|
1
|
Qi W, Zhang Y, Wang L, Hou K, Li T, Lang J, Cong H. Coronary microcirculation dysfunction causing ischemia with non-obstructive coronary arteries: a case report. Front Cardiovasc Med 2025; 12:1556064. [PMID: 40303613 PMCID: PMC12037479 DOI: 10.3389/fcvm.2025.1556064] [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: 01/06/2025] [Accepted: 03/28/2025] [Indexed: 05/02/2025] Open
Abstract
The study presents a case of INOCA attributed to CMVD in a 53-year-old male patient experiencing exertional angina, despite the absence of significant coronary artery stenosis on angiography. The patient presented with reversible myocardial ischemia detected by myocardial perfusion imaging, with an ischemic area accounting for 12% of the left ventricular wall. Diagnostic tests revealed an elevated index of microcirculatory resistance (IMR = 46.3) and a quantitative flow ratio (QFR = 0.94), confirming CMVD. Genetic testing identified a NOTCH1 c.3862G>A variant in the proband and some family members, suggesting a potential contribution to CMVD pathogenesis through impaired vascular remodeling and microcirculatory regulation. After six months of targeted treatment with nicorandil, coenzyme Q10, trimetazidine, and rosuvastatin, the patient's symptoms resolved, and myocardial ischemia reversed. While an MYH7 variant was also detected, its clinical relevance was ruled out due to the family's absence of associated cardiomyopathy phenotypes. The NOTCH1 gene may play a potential role in INOCA caused by CMVD, however, further research is needed to elucidate its underlying regulatory mechanisms. The findings provide a foundation for precise diagnosis and personalized management of INOCA.
Collapse
Affiliation(s)
- Wei Qi
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
| | - Yazheng Zhang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
| | - Le Wang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
| | - Kai Hou
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Research Center, Pu’er People’s Hospital, Pu'er City, Yunnan, China
| | - Ting Li
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
| | - Jiachun Lang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
| | - Hongliang Cong
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
| |
Collapse
|
|
2
|
Iluta S, Nistor M, Buruiana S, Dima D. Notch and Hedgehog Signaling Unveiled: Crosstalk, Roles, and Breakthroughs in Cancer Stem Cell Research. Life (Basel) 2025; 15:228. [PMID: 40003637 PMCID: PMC11856057 DOI: 10.3390/life15020228] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
The development of therapies that target cancer stem cells (CSCs) and bulk tumors is both crucial and urgent. Several signaling pathways, like Notch and Hedgehog (Hh), have been strongly associated with CSC stemness maintenance and metastasis. However, the extensive crosstalk present between these two signaling networks complicates the development of long-term therapies that also minimize adverse effects on healthy tissues and are not overcome by therapy resistance from CSCs. The present work aims to overview the roles of Notch and Hh in cancer outburst and the intersection of the two pathways with one another, as well as with other networks, such as Wnt/β-catenin, TGF, and JAK/STAT3, and to explore the shaping of the tumor microenvironment (TME) with specific influence on CSC development and maintenance.
Collapse
Affiliation(s)
- Sabina Iluta
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania;
| | - Madalina Nistor
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania;
| | - Sanda Buruiana
- Department of Hematology, Nicolae Testemitanu University of Medicine and Pharmacy, MD-2004 Chisinau, Moldova;
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Oncology Institute, 400015 Cluj Napoca, Romania
| |
Collapse
|
|
3
|
Png CW, Weerasooriya M, Li H, Hou X, Teo FY, Huang S, Ser Z, Weng FYK, Rethnam M, Chia G, Sobota RM, Chong CS, Tan KK, Zhang Y. DUSP6 regulates Notch1 signalling in colorectal cancer. Nat Commun 2024; 15:10087. [PMID: 39572549 PMCID: PMC11582695 DOI: 10.1038/s41467-024-54383-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
Notch1 plays various roles in cancer development, and Notch1-induced transactivation is controlled by phosphorylation of its cleaved intracellular domain. However, it is unclear whether there are phosphatases capable of dephosphorylating the cleaved Notch1 transmembrane/intracellular region (NTM) to regulate its function. Here, we show that DUSP6 can function as a phosphatase for Notch1, thereby regulating NTM stability and transcriptional activity, thus influencing colorectal cancer (CRC) development. In human CRC cells, elevated DUSP6 expression correlates with increased NTM levels, leading to enhanced CRC cell proliferation both in vitro and in vivo. High tumoral DUSP6 protein expression is associated with poorer overall CRC patient survival. In mice, DUSP6 deficiency results in reduced CRC development. Mechanistically, DUSP6 dephosphorylates phospho-Y2116, which in turn reduces NTM ubiquitination, leading to increased NTM stability and transcriptional activity. As a result, the expression of Notch1-targeted proliferation genes is increased to promote tumour cell growth.
Collapse
Affiliation(s)
- Chin Wen Png
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Madhushanee Weerasooriya
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Heng Li
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Xiaowen Hou
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Fiona Yayuan Teo
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Shiying Huang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Zheng Ser
- Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
| | - Franklin Yau Kok Weng
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore
| | - Malini Rethnam
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, 117597, Singapore
- Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore, 117597, Singapore
| | - Gloryn Chia
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, 117597, Singapore
- Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore, 117597, Singapore
| | - Radoslaw M Sobota
- Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
| | - Choon Seng Chong
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ker-Kan Tan
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore.
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore, 117456, Singapore.
| |
Collapse
|
|
4
|
Martínez-Pérez J, Torrado C, Domínguez-Cejudo MA, Valladares-Ayerbes M. Targeted Treatment against Cancer Stem Cells in Colorectal Cancer. Int J Mol Sci 2024; 25:6220. [PMID: 38892410 PMCID: PMC11172446 DOI: 10.3390/ijms25116220] [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: 04/27/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/β-catenin, Hedgehog, Notch, TGF-β/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.
Collapse
Affiliation(s)
- Julia Martínez-Pérez
- Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| | - Carlos Torrado
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - María A. Domínguez-Cejudo
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| | - Manuel Valladares-Ayerbes
- Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| |
Collapse
|
|
5
|
Abdolahi M, Ghaedi Talkhounche P, Derakhshan Nazari MH, Hosseininia HS, Khoshdel-Rad N, Ebrahimi Sadrabadi A. Functional Enrichment Analysis of Tumor Microenvironment-Driven Molecular Alterations That Facilitate Epithelial-to-Mesenchymal Transition and Distant Metastasis. Bioinform Biol Insights 2024; 18:11779322241227722. [PMID: 38318286 PMCID: PMC10840405 DOI: 10.1177/11779322241227722] [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: 01/06/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Nowadays, hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths, and identifying the effective factors in causing this disease can play an important role in its prevention and treatment. Tumors provide effective agents for invasion and metastasis to other organs by establishing appropriate communication between cancer cells and the microenvironment. Epithelial-to-mesenchymal transition (EMT) can be mentioned as one of the effective phenomena in tumor invasion and metastasis. Several factors are involved in inducing this phenomenon in the tumor microenvironment, which helps the tumor survive and migrate to other places. It can be effective to identify these factors in the use of appropriate treatment strategies and greater patient survival. This study investigated the molecular differences between tumor border cells and tumor core cells or internal tumor cells in HCC for specific EMT genes. Expression of NOTCH1, ID1, and LST1 genes showed a significant increase at the HCC tumor border. Targeting these genes can be considered as a useful therapeutic strategy to prevent distant metastasis in HCC patients.
Collapse
Affiliation(s)
- Mahnaz Abdolahi
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University, Tehran, Iran
| | - Parnian Ghaedi Talkhounche
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mohammad Hossein Derakhshan Nazari
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Haniyeh Sadat Hosseininia
- Department of Cellular and Molecular Biology, Faculty of Advanced Medical Science, Islamic Azad University of Medical Sciences, Tehran, Iran
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
| | - Niloofar Khoshdel-Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amin Ebrahimi Sadrabadi
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
| |
Collapse
|
|
6
|
Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R, Srivastava V. Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:41-99. [PMID: 38663962 DOI: 10.1016/bs.ircmb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.
