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Chan SW, Ong C, Hong W. The recent advances and implications in cancer therapy for the hippo pathway. Curr Opin Cell Biol 2025; 93:102476. [PMID: 39908768 DOI: 10.1016/j.ceb.2025.102476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/13/2025] [Accepted: 01/17/2025] [Indexed: 02/07/2025]
Abstract
The Hippo pathway is a highly conserved signaling network integrating diverse intracellular, intercellular and extracellular biological cues to regulate complex physiological processes such as organ size, tissue development, homeostasis and regeneration. These cues include cytoskeletal organization, mechanical force, cell-cell interaction, cell polarity, cell-extracellular matrix interaction to govern cell proliferation, differentiation, apoptosis, stem cell property and tissue microenvironment. In this review, we discuss how the emerging role of biomolecular condensates regulates the activity of the pathway components, and how dysregulation of the pathway leads to cancer. Lastly, we highlight the therapeutic modalities which target YAP/TAZ-TEAD interaction for cancer therapy.
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Affiliation(s)
- Siew Wee Chan
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Camellia Ong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
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2
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Zhu R, Jiao Z, Yu FX. Advances towards potential cancer therapeutics targeting Hippo signaling. Biochem Soc Trans 2024; 52:2399-2413. [PMID: 39641583 DOI: 10.1042/bst20240244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/06/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024]
Abstract
Decades of research into the Hippo signaling pathway have greatly advanced our understanding of its roles in organ growth, tissue regeneration, and tumorigenesis. The Hippo pathway is frequently dysregulated in human cancers and is recognized as a prominent cancer signaling pathway. Hence, the Hippo pathway represents an ideal molecular target for cancer therapies. This review will highlight recent advancements in targeting the Hippo pathway for cancer treatment and discuss the potential opportunities for developing new therapeutic modalities.
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Affiliation(s)
- Rui Zhu
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhihan Jiao
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Fa-Xing Yu
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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3
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Zhou ZJ, Ye YH, Hu ZQ, Hou YR, Liu KX, Sun RQ, Wang PC, Luo CB, Li J, Zou JX, Zhou J, Fan J, Song CL, Zhou SL. Whole-exome sequencing reveals genomic landscape of intrahepatic cholangiocarcinoma and identifies SAV1 as a potential driver. Nat Commun 2024; 15:9960. [PMID: 39551842 PMCID: PMC11570600 DOI: 10.1038/s41467-024-54387-8] [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: 01/27/2022] [Accepted: 11/07/2024] [Indexed: 11/19/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, with poor prognosis and limited treatment options. The genomic features of ICC in Chinese patients remain largely unknown. In this study, we perform deep whole-exome sequencing of 204 Chinese primary ICCs and characterize genomic alterations and clonal evolution, and reveal their associations with patient outcomes. We identify six mutational signatures, including Signatures A and F, which are highly similar to previously described signatures linked to aristolochic acid and aflatoxin exposures, respectively. We also identify 13 significantly mutated genes in the ICC samples, including SAV1. We find that SAV1 was mutated in 2.9% (20/672) of 672 ICC samples. SAV1 mutation is associated with lower SAV1 protein levels, higher rates of tumor recurrence, and shorter overall patient survival. Biofunctional investigations reveal a tumor-suppressor role of SAV1: its inactivation suppresses Hippo signaling, leading to YAP activation, thereby promoting tumor growth and metastasis. Collectively, our results delineate the genomic landscape of Chinese ICCs and identify SAV1 as a potential driver of ICC.
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Affiliation(s)
- Zheng-Jun Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu-Hang Ye
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi-Qiang Hu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yue-Ru Hou
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
| | - Kai-Xuan Liu
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rong-Qi Sun
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peng-Cheng Wang
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chu-Bin Luo
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Li
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ji-Xue Zou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng-Li Song
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China.
| | - Shao-Lai Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
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4
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Yang Y, Gan X, Zhang W, Zhu B, Huangfu Z, Shi X, Wang L. Research progress of the Hippo signaling pathway in renal cell carcinoma. Asian J Urol 2024; 11:511-520. [PMID: 39534002 PMCID: PMC11551326 DOI: 10.1016/j.ajur.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 01/15/2024] [Indexed: 11/16/2024] Open
Abstract
Objective This review aimed to summarize the role of the Hippo signaling pathway in renal cell carcinoma (RCC), a urologic malignancy with subtle initial symptoms and high mortality rates due to metastatic RCC. The Hippo signaling pathway, which regulates tissue and organ sizes, plays a crucial role in RCC progression and metastasis. Understanding the involvement of the Hippo signaling pathway in RCC provides valuable insights for the development of targeted therapies and improved patient outcomes. Methods In this review, we explored the impact of the Hippo signaling pathway on RCC. Through an analysis of existing literature, we examined its role in RCC progression and metastasis. Additionally, we discussed potential therapeutic strategies targeting the Hippo pathway for inhibiting RCC cell growth and invasion. We also highlighted the importance of investigating interactions between the Hippo pathway and other signaling pathways such as Wnt, transforming growth factor-beta, and PI3K/AKT, which may uncover additional therapeutic targets. Results The Hippo signaling pathway has shown promise as a target for inhibiting RCC cell growth and invasion. Studies have demonstrated its dysregulation in RCC, with altered expression of key components such as yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). Targeting the Hippo pathway has been associated with suppressed tumor growth and metastasis in preclinical models of RCC. Furthermore, investigating crosstalk between the Hippo pathway and other signaling pathways has revealed potential synergistic effects that could be exploited for therapeutic interventions. Conclusion Understanding the role of the Hippo signaling pathway in RCC is of paramount importance. Elucidating its functions and molecular interactions contributes to RCC diagnosis, treatment, and the discovery of novel mechanisms. This knowledge informs the development of innovative therapeutic strategies and opens new avenues for research in RCC. Further investigations are warranted to fully comprehend the complex interplay between the Hippo pathway and other signaling pathways, ultimately leading to improved outcomes for RCC patients.
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Affiliation(s)
- Yiren Yang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xinxin Gan
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- School of Materials Science and Engineering, University of Shanghai for Science and Technology, China
| | - Wei Zhang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Baohua Zhu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zhao Huangfu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xiaolei Shi
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
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Mondal V, Higgins PJ, Samarakoon R. Emerging Role of Hippo-YAP (Yes-Associated Protein)/TAZ (Transcriptional Coactivator with PDZ-Binding Motif) Pathway Dysregulation in Renal Cell Carcinoma Progression. Cancers (Basel) 2024; 16:2758. [PMID: 39123485 PMCID: PMC11312123 DOI: 10.3390/cancers16152758] [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: 07/01/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024] Open
Abstract
Although Hippo-YAP/TAZ pathway involvement has been extensively studied in the development of certain cancers, the involvement of this cascade in kidney cancer progression is not well-established and, therefore, will be the focus of this review. Renal cell carcinoma (RCC), the most prevalent kidney tumor subtype, has a poor prognosis and a high mortality rate. Core Hippo signaling inactivation (e.g., LATS kinases) leads to the nuclear translocation of YAP/TAZ where they bind to co-transcriptional factors such as TEAD promoting transcription of genes which initiates various fibrotic and neoplastic diseases. Loss of expression of LATS1/2 kinase and activation of YAP/TAZ correlates with poor survival in RCC patients. Renal-specific ablation of LATS1 in mice leads to the spontaneous development of several subtypes of RCC in a YAP/TAZ-dependent manner. Genetic and pharmacological inactivation of YAP/TAZ reverses the oncogenic potential in LATS1-deficient mice, highlighting the therapeutic benefit of network targeting in RCC. Here, we explore the unique upstream controls and downstream consequences of the Hippo-YAP/TAZ pathway deregulation in renal cancer. This review critically evaluates the current literature on the role of the Hippo pathway in RCC progression and highlights the recent scientific evidence designating YAP/TAZ as novel therapeutic targets against kidney cancer.
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Affiliation(s)
| | - Paul J. Higgins
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208-3479, USA;
| | - Rohan Samarakoon
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208-3479, USA;
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Tong T, Huang M, Yan B, Lin B, Yu J, Teng Q, Li P, Pang J. Hippo signaling modulation and its biological implications in urological malignancies. Mol Aspects Med 2024; 98:101280. [PMID: 38870717 DOI: 10.1016/j.mam.2024.101280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/27/2024] [Accepted: 05/19/2024] [Indexed: 06/15/2024]
Abstract
Although cancer diagnosis and treatment have rapidly advanced in recent decades, urological malignancies, which have high morbidity and mortality rates, are among the most difficult diseases to treat. The Hippo signaling is an evolutionarily conserved pathway in organ size control and tissue homeostasis maintenance. Its downstream effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are key modulators of numerous physiological and pathological processes. Recent work clearly indicates that Hippo signaling is frequently altered in human urological malignancies. In this review, we discuss the disparate viewpoints on the upstream regulators of YAP/TAZ and their downstream targets and systematically summarize the biological implications. More importantly, we highlight the molecular mechanisms involved in Hippo-YAP signaling to improve our understanding of its role in every stage of prostate cancer, bladder cancer and kidney cancer progression. A better understanding of the biological outcomes of YAP/TAZ modulation will contribute to the establishment of future therapeutic approaches.
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Affiliation(s)
- Tongyu Tong
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Mengjun Huang
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Binyuan Yan
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Bingbiao Lin
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, Guangdong, 515041, China
| | - Jiaying Yu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Qiliang Teng
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
| | - Jun Pang
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
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Armesto M, Nemours S, Arestín M, Bernal I, Solano-Iturri JD, Manrique M, Basterretxea L, Larrinaga G, Angulo JC, Lecumberri D, Iturregui AM, López JI, Lawrie CH. Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients. Int J Mol Sci 2024; 25:6881. [PMID: 38999991 PMCID: PMC11241516 DOI: 10.3390/ijms25136881] [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: 05/20/2024] [Revised: 06/12/2024] [Accepted: 06/18/2024] [Indexed: 07/14/2024] Open
Abstract
Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.
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Affiliation(s)
- María Armesto
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (S.N.); (M.A.); (I.B.); (L.B.)
| | - Stéphane Nemours
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (S.N.); (M.A.); (I.B.); (L.B.)
| | - María Arestín
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (S.N.); (M.A.); (I.B.); (L.B.)
| | - Iraide Bernal
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (S.N.); (M.A.); (I.B.); (L.B.)
- Pathology Department, Donostia University Hospital, 20014 San Sebastián, Spain; (J.D.S.-I.); (M.M.)
| | - Jon Danel Solano-Iturri
- Pathology Department, Donostia University Hospital, 20014 San Sebastián, Spain; (J.D.S.-I.); (M.M.)
| | - Manuel Manrique
- Pathology Department, Donostia University Hospital, 20014 San Sebastián, Spain; (J.D.S.-I.); (M.M.)
| | - Laura Basterretxea
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (S.N.); (M.A.); (I.B.); (L.B.)
