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An C, Jiang C, Pei W, Li A, Wang M, Wang Y, Wang H, Zuo L. Intestinal epithelial cells in health and disease. Tissue Barriers 2025:2504744. [PMID: 40401816 DOI: 10.1080/21688370.2025.2504744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 04/23/2025] [Accepted: 05/06/2025] [Indexed: 05/23/2025] Open
Abstract
This comprehensive review delves into the pivotal role of intestinal epithelial cells in the context of various diseases. It provides an in-depth analysis of the diverse types and functions of these cells, explores the influence of multiple signaling pathways on their differentiation, and elucidates their critical roles in a spectrum of diseases. The significance of the gastrointestinal tract in maintaining overall health is extremely important and cannot be exaggerated. This complex and elongated organ acts as a crucial link between the internal and external environments, making it vulnerable to various harmful influences. Preserving the normal structure and function of the gut is essential for well-being. Intestinal epithelial cells serve as the primary defense mechanism within the gastrointestinal tract and play a crucial role in preventing harmful substances from infiltrating the body. As the main components of the digestive system, they not only participate in the absorption and secretion of nutrients and the maintenance of barrier function but also play a pivotal role in immune defense. Therefore, the health of intestinal epithelial cells is of vital importance for overall health.
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Affiliation(s)
- Chenchen An
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Chonggui Jiang
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Wangxiang Pei
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
| | - Ao Li
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, China
| | - Minghui Wang
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Yufei Wang
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Hua Wang
- Inflammation and Immune- Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for college students, Anhui Medical University, Hefei, China
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Lukacsovich D, Zambare W, Wu C, Huang H, Zhang W, Kim MJ, Alvarez J, Bercz A, Paty PB, Romesser PB, Wang L, Smith JJ, Chen XS. Integrating Tumor and Organoid DNA Methylation Profiles Reveals Robust Predictors of Chemotherapy Response in Rectal Cancer. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.28.25322951. [PMID: 40093220 PMCID: PMC11908278 DOI: 10.1101/2025.02.28.25322951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Rectal cancer patients display heterogeneous responses to neoadjuvant treatment-including the intensive total neoadjuvant therapy (TNT)-and reliable biomarkers are lacking to guide which tumors will benefit most from these regimens. Here, we profiled DNA methylation in tumor tissue and matched patient-derived organoids (PDOs) from 18 rectal cancer cases (50 total samples), leveraging the Illumina MethylationEPIC array and quality control filters that retained 771,964 CpG sites. Analyses used linear models (for tissue-only or PDO-only) and a joint linear mixed-effects approach (accounting for patient-level random effects) to identify significant CpGs associated with log-transformed FOLFOX IC50. We found that PDOs faithfully recapitulate patient-tumor methylation patterns (Spearman's correlation >0.95 among replicate organoids), and the joint model uncovered 745 CpGs tied to FOLFOX sensitivity, many of which were missed in tissue-only analyses. Differentially methylated regions reinforced that broader epigenetic blocks near TSS or enhancer regions may modulate chemo-resistance, while pathway enrichment pinpointed focal adhesion, ECM-receptor interaction, calcium signaling, and folate metabolism as key processes. A methylation risk score derived from these CpGs significantly predicted progression-free survival in an independent colorectal cancer cohort (p=0.019), outperforming single-sample-based signatures. These findings suggest that combining methylation profiles from both tumors and PDOs can expose robust epigenetic drivers of therapy response, aiding the development of clinically actionable biomarkers for rectal cancer TNT.
