with microRNA-566 to inhibit the growth, invasion and metastasis of hepatocellular carcinoma cells. Cancer Cell Int 2019; 19:150. [PMID: 31624469 PMCID: PMC6784333 DOI: 10.1186/s12935-019-0857-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 05/10/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND This study is conducted to investigate the effect of lncRNA PIK3CD-AS1 on the growth and metastasis of hepatocellular carcinoma (HCC) and its potential mechanism. METHODS Hepatocellular carcinoma tissues and adjacent normal tissues together with HCC cells and normal liver cells were obtained for detecting expression of PIK3CD-AS1, microRNA-566 (miR-566) and LATS1. Additionally, a series of experiments were performed to determine cell proliferation, migration, invasion, cell cycle distribution and apoptosis of HCC cells. The xenograft tumor model of HCC was established and the growth rate and weight of xenograft tumor in nude mice were compared. Furthermore, the binding site between PIK3CD-AS1 and miR-566 as well as between miR-566 and LATS1 were verified. RESULTS LncRNA PIK3CD-AS1 was downregulated in HCC tissues and cells, and mainly located in cytoplasm. Overexpression of PIK3CD-AS1 inhibited proliferation, colony formation, invasion, migration, epithelial-mesenchymal transition (EMT) and cell cycle progression and promoted apoptosis of HCC cells. Overexpression of PIK3CD-AS1 decreased the growth rate and weight of xenograft tumor in nude mice PIK3CD-AS1 competitively combined with miR-566 to regulate expression of LAST1. CONCLUSION Collectively, our study suggests that the expression of PIK3CD-AS1 was down-regulated in HCC, and overexpression of PIK3CD-AS1 promoted the expression of LATS1 by competitive binding of miR-566 to inhibit the growth, invasion and metastasis of HCC cells.
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Affiliation(s)
- Wei Song
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, No. 127 Dongming Road, Zhengzhou, 450000 People’s Republic of China
| | - Jingjing Zhang
- Department of Cardiovascularology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450000 People’s Republic of China
| | - Jianbo Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, No. 127 Dongming Road, Zhengzhou, 450000 People’s Republic of China
| | - Miaomiao Sun
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, No. 127 Dongming Road, Zhengzhou, 450000 People’s Republic of China
| | - Qingxin Xia
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, No. 127 Dongming Road, Zhengzhou, 450000 People’s Republic of China
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Impact of Taurine on the proliferation and apoptosis of human cervical carcinoma cells and its mechanism. Chin Med J (Engl) 2019; 132:948-956. [PMID: 30958437 PMCID: PMC6595772 DOI: 10.1097/cm9.0000000000000162] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Cervical cancer has the fourth highest incidence and mortality rate of all cancers in women worldwide; it seriously harms their physical and mental health. The aim of this study was to observe the roles and preliminary mechanism of Taurine (Tau)-induced apoptosis in cervical cancer cells. METHODS Cells from the human cervical cancer cell line SiHa were transfected with the recombinant plasmid pEGFP-N1-MST1 (mammalian sterile 20-like kinase 1); then, the cell proliferation activity was analyzed by the MTT assay, cell apoptosis by flow cytometry, and the related protein levels by Western blotting. RESULTS Tau inhibited the proliferation of SiHa cells and induced apoptosis in these cells (the apoptotic rate was 21.95% in the Tau 160 mmol/L group and 30% in the Tau 320 mmol/L group), upregulated the expression of the MST1 (control, 0.53; Tau 40-320 mmol/L groups, 0.84-1.45) and Bax (control, 0.45; Tau 40-320 mmol/L groups, 0.64-1.51) proteins (P < 0.01), and downregulated the expression of Bcl-2 (control, 1.28, Tau 40-320 mmol/L groups, 0.93-0.47) (P < 0.01). The overexpression of MST1 promoted the apoptosis of SiHa cells, enhanced the apoptosis-inductive effects of Tau (P < 0.01), upregulated the expression of the proapoptotic proteins p73, p53, PUMA (p53 upregulated modulator of apoptosis), and caspase-3, and promoted the phosphorylation of YAP (Yes-associated protein). CONCLUSIONS Tau inhibited the proliferation and induced the apoptosis of cervical cancer SiHa cells. The MST1 protein plays an important role in the Tau-induced apoptosis of cervical cancer cells.