- Medical Oncology Department, Donostia University Hospital, 20014 San Sebastián, Spain
| | - Gorka Larrinaga
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (G.L.); (J.I.L.)
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
| | - Javier C. Angulo
- Clinical Department, Faculty of Medical Sciences, European University of Madrid, 28905 Getafe, Spain;
- Department of Urology, University Hospital of Getafe, 28907 Madrid, Spain
| | - David Lecumberri
- Department of Urology, Urduliz University Hospital, 48610 Urduliz, Spain;
| | | | - José I. López
- Biobizkaia Health Research Institute, 48903 Barakaldo, Spain; (G.L.); (J.I.L.)
- Pathology Department, Cruces University Hospital, 48903 Barakaldo, Spain
| | - Charles H. Lawrie
- Molecular Oncology Group, Biogipuzkoa Health Research Institute, 20014 San Sebastián, Spain; (M.A.); (S.N.); (M.A.); (I.B.); (L.B.)
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
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8
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Liang H, Xu Y, Zhao J, Chen M, Wang M. Hippo pathway in non-small cell lung cancer: mechanisms, potential targets, and biomarkers. Cancer Gene Ther 2024; 31:652-666. [PMID: 38499647 PMCID: PMC11101353 DOI: 10.1038/s41417-024-00761-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/04/2024] [Accepted: 03/07/2024] [Indexed: 03/20/2024]
Abstract
Lung cancer is the primary contributor to cancer-related deaths globally, and non-small cell lung cancer (NSCLC) constitutes around 85% of all lung cancer cases. Recently, the emergence of targeted therapy and immunotherapy revolutionized the treatment of NSCLC and greatly improved patients' survival. However, drug resistance is inevitable, and extensive research has demonstrated that the Hippo pathway plays a crucial role in the development of drug resistance in NSCLC. The Hippo pathway is a highly conserved signaling pathway that is essential for various biological processes, including organ development, maintenance of epithelial balance, tissue regeneration, wound healing, and immune regulation. This pathway exerts its effects through two key transcription factors, namely Yes-associated protein (YAP) and transcriptional co-activator PDZ-binding motif (TAZ). They regulate gene expression by interacting with the transcriptional-enhanced associate domain (TEAD) family. In recent years, this pathway has been extensively studied in NSCLC. The review summarizes a comprehensive overview of the involvement of this pathway in NSCLC, and discusses the mechanisms of drug resistance, potential targets, and biomarkers associated with this pathway in NSCLC.
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Affiliation(s)
- Hongge Liang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Zhao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Minjiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengzhao Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Kowalczyk AE, Krazinski BE, Piotrowska A, Grzegrzolka J, Godlewski J, Dziegiel P, Kmiec Z. Impaired Expression of the Salvador Homolog-1 Gene Is Associated with the Development and Progression of Colorectal Cancer. Cancers (Basel) 2023; 15:5771. [PMID: 38136317 PMCID: PMC10742029 DOI: 10.3390/cancers15245771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/24/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
Salvador homolog-1 (SAV1) is a component of the Hippo pathway that regulates tissue growth and homeostasis by affecting diverse cell processes, including apoptosis, cell division, and differentiation. The aberrant expression of Hippo pathway components has been observed in various human cancers. This study aimed to examine the expression level of the SAV1 gene in colorectal cancer (CRC) and its prognostic value and associations with tumor progression. We obtained matched pairs of tumor tissue and non-cancerous mucosa of the large intestine from 94 CRC patients as well as 40 colon biopsies of healthy subjects collected during screening colonoscopy. The tissue samples and CRC cell lines were quantified for SAV1 mRNA levels using the quantitative polymerase chain reaction method, while SAV1 protein expression was estimated in the paired tissues of CRC patients using immunohistochemistry. The average level of SAV1 mRNA was decreased in 93.6% of the tumor tissues compared to the corresponding non-cancerous tissues and biopsies of healthy colon mucosa. A downregulated expression of SAV1 mRNA was also noted in the CRC cell lines. Although the average SAV1 immunoreactivity was increased in the CRC samples compared to the non-cancerous tissues, a decreased immunoreactivity of the SAV1 protein in the tumor specimens was associated with lymph node involvement and higher TNM disease stage and histological grade. The results of our study suggest that the impaired expression of SAV1 is involved in CRC progression.
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Affiliation(s)
- Anna Ewa Kowalczyk
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland; (B.E.K.); (J.G.)
| | - Bartlomiej Emil Krazinski
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland; (B.E.K.); (J.G.)
| | - Aleksandra Piotrowska
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.P.); (J.G.); (P.D.)
| | - Jedrzej Grzegrzolka
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.P.); (J.G.); (P.D.)
| | - Janusz Godlewski
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland; (B.E.K.); (J.G.)
| | - Piotr Dziegiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.P.); (J.G.); (P.D.)
| | - Zbigniew Kmiec
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland;
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10
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Franklin JM, Wu Z, Guan KL. Insights into recent findings and clinical application of YAP and TAZ in cancer. Nat Rev Cancer 2023:10.1038/s41568-023-00579-1. [PMID: 37308716 DOI: 10.1038/s41568-023-00579-1] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2023] [Indexed: 06/14/2023]
Abstract
Decades of research have mapped out the basic mechanics of the Hippo pathway. The paralogues Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), as the central transcription control module of the Hippo pathway, have long been implicated in the progression of various human cancers. The current literature regarding oncogenic YAP and TAZ activities consists mostly of context-specific mechanisms and treatments of human cancers. Furthermore, a growing number of studies demonstrate tumour-suppressor functions of YAP and TAZ. In this Review we aim to synthesize an integrated perspective of the many disparate findings regarding YAP and TAZ in cancer. We then conclude with the various strategies for targeting and treating YAP- and TAZ-dependent cancers.
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Affiliation(s)
- J Matthew Franklin
- Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Zhengming Wu
- Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Kun-Liang Guan
- Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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11
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Kruk L, Mamtimin M, Braun A, Anders HJ, Andrassy J, Gudermann T, Mammadova-Bach E. Inflammatory Networks in Renal Cell Carcinoma. Cancers (Basel) 2023; 15:cancers15082212. [PMID: 37190141 DOI: 10.3390/cancers15082212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Cancer-associated inflammation has been established as a hallmark feature of almost all solid cancers. Tumor-extrinsic and intrinsic signaling pathways regulate the process of cancer-associated inflammation. Tumor-extrinsic inflammation is triggered by many factors, including infection, obesity, autoimmune disorders, and exposure to toxic and radioactive substances. Intrinsic inflammation can be induced by genomic mutation, genome instability and epigenetic remodeling in cancer cells that promote immunosuppressive traits, inducing the recruitment and activation of inflammatory immune cells. In RCC, many cancer cell-intrinsic alterations are assembled, upregulating inflammatory pathways, which enhance chemokine release and neoantigen expression. Furthermore, immune cells activate the endothelium and induce metabolic shifts, thereby amplifying both the paracrine and autocrine inflammatory loops to promote RCC tumor growth and progression. Together with tumor-extrinsic inflammatory factors, tumor-intrinsic signaling pathways trigger a Janus-faced tumor microenvironment, thereby simultaneously promoting or inhibiting tumor growth. For therapeutic success, it is important to understand the pathomechanisms of cancer-associated inflammation, which promote cancer progression. In this review, we describe the molecular mechanisms of cancer-associated inflammation that influence cancer and immune cell functions, thereby increasing tumor malignancy and anti-cancer resistance. We also discuss the potential of anti-inflammatory treatments, which may provide clinical benefits in RCCs and possible avenues for therapy and future research.
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Affiliation(s)
- Linus Kruk
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Medina Mamtimin
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Attila Braun
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
| | - Joachim Andrassy
- Division of General, Visceral, Vascular and Transplant Surgery, Hospital of LMU, 81377 Munich, Germany
| | - Thomas Gudermann
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- German Center for Lung Research (DZL), 80336 Munich, Germany
| | - Elmina Mammadova-Bach
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, Germany
- Division of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, Germany
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12
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Bao D, Gao L, Xin H, Wang L. lncRNA-FMR6 directly binds SAV1 to increase apoptosis of granulosa cells in premature ovarian failure. J Ovarian Res 2023; 16:65. [PMID: 37005611 PMCID: PMC10068166 DOI: 10.1186/s13048-023-01121-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 02/17/2023] [Indexed: 04/04/2023] Open
Abstract
BACKGROUND A regulatory mechanism of lncRNA binding to protein has been detected in premature ovarian failure (POF). Therefore, this study was expected to illustrate the mechanism of lncRNA-FMR6 and SAV1 regulating POF. METHODS Follicular fluid and ovarian granulosa cells (OGCs) from POF patients and healthy volunteers were collected. Using RT-qPCR and western blotting, lncRNA-FMR6 and SAV1 expression were detected. KGN cells were cultured, and the subcellular localization analysis of lncRNA-FMR6 was carried out. In addition, KGN cells were treated with lncRNA-FMR6 knockdown/overexpression or SAV1 knockdown. Then, cell optical density (proliferation), apoptosis rate, Bax and Bcl-2 mRNA expression were explored by CCK-8, caspase-3 activity, flow cytometry and RT-qPCR analysis. By performing RIP and RNA pull-down experiments, the interactions among lncRNA-FMR6 and SAV1 was investigated. RESULTS Up-regulation of lncRNA-FMR6 was shown in follicular fluid and OGCs of POF patients, and ectopic overexpression of lncRNA-FMR6 promoted KGN cells apoptosis and inhibited proliferation. lncRNA-FMR6 was localized in the cytoplasm of KGN cells. SAV1 bounding to lncRNA-FMR6 was negatively regulated by lncRNA-FMR6, and was down-regulated in POF. SAV1 knockdown promoted KGN cells proliferation and inhibited apoptosis, and partially eliminated the effect of lncRNA-FMR6 low expression on KGN cells. CONCLUSION Overall, lncRNA-FMR6 accelerates POF progression by binding to SAV1.
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Affiliation(s)
- Dongqin Bao
- Center for Reproductive Medicine, The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian City, Jiangsu Province, 221004, China
| | - Lei Gao
- Reproductive Medicine Center of Qingdao Women and Children's Hospital, Qingdao City, Shandong Province, 266034, China
| | - Haiyan Xin
- Reproductive Medicine Center of Qingdao Women and Children's Hospital, Qingdao City, Shandong Province, 266034, China
| | - Lie Wang
- Reproductive Medicine Center of Qingdao Women and Children's Hospital, Qingdao City, Shandong Province, 266034, China.