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Affiliation(s)
- David Lukacsovich
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Department of Radiation Oncology, Colorectal and Anal Cancer Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Wini Zambare
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Chao Wu
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Hanchen Huang
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Department of Radiation Oncology, Colorectal and Anal Cancer Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Wei Zhang
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Min Jung Kim
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Janet Alvarez
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Aron Bercz
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Philip B Paty
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Paul B Romesser
- Department of Radiation Oncology, Colorectal and Anal Cancer Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Lily Wang
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - J Joshua Smith
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - X Steven Chen
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
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Bordin F, Terriaca G, Apostolico A, Di Fiore A, Mir FT, Bellardinelli S, Bufalieri F, Bordone R, Bellardinilli F, Giannini G, Canettieri G, Di Marcotullio L, Ferretti E, Moretti M, De Smaele E. SMURF1 and SMURF2 directly target GLI1 for ubiquitination and proteasome-dependent degradation. Cell Death Discov 2024; 10:498. [PMID: 39695131 DOI: 10.1038/s41420-024-02260-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
The transcription factor GLI1 is the main and final effector of the Hedgehog signaling pathway, which is involved in embryonic development, cell proliferation and stemness. Whether activated through canonical or non-canonical mechanisms, GLI1 aberrant activity is associated with Hedgehog-dependent cancers, including medulloblastoma, as well as other tumoral contexts. Notwithstanding a growing body of evidence, which have highlighted the potential role of post translational modifications of GLI1, the complex mechanisms modulating GLI1 stability and activity have not been fully elucidated. Here, we present a novel role played by SMURF1 and SMURF2 in the suppression of the Hedgehog/GLI signaling pathway through a direct targeting of GLI1. Indeed, the two SMURFs can interact with GLI1, exploiting the proline rich regions present on GLI1 protein, and trigger its polyubiquitination and proteasomal degradation, leading to a suppression of the Hedgehog pathway activity and a reduction of Hh-dependent tumor cell proliferation. Overall, this study adds new relevance to a tumor suppressive role of SMURFs on the Hedgehog pathway and confers upon them the status of potential therapeutic tools, either in canonical or non-canonical Hedgehog pathway aberrant activation.
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Affiliation(s)
- Fabio Bordin
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Gloria Terriaca
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Adriano Apostolico
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Di Fiore
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Faranak Taj Mir
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Sara Bellardinelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Rosa Bordone
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Giuseppe Giannini
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | | | | | - Elisabetta Ferretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Marta Moretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
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Nie S, Zhang S, Wu R, Zhao Y, Wang Y, Wang X, Zhu M, Huang P. Scutellarin: pharmacological effects and therapeutic mechanisms in chronic diseases. Front Pharmacol 2024; 15:1470879. [PMID: 39575387 PMCID: PMC11578714 DOI: 10.3389/fphar.2024.1470879] [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: 07/26/2024] [Accepted: 10/17/2024] [Indexed: 11/24/2024] Open
Abstract
Scutellarin (SCU), a flavonoid glucuronide derived from Scutellaria barbata and Erigeron breviscapus, exhibits broad pharmacological effects with promising therapeutic potential in treating various chronic diseases. It has demonstrated efficacy in modulating multiple biological pathways, including antioxidant, anti-inflammatory, anti-apoptotic, and vasodilatory mechanisms. These protective roles make SCU a valuable compound in treating chronic diseases such as cerebrovascular diseases, cardiovascular diseases, neurodegenerative disorders, and metabolic diseases. Despite its multi-targeted effects, SCU faces challenges such as low bioavailability and limited clinical data, which hinder its widespread therapeutic application. Current research supports its potential to prevent oxidative stress, reduce inflammatory responses, and enhance cell survival in cells and rats. However, more comprehensive studies are required to clarify its molecular mechanisms and to develop strategies that enhance its bioavailability for clinical use. SCU could emerge as a potent therapeutic agent for the treatment of chronic diseases with complex pathophysiological mechanisms. This review examines the current literature on Scutellarin to provide a comprehensive understanding of its pharmacological activity, mechanisms of action, and therapeutic potential in treating chronic diseases.
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Affiliation(s)
- Shanshan Nie
- Department of Cardiovascular Disease, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Shan Zhang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Ruipeng Wu
- Department of Cardiovascular Disease, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yuhang Zhao
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yongxia Wang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinlu Wang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Mingjun Zhu
- Department of Cardiovascular Disease, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Peng Huang
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Berrino C, Omar A. Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation. Curr Issues Mol Biol 2024; 46:5397-5419. [PMID: 38920995 PMCID: PMC11202538 DOI: 10.3390/cimb46060323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 05/24/2024] [Accepted: 05/25/2024] [Indexed: 06/27/2024] Open
Abstract
The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies.