Collapse
Affiliation(s)
- Afza Ahmad
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Saleha Siddiqui
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Muskan Chadha
- Department of Nutrition and Dietetics, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Ratnakar Shukla
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vivek Srivastava
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Greater Noida, Uttar Pradesh, India.
| |
Collapse
|
|
7
|
Doghish AS, Zaki MB, Eldeib MG, Radwan AF, Moussa R, Abdel-Wahab MM, Kizilaslan EZ, Alhamshry NAA, Ashour AE, Elimam H. The potential relevance of long non-coding RNAs in colorectal cancer pathogenesis and treatment: A review focus on signaling pathways. Pathol Res Pract 2024; 253:155044. [PMID: 38141573 DOI: 10.1016/j.prp.2023.155044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023]
Abstract
Colorectal cancer (CRC) is one of the most frequent cancers in incidence and mortality. Despite advances in cancer biology, molecular genetics, and targeted treatments, CRC prognosis and survival have not kept pace. This is usually due to advanced staging and metastases at diagnosis. Thus, great importance has been placed upon understanding the molecular pathophysiology behind the development of CRC, which has highlighted the significance of non-coding RNA's role and associated intracellular signaling pathways in the pathogenesis of the disease. According to recent studies, long non-coding RNAs (lncRNA), a subtype of ncRNAs whose length exceeds 200 nucleotides, have been found to have regulatory functions on multiple levels. Their actions at the transcription, post-transcriptional, translational levels, and epigenetic regulation have made them prime modulators of gene expression. Due to their role in cellular cancer hallmarks, their dysregulation has been linked to several illnesses, including cancer. Furthermore, their clinical relevance has expanded due to their possible detection in blood which has cemented them as potential future biomarkers and thus, potential targets for new therapy. This review will highlight the importance of lncRNAs and related signaling pathways in the development of CRC and their subsequent clinical applications.
Collapse
Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt
| | - Mahmoud Gomaa Eldeib
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Sinai University - Kantara Branch, 41636 Ismailia, Egypt
| | - Abdullah F Radwan
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt
| | - Rewan Moussa
- Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Maie M Abdel-Wahab
- Department of Biochemistry, Faculty of Pharmacy, Sinai University - Kantara Branch, 41636 Ismailia, Egypt
| | | | - Nora A A Alhamshry
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt
| | - Abdelkader E Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Salman International University, Ras Sudr, South Sinai, Egypt
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt.
| |
Collapse
|
|
8
|
Wang L, Gu W, Zou B, Kalady M, Xin W, Zhou L. Loss of HES1 expression is associated with extracellular matrix remodeling and tumor immune suppression in KRAS mutant colon adenocarcinomas. Sci Rep 2023; 13:15999. [PMID: 37749297 PMCID: PMC10519992 DOI: 10.1038/s41598-023-42234-7] [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: 01/18/2023] [Accepted: 09/07/2023] [Indexed: 09/27/2023] Open
Abstract
The loss of HES1, a canonical Notch signaling target, may cooperate with KRAS mutations to remodel the extracellular matrix and to suppress the anti-tumor immune response. While HES1 expression is normal in benign hyperplastic polyps and normal colon tissue, HES1 expression is often lost in sessile serrated adenomas/polyps (SSAs/SSPs) and colorectal cancers (CRCs) such as those right-sided CRCs that commonly harbor BRAF or KRAS mutations. To develop a deeper understanding of interaction between KRAS and HES1 in colorectal carcinogenesis, we selected microsatellite stable (MSS) and KRAS mutant or KRAS wild type CRCs that show aberrant expression of HES1 by immunohistochemistry. By comparing the transcriptional landscapes of microsatellite stable (MSS) CRCs with or without nuclear HES1 expression, we investigated differentially expressed genes and activated pathways. We identified pathways and markers in the extracellular matrix and immune microenvironment that are associated with mutations in KRAS. We found that loss of HES1 expression positively correlated with matrix remodeling and epithelial-mesenchymal transition but negatively correlated with tumor cell proliferation. Furthermore, loss of HES1 expression in KRAS mutant CRCs correlates with a higher M2 macrophage polarization and activation of IL6 and IL10 immunosuppressive signature. Identifying these HES1-related markers may be useful for prognosis stratification and developing treatment for KRAS-mutant CRCs.
Collapse
Affiliation(s)
- Lei Wang
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wenchao Gu
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Bingqing Zou
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Matthew Kalady
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
- Division of Colon and Rectal Surgery, Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Wei Xin
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, University of South Alabama Hospital, Mobile, AL, USA
| | - Lan Zhou
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
- Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
| |
Collapse
|
|
9
|
Wang L, Gu W, Kalady M, Xin W, Zhou L. Loss of HES1 Expression is Associated with Extracellular Matrix Remodeling and Tumor Immune Suppression in KRAS Mutant Colon Adenocarcinomas. RESEARCH SQUARE 2023:rs.3.rs-2489562. [PMID: 36824959 PMCID: PMC9949260 DOI: 10.21203/rs.3.rs-2489562/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
The loss of HES1, a canonical Notch signaling target, may cooperate with KRAS mutations to remodel the extracellular matrix and to suppress the anti-tumor immune response. While HES1 expression is normal in benign hyperplastic polyps and normal colon tissue, HES1 expression is often lost in sessile serrated adenomas/polyps (SSAs/SSPs) and colorectal cancers (CRCs) such as those right-sided CRCs that commonly harbor BRAF or KRAS mutations. To develop a deeper understanding of interaction between KRAS and HES1 in colorectal carcinogenesis, we selected microsatellite stable (MSS) and KRAS mutant or KRAS wild type CRCs that show aberrant expression of HES1 by immunohistochemistry. By comparing the transcriptional landscapes of microsatellite stable (MSS) CRCs with or without nuclear HES1 expression, we investigated differentially expressed genes and activated pathways. We identified pathways and markers in the extracellular matrix and immune microenvironment that are associated with mutations in KRAS. We found that loss of HES1 expression positively correlated with matrix remodeling and epithelial-mesenchymal transition (EMT) but negatively correlated with tumor cell proliferation. Furthermore, loss of HES1 expression in KRAS mutant CRCs correlates with a higher M2 macrophage polarization and activation of IL6 and IL10 immunosuppressive signature. Identifying these HES1-related markers may be useful for prognosis and developing treatment of KRAS-mutant CRCs.
Collapse
Affiliation(s)
| | | | | | - Wei Xin
- University of South Alabama Hospital
| | | |
Collapse
|
|
10
|
Kajiwara T, Nishina T, Nakasya A, Yamashita N, Yamashita R, Nakamura Y, Shiozawa M, Yuki S, Taniguchi H, Hara H, Ohta T, Esaki T, Shinozaki E, Takashima A, Moriwaki T, Denda T, Ohtsubo K, Sunakawa Y, Horita Y, Kawakami H, Kato T, Satoh T, Ando K, Mizutani T, Yasui H, Goto M, Okuyama H, Yamazaki K, Yoshino T, Hyodo I. NOTCH gene alterations in metastatic colorectal cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN). J Cancer Res Clin Oncol 2022; 148:2841-2854. [PMID: 35622165 DOI: 10.1007/s00432-022-04064-4] [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: 03/27/2022] [Accepted: 05/09/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.
Collapse
Affiliation(s)
- Takeshi Kajiwara
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan.