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13
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Duong NX, Le M, Kondo T, Mitsui T. Heterogeneity of Hippo signalling activity in different histopathologic subtypes of renal cell carcinoma. J Cell Mol Med 2022; 27:66-75. [PMID: 36478130 PMCID: PMC9806300 DOI: 10.1111/jcmm.17632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
This study aimed to reveal the prognostic role of the Hippo pathway in different histopathological subtypes of renal cell carcinoma (RCC). The TCGA-KIRC (n = 537), TCGA-KIRP (n = 291) and TCGA-KICH (n = 113), which contain data about clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC), respectively, were investigated. Gene Set Variation Analysis was used to compare the activity of many pathways within a single sample. Oncogenic pathway-related expression differed between cases of ccRCC involving low and high Hippo pathway activity. There were two subsets of ccRCC, in which the cancer exhibited lower and higher Hippo signalling activity, respectively, compared with normal tissue. In the ccRCC cohort, lower Hippo pathway activity was associated with a higher clinical stage (p < 0.001). The Hippo pathway (HR = 0.29; 95% CI = 0.17-0.50, p < 0.001), apoptosis (HR = 6.02; 95% CI = 1.47-24.61; p = 0.013) and the p53 pathway (HR = 0.09; 95% CI = 0.02-0.36; p < 0.001) were identified as independent prognostic factors for ccRCC. The 5-year overall survival of the ccRCC patients with low and high Hippo pathway activity were 51.9% (95% CI = 45.0-59.9) and 73.6% (95% CI = 67.8-79.9), respectively. In conclusion, the Hippo pathway plays an important role in the progression of ccRCC. Low Hippo pathway activity is associated with poor outcomes in ccRCC, indicating the tumour suppressor function of this pathway.
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Affiliation(s)
- Nguyen Xuong Duong
- Department of UrologyUniversity of Yamanashi Graduate School of Medical SciencesChuo‐cityJapan
| | - Minh‐Khang Le
- Department of PathologyUniversity of Yamanashi Graduate School of Medical SciencesChuo‐cityJapan
| | - Tetsuo Kondo
- Department of PathologyUniversity of Yamanashi Graduate School of Medical SciencesChuo‐cityJapan
| | - Takahiko Mitsui
- Department of UrologyUniversity of Yamanashi Graduate School of Medical SciencesChuo‐cityJapan
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14
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Sun Y, Jin D, Zhang Z, Jin D, Xue J, Duan L, Zhang Y, Kang X, Lian F. The critical role of the Hippo signaling pathway in kidney diseases. Front Pharmacol 2022; 13:988175. [PMID: 36483738 PMCID: PMC9723352 DOI: 10.3389/fphar.2022.988175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/03/2022] [Indexed: 09/14/2023] Open
Abstract
The Hippo signaling pathway is involved in cell growth, proliferation, and apoptosis, and it plays a key role in regulating organ size, tissue regeneration, and tumor development. The Hippo signaling pathway also participates in the occurrence and development of various human diseases. Recently, many studies have shown that the Hippo pathway is closely related to renal diseases, including renal cancer, cystic kidney disease, diabetic nephropathy, and renal fibrosis, and it promotes the transformation of acute kidney disease to chronic kidney disease (CKD). The present paper summarizes and analyzes the research status of the Hippo signaling pathway in different kidney diseases, and it also summarizes the expression of Hippo signaling pathway components in pathological tissues of kidney diseases. In addition, the present paper discusses the positive therapeutic significance of traditional Chinese medicine (TCM) in regulating the Hippo signaling pathway for treating kidney diseases. This article introduces new targets and ideas for drug development, clinical diagnosis, and treatment of kidney diseases.
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Affiliation(s)
- Yuting Sun
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - De Jin
- Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Ziwei Zhang
- College of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China
| | - Di Jin
- College of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China
| | - JiaoJiao Xue
- College of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China
| | - LiYun Duan
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - YuQing Zhang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - XiaoMin Kang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - FengMei Lian
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- College of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China
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15
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Hsu SC, Lin CY, Lin YY, Collins CC, Chen CL, Kung HJ. TEAD4 as an Oncogene and a Mitochondrial Modulator. Front Cell Dev Biol 2022; 10:890419. [PMID: 35602596 PMCID: PMC9117765 DOI: 10.3389/fcell.2022.890419] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4’s functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.
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Affiliation(s)
- Sheng-Chieh Hsu
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Ching-Yu Lin
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yen-Yi Lin
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Colin C. Collins
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Chia-Lin Chen
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Chia-Lin Chen, ; Hsing-Jien Kung,
| | - Hsing-Jien Kung
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
- Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, United States
- *Correspondence: Chia-Lin Chen, ; Hsing-Jien Kung,
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Peired AJ, Lazzeri E, Guzzi F, Anders HJ, Romagnani P. From kidney injury to kidney cancer. Kidney Int 2021; 100:55-66. [PMID: 33794229 DOI: 10.1016/j.kint.2021.03.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/04/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer).
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Affiliation(s)
- Anna Julie Peired
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Elena Lazzeri
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Francesco Guzzi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Hans-Joachim Anders
- Division of Nephrology, Medizinische Klinik and Poliklinik IV, Ludwig Maximilian University Klinikum, Munich, Germany
| | - Paola Romagnani
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy; Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
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17
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A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling. Cell Rep 2021; 32:108118. [PMID: 32905778 PMCID: PMC7494017 DOI: 10.1016/j.celrep.2020.108118] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/27/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022] Open
Abstract
The canonical mammalian Hippo pathway contains a core kinase signaling cascade requiring upstream MST to form a stable complex with SAV1 in order to phosphorylate the downstream LATS/MOB complex. Though SAV1 dimerization is essential for the trans-activation of MST, the molecular mechanism underlying SAV1 dimerization is unclear. Here, we discover that the SAV1 WW tandem containing a short Pro-rich extension immediately following the WW tandem (termed as "WW12ex") forms a highly stable homodimer. The crystal structure of SAV1 WW12ex reveals that the Pro-rich extension of one subunit binds to both WW domains from the other subunit. Thus, SAV1 WW12ex forms a domain-swapped dimer instead of a WW2 homodimerization-mediated dimer. The WW12ex-mediated dimerization of SAV1 is required for the MST/SAV1 complex assembly and MST kinase activation. Finally, we show that several cancer-related SAV1 variants disrupt SAV1 dimer formation, and thus, these mutations may impair the tumor-suppression activity of SAV1.
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18
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Zhuang Q, Fan M, Shen J, Chen Z, Xue D, Lu H, Xu R, He X, Hou J. Overexpression of Capns1 Predicts Poor Prognosis and Correlates with Tumor Progression in Renal Cell Carcinoma. Urol Int 2021; 105:697-704. [PMID: 33887737 DOI: 10.1159/000511638] [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: 07/21/2020] [Accepted: 09/11/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Calpain small subunit 1 (Capns1) has shown its correlation with the metastasis and invasion of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, the expression and function of Capns1 in human renal cell carcinoma (RCC) have not been clarified. This study aimed to examine the expression of Capns1 in RCC tissues and cell lines and to assess its role performed in RCC. METHODS Capns1 expression was evaluated in 75 pairs of RCC and matched adjacent non-tumor tissues by immunohistochemistry. The prognostic value of Capns1 in RCC was assessed by Kaplan-Meier and Cox regression analyses. The action of Capns1 in the proliferation, adhesion, migration, and invasion of RCC cells and the effects on matrix metalloproteinase (MMP) 2 and 9 expression were evaluated after Capns1 silence. RESULTS Capns1 expression was significantly higher in RCC tissues compared with the adjacent non-tumor tissues. Multivariate analysis showed that Capns1 overexpression was an independent poor prognostic marker in RCC. The silencing of Capns1 prohibited cell adhesion and impaired the migration and invasion ability of 786-O cells in vitro. Furthermore, Capns1 silence reduced MMP2 and MMP9 expression. CONCLUSION Capns1 overexpression predicts poor prognosis and correlates with tumor progression in RCC. Capns1 expression might serve a prognostic marker and therapeutic target for RCC.
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Affiliation(s)
- Qianfeng Zhuang
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Min Fan
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jie Shen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Zhen Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dong Xue
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Hao Lu
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Renfang Xu
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jianquan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
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The tumor suppressor role of salvador family WW domain-containing protein 1 (SAV1): one of the key pieces of the tumor puzzle. J Cancer Res Clin Oncol 2021; 147:1287-1297. [PMID: 33580421 DOI: 10.1007/s00432-021-03552-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/04/2021] [Indexed: 10/22/2022]
Abstract
PURPOSE In the complex tumor scenario, understanding the function of proteins with protumor or antitumor roles is essential to support advances in the cancer clinical area. Among them, the salvador family WW domain-containing protein 1 (SAV1) is highlighted. This protein plays a fundamental role in the tumor suppressor face of the Hippo pathway, which are responsible for controlling cell proliferation, organ size, development and tissue homeostasis. However, the functional dysregulation of this pathway may contribute to tumorigenesis and tumor progression. As SAV1 is a tumor suppressor scaffold protein, we explored the functions performed by SAV1 with its partners, the regulation of its expression, and its antitumor role in various types of cancer. METHODS We selected and analyzed 80 original articles and reviews from Pubmed that focuses on the study of SAV1 in cancer. RESULTS SAV1 interacts with several proteins, has different functions and acts as tumor suppressor by other mechanisms besides Hippo pathway. SAV1 expression regulation seems to occur by microRNAs and rarely by mutation or promoter methylation. It is downregulated in different types of cancer, which leads to cancer promotion and progression and is associated with poor prognosis. In vivo models have shown that the loss of SAV1 contributes to tumorigenesis. CONCLUSION SAV1 plays a relevant role as tumor suppressor in several types of cancer, highlighting SAV1 and the Hippo pathway's importance to cancer. Thus, encouraging further studies to include the SAV1 as a molecular key piece in cancer biology and in clinical approaches to cancer.
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RNA-binding protein Musashi2 regulates Hippo signaling via SAV1 and MOB1 in pancreatic cancer. Med Oncol 2020; 37:84. [PMID: 32780197 DOI: 10.1007/s12032-020-01384-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/02/2020] [Indexed: 10/23/2022]
Abstract
Musashi 2 (MSI2), a member of the Musashi RNA-binding family, is reported to be an oncoprotein in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms of MSI2 in the development and progression of PDAC have not been fully demonstrated. In this research, we studied the clinical significance, biologic effects and the underlying mechanism of MSI2 in the progression of PDAC. The expression of MSI2, Mps-binding protein 1 (MOB1) and Salvador family WW domain-containing protein 1 (SAV1) in PDAC tissues were analyzed immunohistochemically. The biologic effects of MSI2 regarding PDAC cell proliferation, migration and invasion were studied using gain- and loss-of-function assays. MSI2 regulated Hippo signaling pathway via SAV1 and MOB1 was tested in several PDAC cell lines, and the mechanisms were studied using molecular biologic methods. The expression of MSI2 was significantly increased in PDAC cell lines and tissues, and positively associated with tumor poorer differentiation, lymph nodes metastasis and TNM stages. Overexpression of MSI2 promoted PDAC cells proliferation, migration and invasion. Further studies demonstrated that MSI2 regulated the Hippo signaling pathway via directly binding to the mRNAs of SAV1 and MOB1, and controlled the translation and stability of SAV1 and the translation of MOB1. This study demonstrated that MSI2 regulated the Hippo signaling pathway via suppressing SAV1 and MOB1 at post-transcriptional level and promoted PDAC progression.