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Radu P, Zurzu M, Tigora A, Paic V, Bratucu M, Garofil D, Surlin V, Munteanu AC, Coman IS, Popa F, Strambu V, Ramboiu S. The Impact of Cancer Stem Cells in Colorectal Cancer. Int J Mol Sci 2024; 25:4140. [PMID: 38673727 PMCID: PMC11050141 DOI: 10.3390/ijms25084140] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Despite incessant research, colorectal cancer (CRC) is still one of the most common causes of fatality in both men and women worldwide. Over time, advancements in medical treatments have notably enhanced the survival rates of patients with colorectal cancer. Managing metastatic CRC involves a complex tradeoff between the potential benefits and adverse effects of treatment, considering factors like disease progression, treatment toxicity, drug resistance, and the overall impact on the patient's quality of life. An increasing body of evidence highlights the significance of the cancer stem cell (CSC) concept, proposing that CSCs occupy a central role in triggering cancer. CSCs have been a focal point of extensive research in a variety of cancer types, including CRC. Colorectal cancer stem cells (CCSCs) play a crucial role in tumor initiation, metastasis, and therapy resistance, making them potential treatment targets. Various methods exist for isolating CCSCs, and understanding the mechanisms of drug resistance associated with them is crucial. This paper offers an overview of the current body of research pertaining to the comprehension of CSCs in colorectal cancer.
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Affiliation(s)
- Petru Radu
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Mihai Zurzu
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Anca Tigora
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Vlad Paic
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Mircea Bratucu
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Dragos Garofil
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Valeriu Surlin
- Sixth Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova Emergency Clinical 7 Hospital, 200642 Craiova, Romania; (V.S.); (A.C.M.); (S.R.)
| | - Alexandru Claudiu Munteanu
- Sixth Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova Emergency Clinical 7 Hospital, 200642 Craiova, Romania; (V.S.); (A.C.M.); (S.R.)
| | - Ionut Simion Coman
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
- General Surgery Department, “Bagdasar-Arseni” Clinical Emergency Hospital, 12 Berceni Road, 041915 Bucharest, Romania
| | - Florian Popa
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Victor Strambu
- Tenth Department of Surgery, University of Medicine and Pharmacy “Carol Davila” Bucharest, 050474 Bucharest, Romania; (P.R.); (A.T.); (V.P.); (M.B.); (D.G.); (I.S.C.); (F.P.); (V.S.)
| | - Sandu Ramboiu
- Sixth Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova Emergency Clinical 7 Hospital, 200642 Craiova, Romania; (V.S.); (A.C.M.); (S.R.)
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He L, Zhao C, Xu J, Li W, Lu Y, Gong Y, Gu D, Wang X, Guo F. A potential novel biomarker: comprehensive analysis of prognostic value and immune implication of CES3 in colonic adenocarcinoma. J Cancer Res Clin Oncol 2023; 149:13239-13255. [PMID: 37480527 DOI: 10.1007/s00432-023-05156-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/09/2023] [Indexed: 07/24/2023]
Abstract
PURPOSE Colon cancer is the most common malignant tumor in the intestine. Abnormal Carboxylesterases 3 (CES3) expression had been reported to be correlated to multiple tumor progression. However, the association among CES3 expression and prognostic value and immune effects in colonic adenocarcinoma (COAD) were unclear. PATIENTS AND METHODS The transcription and expression data of CES3 and corresponding clinical information was downloaded from The Cancer Genome Atlas (TCGA). The CES3 protein expression and the prognostic value were verified based on tissue microarray data. The Cancer immune group Atlas (TCIA), Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the GSE78220 immunotherapy cohort were used to forecast immunotherapy efficacy. Finally, a prognostic immune signature was constructed and verified. RESULTS Compared with normal colon tissues, the expression of mRNA and protein levels of CES3 were downregulated in tumor tissues. CES3 expression was associated with TIICs. Hihg-CES3 COAD patients had better efficacy of concurrent immunotherapy. CES3-related immune genes (CRIs) were identified and were then used to construct prognostic immune signature and had been successfully verified in GES39582. CONCLUSION CES3 might be a potential immune-related gene and promising prognostic biomarker in COAD.
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Affiliation(s)
- Lulu He
- Department of Oncology, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Chenyi Zhao
- Department of Oncology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jingjing Xu
- Central Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenjing Li
- Department of Clinical Laboratory, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yujie Lu
- Department of Oncology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yang Gong
- Department of Oncology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Dingyi Gu
- Department of Oncology, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Xiaoyan Wang
- Department of Oncology, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Feng Guo
- Department of Oncology, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China.