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan
| | - Akio Nakasya
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan
| | - Natsumi Yamashita
- Clinical Research Center, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Yosuke Horita
- Department of Medical Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomonori Mizutani
- Department of General Medicine, Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Hiroyuki Okuyama
- Department of Clinical Oncology, Kagawa University Hospital, Kita-gun, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shunto-gun, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan
| |
Collapse
|
|
11
|
Singh AK, Shuaib M, Prajapati KS, Kumar S. Rutin Potentially Binds the Gamma Secretase Catalytic Site, Down Regulates the Notch Signaling Pathway and Reduces Sphere Formation in Colonospheres. Metabolites 2022; 12:926. [PMID: 36295828 PMCID: PMC9610901 DOI: 10.3390/metabo12100926] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Rutin, a natural flavonol, can modulate molecular signaling pathways and has considerable potential in cancer treatment. However, little is known about the effect of rutin on the notch signaling pathway (NSP) in cancer and cancer stem-like cells. In this study, we explored the effect of rutin on gamma secretase (GS, a putative notch signaling target) inhibition mediated NICD (Notch Intracellular Domain) production in colon cancer cells. Molecular docking, MM-GBSA, and Molecular dynamics (MD) simulation experiments were performed to check rutin's GS catalytic site binding potential. The HCT-116 colon cancer and cancer stem-like cells (colonospheres) were utilized to validate the in silico findings. The NICD production, notch promoter assay, expression of notch target genes, and cancer stemness/self-renewal markers were studied at molecular levels. The results were compared with the Notch-1 siRNA transfected test cells. The in silico study revealed GS catalytic site binding potential in rutin. The in vitro results showed a decreased NICD formation, an altered notch target gene (E-cad, Hes-1, and Hey-1) expression, and a reduction in stemness/self-renewal markers (CD44, c-Myc, Nanog, and Sox2) in test cells in a time and dose-dependent manner. In conclusion, rutin inhibits the notch signaling pathway and reduces the stemness/self-renewal property in colon cancer cells and the colonospheres by targeting gamma secretase. The clinical efficacy of rutin in combination therapy in colon cancer may be studied in the future.
Collapse
Affiliation(s)
| | | | | | - Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, Punjab, India
| |
Collapse
|
|
12
|
Wang J, Sun M, Ma R, Wang G, Li W, Yang B, Yang Y. Down-regulation of NOTCH1 and PKM2 can inhibit the growth and metastasis of colorectal cancer cells. Am J Transl Res 2022; 14:5455-5465. [PMID: 36105047 PMCID: PMC9452328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/15/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Previous studies have revealed the overexpression of Notch receptor 1 (NOTCH1) and pyruvate kinase M2 (PKM2) in colorectal cancer (CRC) tissue and their relationship to disease development. However, whether there is synergy between PKM2 and NOTCH1 needs to be verified. This study aims to analyze the mechanism and relationship between NOTCH1 and PKM2 in CRC. METHODS Immunohistochemistry was used to measure the expression of NOTCH1 and PKM2 in colorectal cancer, and the correlation between them was analyzed by Pearson test. The protein and mRNA expressions in CRC cell lines were determined by western blot (WB) and real-time quantitative reverse transcription PCR (qRT-PCR). Compound 3K and tangeretin (TGN) were used to inhibit the expressions of PKM2 and NOTCH1, respectively. The wound healing assay and CCK-8 assay were applied to measure the migration and proliferation of cancer cells. RESULTS Immunohistochemical analysis showed that NOTCH1 and PKM2 were overexpressed in patients with colorectal cancer, and patients with overexpression showed a higher number of lymph node metastases and high tumor stage (III+IV) (P<0.05). In addition, Pearson test showed that the level of NOTCH1 was positively correlated with the level of PKM2 (P<0.05). WB and qRT-PCR showed that the protein and mRNA levels of NOTCH1 and PKM2 in colorectal cancer cells were significantly up-regulated (P<0.05). The inhibition of PKM2 and NOTCH1 had a synergistic effect on reducing the invasion and proliferation of CRC cells. CONCLUSION NOTCH1 and PKM2 are highly expressed in CRC patients. Inhibiting the expression of NOTCH1 and PKM2 can inhibit the growth and metastasis of CRC cells, providing therapeutic targets for the treatment of CRC.
Collapse
Affiliation(s)
- Jia Wang
- Department of General Surgery, Baoji City People’s HospitalBaoji 721000, Shaanxi, China
| | - Meijuan Sun
- Department of Pharmacy, Baoji Second People’s HospitalBaoji 721000, Shaanxi, China
| | - Rong Ma
- Department of Pathology, Baoji City People’s HospitalBaoji 721000, Shaanxi, China
| | - Gaobo Wang
- Department of General Surgery, Baoji City People’s HospitalBaoji 721000, Shaanxi, China
| | - Wenqing Li
- Department of General Surgery, Baoji City People’s HospitalBaoji 721000, Shaanxi, China
| | - Bowei Yang
- Department of General Surgery, Baoji City People’s HospitalBaoji 721000, Shaanxi, China
| | - Yang Yang
- Department of General Surgery, Baoji City People’s HospitalBaoji 721000, Shaanxi, China
| |
Collapse
|
|
13
|
Discovery of Long Non-Coding RNA MALAT1 Amplification in Precancerous Colorectal Lesions. Int J Mol Sci 2022; 23:ijms23147656. [PMID: 35887000 PMCID: PMC9318831 DOI: 10.3390/ijms23147656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 12/12/2022] Open
Abstract
A colorectal adenoma, an aberrantly growing tissue, arises from the intestinal epithelium and is considered as precursor of colorectal cancer (CRC). In this study, we investigated structural and numerical chromosomal aberrations in adenomas, hypothesizing that chromosomal instability (CIN) occurs early in adenomas. We applied array comparative genomic hybridization (aCGH) to fresh frozen colorectal adenomas and their adjacent mucosa from 16 patients who underwent colonoscopy examination. In our study, histologically similar colorectal adenomas showed wide variability in chromosomal instability. Based on the obtained results, we further stratified patients into four distinct groups. The first group showed the gain of MALAT1 and TALAM1, long non-coding RNAs (lncRNAs). The second group involved patients with numerous microdeletions. The third group consisted of patients with a disrupted karyotype. The fourth group of patients did not show any CIN in adenomas. Overall, we identified frequent losses in genes, such as TSC2, COL1A1, NOTCH1, MIR4673, and GNAS, and gene gain containing MALAT1 and TALAM1. Since long non-coding RNA MALAT1 is associated with cancer cell metastasis and migration, its gene amplification represents an important event for adenoma development.
Collapse
|
|
14
|
Combined Curcumin and Luteolin Synergistically Inhibit Colon Cancer Associated with Notch1 and TGF-β Signaling Pathways in Cultured Cells and Xenograft Mice. Cancers (Basel) 2022; 14:cancers14123001. [PMID: 35740666 PMCID: PMC9221484 DOI: 10.3390/cancers14123001] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/06/2022] [Accepted: 06/16/2022] [Indexed: 02/01/2023] Open
Abstract
This study aimed to select a combination of curcumin and luteolin, two phytochemicals from food, at lower concentrations with a higher inhibitory effect on colon cancer growth and investigate possible molecular mechanisms of this anti-colon cancer effect. By pairwise combination screening, we identified that the combination of curcumin (CUR) at 15 μM and luteolin (LUT) at 30 μM (C15L30) synergistically suppressed the proliferation of human colon cancer CL-188 cells, but the individual chemicals had a little inhibitory effect at the selected concentrations. This result was also confirmed in other colon cancer DLD-1cells, suggesting that this synergistic inhibitory effect of C15L30 applies to different colon cancer cells. The combination C15L30 synergistically suppressed the wound closure (wound healing assay) in CL-188 cells. We also found that the combination of CUR and LUT (at 20 mg/kg/day and 10 mg/kg/day, respectively, IP injection, 5 days for 2 weeks) synergistically suppressed tumor growth in CL-188 cell-derived xenograft mice. Western blot results showed that protein levels of Notch1 and TGF-β were synergistically reduced by the combination, both in CL-188 cells and xenograft tumors. Tumor pathological analysis revealed that combined CUR and LUT synergistically increased necrosis, but the individual treatment with CUR and LUT had no significant effect on tumor necrosis. Therefore, combined curcumin and luteolin synergically inhibit colon cancer development by suppressing cell proliferation, necrosis, and migration associated with Notch1 and TGF-β pathways. This study provides evidence that colon cancer may be prevented/treated by consuming foods having high levels of luteolin and curcumin in humans.