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21
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Zhao Z, Xiang S, Qi J, Wei Y, Zhang M, Yao J, Zhang T, Meng M, Wang X, Zhou Q. Correction of the tumor suppressor Salvador homolog-1 deficiency in tumors by lycorine as a new strategy in lung cancer therapy. Cell Death Dis 2020; 11:387. [PMID: 32439835 PMCID: PMC7242319 DOI: 10.1038/s41419-020-2591-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 12/12/2022]
Abstract
Salvador homolog-1 (SAV1) is a tumor suppressor required for activation of the tumor-suppressive Hippo pathway and inhibition of tumorigenesis. SAV1 is defective in several cancer types. SAV1 deficiency in cells promotes tumorigenesis and cancer metastasis, and is closely associated with poor prognosis for cancer patients. However, investigation of therapeutic strategies to target SAV1 deficiency in cancer is lacking. Here we found that the small molecule lycorine notably increased SAV1 levels in lung cancer cells by inhibiting SAV1 degradation via a ubiquitin-lysosome system, and inducing phosphorylation and activation of the SAV1-interacting protein mammalian Ste20-like 1 (MST1). MST1 activation then caused phosphorylation, ubiquitination, and degradation of the oncogenic Yes-associated protein (YAP), therefore inhibiting YAP-activated transcription of oncogenic genes and tumorigenic AKT and NF-κB signal pathways. Strikingly, treating tumor-bearing xenograft mice with lycorine increased SAV1 levels, and strongly inhibited tumor growth, vasculogenic mimicry, and metastasis. This work indicates that correcting SAV1 deficiency in lung cancer cells is a new strategy for cancer therapy. Our findings provide a new platform for developing novel cancer therapeutics.
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Affiliation(s)
- Zhe Zhao
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China
| | - Shufen Xiang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China
| | - Jindan Qi
- School of Nursing, Soochow University, Suzhou, Jiangsu, 215006, P. R. China
| | - Yijun Wei
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Mengli Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China
| | - Jun Yao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Tong Zhang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China
| | - Mei Meng
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China
| | - Xiaohua Wang
- School of Nursing, Soochow University, Suzhou, Jiangsu, 215006, P. R. China
| | - Quansheng Zhou
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. .,State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. .,Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and the Chinese Ministry of Science and Technology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
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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: 17] [Impact Index Per Article: 3.4] [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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23
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Padella A, Simonetti G, Paciello G, Giotopoulos G, Baldazzi C, Righi S, Ghetti M, Stengel A, Guadagnuolo V, De Tommaso R, Papayannidis C, Robustelli V, Franchini E, Ghelli Luserna di Rorà A, Ferrari A, Fontana MC, Bruno S, Ottaviani E, Soverini S, Storlazzi CT, Haferlach C, Sabattini E, Testoni N, Iacobucci I, Huntly BJP, Ficarra E, Martinelli G. Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia. Cancers (Basel) 2019; 11:E1951. [PMID: 31817495 PMCID: PMC6966504 DOI: 10.3390/cancers11121951] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/15/2019] [Accepted: 12/02/2019] [Indexed: 02/07/2023] Open
Abstract
Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied the transcriptome of 8 adult AML patients with poorly described chromosomal translocation(s), with the aim of identifying novel and rare fusion transcripts. We integrated RNA-sequencing data with multiple approaches including computational analysis, Sanger sequencing, fluorescence in situ hybridization and in vitro studies to assess the oncogenic potential of the ZEB2-BCL11B chimera. We detected 7 different fusions with partner genes involving transcription factors (OAZ-MAFK, ZEB2-BCL11B), tumor suppressors (SAV1-GYPB, PUF60-TYW1, CNOT2-WT1) and rearrangements associated with the loss of NF1 (CPD-PXT1, UTP6-CRLF3). Notably, ZEB2-BCL11B rearrangements co-occurred with FLT3 mutations and were associated with a poorly differentiated or mixed phenotype leukemia. Although the fusion alone did not transform murine c-Kit+ bone marrow cells, 45.4% of 14q32 non-rearranged AML cases were also BCL11B-positive, suggesting a more general and complex mechanism of leukemogenesis associated with BCL11B expression. Overall, by combining different approaches, we described rare fusion events contributing to the complexity of AML and we linked the expression of some chimeras to genomic alterations hitting known genes in AML.
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Affiliation(s)
- Antonella Padella
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Giorgia Simonetti
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy; (G.S.); (M.G.); (E.F.); (A.G.L.d.R.); (A.F.)
| | - Giulia Paciello
- Department of Control and Computer Engineering DAUIN, Politecnico di Torino, 10129 Turin, Italy; (G.P.); (E.F.)
| | - George Giotopoulos
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, UK; (G.G.); (B.J.P.H.)
- Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0XY, UK
| | - Carmen Baldazzi
- Institute of Hematology “L. and A. Seràgnoli”, Sant’Orsola-Malpighi University Hospital, 40138 Bologna, Italy;
| | - Simona Righi
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Martina Ghetti
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy; (G.S.); (M.G.); (E.F.); (A.G.L.d.R.); (A.F.)
| | - Anna Stengel
- MLL-Munich Leukemia Laboratory, 81377 Munich, Germany; (A.S.); (C.H.)
| | - Viviana Guadagnuolo
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Rossella De Tommaso
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Cristina Papayannidis
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Valentina Robustelli
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Eugenia Franchini
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy; (G.S.); (M.G.); (E.F.); (A.G.L.d.R.); (A.F.)
| | - Andrea Ghelli Luserna di Rorà
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy; (G.S.); (M.G.); (E.F.); (A.G.L.d.R.); (A.F.)
| | - Anna Ferrari
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy; (G.S.); (M.G.); (E.F.); (A.G.L.d.R.); (A.F.)
| | - Maria Chiara Fontana
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Samantha Bruno
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Emanuela Ottaviani
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Simona Soverini
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | | | - Claudia Haferlach
- MLL-Munich Leukemia Laboratory, 81377 Munich, Germany; (A.S.); (C.H.)
| | - Elena Sabattini
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Nicoletta Testoni
- Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, 40138 Bologna, Italy; (A.P.); (S.R.); (V.G.); (R.D.T.); (C.P.); (V.R.); (M.C.F.); (S.B.); (E.O.); (S.S.); (E.S.); (N.T.)
| | - Ilaria Iacobucci
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;
| | - Brian J. P. Huntly
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, UK; (G.G.); (B.J.P.H.)
- Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0XY, UK
| | - Elisa Ficarra
- Department of Control and Computer Engineering DAUIN, Politecnico di Torino, 10129 Turin, Italy; (G.P.); (E.F.)
| | - Giovanni Martinelli
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy; (G.S.); (M.G.); (E.F.); (A.G.L.d.R.); (A.F.)
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24
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Yin H, Cao Q, Zhao H, Wang S, Chen W, Zhang X, Chang Z, Xu T, Ye X. Expression of CREPT is associated with poor prognosis of patients with renal cell carcinoma. Oncol Lett 2019; 18:4789-4797. [PMID: 31611989 PMCID: PMC6781659 DOI: 10.3892/ol.2019.10831] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 07/11/2019] [Indexed: 12/11/2022] Open
Abstract
Cell-cycle-associated and expression-elevated protein in tumor (CREPT) functions as a cell cycle modulator that enhances the transcription of cyclin D1 by interacting with RNA polymerase II. CREPT has been identified to be overexpressed in various human cancer types; however, the expression and significance of CREPT in renal cell carcinoma (RCC) has remained largely elusive. In the present study, increased expression of CREPT was identified in 46.7% RCC tissues compared with adjacent normal tissue (31.1%; P=0.032) using immunohistochemistry. Furthermore, overexpression of CREPT was significantly associated with the Tumor-Node-Metastasis stage (χ2=11.967, P=0.001) and Fuhrman grade (χ2=15.453, P<0.001). In addition, increased expression of CREPT was associated with poor overall survival (P=0.021) and disease-free survival (P=0.015) of patients according to Kaplan-Meier analysis. Cellular function assays demonstrated that knockdown of CREPT in the 786-O and 769P RCC cell lines suppressed their proliferative, colony formation, migratory and invasive capacity and led to cell cycle arrest in the G1 phase. In addition, the western blotting analysis demonstrated that CREPT may control the cell cycle through downregulation of cyclin D1 and c-myc. Collectively, the overexpression of CREPT was indicated to be a negative prognostic factor for RCC, and CREPT may serve as a novel therapeutic target for the treatment of RCC.
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Affiliation(s)
- Huaqi Yin
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
| | - Qingfei Cao
- Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - Haiyue Zhao
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
| | - Shenheng Wang
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
| | - Weinan Chen
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
| | - Xiaowei Zhang
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
| | - Zhijie Chang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing 100084, P.R. China
| | - Tao Xu
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
| | - Xiongjun Ye
- Department of Urology, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China.,Urology and Lithotripsy Center, Peking University People's Hospital, The Second Clinical Medical College of Peking University, Beijing 100044, P.R. China
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25
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MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. Nat Commun 2019; 10:1515. [PMID: 30944303 PMCID: PMC6447540 DOI: 10.1038/s41467-019-09233-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 02/27/2019] [Indexed: 12/14/2022] Open
Abstract
Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt’s movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets. Hyperactivation of Akt promotes tumorigenesis. Here, the authors show that SAV1, a member of Hippo signalling, interacts with Akt to suppress Akt activity and MERTK-mediated Akt phosphorylation relieves this suppression to facilitate Akt oncogenic activity in clear cell renal carcinomas.
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26
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Jiang J, Chang W, Fu Y, Gao Y, Zhao C, Zhang X, Zhang S. SAV1, regulated by microRNA-21, suppresses tumor growth in colorectal cancer. Biochem Cell Biol 2019; 97:91-99. [PMID: 30681889 DOI: 10.1139/bcb-2018-0034] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
This study investigated the role and action of the Salvador 1 protein (SAV1, also called WW45) in colorectal cancer (CRC). For this, CRC SW480 and HCT116 cells were infected with lentiviruses of SAV1 overexpression vector (lenti-SAV1) and SAV1 short hairpin RNA (sh-SAV1) to overexpress and silence SAV1 respectively, or transfected with microRNA-21 (miR-21) mimic to overexpress miR-21. Relative mRNA levels of SAV1 and relative miR-21 levels in CRC tissues or cells were detected. The effects of SAV1 and miR-21 on cell proliferation and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and annexin V – fluorescein isothiocyanate (FITC) – propidium iodide (PI) flow cytometry, respectively. Our results revealed that SAV1 was downregulated in CRC tissues compared with the adjacent noncancerous tissues. Furthermore, SAV1 overexpression inhibited proliferation and promoted apoptosis in SW480 and HCT116 cells, whereas knockdown of SAV1 exerted the opposite effect. Additionally, the tumorigenesis of SW480 cells in xenografted mice was significantly inhibited by SAV1 overexpression but promoted by SAV1 knockdown. MiR-21 levels significantly and negatively correlated with SAV1 expression in CRC tissues. More importantly, miR-21 overexpression significantly abolished the SAV1-mediated inhibition of proliferation and stimulation of apoptosis of SW480. In conclusion, SAV1 suppresses tumor growth in CRC and is regulated by miR-21.