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Alshahrani SH, Al-Hadeithi ZSM, Almalki SG, Malviya J, Hjazi A, Mustafa YF, Alawady AHR, Alsaalamy AH, Joshi SK, Alkhafaji AT. LncRNA-miRNA interaction is involved in colorectal cancer pathogenesis by modulating diverse signaling pathways. Pathol Res Pract 2023; 251:154898. [PMID: 37924797 DOI: 10.1016/j.prp.2023.154898] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/12/2023] [Accepted: 10/14/2023] [Indexed: 11/06/2023]
Abstract
LncRNAs function as molecular sponges for miRNAs to control their availability for targeting mRNA molecules. This procedure indirectly regulates the expression of cancer-related genes. Some lncRNAs also directly interact with miRNAs, leading to their degradation or sequestration, which can negatively impact gene expression. miRNAs, on the other hand, play a critical role in controlling the expression of genes, including oncogenes and tumor suppressor genes. Multiple types of cancer have been linked to the onset and progression of miRNA dysregulation. Even though there is a lot of potential for treating CRC by targeting the LncRNA-miRNA axis, several challenges remain to be overcome. The specificity of the targeting approach, delivery methods, resistance, safety, and cost-effectiveness are critical research areas that must be addressed to advance this field and improve treatment outcomes for people with CRC.
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Affiliation(s)
| | | | - Sami G Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia.
| | - Jitendra Malviya
- Department of Life Sciences and Biological Sciences, IES University Bhopal, Madhya Pradesh, India
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Ahmed Hussien Radie Alawady
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Babylon, Iraq
| | - Ali Hashiem Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - S K Joshi
- Mechanical Engineering Department, Uttaranchal Institute of Technology, Uttaranchal University, Dehradun 248007, India
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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10
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Sénicourt B, Cloutier G, Basora N, Fallah S, Laniel A, Lavoie C, Beaulieu JF. Primary Cilium Identifies a Quiescent Cell Population in the Human Intestinal Crypt. Cells 2023; 12:1059. [PMID: 37048132 PMCID: PMC10093653 DOI: 10.3390/cells12071059] [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: 10/27/2022] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Primary cilia are sensory antennae located at the cell surface which mediate a variety of extracellular signals involved in development, tissue homeostasis, stem cells and cancer. Primary cilia are found in an extensive array of vertebrae cells but can only be generated when cells become quiescent. The small intestinal epithelium is a rapidly self-renewing tissue organized into a functional unit called the crypt-villus axis, containing progenitor and differentiated cells, respectively. Terminally differentiated villus cells are notoriously devoid of primary cilia. We sought to determine if intestinal crypts contain a quiescent cell population that could be identified by the presence of primary cilia. Here we show that primary cilia are detected in a subset of cells located deep in the crypts slightly above a Paneth cell population. Using a normal epithelial proliferative crypt cell model, we show that primary cilia assembly and activity correlate with a quiescent state. These results provide further evidence for the existence of a quiescent cell population in the human small intestine and suggest the potential for new modes of regulation in stem cell dynamics.