Collapse
|
|
15
|
Jo MK, Moon CM, Kim EJ, Kwon JH, Fei X, Kim SE, Jung SA, Kim M, Mun YC, Ahn YH, Seo SY, Kim TI. Suppressive effect of α-mangostin for cancer stem cells in colorectal cancer via the Notch pathway. BMC Cancer 2022; 22:341. [PMID: 35351071 PMCID: PMC8962146 DOI: 10.1186/s12885-022-09414-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 03/08/2022] [Indexed: 12/14/2022] Open
Abstract
Abstract
Background
Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. α-mangostin (αM) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of αM on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs.
Methods
The cell viability assay was performed to determine the optimal concentration of αM. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the αM-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of αM on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of αM in combination with 5-FU was investigated using a xenograft mouse model.
Results
αM inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. αM treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. αM markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, αM attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the αM group and in the αM group with 5-FU treatment.
Conclusion
This study shows that low-dose αM inhibits CSCs in CRC and suppresses 5-FU–induced augmentation of CSCs via the Notch signaling pathway.
Collapse
|
|
16
|
Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
Collapse
Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| |
Collapse
|
|
17
|
Zhang Y, Murphy S, Lu X. Cancer-cell-intrinsic mechanisms regulate MDSCs through cytokine networks. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 375:1-31. [PMID: 36967150 DOI: 10.1016/bs.ircmb.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Immunotherapy has shifted the paradigm of cancer treatment. However, the majority of cancer patients display de novo or acquired resistance to immunotherapy. One of the main mechanisms of immunotherapy resistance is the immunosuppressive microenvironment dominated by the myeloid-derived suppressor cells (MDSCs). Emerging evidence demonstrates that genetic or epigenetic aberrations in cancer cells shape the accumulation and activation of MDSCs. Understanding this genotype-immunophenotype relationship is critical to the rational design of combination immunotherapy. Here, we review the mechanisms of how molecular changes in cancer cells induce recruitment and reprogram the function of tumor-infiltrating myeloid cells, particularly MDSCs. Tumor-infiltrating MDSCs elicit various pro-tumor functions to promote tumor cell fitness, immune evasion, angiogenesis, tissue remodeling, and metastasis. Through understanding the genotype-immunophenotype relationship between neoplastic cells and MDSCs, new approaches can be developed to tailor current immunotherapy strategies to improve cancer patient outcomes.
Collapse
|
|
18
|
Martinez Lyons A, Boulter L. The developmental origins of Notch-driven intrahepatic bile duct disorders. Dis Model Mech 2021; 14:dmm048413. [PMID: 34549776 PMCID: PMC8480193 DOI: 10.1242/dmm.048413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The Notch signaling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, cell fate specification, and maintenance of stem and progenitor cell populations. In the vertebrate liver, an absence of Notch signaling results in failure to form bile ducts, a complex tubular network that radiates throughout the liver, which, in healthy individuals, transports bile from the liver into the bowel. Loss of a functional biliary network through congenital malformations during development results in cholestasis and necessitates liver transplantation. Here, we examine to what extent Notch signaling is necessary throughout embryonic life to initiate the proliferation and specification of biliary cells and concentrate on the animal and human models that have been used to define how perturbations in this signaling pathway result in developmental liver disorders.
Collapse
Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
| |
Collapse
|
|
19
|
Wang HW, Yan XL, Wang LJ, Zhang MH, Yang CH, Wei-Liu, Jin KM, Bao Q, Li J, Wang K, Xing BC. Characterization of genomic alterations in Chinese colorectal cancer patients with liver metastases. J Transl Med 2021; 19:313. [PMID: 34281583 PMCID: PMC8287676 DOI: 10.1186/s12967-021-02986-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/10/2021] [Indexed: 12/13/2022] Open
Abstract
Background The exploration of genomic alterations in Chinese colorectal liver metastasis (CRLM) is limited, and corresponding genetic biomarkers for patient’s perioperative management are still lacking. This study aims to understand genome diversification and complexity that developed in CRLM. Methods A custom-designed IDT capture panel including 620 genes was performed in the Chinese CRLM cohort, which included 396 tumor samples from metastatic liver lesions together with 133 available paired primary tumors. Results In this Chinese CRLM cohort, the top-ranked recurrent mutated genes were TP53 (324/396, 82%), APC (302/396, 76%), KRAS (166/396, 42%), SMAD4 (54/396, 14%), FLG (52/396, 13%) and FBXW7 (43/396, 11%). A comparison of CRLM samples derived from left- and right-sided primary lesions confirmed that the difference in survival for patients with different primary tumor sites could be driven by variations in the transforming growth factor β (TGF-β), phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways. Certain genes had a higher variant rate in samples with metachronous CRLM than in samples with simultaneous metastasis. Overall, the metastasis and primary tumor samples displayed highly consistent genomic alterations, but there were some differences between individually paired metastases and primary tumors, which were mainly caused by copy number variations. Conclusion We provide a comprehensive depiction of the genomic alterations in Chinese patients with CRLM, providing a fundamental basis for further personalized therapy applications. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02986-0.
Collapse
Affiliation(s)
- Hong-Wei Wang
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Xiao-Luan Yan
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Li-Jun Wang
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Meng-Huan Zhang
- GloriousMed Clinical Laboratory (Shanghai) Co., Ltd, Shanghai, China
| | - Chun-He Yang
- GloriousMed Clinical Laboratory (Shanghai) Co., Ltd, Shanghai, China
| | - Wei-Liu
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Ke-Min Jin
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Quan Bao
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Juan Li
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Kun Wang
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China
| | - Bao-Cai Xing
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Haidian District, Beijing, China.
| |
Collapse
|
|
20
|
Jimenez-Luna C, González-Flores E, Ortiz R, Martínez-González LJ, Antúnez-Rodríguez A, Expósito-Ruiz M, Melguizo C, Caba O, Prados J. Circulating PTGS2, JAG1, GUCY2C and PGF mRNA in Peripheral Blood and Serum as Potential Biomarkers for Patients with Metastatic Colon Cancer. J Clin Med 2021; 10:2248. [PMID: 34067294 PMCID: PMC8196898 DOI: 10.3390/jcm10112248] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 12/24/2022] Open
Abstract
Genes involved in the angiogenic process have been proposed for the diagnosis and therapeutic response of metastatic colorectal cancer (CRC). This study aimed to investigate the value of PTGS2, JAG1, GUCY2C and PGF-circulating RNA as biomarkers in metastatic CRC. Blood cells and serum mRNA from 59 patients with metastatic CRC and 47 healthy controls were analyzed by digital PCR. The area under the receiver operating characteristic curve (AUC) was used to estimate the diagnostic value of each mRNA alone or mRNA combinations. A significant upregulation of the JAG1, PTGS2 and GUCY2C genes in blood cells and serum samples from metastatic CRC patients was detected. Circulating mRNA levels in the serum of all genes were significantly more abundant than in blood. The highest discrimination ability between metastatic CRC patients and healthy donors was obtained with PTGS2 (AUC of 0.984) and GUCY2C (AUC of 0.896) in serum samples. Biomarker combinations did not improve the discriminatory capacity of biomarkers separately. Analyzed biomarkers showed no correlation with overall survival or progression-free survival, but GUCY2C and GUCY2C/PTGS2 expression in serum correlated significantly with the response to antiangiogenic agents. These findings demonstrate that assessment of genes involved in the angiogenic process may be a potential non-invasive diagnostic tool for metastatic CRC and its response to antiangiogenic therapy.
Collapse
Affiliation(s)
- Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; (C.J.-L.); (R.O.); (O.C.); (J.P.)
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain;
| | - Encarnación González-Flores
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain;
- Medical Oncology Service, Hospital Virgen de las Nieves, 18014 Granada, Spain
| | - Raul Ortiz
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; (C.J.-L.); (R.O.); (O.C.); (J.P.)