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Dong X, Meng L, Liu P, Ji R, Su X, Xin Y, Jiang X. YAP/TAZ: a promising target for squamous cell carcinoma treatment. Cancer Manag Res 2019; 11:6245-6252. [PMID: 31360073 PMCID: PMC6625644 DOI: 10.2147/cmar.s197921] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/04/2019] [Indexed: 12/03/2022] Open
Abstract
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two homologous transcriptional coactivators and the final effectors of the Hippo signaling transduction pathway. The transcriptional activity of YAP/TAZ is dependent on their recruitment to the nucleus, which promotes binding to the transcription factor of TEA domain family members 1–4 (TEAD1-4). In Hippo-signaling pathway, YAP/TAZ is inactivated and its translocation to the nucleus is blocked via a core kinase cascade stimulated by a variety of upstream signals, such as G-protein-coupled receptor signaling, mechanical pressure, and adherens junction signaling. This pathway plays a very important role in regulating organ size, tissue homeostasis, and tumor development. In recent years, many studies have reported upregulation or nuclear localization of YAP/TAZ in a number of human malignancies, such as breast cancer, melanoma, lung cancer, especially squamous cell carcinoma in different organs. A large number of experiments demonstrate that YAP/TAZ activation promotes cancer formation, progression, and metastasis. Therefore, in this review, we summarize the evidence of regulation and function of YAP/TAZ and discuss its role in squamous cell carcinoma. Collectively, this summary strongly suggests that targeting aberrant YAP/TAZ activation is a promising strategy for the suppression of squamous cell carcinoma.
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Affiliation(s)
- Xiaoming Dong
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China.,Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, People's Republic of China
| | - Lingbin Meng
- Department of Internal Medicine, Florida Hospital, Orlando, FL 32804, USA
| | - Pinyi Liu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, People's Republic of China
| | - Rui Ji
- Department of Biology, Valencia College, Orlando, FL 32804, USA
| | - Xuling Su
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, People's Republic of China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, People's Republic of China
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
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Wu Y, Shen L, Liang X, Li S, Ma L, Zheng L, Li T, Yu H, Chan H, Chen C, Yu J, Jia J. Helicobacter pylori-induced YAP1 nuclear translocation promotes gastric carcinogenesis by enhancing IL-1β expression. Cancer Med 2019; 8:3965-3980. [PMID: 31145543 PMCID: PMC6639191 DOI: 10.1002/cam4.2318] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 05/10/2019] [Accepted: 05/15/2019] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp)-induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes-associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor-promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL-1β in gastric cells infected with Hp. As IL-1ß accounts for inflammation-associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP-5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1-TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.
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Affiliation(s)
- Yujiao Wu
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Li Shen
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Xiuming Liang
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Shuyan Li
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Lin Ma
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Lixin Zheng
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Tongyu Li
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Han Yu
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Hillary Chan
- The Faculty of MedicineThe University of TorontoTorontoCanada
| | - Chunyan Chen
- Department of HematologyQilu Hospital, Shandong UniversityJinanShandongP. R. China
| | - Jingya Yu
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
| | - Jihui Jia
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of MedicineShandong UniversityJinanP. R. China
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Huh HD, Kim DH, Jeong HS, Park HW. Regulation of TEAD Transcription Factors in Cancer Biology. Cells 2019; 8:E600. [PMID: 31212916 PMCID: PMC6628201 DOI: 10.3390/cells8060600] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 12/11/2022] Open
Abstract
Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics.
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Affiliation(s)
- Hyunbin D Huh
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
| | - Dong Hyeon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
| | - Han-Sol Jeong
- Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Korea.
| | - Hyun Woo Park
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
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The Role of MicroRNAs in the Regulation of Gastric Cancer Stem Cells: A Meta-Analysis of the Current Status. J Clin Med 2019; 8:jcm8050639. [PMID: 31075910 PMCID: PMC6572052 DOI: 10.3390/jcm8050639] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/04/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains one of the major causes of cancer-related mortality worldwide. As for other types of cancers, several limitations to the success of current therapeutic GC treatments may be due to cancer drug resistance that leads to tumor recurrence and metastasis. Increasing evidence suggests that cancer stem cells (CSCs) are among the major causative factors of cancer treatment failure. The research of molecular CSC mechanisms and the regulation of their properties have been intensively studied. To date, molecular gastric cancer stem cell (GCSC) characterization remains largely incomplete. Among the GCSC-targeting approaches to overcome tumor progression, recent studies have focused their attention on microRNA (miRNA). The miRNAs are short non-coding RNAs which play an important role in the regulation of numerous cellular processes through the modulation of their target gene expression. In this review, we summarize and discuss recent findings on the role of miRNAs in GCSC regulation. In addition, we perform a meta-analysis aimed to identify novel miRNAs involved in GCSC homeostasis.
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