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Affiliation(s)
- Blanche Sénicourt
- Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Shebrooke, Sherbrooke, QC J1H5N4, Canada
| | - Gabriel Cloutier
- Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Shebrooke, Sherbrooke, QC J1H5N4, Canada
| | - Nuria Basora
- Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Shebrooke, Sherbrooke, QC J1H5N4, Canada
| | - Sepideh Fallah
- Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Shebrooke, Sherbrooke, QC J1H5N4, Canada
| | - Andréanne Laniel
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H5N4, Canada
| | - Christine Lavoie
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H5N4, Canada
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H5N4, Canada
| | - Jean-François Beaulieu
- Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Shebrooke, Sherbrooke, QC J1H5N4, Canada
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H5N4, Canada
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11
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Qiu Z, Qiu S, Mao W, Lin W, Peng Q, Chang H. LOXL2 reduces 5-FU sensitivity through the Hedgehog/BCL2 signaling pathway in colorectal cancer. Exp Biol Med (Maywood) 2023; 248:457-468. [PMID: 36573458 PMCID: PMC10281539 DOI: 10.1177/15353702221139203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 10/16/2022] [Indexed: 09/29/2023] Open
Abstract
Elevated expression of lysyl oxidase-like 2 (LOXL2) contributes to the malignant tumor progression in multiple cancers. However, the role of LOXL2 in the 5-fluorouracil (5-FU) resistance of colorectal cancer (CRC) remains unclear. This study aimed to explore the effects of LOXL2 on 5-FU sensitivity in CRC. The mRNA and protein levels of LOXL2 were explored in public databases by bioinformatics, validated in clinical tissues using immunohistochemistry, and detected in 5-FU treated cell lines. The 50% inhibitory concentrations (IC50) values were quantified based on the cell viability at different concentrations of 5-FU with CCK-8 assays. Colony formation and flow cytometry assays were performed to measure the proliferation and apoptosis rates. Gene set enrichment and correlation analyses were conducted to identify the probable mechanism of LOXL2 in TCGA samples. Critical molecules of the Hedgehog signaling pathway and anti-apoptotic BCL2 in protein levels were detected with Western blotting. It concluded that LOXL2 was up-regulated and positively linked to the unfavorable prognosis of CRC patients. The LOXL2 expression increased with the rising 5-FU concentrations, especially at 20 and 40 μM. Elevated LOXL2 promoted the resistance to 5-FU, augmented the proliferation, and inhibited 5-FU-induced apoptosis of CRC cells. LOXL2 activated the Hedgehog signaling pathway by promoting the expression of SMO, GLI1, and GLI2, leading to the upregulation of downstream target gene BCL2 in CRC cells. Moreover, the Hedgehog signaling pathway inhibitor cyclopamine blocked the BCL2 upregulation mediated by LOXL2. This study has demonstrated that LOXL2 can reduce 5-FU sensitivity through the Hedgehog/BCL2 signaling pathway in CRC.
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Affiliation(s)
- Zhize Qiu
- Department of General Surgery, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai 519000, China
| | - Shiqi Qiu
- Department of General Surgery, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai 519000, China
| | - Wenli Mao
- Department of General Internal Medicine, The People’s Hospital of Xiangzhou District, Zhuhai 519000, China
| | - Wu Lin
- Department of General Surgery, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai 519000, China
| | - Qiqi Peng
- Department of General Surgery, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai 519000, China
| | - Hao Chang
- Department of Cancer Research, Hanyu Biomed Center Beijing, Beijing, 102488, China
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12
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1'-O-methyl-averantin isolated from the endolichenic fungus Jackrogersella sp. EL001672 suppresses colorectal cancer stemness via sonic Hedgehog and Notch signaling. Sci Rep 2023; 13:2811. [PMID: 36797277 PMCID: PMC9935543 DOI: 10.1038/s41598-023-28773-z] [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: 09/15/2022] [Accepted: 01/24/2023] [Indexed: 02/18/2023] Open
Abstract
Endolichenic fungi are host organisms that live on lichens and produce a wide variety of secondary metabolites. Colorectal cancer stem cells are capable of self-renewal and differentiation into cancer cells, which makes cancers difficult to eradicate. New alternative therapeutics are needed to inhibit the growth of tumor stem cells. This study examined the ability of an extract of Jackrogersella sp. EL001672 (derived from the lichen Cetraria sp.) and the isolated compound 1'-O-methyl-averantin to inhibit development of cancer stemness. The endolichenic fungus Jackrogersella sp. EL001672 (KACC 83021BP), derived from Cetraria sp., was grown in culture medium. The culture broth was extracted with acetone to obtain a crude extract. Column chromatography and reverse-phase HPLC were used to isolate an active compound. The anticancer activity of the extract and the isolated compound was evaluated by qRT-PCR and western blotting, and in cell viability, spheroid formation, and reporter assays. The acetone extract of EL001672 did not affect cell viability. However, 1'-O-methyl-averantin showed cytotoxic effects against cancer cell lines at 50 μg/mL and 25 μg/mL. Both the crude extract and 1'-O-methyl-averantin suppressed spheroid formation in CRC cell lines, and downregulated expression of stemness markers ALDH1, CD44, CD133, Lgr-5, Msi-1, and EphB1. To further characterize the mechanism underlying anti-stemness activity, we examined sonic Hedgehog and Notch signaling. The results showed that the crude extract and the 1'-O-methyl-averantin inhibited Gli1, Gli2, SMO, Bmi-1, Notch-1, Hes-1, and the CSL complex. Consequently, an acetone extract and 1'-O-methyl-averantin isolated from EL001672 suppresses colorectal cancer stemness by regulating the sonic Hedgehog and Notch signaling pathways.