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain;
| | - Luis J. Martínez-González
- GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain; (L.J.M.-G.); (A.A.-R.)
| | - Alba Antúnez-Rodríguez
- GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain; (L.J.M.-G.); (A.A.-R.)
| | - Manuela Expósito-Ruiz
- Unit of Biostatistics, Department of Statistics and Operations Research, School of Medicine, University of Granada, 18071 Granada, Spain;
| | - Consolación Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; (C.J.-L.); (R.O.); (O.C.); (J.P.)
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain;
| | - Octavio Caba
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; (C.J.-L.); (R.O.); (O.C.); (J.P.)
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain;
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; (C.J.-L.); (R.O.); (O.C.); (J.P.)
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain;
| |
Collapse
|
|
21
|
Meisel CT, Porcheri C, Mitsiadis TA. Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression. Cells 2020; 9:cells9081879. [PMID: 32796631 PMCID: PMC7463613 DOI: 10.3390/cells9081879] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/06/2023] Open
Abstract
The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.
Collapse
|
|
22
|
Gonulcu SC, Unal B, Bassorgun IC, Ozcan M, Coskun HS, Elpek GO. Expression of Notch pathway components (Numb, Itch, and Siah-1) in colorectal tumors: A clinicopathological study. World J Gastroenterol 2020; 26:3814-3833. [PMID: 32774060 PMCID: PMC7383841 DOI: 10.3748/wjg.v26.i26.3814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/18/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs, including the colon. Accordingly, studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression. Although Numb, Itch, and seven in absentia homolog-1 (Siah-1) have been shown to contribute to the regulation of Notch signaling, their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date. AIM To evaluate Numb, Itch, and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior. METHODS Expression of Notch-1, Numb, Itch, and Siah-1 was investigated in 50 colorectal carcinomas, 30 adenomas, and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) analyses. RESULTS In contrast to Notch-1, which is expressed at higher levels in tumor tissues and adenomas, expression of Numb, Itch, and Siah-1 was stronger and more frequent in normal mucosa (P < 0.01). There was a positive correlation between Notch-1 expression and high histological grade, the presence of lymph node metastasis, and advanced-stage tumors, whereas expression of Numb, Itch, and Siah-1 was absent or reduced in tumors with these clinicopathological parameters (P < 0.05). In survival analysis, expression of Notch was related to poor prognosis but that of Numb, Itch, and Siah-1 correlated with improved survival (P < 0.05). Multivariate analysis revealed Notch-1 expression and loss of Numb expression to be independent prognostic parameters together with lymph node metastasis (P < 0.05). CONCLUSION Our findings support the role of Notch-1 in colorectal carcinoma and indicate that loss of Numb, Itch, and Siah-1 expression is associated with carcinogenesis. Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma (CRC) progression and might play an essential role in approaches targeting Notch as novel molecular therapies for CRC.
Collapse
Affiliation(s)
- Sinem Cil Gonulcu
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | - Betul Unal
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | | | - Mualla Ozcan
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | - Hasan Senol Coskun
- Department of Oncology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| |
Collapse
|
|
23
|
A Review on Notch Signaling and Colorectal Cancer. Cells 2020; 9:cells9061549. [PMID: 32630477 PMCID: PMC7349609 DOI: 10.3390/cells9061549] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression.
Collapse
|
|
24
|
Matsuoka T, Yashiro M. Precision medicine for gastrointestinal cancer: Recent progress and future perspective. World J Gastrointest Oncol 2020; 12:1-20. [PMID: 31966910 PMCID: PMC6960076 DOI: 10.4251/wjgo.v12.i1.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 10/12/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.
Collapse
Affiliation(s)
- Tasuku Matsuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| |
Collapse
|
|
25
|
Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell 2019; 36:319-336.e7. [PMID: 31526760 PMCID: PMC6853173 DOI: 10.1016/j.ccell.2019.08.003] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/31/2019] [Accepted: 08/06/2019] [Indexed: 12/14/2022]
Abstract
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
Collapse
Affiliation(s)
| | - Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Joshua D Leach
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | | | | | | | - Valérie M Wouters
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Jatin Roper
- Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA
| | - Timothy J Kendall
- Division of Pathology/Centre for Inflammation Research, University of Edinburgh, UK
| | - Campbell S Roxburgh
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Craig Nourse
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany
| | | | - Ann Hedley
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Omer H Yilmaz
- Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Mamunur Rashid
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Andrew V Biankin
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | | | - David J Adams
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Simon T Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Colin W Steele
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
| |
Collapse
|
|
26
|
Zhang L, Chen J, Yong J, Qiao L, Xu L, Liu C. An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:384. [PMID: 31477177 PMCID: PMC6720101 DOI: 10.1186/s13046-019-1382-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 08/13/2019] [Indexed: 12/29/2022]
Abstract
Background Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its expression pattern and biological function in HCC are unknown. Methods The expression levels of Notch1 and RNF187 were assessed in two independent cohorts of HCC tissues, and modulation of Notch1 in HCC cells was performed to explore the regulatory role of Notch1 in HCC metastasis. RNA-sequencing (RNA-seq), bioinformatics analysis, luciferase reporter analysis, and chromatin immunoprecipitation assay (ChIP) were used to clarify the relationship between Notch1 signaling and its potential target Ring finger protein 187 (RNF187). Gain- and loss-of-function studies were used to dissect the role of Notch1-RNF187 signaling in promoting HCC metastasis. The impact of Notch1-RNF187 activity in determining clinical prognosis for HCC patients was evaluated by multivariate Cox regression. Results By RNA-seq, luciferase reporter analysis, and ChIP assay, RNF187 was confirmed to be a direct transcriptional target of Notch1, as Notch1 could activate RNF187 promoter whereas the pro-migratory and pro-invasive effects of Notch1 were significantly attenuated by RNF187 knockdown. Meanwhile, RNF187 silencing could attenuate the Notch1-dependent epithelial-mesenchymal transition (EMT). Moreover, overexpression of RNF187 counteracted the inhibitory effect of Notch1 knockdown on cancer progression. Importantly, HCC patients with high level of hepatic Notch1 expression had shorter disease-free survival (DFS) than those with low level of hepatic Notch1 expression. Furthermore, patients with high level of Notch1 and RNF187 co-expression showed the shortest DFS. The expression level of Notch1 and RNF187 was an independent prognostic factor for HCC. Conclusions For the first time we identified that RNF187 is an essential factor for Notch1 to promote invasion and metastasis of HCC. Of highly clinical relevance, we found that activation of Notch1-RNF187 correlates with a worse prognosis of HCC patients. These findings provide a solid foundation for developing novel strategies to tackle HCC metastasis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1382-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Lei Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Rd, Guangzhou, 510120, China
| | - Jiewei Chen
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Juanjuan Yong
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Leibo Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Rd, Guangzhou, 510120, China.
| | - Chao Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Rd, Guangzhou, 510120, China.
| |
Collapse
|
|
27
|
Du Y, Li D, Li N, Su C, Yang C, Lin C, Chen M, Wu R, Li X, Hu G. POFUT1 promotes colorectal cancer development through the activation of Notch1 signaling. Cell Death Dis 2018; 9:995. [PMID: 30250219 PMCID: PMC6155199 DOI: 10.1038/s41419-018-1055-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 09/08/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022]
Abstract
Copy number variations (CNVs) are key drivers of colorectal cancer (CRC). Our previous studies revealed that protein O-fucosyltransferase 1 (POFUT1) overexpression is driven by CNVs during CRC development. The potential role and underlying mechanisms of POFUT1 in CRC were not investigated. In this study, we analyzed the expression of POFUT1 in CRC from cosmic and TCGA databases and confirmed that POFUT1 is highly expressed in CRC. We used well characterized CRC cell lines, including SW620 and HCT116 to establish a model POFUT1 knockdown cell line. Using these cells, we investigated the role of POFUT1 in CRC. Our data revealed that silencing POFUT1 in CRC cells inhibits cell proliferation, decreases cell invasion and migration, arrests cell cycle progression, and stimulates CRC cell apoptosis in vitro. We further demonstrate that POFUT1 silencing dramatically suppresses CRC tumor growth and transplantation in vivo. We additionally reveal new mechanistic insights into the role of POFUT1 during CRC, through demonstrating that POFUT1 silencing inhibits Notch1 signaling. Taken together, our findings demonstrate that POFUT1 is a tumor activating gene during CRC development, which positively regulates CRC tumor progression through activating Notch1.