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Affiliation(s)
- Jianwu Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wei Chang
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yang Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Chunlin Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiefu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Shuijun Zhang
- Department of Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
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27
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Nguyen TH, Kugler JM. Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer. Cancers (Basel) 2018; 10:cancers10040121. [PMID: 29673168 PMCID: PMC5923376 DOI: 10.3390/cancers10040121] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/08/2018] [Accepted: 04/13/2018] [Indexed: 12/12/2022] Open
Abstract
The Hippo pathway serves as a key barrier for oncogenic transformation. It acts by limiting the activity of the proto-oncogenes YAP and TAZ. Reduced Hippo signaling and elevated YAP/TAZ activities are frequently observed in various types of tumors. Emerging evidence suggests that the ubiquitin system plays an important role in regulating Hippo pathway activity. Deregulation of ubiquitin ligases and of deubiquitinating enzymes has been implicated in increased YAP/TAZ activity in cancer. In this article, we review recent insights into the ubiquitin-mediated regulation of the mammalian Hippo pathway, its deregulation in cancer, and possibilities for targeting the Hippo pathway through the ubiquitin system.
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Affiliation(s)
- Thanh Hung Nguyen
- Institute of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
| | - Jan-Michael Kugler
- Institute of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
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28
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Wang Z, Zhang Z, Zhang C, Xu Y. Identification of potential pathogenic biomarkers in clear cell renal cell carcinoma. Oncol Lett 2018; 15:8491-8499. [PMID: 29805586 PMCID: PMC5950538 DOI: 10.3892/ol.2018.8398] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 02/16/2018] [Indexed: 12/21/2022] Open
Abstract
The purpose of the present study was to screen potential pathogenic biomarkers of clear cell renal cell carcinoma (ccRCC) via microarray analysis. The mRNA and microRNA (miRNA) expression profiles of GSE96574 and GSE71302 were downloaded from the Gene Expression Omnibus (GEO) database, as well as the methylation profile of GSE61441. A total of 5 ccRCC tissue samples and 5 normal kidney tissue samples were contained in each profile of GSE96574 and GSE71302, and 46 ccRCC tissue samples and 46 normal kidney tissue samples were involved in GSE61441. The differentially expressed genes (DEGs) and the differentially expressed miRNAs (DEMs) were obtained via limma package in ccRCC tissues compared with normal kidney tissues. The Two Sample t-test and the Beta distribution test were used to identify the differentially methylated sites (DMSs). The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs. The targets of the DEMs were screened with the miRWalk database, and the further combination analyses of DEGs, DEMs and DMSs were conducted. Additionally, reverse transcription PCR (RT-PCR) and methylation-specific PCR (MS-PCR) were performed to detect the mRNA level and methylation status of HAPLN1. The mRNA levels of hsa-miR-204 and hsa-miR-218 were tested by RT-PCR. A total of 2,172 DEGs, 202 DEMs and 2,172 DMSs were identified in RCC samples compared with normal samples. The DEGs were enriched in 1,015 GO terms and 69 KEGG pathways. A total of 10,601 miRNA-gene pairs were identified in at least 5 algorithms of the miRWalk database. A total of 143 overlaps were identified between the DEGs and the differentially methylated genes. Furthermore, the DEGs were involved in 851 miRNA-gene pairs, including 127 pairs in which the target genes were negatively associated with their corresponding DEMs and DMSs. HAPLN1 was lowly expressed and highly methylated in ccRCC tissues, while hsa-miR-204 and hsa-miR-218 were highly expressed. The results of the present study indicated that HAPLN1, hsa-miR-204 and hsa-miR-218 may be involved in the pathogenesis of ccRCC.
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Affiliation(s)
- Zengzeng Wang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Department of Urology, Tianjin Beichen Hospital, Tianjin 300400, P.R. China
| | - Zhihong Zhang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Changwen Zhang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Yong Xu
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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29
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The prognostic impacts of TEA domain (TEAD) transcription factor polymorphisms in Chinese hepatocellular carcinoma patients. Oncotarget 2017; 8:69823-69832. [PMID: 29050244 PMCID: PMC5642519 DOI: 10.18632/oncotarget.19310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 06/20/2017] [Indexed: 11/25/2022] Open
Abstract
TEA domain (TEAD) transcription factors play an important role in hepatocellular carcinoma (HCC) development and progression by regulating the expression of a number of genes. However, the association of their genetic variations with HCC prognosis remains elusive. Seven potentially functional single nucleotide polymorphisms in TEAD1-4 (rs2304733, rs10831923, rs12104362, rs3745305, rs11756089, rs2076173, rs7135838) were genotyped from 331 hepatitis B virus positive HCC patients using the Sequenom MassARRAY iPLEX platform. The TEAD3 rs2076173 C allele and rs11756089 T allele were identified as protective alleles as they were significantly associated with longer median overall survival time (MST). The T allele of rs2076173 was significantly associated with HCC survival independent of age, gender, smoking and drinking status, BCLC stage, and chemotherapy or TACE status (HR = 0.73, 95% CI = 0.56-0.93, P = 0.012). This protective effect was more prominent for patients who were non-drinkers (P for multiplicative interaction = 0.002). Patients had more than one of these protective alleles had significant longer MST of 19.25 months than those had none (MST=12.85 months, adjusted HR = 0.56, 95% CI = 0.33-0.95, P=0.030), especially for those non-drinkers (adjusted HR = 0.48, 95% CI = 0.32-0.74, P = 0.001). These findings suggested that rs2076173 and rs11756089 in TEAD3 gene could serve as genetic markers for favorable survival in the Chinese HCC patients.
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30
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Jiang J, Chang W, Fu Y, Gao Y, Zhao C, Zhang X, Zhang S. SAV1 represses the development of human colorectal cancer by regulating the Akt-mTOR pathway in a YAP-dependent manner. Cell Prolif 2017; 50. [PMID: 28618450 DOI: 10.1111/cpr.12351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 04/24/2017] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES SAV1 is a human homologue of Salvador that contains two protein-protein interaction modules known as WW domains and acts as a scaffolding protein. SAV1 participates in the development of diverse types of cancer. We aimed to investigate the role of SAV1 in human colorectal cancer. MATERIALS AND METHODS Human colorectal cancer samples were used to study the expression of SAV1 and YAP. Loss-of-function and gain-of-function strategies were used to study the effects of SAV1 on colorectal cancer cell growth. Rapamycin was used to treat cells and mice to investigate the effect of mTOR signalling. RESULTS SAV1 represses the development of colorectal cancer by inhibiting the Akt-mTOR signalling in a YAP-dependent manner. The mRNA and protein levels of SAV1 are down-regulated in human colorectal cancer tissues compared with adjacent non-cancer tissues. SAV1 knockdown promotes the growth of colorectal cancer cells in vitro and in vivo, whereas SAV1 overexpression leads to opposing results. SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells. Finally, we show that SAV1 promotes the phosphorylation and inactivation of YAP, which contributes to the effect of SAV1 on Akt-mTOR signalling pathway. CONCLUSIONS SAV1 is a repressor during the development of human colorectal cancer by inhibiting the YAP-Akt-mTOR signalling pathway.
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Affiliation(s)
- Jianwu Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.,Department of Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.,Department of ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wei Chang
- Department of Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yang Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunlin Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiefu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuijun Zhang
- Department of Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.,Department of Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.,Department of ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
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Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis. Mol Cell Biol 2017; 37:MCB.00565-16. [PMID: 28320873 DOI: 10.1128/mcb.00565-16] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 03/09/2017] [Indexed: 01/02/2023] Open
Abstract
Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.
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Wang L, Wang M, Hu C, Li P, Qiao Y, Xia Y, Liu L, Jiang X. Protein salvador homolog 1 acts as a tumor suppressor and is modulated by hypermethylation in pancreatic ductal adenocarcinoma. Oncotarget 2017; 8:62953-62961. [PMID: 28968962 PMCID: PMC5609894 DOI: 10.18632/oncotarget.17972] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 04/11/2017] [Indexed: 01/17/2023] Open
Abstract
Salvador (SAV) is a gene product that contains two protein-protein interaction modules known as WW domains and is believed to act as a scaffolding protein for Hippo and Warts. SAV1 is the human homolog of Salvador, which is the most well characterized upstream signaling component of Hippo pathway. Although its role in some tumors is known, SAV1 function in other types of tumors, including pancreatic tumor, is still obscure. Here, we determined the role of SAV1 in pancreatic ductal adenocarcinoma (PDAC) development and progression. Our results revealed that SAV1 suppressed expression promoted PDAC invasion and migration, and repressed pancreatic cancer cells apoptosis. Moreover, SAV1 was silenced by hypermethylation. Thus, SAV1 worked as a cancer suppressor and it might be considered as a target for pancreatic cancer therapy.
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Affiliation(s)
- Lei Wang
- Department of Radiation Oncology, Lianyungang First People's Hospital, Jiangsu, People's Republic of China
| | - Mei Wang
- Tumor Laboratory, Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Jiangsu, People's Republic of China
| | - Chenxi Hu
- Tumor Laboratory, Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Jiangsu, People's Republic of China
| | - Pengping Li
- Department of Bioinformatics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yun Qiao
- Department of Radiation Oncology, Lianyungang First People's Hospital, Jiangsu, People's Republic of China
| | - Youyou Xia
- Department of Radiation Oncology, Lianyungang First People's Hospital, Jiangsu, People's Republic of China
| | - Liang Liu
- Department of Radiation Oncology, Lianyungang First People's Hospital, Jiangsu, People's Republic of China
| | - Xiaodong Jiang
- Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Jiangsu, People's Republic of China
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The long noncoding RNA HOTAIR activates the Hippo pathway by directly binding to SAV1 in renal cell carcinoma. Oncotarget 2017; 8:58654-58667. [PMID: 28938586 PMCID: PMC5601682 DOI: 10.18632/oncotarget.17414] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Accepted: 03/14/2017] [Indexed: 12/05/2022] Open
Abstract
The long noncoding RNA HOTAIR promotes the development and progression of several tumors. Here, the clinical significance and role of HOTAIR in renal cell carcinoma (RCC) tumorigenesis were explored. The results showed that increased expression of HOTAIR predicted a poor prognosis of RCC after surgery. HOTAIR promoted RCC cell proliferation and growth in vitro and in vivo. The expressions of HOTAIR and Salvador homolog 1 (SAV1) were inversely correlated in clinical RCC samples. HOTAIR downregulated SAV1 by directly binding to the SAV1 protein and enhanced histone H3K27 methylation. Loss of function of SAV1 activated the Hippo pathway. HOTAIR could be a potential therapeutic target in RCC.