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13
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Chen JF, Wu SW, Shi ZM, Hu B. Traditional Chinese medicine for colorectal cancer treatment: potential targets and mechanisms of action. Chin Med 2023; 18:14. [PMID: 36782251 PMCID: PMC9923939 DOI: 10.1186/s13020-023-00719-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/30/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is a disease with complex pathogenesis, it is prone to metastasis, and its development involves abnormalities in multiple signaling pathways. Surgery, chemotherapy, radiotherapy, target therapy, and immunotherapy remain the main treatments for CRC, but improvement in the overall survival rate and quality of life is urgently needed. Traditional Chinese medicine (TCM) has a long history of preventing and treating CRC. It could affect CRC cell proliferation, apoptosis, cell cycle, migration, invasion, autophagy, epithelial-mesenchymal transition, angiogenesis, and chemoresistance by regulating multiple signaling pathways, such as PI3K/Akt, NF-κB, MAPK, Wnt/β-catenin, epidermal growth factor receptors, p53, TGF-β, mTOR, Hedgehog, and immunomodulatory signaling pathways. In this paper, the main signaling pathways and potential targets of TCM and its active ingredients in the treatment of CRC were systematically summarized, providing a theoretical basis for treating CRC with TCM and new ideas for further exploring the pathogenesis of CRC and developing new anti-CRC drugs.
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Affiliation(s)
- Jin-Fang Chen
- grid.412540.60000 0001 2372 7462Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, People’s Republic of China ,grid.412540.60000 0001 2372 7462Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, People’s Republic of China
| | - Shi-Wei Wu
- grid.412540.60000 0001 2372 7462Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, People’s Republic of China ,grid.412540.60000 0001 2372 7462Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, People’s Republic of China
| | - Zi-Man Shi
- grid.412540.60000 0001 2372 7462Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, People’s Republic of China ,grid.412540.60000 0001 2372 7462Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032 Shanghai, People’s Republic of China
| | - Bing Hu
- Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032, Shanghai, People's Republic of China. .,Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032, Shanghai, People's Republic of China.
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14
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Wang J, Cui B, Li X, Zhao X, Huang T, Ding X. The emerging roles of Hedgehog signaling in tumor immune microenvironment. Front Oncol 2023; 13:1171418. [PMID: 37213270 PMCID: PMC10196179 DOI: 10.3389/fonc.2023.1171418] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/26/2023] [Indexed: 05/23/2023] Open
Abstract
The Hedgehog (Hh) signaling pathway is pervasively involved in human malignancies, making it an effective target for cancer treatment for decades. In addition to its direct role in regulating cancer cell attributes, recent work indicates that it has an immunoregulatory effect on tumor microenvironments. An integrated understanding of these actions of Hh signaling pathway in tumor cells and tumor microenvironments will pave the way for novel tumor treatments and further advances in anti-tumor immunotherapy. In this review, we discuss the most recent research about Hh signaling pathway transduction, with a particular emphasis on its role in modulating tumor immune/stroma cell phenotype and function, such as macrophage polarity, T cell response, and fibroblast activation, as well as their mutual interactions between tumor cells and nonneoplastic cells. We also summarize the recent advances in the development of Hh pathway inhibitors and nanoparticle formulation for Hh pathway modulation. We suggest that targeting Hh signaling effects on both tumor cells and tumor immune microenvironments could be more synergistic for cancer treatment.