Collapse
Affiliation(s)
- Yuheng Du
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Daojiang Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Nanpeng Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Chen Su
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Chunxing Yang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Miao Chen
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Runliu Wu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Xiaorong Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Gui Hu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
| |
Collapse
|
|
28
|
Zhang W, Chen H, Sun Z, Qiu C, Xiao J, Luo W, Liu D, Yan Z, Ou H, Wen X, Li G, Huang G. A systematic analysis of the association between Notch1 expression and the patients with digestive tract cancers. Biomark Med 2018; 12:1049-1062. [PMID: 30043645 DOI: 10.2217/bmm-2017-0429] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
AIM Notch1 expression remains controversial on digestive tract cancers. This meta-analysis was performed to assess the clinicopathological significance of Notch1 expression in individuals with digestive tract cancers, mainly involving esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), pancreatic cancer (PC) and colorectal cancer (CRC). METHODS Available articles were searched from the online databases, and the meta-analysis was done using Review Manager software 5.3. RESULTS 35 studies were included in this analysis (6187 samples). Notch1 is downregulated in esophageal squamous cell carcinoma (p < 0.00001), Notch1 expression at high levels was detected in GC (p = 0.02) and CRC (p < 0.001), and no significant difference exists between PC and normal tissue (p = 0.76). CONCLUSION Notch1 overexpression in GC and CRC suggested aggressive biological behaviors, and Notch1 may be a biomarker in digestive tract cancers.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Hong Chen
- The First Hospital of Qiqihaer City, Qiqihaer, Heilongjiang, 161005, PR China
| | - Zhihui Sun
- The First Hospital of Qiqihaer City, Qiqihaer, Heilongjiang, 161005, PR China
| | - Chengyu Qiu
- The First Hospital of Qiqihaer City, Qiqihaer, Heilongjiang, 161005, PR China
| | - Jingjie Xiao
- Department of Physiology Medicine School of Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Wenli Luo
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Da Liu
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Zhitao Yan
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Huajing Ou
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Xiaoman Wen
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Ganxiong Li
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| | - Gang Huang
- Department of Gerontology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, PR China
| |
Collapse
|
|
29
|
Huang XY, Gan RH, Xie J, She L, Zhao Y, Ding LC, Su BH, Zheng DL, Lu YG. The oncogenic effects of HES1 on salivary adenoid cystic carcinoma cell growth and metastasis. BMC Cancer 2018; 18:436. [PMID: 29665790 PMCID: PMC5904989 DOI: 10.1186/s12885-018-4350-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 04/08/2018] [Indexed: 12/19/2022] Open
Abstract
Background Our previous study demonstrated a close relationship between NOTCH signaling pathway and salivary adenoid cystic carcinoma (SACC). HES1 is a well-known target gene of NOTCH signaling pathway. The purpose of the present study was to further explore the molecular mechanism of HES1 in SACC. Methods Comparative transcriptome analyses by RNA-Sequencing (RNA-Seq) were employed to reveal NOTCH1 downstream gene in SACC cells. Immunohistochemical staining was used to detect the expression of HES1 in clinical samples. After HES1-siRNA transfected into SACC LM cells, the cell proliferation and cell apoptosis were tested by suitable methods; animal model was established to detect the change of growth ability of tumor. Transwell and wound healing assays were used to evaluate cell metastasis and invasion. Results We found that HES1 was strongly linked to NOTCH signaling pathway in SACC cells. The immunohistochemical results implied the high expression of HES1 in cancerous tissues. The growth of SACC LM cells transfected with HES1-siRNAs was significantly suppressed in vitro and tumorigenicity in vivo by inducing cell apoptosis. After HES1 expression was silenced, the SACC LM cell metastasis and invasion ability was suppressed. Conclusions The results of this study demonstrate that HES1 is a specific downstream gene of NOTCH1 and that it contributes to SACC proliferation, apoptosis and metastasis. Our findings serve as evidence indicating that HES1 may be useful as a clinical target in the treatment of SACC. Electronic supplementary material The online version of this article (10.1186/s12885-018-4350-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Xiao-Yu Huang
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China
| | - Rui-Huan Gan
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China
| | - Jian Xie
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China
| | - Lin She
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China
| | - Yong Zhao
- Department of Pathology, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China
| | - Lin-Can Ding
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China
| | - Bo-Hua Su
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China
| | - Da-Li Zheng
- Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China.
| | - You-Guang Lu
- Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China. .,Key laboratory of stomatology, School of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, China.
| |
Collapse
|
|
30
|
The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance. Oncotarget 2017; 7:28273-85. [PMID: 27070088 PMCID: PMC5053726 DOI: 10.18632/oncotarget.8626] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 02/28/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Dysregulation of the canonical Wnt signaling pathway has been implicated in colorectal cancer (CRC) development as well as incipient stages of malignant transformation. In this study, we investigated the antitumor effects of AZ1366 (a novel tankyrase inhibitor) as a single agent and in combination with irinotecan in our patient derived CRC explant xenograft models. RESULTS Six out of 18 CRC explants displayed a significant growth reduction to AZ1366. There was one CRC explant (CRC040) that reached the threshold of sensitivity (TGII ≤ 20%) in this study. In addition, the combination of AZ1366 + irinotecan demonstrated efficacy in 4 out of 18 CRC explants. Treatment effects on the WNT pathway revealed that tankyrase inhibition was ineffective at reducing WNT dependent signaling. However, the anti-tumor effects observed in this study were likely a result of alternative tankyrase effects whereby tankyrase inhibition reduced NuMA levels. MATERIALS AND METHODS Eighteen CRC explants were treated with AZ1366 single agent or in combination for 28 days and treatment responses were assessed. Pharmacokinetic (AZ1366 drug concentrations) and pharmacodynamic effects (Axin2 levels) were investigated over 48 hours. Immunohistochemistry of nuclear β-catenin levels as well as western blot was employed to examine the treatment effects on the WNT pathway as well as NuMA. CONCLUSIONS Combination AZ1366 and irinotecan achieved greater anti-tumor effects compared to monotherapy. Activity was limited to CRC explants that displayed irinotecan resistance and increased protein levels of tankyrase and NuMA.
Collapse
|
|
31
|
Cao F, Wang S, Wang H, Tang W. Fibroblast activation protein-α in tumor cells promotes colorectal cancer angiogenesis via the Akt and ERK signaling pathways. Mol Med Rep 2017; 17:2593-2599. [PMID: 29207091 DOI: 10.3892/mmr.2017.8155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 09/06/2017] [Indexed: 11/06/2022] Open
Abstract
Fibroblast activation protein-α (FAP-α) is a cell surface serine protease of the post-prolyl peptidase family, and stromal FAP-α expression may serve important functions in tumor occurrence and progression. In recent years, FAP-α expression in tumor cells has been detected in a number of types of tumor, and its roles in tumor growth and metastasis have been reported. However, the presence of FAP-α in colorectal cancer (CRC) cells lacks sufficient evidence and its role in angiogenesis remains unknown. The present study confirmed FAP-α expression in CRC cells at the tissue and cellular level, using immunohistochemistry and western blot analysis, respectively; it additionally identified that FAP-α in CRC cells was positively associated with vascular endothelial growth factor (VEGF)-A expression and microvessel density in stained tissue samples for the first time. In addition, western blotting identified that FAP-α overexpression in SW1116 cells significantly upregulated VEGF-A expression, and silencing of FAP-α in HT29 cells markedly inhibited VEGF-A expression. Survival analysis demonstrated that patients with high expression of FAP-α and VEGF-A had the shortest survival time. To detect the effects of FAP-α on human umbilical vein endothelial cells (HUVECs), conditioned medium (CM) from CRC cell lines was used and it was identified that CM from SW1116 cells with overexpressed FAP-α exhibited significantly increased VEGF-R2, phosphorylated extracellular signal-regulated kinase (p-ERK) and p-RAC-α serine/threonine-protein kinase (Akt) in HUVECs, in addition to the proliferation rate. Conversely, CM from HT29 cells with FAP-α silenced exhibited a significantly inhibited proliferation rate. Molecular mechanism analysis demonstrated that p-ERK and p-Akt in SW1116 and HT29 cells were affected by alterations in FAP-α expression, and treatment with a p-ERK inhibitor (U0126) and p-Akt inhibitor (LY294002) ameliorated VEGF-A upregulation induced by FAP-α overexpression. All the results confirmed the presence of FAP-α in CRC cells and suggested that FAP-α may effectively promote angiogenesis in CRC via the Akt and ERK signaling pathways.