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Kaneko S, Matsumoto K, Minamida S, Hirayama T, Fujita T, Kodera Y, Iwamura M. Incremental Expression of 14-3-3 Protein Beta/Alpha in Urine Correlates with Advanced Stage and Poor Survival in Patients with Clear Cell Renal Cell Carcinoma. Asian Pac J Cancer Prev 2017; 17:1399-404. [PMID: 27039779 DOI: 10.7314/apjcp.2016.17.3.1399] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
We investigated the urinary levels of 14-3-3 protein beta/alpha to evaluate their diagnostic significance with regard to clear cell renal cell carcinoma (ccRCC) and angiomyolipoma (AML). Urine samples from 91 patients with ccRCC, 16 patients with AML and 24 healthy volunteers were assessed. We used an enzyme-linked immunosorbent assay (ELISA) to quantify 14-3-3 protein beta/alpha levels in urine. Values were higher in patients with ccRCC than in those with AML and in healthy volunteers. High levels were associated with pathologic stage, lymph node status, distant metastasis and poor survival. Urinary levels of 14-3-3 protein beta/alpha were significantly increased in patients with small-sized carcinoma, irrespective of being less than 4.0 cm and 2.0 cm, compared with levels in patients with AML. This study is the first to report that increased expression of 14-3- 3 protein beta/alpha in urine is associated with advanced stage and poor survival in patients with ccRCC. In addition, urinary 14-3-3 protein beta/alpha may differentiate AML from RCC, even when small sized. These results suggest that examination of urinary 14-3-3 protein beta/alpha could serve as a diagnostic and prognostic marker in patients with ccRCC.
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Affiliation(s)
- Shiho Kaneko
- Department of Urology, Kitasato University School of Science, Sagamihara, Japan E-mail :
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35
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Abduch RH, Bueno AC, Leal LF, Cavalcanti MM, Gomes DC, Brandalise SR, Masterallo MJ, Yunes JA, Martinelli CE, Tone LG, Tucci S, Molina CA, Ramalho FS, Moreira AC, Cardinalli IA, Scrideli CA, Ramalho LN, de Castro M, Antonini SR. Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients. Oncotarget 2016; 7:84634-84644. [PMID: 27705928 PMCID: PMC5356687 DOI: 10.18632/oncotarget.12382] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 09/12/2016] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Overexpression of the oncogene yes-associated-protein-1 (YAP1) is associated with increased cell proliferation in human cancers. YAP1 is a potential target of the Wnt/beta-catenin pathway, which plays an important role in adrenocortical tumors (ACT). The role of YAP1 in adrenocortical tumorigenesis has not been assessed. AIMS To evaluate YAP1 expression in normal adrenals and pediatric ACT and its association with disease outcome. To investigate the interaction between YAP1 and the Wnt/beta-catenin pathway in adrenocortical cells. RESULTS Strong YAP1 staining was present in fetal adrenals and pediatric ACT but weak in postnatal adrenals. In pediatric ACT, YAP1 mRNA overexpression was associated with death, recurrent/metastatic disease and lower overall survival. The inhibition of the Wnt/beta-catenin pathway increased YAP1 mRNA expression. siYAP1 increased CTNNB1/beta-catenin expression and nuclear staining regardless of DLV2, moreover, it decreased cell growth and impaired cell migration. MATERIALS AND METHODS We assessed in 42 pediatric ACT samples the YAP1 protein expression by immunohistochemistry and mRNA expression by RT-qPCR and analyzed their association with outcome. As controls, we resort 32 fetal and postnatal normal adrenals for IHC and 10 normal adrenal cortices for RT-qPCR. The interaction between YAP1 and the Wnt/beta-catenin pathway was assessed in NCI-H295 adrenocortical cells by inhibiting the TCF/beta-catenin complex and by knocking down YAP1. CONCLUSION YAP1 overexpression is a marker of poor prognosis for pediatric patients with ACT. In adrenocortical cells, there is a close crosstalk between YAP1 and Wnt/beta-catenin. These data open the possibility of future molecular therapies targeting Hippo/YAP1 signaling to treat advanced ACT.
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Affiliation(s)
- Rafael H. Abduch
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Ana Carolina Bueno
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Leticia F. Leal
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Marcelo M. Cavalcanti
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | | | | | | | - Carlos E. Martinelli
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Luiz G. Tone
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Silvio Tucci
- Department of Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Carlos A.F. Molina
- Department of Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Fernando S. Ramalho
- Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Ayrton C. Moreira
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | - Carlos A. Scrideli
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Leandra N.Z. Ramalho
- Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Margaret de Castro
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Sonir R. Antonini
- Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
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36
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Wang L, Wang Y, Li PP, Wang R, Zhu Y, Zheng F, Li L, Cui JJ, Wang LW. Expression profile and prognostic value of SAV1 in patients with pancreatic ductal adenocarcinoma. Tumour Biol 2016; 37:16207–16213. [PMID: 27747589 DOI: 10.1007/s13277-016-5457-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 09/23/2016] [Indexed: 12/11/2022] Open
Abstract
SAV1 is a human homolog of salvador that contains two protein-protein interaction modules known as WW domains and acts as a scaffolding protein for Hpo and Warts. SAV1 is known to be a tumor suppressor, but its clinical and prognostic implications remain elusive. This study aimed at evaluating the prognostic significance and associated expression of SAV1 in pancreatic ductal adenocarcinoma (PDAC) patients. The expression of SAV1 in tissue specimens of PDAC patients were assayed with immunohistochemistry on a tissue microarray. The correlations between SAV1 expression and clinicopathological characteristics were analyzed by Pearson's chi-square test, Fisher's exact test, and Spearman's rank. The prognostic factors for overall survival were analyzed by univariate and multivariate Cox regression. The percentage of SAV1 expression in PDAC (50.6 %) was significantly lower than those in paratumor tissues (69.9 %) (P = 0.017). Expression of SAV1 was only significantly correlated with histological differentiation (P = 0.025) and N classification (P = 0.009). On multivariate analysis, elevated expression of SAV1 and N0 was a significant favorable prognostic factor of OS. Our study demonstrated for the first time that lower expression of SAV1 might be involved in the progression of PDAC, suggesting that SAV1 may be a potential prognostic marker and target for PDAC therapy.
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Affiliation(s)
- Lei Wang
- Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China
| | - Yu Wang
- Department of Oncology and Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Shanghai, 201620, China
| | - Peng-Ping Li
- Department of Bioinformatics, School of Basic Medical Sciences, Nanjing Medical University , Nanjing, 211166, China
| | - Rui Wang
- Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China
| | - Yue Zhu
- Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China
| | - Fang Zheng
- Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China
| | - Lin Li
- Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China
| | - Jiu-Jie Cui
- Department of Oncology and Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Shanghai, 201620, China.
| | - Li-Wei Wang
- Department of Oncology, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China.
- Department of Oncology and Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Shanghai, 201620, China.
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37
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The Hippo/MST Pathway Member SAV1 Plays a Suppressive Role in Development of the Prehierarchical Follicles in Hen Ovary. PLoS One 2016; 11:e0160896. [PMID: 27505353 PMCID: PMC4978403 DOI: 10.1371/journal.pone.0160896] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 07/26/2016] [Indexed: 11/19/2022] Open
Abstract
The Hippo/MST signaling pathway is a critical player in controlling cell proliferation, self-renewal, differentiation, and apoptosis of most tissues and organs in diverse species. Previous studies have shown that Salvador homolog 1 (SAV1), a scaffolding protein which functions in the signaling system is expressed in mammalian ovaries and play a vital role in governing the follicle development. But the exact biological effects of chicken SAV1 in prehierarchical follicle development remain poorly understood. In the present study, we demonstrated that the SAV1 protein is predominantly expressed in the oocytes and undifferentiated granulosa cells in the various sized prehierarchical follicles of hen ovary, and the endogenous expression level of SAV1 mRNA appears down-regulated from the primordial follicles to the largest preovulatory follicles (F2-F1) by immunohistochemistry and real-time RT-PCR, respectively. Moreover, we found the intracellular SAV1 physically interacts with each of the pathway members, including STK4/MST1, STK3/MST2, LATS1 and MOB2 using western blotting. And SAV1 significantly promotes the phosphorylation of LATS1 induced by the kinase of STK4 or STK3 in vitro. Furthermore, SAV1 knockdown by small interfering RNA (siRNA) significantly increased proliferation of granulosa cells from the prehierarchical follicles (6-8 mm in diameter) by BrdU-incorporation assay, in which the expression levels of GDF9, StAR and FSHR mRNA was notably enhanced. Meanwhile, these findings were consolidated by the data of SAV1 overexpression. Taken together, the present results revealed that SAV1 can inhibit proliferation of the granulosa cells whereby the expression levels of GDF9, StAR and FSHR mRNA were negatively regulated. Accordingly, SAV1, as a member of the hippo/MST signaling pathway plays a suppressive role in ovarian follicle development by promoting phosphorylation and activity of the downstream LATS1, may consequently lead to prevention of the follicle selection during ovary development.