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Affiliation(s)
- Juan Wang
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, China
| | - Baiping Cui
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, China
| | - Xiaojie Li
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, China
| | - Xinyue Zhao
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, China
| | - Taomin Huang
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, China
- *Correspondence: Taomin Huang, ; Xiaolei Ding,
| | - Xiaolei Ding
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, China
- *Correspondence: Taomin Huang, ; Xiaolei Ding,
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15
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Chen L, Liu M, Yang H, Ren S, Sun Q, Zhao H, Ming T, Tang S, Tao Q, Zeng S, Meng X, Xu H. Ursolic acid inhibits the activation of smoothened-independent non-canonical hedgehog pathway in colorectal cancer by suppressing AKT signaling cascade. Phytother Res 2022; 36:3555-3570. [PMID: 35708264 DOI: 10.1002/ptr.7523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/19/2022] [Accepted: 04/23/2022] [Indexed: 11/07/2022]
Abstract
It is being brought to light that smoothened (SMO)-independent non-canonical Hedgehog signaling is associated with the pathogenesis of various cancers. Ursolic acid (UA), a pentacyclic triterpenoid present in many medicinal herbs, manifests potent effectiveness against multiple malignancies including colorectal cancer (CRC). In our previous study, UA was found to protect against CRC in vitro by suppression of canonical Hedgehog signaling cascade. Here, the influence of UA on SMO-independent non-canonical Hedgehog signaling in CRC was investigated in the present study, which demonstrated that UA hampered the proliferation and migration, induced the apoptosis of HCT-116hSMO- cells with SMO gene knockdown, accompanied by the augmented expression of the suppressor of fused (SUFU), and lessened levels of MYC (c-Myc), glioma-associated oncogene (GLI1) and Sonic Hedgehog (SHH), and lowered phosphorylation of protein kinase B (PKB, AKT), suggesting that UA diminished non-canonical Hedgehog signal transduction in CRC. In HCT-116hSMO- xenograft tumor, UA ameliorated the symptoms, impeded the growth and caused the apoptosis of CRC, with heightened SUFU expression, and abated levels of MYC, GLI1, and SHH, and mitigated phosphorylation of AKT, indicating that UA down-regulated non-canonical Hedgehog signaling cascade in CRC. Taken together, UA may alleviate CRC by suppressing AKT signaling-dependent activation of SMO-independent non-canonical Hedgehog pathway.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Maolun Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Han Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiang Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hui Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tianqi Ming
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shun Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiu Tao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sha Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haibo Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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16
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Sun Q, Yang H, Liu M, Ren S, Zhao H, Ming T, Tang S, Tao Q, Chen L, Zeng S, Duan DD, Xu H. Berberine suppresses colorectal cancer by regulation of Hedgehog signaling pathway activity and gut microbiota. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 103:154227. [PMID: 35679795 DOI: 10.1016/j.phymed.2022.154227] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND A growing body of evidence reveals that dysregulation of Hedgehog signaling pathway and dysbiosis of gut microbiota are associated with the pathogenesis of colorectal cancer (CRC). Berberine, a botanical benzylisoquinoline alkaloid, possesses powerful activities against various malignancies including CRC, with the underlying mechanisms to be illuminated. PURPOSE The present study investigated the potencies of berberine on CRC and deciphered the action mechanisms in the context of Hedgehog signaling cascade and gut microbiota. METHODS The effects of berberine on the malignant phenotype, apoptosis, cell cycle and Hedgehog signaling of CRC cells were examined in vitro. In azoxymethane/dextran sulfate sodium-caused mouse CRC, the efficacies of berberine on the carcinogenesis, pathological profile, apoptosis, cell cycle and Hedgehog signaling were determined in vivo. Also, the influences of berberine on gut microbiota in CRC mice were assessed by high-throughput DNA sequencing analysis of 16S ribosomal RNA of fecal microbiome in CRC mice. RESULTS In the present study, berberine was found to dampen the proliferation, migration, invasion and colony formation of CRC cells, without toxicity to normal colonic cells. Additionally, berberine induced apoptosis and arrested cell cycle at G0/G1 phase in CRC cells, accompanied by reduced Hedgehog signaling pathway activity in vitro. In mouse CRC, berberine suppressed tumor growth, ameliorated pathological manifestations, and potentially induced the apoptosis and cell cycle arrest of CRC, with lowered Hedgehog signaling cascade in vivo. Additionally, berberine decreased β-diversity of gut microbiota in CRC mice, without influence on α-diversity. Berberine also enriched probiotic microbes and depleted pathogenic microbes, and modulated the functionality of gut microbiota in CRC mice. CONCLUSIONS Overall, berberine may suppress colorectal cancer, orchestrated by down-regulation of Hedgehog signaling pathway activity and modulation of gut microbiota.