Collapse
Affiliation(s)
- Feng Cao
- Department of Medicine 13, Xintai People's Hospital, Taian, Shandong 271000, P.R. China
| | - Songsong Wang
- Department of Medicine 13, Xintai People's Hospital, Taian, Shandong 271000, P.R. China
| | - Huanqin Wang
- Department of Medicine 13, Xintai People's Hospital, Taian, Shandong 271000, P.R. China
| | - Wei Tang
- Department of Anesthesiology, 88 Hospital of PLA, Taian, Shandong 271000, P.R. China
| |
Collapse
|
|
32
|
Li G, Zhou Z, Zhou H, Zhao L, Chen D, Chen H, Zou H, Qi Y, Jia W, Pang L. The expression profile and clinicopathological significance of Notch1 in patients with colorectal cancer: a meta-analysis. Future Oncol 2017; 13:2103-2118. [PMID: 28984154 DOI: 10.2217/fon-2017-0178] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
AIM This meta-analysis was conducted to evaluate the clinicopathological significance of Notch1 expression in patients with colorectal cancer (CRC). METHODS Available articles were searched from diverse databases, and the meta-analysis was done by using Stata 12.0 software. RESULTS Thirteen studies were included in this analysis (3401 samples). The Notch1 expression in CRC tissues was significantly higher than that in normal tissues statistically (OR: 15.46; 95% CI: 8.11-29.45; p = 0.003), and were associated with lymph node metastasis, tumor stage, depth of infiltration and histological differentiation. DISCUSSION There is a close relationship between higher Notch1 expression in CRC. Notch1 may be involved in tumor progression, invasion and metastasis with CRC. CONCLUSION Notch1 overexpression in CRC suggested aggressive biological behaviors and thus implying that Notch1 may be a useful biomarker in CRCs.
Collapse
Affiliation(s)
- Ganxiong Li
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zheng Zhou
- Department of Stomatology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Hongrun Zhou
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Lili Zhao
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Dongdong Chen
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Hongzhi Chen
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Hong Zou
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yan Qi
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Wei Jia
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Lijuan Pang
- Department of Pathology & Key Laboratory of Xinjiang Endemic & Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China.,Department of Pathology, the First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| |
Collapse
|
|
33
|
Robinson SC, Klobucar K, Pierre CC, Ansari A, Zhenilo S, Prokhortchouk E, Daniel JM. Kaiso differentially regulates components of the Notch signaling pathway in intestinal cells. Cell Commun Signal 2017. [PMID: 28637464 PMCID: PMC5480165 DOI: 10.1186/s12964-017-0178-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Background In mammalian intestines, Notch signaling plays a critical role in mediating cell fate decisions; it promotes the absorptive (or enterocyte) cell fate, while concomitantly inhibiting the secretory cell fate (i.e. goblet, Paneth and enteroendocrine cells). We recently reported that intestinal-specific Kaiso overexpressing mice (KaisoTg) exhibited chronic intestinal inflammation and had increased numbers of all three secretory cell types, hinting that Kaiso might regulate Notch signaling in the gut. However, Kaiso’s precise role in Notch signaling and whether the KaisoTg secretory cell fate phenotype was linked to Kaiso-induced inflammation had yet to be elucidated. Methods Intestines from 3-month old Non-transgenic and KaisoTg mice were “Swiss” rolled and analysed for the expression of Notch1, Dll-1, Jagged-1, and secretory cell markers by immunohistochemistry and immunofluorescence. To evaluate inflammation, morphological analyses and myeloperoxidase assays were performed on intestines from 3-month old KaisoTg and control mice. Notch1, Dll-1 and Jagged-1 expression were also assessed in stable Kaiso-depleted colon cancer cells and isolated intestinal epithelial cells using real time PCR and western blotting. To assess Kaiso binding to the DLL1, JAG1 and NOTCH1 promoter regions, chromatin immunoprecipitation was performed on three colon cancer cell lines. Results Here we demonstrate that Kaiso promotes secretory cell hyperplasia independently of Kaiso-induced inflammation. Moreover, Kaiso regulates several components of the Notch signaling pathway in intestinal cells, namely, Dll-1, Jagged-1 and Notch1. Notably, we found that in KaisoTg mice intestines, Notch1 and Dll-1 expression are significantly reduced while Jagged-1 expression is increased. Chromatin immunoprecipitation experiments revealed that Kaiso associates with the DLL1 and JAG1 promoter regions in a methylation-dependent manner in colon carcinoma cell lines, suggesting that these Notch ligands are putative Kaiso target genes. Conclusion Here, we provide evidence that Kaiso’s effects on intestinal secretory cell fates precede the development of intestinal inflammation in KaisoTg mice. We also demonstrate that Kaiso inhibits the expression of Dll-1, which likely contributes to the secretory cell phenotype observed in our transgenic mice. In contrast, Kaiso promotes Jagged-1 expression, which may have implications in Notch-mediated colon cancer progression. Electronic supplementary material The online version of this article (doi:10.1186/s12964-017-0178-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Shaiya C Robinson
- Department of Biology, McMaster University, Hamilton, L8S 4K1, ON, Canada
| | - Kristina Klobucar
- Department of Biology, McMaster University, Hamilton, L8S 4K1, ON, Canada.,Current address: Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, L8N 3Z5, ON, Canada
| | - Christina C Pierre
- Department of Biology, McMaster University, Hamilton, L8S 4K1, ON, Canada.,Current address: Department of Life Science, University of the West Indies at St. Augustine, St. Augustine, Trinidad and Tobago
| | - Amna Ansari
- Department of Biology, McMaster University, Hamilton, L8S 4K1, ON, Canada
| | - Svetlana Zhenilo
- Federal Research Centre of Biotechnology, Russian Academy of Sciences, Moscow, Russian Federation, 117312
| | - Egor Prokhortchouk
- Federal Research Centre of Biotechnology, Russian Academy of Sciences, Moscow, Russian Federation, 117312
| | - Juliet M Daniel
- Department of Biology, McMaster University, Hamilton, L8S 4K1, ON, Canada.
| |
Collapse
|
|
34
|
Sugiyama M, Oki E, Nakaji Y, Tsutsumi S, Ono N, Nakanishi R, Sugiyama M, Nakashima Y, Sonoda H, Ohgaki K, Yamashita N, Saeki H, Okano S, Kitao H, Morita M, Oda Y, Maehara Y. High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer. Cancer Sci 2017; 107:1705-1716. [PMID: 27589478 PMCID: PMC5132269 DOI: 10.1111/cas.13075] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 08/21/2016] [Accepted: 08/28/2016] [Indexed: 12/20/2022] Open
Abstract
The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged‐1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens. Expression of JAG1 and E‐cadherin and their associations with clinicopathologic characteristics, overall survival (OS) and relapse‐free survival (RFS) were evaluated. In vitro studies using compounds to regulate intracellular signaling and small interfering RNA to silence JAG1 were performed in a colon cancer cell line. JAG1 expression in cancerous tissues was weak, moderate or strong in 32%, 36% and 32% of specimens, respectively, and correlated with histologic type and T stage. In multivariate analysis, JAG1 expression, histologic type and lymphatic invasion independently correlated with OS and RFS. The combination of high JAG1 expression and low E‐cadherin expression had an additive effect toward poorer OS and RFS compared with the low JAG1/high E‐cadherin expression subtype. A significant correlation between JAG1 expression and KRAS status was detected in groups stratified as high E‐cadherin expression. In vitro studies suggested that RAS‐MEK‐MAP kinase and the Wnt pathways positively regulated JAG1 expression. Gene silencing with siJAG1 indicated that JAG1 promotes the transition from epithelial to mesenchymal characteristics and cell growth. High expression of JAG1 is regulated by various pathways and is associated with poor prognosis through promoting the epithelial to mesenchymal transition and cell proliferation or maintaining cell survival in CRC.