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Kai T, Tsukamoto Y, Hijiya N, Tokunaga A, Nakada C, Uchida T, Daa T, Iha H, Takahashi M, Nomura T, Sato F, Mimata H, Ikawa M, Seto M, Matsuura K, Moriyama M. Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway. J Pathol 2016; 239:97-108. [DOI: 10.1002/path.4706] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 01/18/2016] [Accepted: 02/12/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Tomoki Kai
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
- Department of Urology, Faculty of Medicine; Oita University; Yufu Japan
| | - Yoshiyuki Tsukamoto
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
| | - Naoki Hijiya
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
| | - Akinori Tokunaga
- Section of Physiology, Department of Integrative Aging Neuroscience; National Center for Geriatrics and Gerontology; Obu Japan
| | - Chisato Nakada
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
| | - Tomohisa Uchida
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
| | - Tsutomu Daa
- Department of Diagnostic Pathology, Faculty of Medicine; Oita University; Yufu Japan
| | - Hidekatsu Iha
- Department of Microbiology, Faculty of Medicine; Oita University; Yufu Japan
| | - Mika Takahashi
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
- Department of Urology, Faculty of Medicine; Oita University; Yufu Japan
| | - Takeo Nomura
- Department of Urology, Faculty of Medicine; Oita University; Yufu Japan
| | - Fuminori Sato
- Department of Urology, Faculty of Medicine; Oita University; Yufu Japan
| | - Hiromitsu Mimata
- Department of Urology, Faculty of Medicine; Oita University; Yufu Japan
| | - Masahito Ikawa
- Animal Resource Center for Infectious Diseases; Research Institute for Microbial Diseases; Suita Japan
| | - Masao Seto
- Division of Molecular Medicine; Aichi Cancer Institute; Nagoya Japan
| | - Keiko Matsuura
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
- Department of Biology, Faculty of Medicine; Oita University; Yufu Japan
| | - Masatsugu Moriyama
- Department of Molecular Pathology, Faculty of Medicine; Oita University; Yufu Japan
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Takahashi M, Tsukamoto Y, Kai T, Tokunaga A, Nakada C, Hijiya N, Uchida T, Daa T, Nomura T, Sato F, Mimata H, Matsuura K, Moriyama M. Downregulation of WDR20 due to loss of 14q is involved in the malignant transformation of clear cell renal cell carcinoma. Cancer Sci 2016; 107:417-23. [PMID: 26790128 PMCID: PMC4832870 DOI: 10.1111/cas.12892] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 01/13/2016] [Accepted: 01/14/2016] [Indexed: 12/22/2022] Open
Abstract
Previously, we reported that genomic loss of 14q occurs more frequently in high-grade than in low-grade clear cell renal cell carcinomas (ccRCCs), and has a significant impact on the levels of expression of genes located in this region, suggesting that such genes may be involved in the malignant transformation of ccRCCs. Here, we found that six of the genes located in the minimal common region of 14q loss were significantly downregulated in high-grade ccRCCs due to copy number loss. Using a dataset from The Cancer Genome Atlas Research Network, we found that downregulation of one of these six genes, WDR20, was significantly associated with poorer outcome in patients with ccRCC, suggesting that WDR20 downregulation may be involved in the malignant transformation of ccRCCs. In functional assays, exogenous WDR20 significantly inhibited the growth of RCC cell lines and induced apoptosis. Interestingly, the phosphorylation levels of ERK and protein kinase B/AKT, which reportedly contribute to the malignant phenotype of RCC cells, were clearly reduced by exogenous expression of WDR20. Thus, our data suggest that downregulation of WDR20 due to 14q loss may be involved in the malignant transformation of ccRCCs, in part through activation of the ERK and protein kinase B/AKT pathways.
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Affiliation(s)
- Mika Takahashi
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.,Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Yoshiyuki Tsukamoto
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Tomoki Kai
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.,Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Akinori Tokunaga
- Research Promotion Institute, Faculty of Medicine, Oita University, Oita, Japan
| | - Chisato Nakada
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Naoki Hijiya
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Tomohisa Uchida
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Tsutomu Daa
- Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Oita, Japan
| | - Takeo Nomura
- Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Fuminori Sato
- Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Hiromitsu Mimata
- Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Keiko Matsuura
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan.,Department of Biology, Faculty of Medicine, Oita University, Oita, Japan
| | - Masatsugu Moriyama
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan
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40
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Hijiya N, Tsukamoto Y, Nakada C, Tung Nguyen L, Kai T, Matsuura K, Shibata K, Inomata M, Uchida T, Tokunaga A, Amada K, Shirao K, Yamada Y, Mori H, Takeuchi I, Seto M, Aoki M, Takekawa M, Moriyama M. Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma. Cancer Res 2016; 76:2612-25. [DOI: 10.1158/0008-5472.can-15-1846] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 02/14/2016] [Indexed: 11/16/2022]
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41
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Zhou Y, Huang T, Cheng ASL, Yu J, Kang W, To KF. The TEAD Family and Its Oncogenic Role in Promoting Tumorigenesis. Int J Mol Sci 2016; 17:ijms17010138. [PMID: 26805820 PMCID: PMC4730377 DOI: 10.3390/ijms17010138] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 01/14/2016] [Accepted: 01/15/2016] [Indexed: 01/22/2023] Open
Abstract
The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators to transmit the signal of pathways for the downstream signaling processes. TEADs also play an important role in tumor initiation and facilitate cancer progression via activating a series of progression-inducing genes, such as CTGF, Cyr61, Myc and Gli2. Recent studies have highlighted that TEADs, together with their coactivators, promote or even act as the crucial parts in the development of various malignancies, such as liver, ovarian, breast and prostate cancers. Furthermore, TEADs are proposed to be useful prognostic biomarkers due to the ideal correlation between high expression and clinicopathological parameters in gastric, breast, ovarian and prostate cancers. In this review, we summarize the functional role of TEAD proteins in tumorigenesis and discuss the key role of TEAD transcription factors in the linking of signal cascade transductions. Improved knowledge of the TEAD proteins will be helpful for deep understanding of the molecular mechanisms of tumorigenesis and identifying ideal predictive or prognostic biomarkers, even providing clinical translation for anticancer therapy in human cancers.
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Affiliation(s)
- Yuhang Zhou
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China.
| | - Tingting Huang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China.
| | - Alfred S L Cheng
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China.
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518000, China.
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42
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Nikooienejad A, Wang W, Johnson VE. Bayesian variable selection for binary outcomes in high-dimensional genomic studies using non-local priors. Bioinformatics 2016; 32:1338-45. [PMID: 26740524 PMCID: PMC4848399 DOI: 10.1093/bioinformatics/btv764] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 12/28/2015] [Indexed: 01/10/2023] Open
Abstract
Motivation: The advent of new genomic technologies has resulted in the production of massive data sets. Analyses of these data require new statistical and computational methods. In this article, we propose one such method that is useful in selecting explanatory variables for prediction of a binary response. Although this problem has recently been addressed using penalized likelihood methods, we adopt a Bayesian approach that utilizes a mixture of non-local prior densities and point masses on the binary regression coefficient vectors. Results: The resulting method, which we call iMOMLogit, provides improved performance in identifying true models and reducing estimation and prediction error in a number of simulation studies. More importantly, its application to several genomic datasets produces predictions that have high accuracy using far fewer explanatory variables than competing methods. We also describe a novel approach for setting prior hyperparameters by examining the total variation distance between the prior distributions on the regression parameters and the distribution of the maximum likelihood estimator under the null distribution. Finally, we describe a computational algorithm that can be used to implement iMOMLogit in ultrahigh-dimensional settings (p>>n) and provide diagnostics to assess the probability that this algorithm has identified the highest posterior probability model. Availability and implementation: Software to implement this method can be downloaded at: http://www.stat.tamu.edu/∼amir/code.html. Contact:wwang7@mdanderson.org or vjohnson@stat.tamu.edu Supplementary information:Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Amir Nikooienejad
- Department of Statistics, Texas A&M University, College Station, TX 77843, USA and
| | - Wenyi Wang
- Department of Bioinformatics and Computational Biology, M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Valen E Johnson
- Department of Statistics, Texas A&M University, College Station, TX 77843, USA and
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Meng F, Feng W, Xin H, Tian Z, Zhang Y, Zhang L. 14-3-3 Proteins interact with FRMD6 and regulate its subcellular localization in breast cancer cells. Chem Res Chin Univ 2015. [DOI: 10.1007/s40242-015-5097-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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44
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Kang XL, Zou H, Pang LJ, Hu WH, Zhao J, Qi Y, Liu CX, Hu JM, Tang JX, LI HA, Liang WH, Yuan XL, Li F. Chromosomal imbalances revealed in primary renal cell carcinomas by comparative genomic hybridization. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:3636-47. [PMID: 26097545 PMCID: PMC4466932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 03/30/2015] [Indexed: 06/04/2023]
Abstract
Renal cell carcinoma (RCC) accounts for approximately 3% of all new cancer cases. Although the classification of RCC is based mainly on histology, this method is not always accurate. We applied comparative genomic hybridization (CGH) to determine genomic alterations in 46 cases of different RCC histological subtypes [10 cases of clear cell RCC (CCRCC), 13 cases of papillary RCC (PRCC), 12 cases of chromophobe RCC (CRCC), 9 cases of Xp11.2 translocation RCC (Xp11.2RCC), 2 cases of undifferentiated RCC (unRCC)], and investigated the relationships between clinical parameters and genomic aberrations. Changes involving one or more regions of the genome were seen in all RCC patients; DNA sequence gains were most frequently (>30%) seen in chromosomes 7q, 16p, and 20q; losses from 1p, 3p, 13q, 14q, and 8p. We conclude CGH is a useful complementary method for differential diagnosis of RCC. Loss of 3p21-25, 15q, and gain of 16p11-13 are relatively particular to CCRCC vs. other types of RCC. Gain of 7p13-22, 8q21-24, and loss of 18q12-ter, 14q13-24, and Xp11-q13/Y are more apparent in PRCC, and gain of 8q21-24 is characteristic of type 2 PRCC vs. type 1 PRCC. Loss of 2q12-32, 10p12-15, and 11p11-15, 13p are characteristic of CRCC, and gain of 3p and loss of 11p11-15 and 13p are significant differentiators between common CRCC and CRCC accompanied by sarcomatous change groups. Gain of Xp11-12 is characteristic of the Xp11.2RCC group. Based on Multivariate Cox regression analysis, aberration in 5 chromosome regions were poor prognostic markers of RCC, and include the gain of chromosome 12p12-ter (P = 0.034, RR = 3.502, 95% CI 1.097-11.182), 12q14-ter (P = 0.002, RR = 5.115, 95% CI 1.847-14.170), 16q21-24 (P = 0.044, RR = 2.629, 95% CI 1.027-6.731), 17p12-ter (P = 0.017, RR = 3.643, 95% CI 1.262-10.512) and the loss of 18q12-23 (P = 0.049, RR = 2.911, 95% CI 1.006-8.425), which may provide clues of new genes involved in RCC tumorigenesis.
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Affiliation(s)
- Xue-Ling Kang
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
- Department of Pathology and Pathophysiology, Fudan University School of MedicineShanghai, China
| | - Hong Zou
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
- Tongji Hospital Cancer Center, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei, China
| | - Li Juan Pang
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Wen Hao Hu
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Jin Zhao
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Yan Qi
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Chun-Xia Liu
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Jian Ming Hu
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Jing-Xia Tang
- Department of Preventive Medicine, Medical College of Shihezi UniversityShihezi, Xinjiang, China
| | - Hong An LI
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Wei Hua Liang
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
| | - Xiang-Lin Yuan
- Tongji Hospital Cancer Center, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei, China
| | - Feng Li
- Department of Pathology, Shihezi University School of Medicine, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education of ChinaShihezi, Xinjiang, China
- Tongji Hospital Cancer Center, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei, China
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Narimatsu T, Matsuura K, Nakada C, Tsukamoto Y, Hijiya N, Kai T, Inoue T, Uchida T, Nomura T, Sato F, Seto M, Takeuchi I, Mimata H, Moriyama M. Downregulation of NDUFB6 due to 9p24.1-p13.3 loss is implicated in metastatic clear cell renal cell carcinoma. Cancer Med 2014; 4:112-24. [PMID: 25315157 PMCID: PMC4312125 DOI: 10.1002/cam4.351] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 08/24/2014] [Accepted: 08/27/2014] [Indexed: 12/14/2022] Open
Abstract
This study was conducted to clarify the genomic profiles of metastatic clear cell renal cell carcinomas (ccRCCs) and identify the genes responsible for development of metastasis. We analyzed the genomic profiles of 20 cases of primary ccRCC and their corresponding metastases using array-based comparative genomic hybridization, and identified 32 chromosomal regions in which gene copy number alterations were detected more frequently in metastases than in the primary tumors. Among these 32 regions, 9p24.1-p13.3 loss was the most statistically significant alteration. Furthermore, we found that patients with 9p24.1-p13.3 loss in primary tumors exhibited significantly lower rates of recurrence-free and cancer-specific survival, suggesting that 9p loss in the primary tumor is a potential biomarker predicting early recurrence of metastasis. Interestingly, the genomic profiles of primary tumors with 9p loss resembled those of their corresponding metastases, though 9p loss was accumulated in the metastases derived from the primary tumors without 9p loss. Comparison of the mRNA expression levels revealed that 2 of 58 genes located at 9p24.1-p13.3 were downregulated due to gene copy number loss in ccRCCs. An overexpression study of these two genes in ccRCC cell lines revealed that downregulation of NDUFB6 due to loss at 9p24.1-p13.3 may confer a growth advantage on metastatic ccRCC cells. These results were confirmed by analyzing the data of 405 cases of ccRCC obtained from The Cancer Genome Atlas (TCGA). On the basis of our present data, we propose that NDUFB6 is a possible tumor suppressor of metastatic ccRCCs.