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Affiliation(s)
- Qiang Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Han Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Maolun Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tianqi Ming
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shun Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiu Tao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Li Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Sha Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Dayue Darrel Duan
- Center for Phenomics of Traditional Chinese Medicine and the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Haibo Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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17
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Kast RE, Alfieri A, Assi HI, Burns TC, Elyamany AM, Gonzalez-Cao M, Karpel-Massler G, Marosi C, Salacz ME, Sardi I, Van Vlierberghe P, Zaghloul MS, Halatsch ME. MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen. Cancers (Basel) 2022; 14:2563. [PMID: 35626167 PMCID: PMC9140192 DOI: 10.3390/cancers14102563] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/11/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells' growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass-by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs-celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan-to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of-not a replacement for-previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.
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Affiliation(s)
| | - Alex Alfieri
- Department of Neurosurgery, Cantonal Hospital of Winterthur, 8400 Winterthur, Switzerland; (A.A.); (M.-E.H.)
| | - Hazem I. Assi
- Naef K. Basile Cancer Center, American University of Beirut, Beirut 1100, Lebanon;
| | - Terry C. Burns
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN 55905, USA;
| | - Ashraf M. Elyamany
- Oncology Unit, Hemato-Oncology Department, SECI Assiut University Egypt/King Saud Medical City, Riyadh 7790, Saudi Arabia;
| | - Maria Gonzalez-Cao
- Translational Cancer Research Unit, Dexeus University Hospital, 08028 Barcelona, Spain;
| | | | - Christine Marosi
- Clinical Division of Medical Oncology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria;
| | - Michael E. Salacz
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA;
| | - Iacopo Sardi
- Department of Pediatric Oncology, Meyer Children’s Hospital, Viale Pieraccini 24, 50139 Florence, Italy;
| | - Pieter Van Vlierberghe
- Department of Biomolecular Medicine, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium;
| | - Mohamed S. Zaghloul
- Children’s Cancer Hospital & National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Marc-Eric Halatsch
- Department of Neurosurgery, Cantonal Hospital of Winterthur, 8400 Winterthur, Switzerland; (A.A.); (M.-E.H.)
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18
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Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease. Cell Death Discov 2021; 7:314. [PMID: 34702800 PMCID: PMC8548344 DOI: 10.1038/s41420-021-00679-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/15/2021] [Accepted: 09/29/2021] [Indexed: 12/18/2022] Open
Abstract
The Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.
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19
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Rab1A promotes cell proliferation and migration by upregulating Gli1 in colorectal cancer. Sci Rep 2021; 11:16243. [PMID: 34376787 PMCID: PMC8355269 DOI: 10.1038/s41598-021-95798-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 07/31/2021] [Indexed: 11/16/2022] Open
Abstract
Rab1A, as a highly conserved small guanosine triphosphatase (GTPase), plays contentious roles in different types of cancers. The role of Rab1A in colorectal cancer (CRC) has been described in previous studies, but the molecular mechanisms of Rab1A in CRC remain far from being addressed. In the present study, we found that Rab1A expression was significantly upregulated in CRC tissues and increased Rab1A expression correlated with tumor size, lymph node metastasis (LNM) and tumor-node-metastasis (TNM) stage of CRC patients. We also found that Rab1A exerts its promotive effect on CRC cell proliferation, migration and EMT progress. Further mechanistic experiments showed that glioma-associated oncogene-1 (Gli1), as a key transcriptional factor of the Hedgehog pathway, was implicated in Rab1A-mediated regulation of CRC cell proliferation and migration. In addition, Rab1A upregulated Gli1 expression through Smoothened homolog (SMO)-independent pathway. Finally, Rab1A activated mechanistic target of rapamycin (mTOR) signaling in CRC cells. Collectively, our results define Rab1A as a novel regulator of Gli1 to promote CRC cell proliferation and migration, and suggest that the Rab1A/mTOR/Gli1 axis may serve as a promising therapeutic target for the treatment of CRC.
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