Collapse
Affiliation(s)
- Masakazu Sugiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yu Nakaji
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoshi Tsutsumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naomi Ono
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryota Nakanishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masahiko Sugiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichiro Nakashima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideto Sonoda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kippei Ohgaki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nami Yamashita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Okano
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroyuki Kitao
- Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaru Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
35
|
Huang T, Zhou Y, Cheng ASL, Yu J, To KF, Kang W. NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors? Mol Cancer 2016; 15:80. [PMID: 27938406 PMCID: PMC5148895 DOI: 10.1186/s12943-016-0566-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 12/01/2016] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC.
Collapse
Affiliation(s)
- 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, Shatin, N.T, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - 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, Shatin, N.T, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Alfred S L Cheng
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People's Republic of 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, Shatin, N.T, Hong Kong, SAR, People's Republic of China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of 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, Shatin, N.T, Hong Kong, SAR, People's Republic of China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
| |
Collapse
|
|
36
|
van Niekerk G, Davids LM, Hattingh SM, Engelbrecht AM. Cancer stem cells: A product of clonal evolution? Int J Cancer 2016; 140:993-999. [PMID: 27676693 DOI: 10.1002/ijc.30448] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 09/19/2016] [Indexed: 12/30/2022]
Abstract
The cancer stem cell (CSC) model has emerged as a prominent paradigm for explaining tumour heterogeneity. CSCs in tumour recurrence and drug resistance have also been implicated in a number of studies. In fact, CSCs are often identified by their expression of drug-efflux proteins which are also highly expressed in normal stem cells. Similarly, pro-survival or proliferation signalling often exhibited by stem cells is regularly reported as being upregulated by CSC. Here we review evidence suggesting that many aspects of CSCs are more readily described by clonal evolution. As an example, cancer cells often exhibit copy number gains of genes involved in drug-efflux proteins and pro-survival signalling. Consequently, clonal selection for stem cell traits may result in cancer cells developing "stemness" traits which impart a fitness advantage, without strictly following a CSC model. Finally, since symmetric cell division would give rise to more cells than asymmetric division, it is expected that more advanced tumours would depart from a CSC. Collectively, these observations suggest clonal evolution may explain many aspects of the CSC.
Collapse
Affiliation(s)
- Gustav van Niekerk
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Lester M Davids
- Department of Human Biology, Division of Cell Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Suzèl M Hattingh
- Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| |
Collapse
|
|
37
|
Bagby S, Messersmith WA, Pitts TM, Capasso A, Varella-Garcia M, Klauck PJ, Kim J, Tan AC, Eckhardt SG, Tentler JJ, Arcaroli J. Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies. J Vis Exp 2016. [PMID: 27768028 DOI: 10.3791/54393] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor pieces are injected subcutaneously into athymic nude mice (immunocompromised, T cell deficient) to create a bank of tumors and subsequently are passaged into different generations of mice in order to maintain these tumors from patients. Importantly, cellular heterogeneity of the original tumor is closely emulated in this model, which provides a more clinically relevant model for evaluation of drug efficacy studies (single agent and combination), biomarker analysis, resistant pathways and cancer stem cell biology. Some limitations of the PDTX model include the replacement of the human stroma with mouse stroma after the first generation in mice, inability to investigate treatment effects on metastasis due to the subcutaneous injections of the tumors, and the lack of evaluation of immunotherapies due to the use of immunocompromised mice. However, even with these limitations, the PDTX model provides a powerful preclinical platform in the drug discovery process.
Collapse
Affiliation(s)
- Stacey Bagby
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | | | - Todd M Pitts
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | - Anna Capasso
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | | | - Peter J Klauck
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | - Jihye Kim
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | - Aik-Choon Tan
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | - S Gail Eckhardt
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | - John J Tentler
- Medicine, University of Colorado Denver Anschutz Medical Campus
| | - John Arcaroli
- Medicine, University of Colorado Denver Anschutz Medical Campus;
| |
Collapse
|
|
38
|
Zhang C, Ma X, Du J, Yao Z, Shi T, Ai Q, Chen X, Zhang Z, Zhang X, Yao X. MicroRNA-30a as a prognostic factor in urothelial carcinoma of bladder inhibits cellular malignancy by antagonising Notch1. BJU Int 2016; 118:578-89. [PMID: 26775686 DOI: 10.1111/bju.13407] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To explore the relation between microRNA-30a (miR-30a) and Notch1, and to evaluate the potential prognostic role of miR-30a in invasive urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS In all, 50 invasive UCB tissue specimens, along with the adjacent bladder tissue specimens were obtained, and the clinical parameters of the 50 patients were analysed. Bioinformatics analysis was performed and miR-30a was selected as a potential miRNA targeting Notch1, with a luciferase assay performed to verify the binding site between miR-30a and Notch1. Quantitative real-time reverse transcriptase-polymerase chain reaction was used to assess the RNA expressions of miR-30a and Notch1, while Western Blotting and immunohistochemical staining were used to assess the protein expression of Notch1. Finally, cell proliferation, cell cycle, cell migration and invasion assays were used to evaluate the cellular effects of miR-30a and Notch1 on the UCB cell lines T24 and 5637. RESULTS MiR-30a was downregulated in tumour tissues when compared with adjacent bladder tissues (P < 0.001), negatively correlating with Notch1 messenger RNA (R(2) 0.106, P = 0.021) in invasive UCB, and miR-30a expression further decreased in patients with shorter overall survival and disease-free survival (P = 0.039 and P = 0.037, respectively). The luciferase assay showed that miR-30a inhibited the Notch1 3'-untranslated region reporter activities in the T24 and 5637 cell lines (both P < 0.001). Both miR-30a and small interfering RNA Notch1 negatively regulated cell proliferation (P = 0.002 and P = 0.035 in T24; P = 0.029 and P = 0.037 in 5637 cell lines), activated cell cycle arrest (both P < 0.001 in T24; both P < 0.001 in 5637 cell lines), and prevented cellular migration (both P < 0.001 in T24; P = 0.003 and P < 0.001 in 5637 cell lines) and invasion (P = 0.009 and P = 0.006 in T24; P = 0.006 and P = 0.002 in 5637 cell lines) abilities. Ectopic Notch1 without the 3'untranslated region partially rescued the above-mentioned cellular effects of over-expressed miR-30a on T24 and 5637 cells. CONCLUSIONS MiR-30a lessens cellular malignancy by antagonising oncogene Notch1 and plays an effective prognostic role in invasive UCB.
Collapse
Affiliation(s)
- Chao Zhang
- Department of Genitourinary Oncology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xin Ma
- Department of Urology, China PLA General Hospital, Beijing, China
| | - Jun Du
- Department of Genitourinary Oncology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhiyong Yao
- Department of Urology, Air Force General Hospital, PLA, Beijing, China
| | - Taoping Shi
- Department of Urology, China PLA General Hospital, Beijing, China
| | - Qing Ai
- Department of Urology, China PLA General Hospital, Beijing, China
| | - Xusheng Chen
- Department of Genitourinary Oncology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhenting Zhang
- Department of Genitourinary Oncology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xu Zhang
- Department of Urology, China PLA General Hospital, Beijing, China
| | - Xin Yao
- Department of Genitourinary Oncology, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
| |
Collapse
|