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Affiliation(s)
- Takahiro Narimatsu
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan; Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
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46
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Increased expression of Chitinase 3-like 1 and microvessel density predicts metastasis and poor prognosis in clear cell renal cell carcinoma. Tumour Biol 2014; 35:12131-7. [PMID: 25142236 DOI: 10.1007/s13277-014-2518-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/15/2014] [Indexed: 10/24/2022] Open
Abstract
Increasing evidence demonstrated that Chitinase 3-like 1 (hereafter termed CHI3L1 or YKL-40) was highly expressed and tightly associated with human tumor development and progression. However, its precise role in clear cell renal cell carcinoma (hereafter termed RCC) remains to be delineated. In the present study, we investigated the relationship between CHI3L1 expression and microvessel density (MVD), a reflection of angiogenesis, with metastasis and prognosis in patients with clear cell renal cell carcinoma (RCC). Formalin-fixed, paraffin-embedded tissue sections of clear cell RCC from 73 patients who had undergone radical nephrectomy were stained immunohistochemically with specific antibodies against CHI3L1 and CD34. CHI3L1 immunostaining was semi-quantitatively estimated based on the proportion (percentage of positive cells) and intensity. MVD was determined with CD34-stained slides. The expression pattern of CHI3L1 and MVD was compared with the clinicopathological variables. Twenty patients had either synchronous or metachronous metastases and 12 died during the follow-up. CHI3L1 intensity was significantly correlated with tumor size (P = 0.005), TNM stage (P = 0.027), M stage (P = 0.011), grade (P = 0.014), and metastasis (synchronous or metachronous; P < 0.001). The CHI3L1 proportion (P = 0.038) and MVD (P = 0.012) were significantly correlated with metastasis. MVD was correlated with CHI3L1 intensity (r = 0.376, P = 0.001) and CHI3L1 proportion (r = 0.364, P = 0.002). There was no difference in the expression of CHI3L1 and MVD between primary and metastatic sites. The survival of patients with higher CHI3L1 intensity was significantly worse than that of patients with lower CHI3L1 intensity. Multivariate analyses indicated that only M stage was an independent prognostic factor for cancer-specific survival and CHI3L1 expression was not an independent factor. Taken altogether, increased expression of CHI3L1 and MVD is associated with metastasis and a worse prognosis in clear cell RCC. CHI3L1 expression is correlated with MVD. The results suggest that CHI3L1 may be important in the progression and angiogenesis of clear cell RCC and CHI3L1 might be a novel strategy for therapy of the patients with RCC.
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Barron DA, Kagey JD. The role of the Hippo pathway in human disease and tumorigenesis. Clin Transl Med 2014; 3:25. [PMID: 25097728 PMCID: PMC4112623 DOI: 10.1186/2001-1326-3-25] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 07/09/2014] [Indexed: 12/13/2022] Open
Abstract
Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
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Affiliation(s)
- Daniel A Barron
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jacob D Kagey
- Department of Biology, University of Detroit Mercy, 4001 West McNichols Road, Detroit, MI, USA
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Zhao JJ, Chen PJ, Duan RQ, Li KJ, Wang YZ, Li Y. Up-regulation of miR-630 in clear cell renal cell carcinoma is associated with lower overall survival. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:3318-3323. [PMID: 25031755 PMCID: PMC4097229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 04/30/2014] [Indexed: 06/03/2023]
Abstract
INTRODUCTION MicroRNAs (miRNAs) are noncoding RNAs that regulate multiple cellular processes during cancer progression. MiR-630 has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer and gastric cancer. However, the regulation of miR-630 in clear cell renal cell carcinoma (ccRCC) has not yet been reported before. METHODS Expression of miR-630 was evaluated by quantitative real-time PCR in tumour and their normal matched tissues in n = 92 ccRCC patients, and its association with overall survival of patients was analyzed by statistical analysis. RESULTS The expression level of miR-630 was significantly higher in renal cancer in comparison to normal matched tissue (P < 0.05). It is also proved that miR-630 expression was to be associated with renal cancer histologic grade, lymphnode metastasis, distant metastasis (P < 0.05). In addition, the Kaplan-Meier survival curves revealed that high miR-630 expression was associated with poor prognosis in ccRCC patients. miR-630 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis. CONCLUSIONS The study proves for the first time that miR-630 is upregulated in a majority of ccRCC patients. It also shows that miR-630 expression is an independent prognostic factor for patients with renal cancer, which might be a potential valuable biomarker for ccRCC.
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Affiliation(s)
- Jian-Jun Zhao
- Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang, 050011, Hebei, China
- Department of Urology, Affiliated Hospital of Hebei University of EngineeringHandan, 056002, Hebei, China
| | - Peng-Jie Chen
- Department of Neurology, Handan Central HospitalHandan, 056001, Hebei, China
| | - Rui-Qin Duan
- Department of Urology, Affiliated Hospital of Hebei University of EngineeringHandan, 056002, Hebei, China
| | - Ke-Ji Li
- Department of Urology, Affiliated Hospital of Hebei University of EngineeringHandan, 056002, Hebei, China
| | - Yu-Zhong Wang
- Department of Urology, Affiliated Hospital of Hebei University of EngineeringHandan, 056002, Hebei, China
| | - Yong Li
- Department of Surgery, The Fourth Hospital of Hebei Medical UniversityShijiazhuang, 050011, Hebei, China
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Schütte U, Bisht S, Heukamp LC, Kebschull M, Florin A, Haarmann J, Hoffmann P, Bendas G, Buettner R, Brossart P, Feldmann G. Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma. Transl Oncol 2014; 7:309-21. [PMID: 24913676 PMCID: PMC4101344 DOI: 10.1016/j.tranon.2014.02.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 02/03/2014] [Accepted: 02/04/2014] [Indexed: 01/15/2023] Open
Abstract
Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC. Immunostaining was particularly prominent at the tumor margins and highlighted neoplastic cells invading the tumor-adjacent stroma. Short hairpin RNA-mediated knockdown of YAP significantly inhibited proliferation, migration, and anchorage-independent growth of ccRCC cells in soft agar and led to significantly reduced murine xenograft growth. Microarray analysis of YAP knockdown versus mock-transduced ccRCC cells revealed down-regulation of endothelin 1, endothelin 2, cysteine-rich, angiogenic inducer, 61 (CYR61), and c-Myc in ccRCC cells as well as up-regulation of the cell adhesion molecule cadherin 6. Signaling pathway impact analysis revealed activation of the p53 signaling and cell cycle pathways as well as inhibition of mitogen-activated protein kinase signaling on YAP down-regulation. Our data suggest CYR61 and c-Myc as well as signaling through the endothelin axis as bona fide downstream effectors of YAP and establish aberrant Hippo signaling as a potential therapeutic target in ccRCC.
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Affiliation(s)
- Ute Schütte
- Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, Bonn, Germany
| | - Savita Bisht
- Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, Bonn, Germany
| | - Lukas C Heukamp
- Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
| | - Moritz Kebschull
- Department of Periodontology, Operative and Preventive Dentistry, University Hospital of Bonn, Bonn, Germany
| | - Alexandra Florin
- Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
| | - Jens Haarmann
- Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, Bonn, Germany
| | - Per Hoffmann
- Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University Hospital of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gerd Bendas
- Department of Pharmacy, University of Bonn, Bonn, Germany
| | - Reinhard Buettner
- Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, Cologne, Germany
| | - Peter Brossart
- Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, Bonn, Germany
| | - Georg Feldmann
- Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, Bonn, Germany.
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Li J, Sheng C, Li W, Zheng JH. Protein phosphatase-2A is down-regulated in patients within clear cell renal cell carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2014; 7:1147-53. [PMID: 24696731 PMCID: PMC3971320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 02/10/2014] [Indexed: 06/03/2023]
Abstract
BACKGROUND Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases. It positively regulates apoptosis and negatively regulates the mitogenic pathway, suggesting that loss of it might be involved in cancer development. Recent studies found its association with breast, lung and colorectal cancer; however, its expression profile and its prognostic value in clear cell renal cell carcinoma (ccRCC) have not been investigated. METHODS Real-time quantitative PCR (qRT-PCR) and Western blot were used to explore PP2A expression in ccRCC and normal renal tissues. Moreover immunohistochemistry (ICH) was used to detect the expression of PP2A in ccRCC. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS Down-regulated expression of PP2A mRNA and protein was observed in the majority of ccRCC by qRT-PCR and Western blot when compared with their paired normal renal tissues. Clinic pathological analysis was showed a significant correlation existed between the lower expression of PP2A protein with the histological grade, lymph node metastasis and tumor distant metastasis (P<0.05); Survival analysis by Kaplan-Meier survival curve and log-rank test demonstrated that reduced PP2A expression in cancer tissue predicted poorer overall survival (OS) compared with group in higher expression. Notably, multivariate analyses by Cox's proportional hazard model revealed that expression of PP2A was an independent prognostic factor in ccRCC. CONCLUSIONS These results suggest that the aberrant expression of PP2A in human ccRCC is possibly involved with tumorigenesis and development, and the PP2A protein could act as a potential biomarker for prognosis assessment of renal cancer. Further studies on the cellular functions of PP2A need to address these issues.
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Affiliation(s)
- Jun Li
- Department of Urology, Pudong New Area People’s HospitalShanghai, 201200, China
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji UniversityShanghai, 200072, China
| | - Chang Sheng
- Department of Urology, Pudong New Area People’s HospitalShanghai, 201200, China
| | - Wei Li
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji UniversityShanghai, 200072, China
| | - Jun-Hua Zheng
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji UniversityShanghai, 200072, China
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