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Guo F, Ai Y, Chen Y, Wu G, Wu H, Lin J, Jiang Y, Zhang J, Zhang T. Discovery of 3-phenyl-[1,2,4]triazolo[4,3-a]pyridine derivatives as potent smoothened inhibitors against colorectal carcinoma. Bioorg Med Chem 2025; 125:118214. [PMID: 40318542 DOI: 10.1016/j.bmc.2025.118214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 04/07/2025] [Accepted: 04/25/2025] [Indexed: 05/07/2025]
Abstract
Smoothened (SMO) in Hedgehog (Hh) signaling pathway is intricately associated with the genesis of colorectal carcinoma (CRC), but SMO inhibitor Vismodegib lacks of therapeutic benefits. Based on the principles of preserving critical interactions and ring substitution, a series of 3-phenyl-[1,2,4]triazolo[4,3-a]pyridine derivatives were designed and synthesized. Among them, compound A11 exhibited significant inhibitory activity against SMOWT (IC50 = 0.27 ± 0.06 µM) and SMOD473H (IC50 = 0.84 ± 0.12 µM), respectively, while displayed negligible toxicity towards normal cells. Furthermore, A11 demonstrated superior antiproliferative activity against CRC cells compared to Vismodegib. In additions, A11 competitively bound to SMO and inhibit its downstream signaling pathways. Molecular modeling studies suggested that the triazolopyridine ring of A11 may contribute to the important interaction for binding to SMO. In sum, these results suggest that A11 deserves further investigation as a SMO inhibitor for CRC treatment.
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Affiliation(s)
- Fengqiu Guo
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Yangcheng Ai
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yongxin Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Guowu Wu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Huanxian Wu
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Jingyun Lin
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Ying Jiang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan 442000, China.
| | - Jiajie Zhang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
| | - Tingting Zhang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
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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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3
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Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Cong G, Zhu X, Chen XR, Chen H, Chong W. Mechanisms and therapeutic potential of the hedgehog signaling pathway in cancer. Cell Death Discov 2025; 11:40. [PMID: 39900571 PMCID: PMC11791101 DOI: 10.1038/s41420-025-02327-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/25/2024] [Accepted: 01/24/2025] [Indexed: 02/05/2025] Open
Abstract
A sort of major malignant disease, cancer can compromise human health wherever. Some mechanisms of the occurrence and evolution of cancer still seem elusive even now. Consequently, the therapeutic strategies for cancer must continually evolve. The hedgehog signaling pathway, a critical mediator in the normal development of numerous organs and the pathogenesis of cancer, is typically quiescent but is aberrantly activated in several malignancies. Extensive research has delineated that the aberrant activity of the hedgehog signaling pathway, whether autocrine or paracrine, is implicated in the initiation and progression of various neoplasms, including medulloblastoma (MB), basal cell carcinoma (BCC) and so on. Thus, notably Smo inhibitors, the opening of inhibitors of the hedgehog signaling pathway has become a topic of research attention. This review aims to summarize four aberrant activation pathways and the influence of hedgehog signaling pathway associated chemicals on tumor formation and development. Additionally, it will explore the therapeutic potential of targeted interventions in the hedgehog signaling pathway for cancer treatment.
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Affiliation(s)
- Ge Cong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China
| | - Xingyu Zhu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China
| | - Xin Ru Chen
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China
| | - Hao Chen
- Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, 250021, Jinan, China.
| | - Wei Chong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China.
- Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021, Jinan, China.
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250021, Jinan, China.
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Matsumoto K, Akieda Y, Haraoka Y, Hirono N, Sasaki H, Ishitani T. Foxo3-mediated physiological cell competition ensures robust tissue patterning throughout vertebrate development. Nat Commun 2024; 15:10662. [PMID: 39690179 PMCID: PMC11652645 DOI: 10.1038/s41467-024-55108-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 11/27/2024] [Indexed: 12/19/2024] Open
Abstract
Unfit cells with defective signalling or gene expression are eliminated through competition with neighbouring cells. However, physiological roles and mechanisms of cell competition in vertebrates remain unclear. In addition, universal mechanisms regulating diverse cell competition are unknown. Using zebrafish imaging, we reveal that cell competition ensures robust patterning of the spinal cord and muscle through elimination of cells with unfit sonic hedgehog activity, driven by cadherin-mediated communication between unfit and neighbouring fit cells and subsequent activation of the Smad-Foxo3-reactive oxygen species axis. We identify Foxo3 as a common marker of loser cells in various types of cell competition in zebrafish and mice. Foxo3-mediated physiological cell competition is required for eliminating various naturally generated unfit cells and for the consequent precise patterning during zebrafish embryogenesis and organogenesis. Given the implication of Foxo3 downregulation in age-related diseases, cell competition may be a defence system to prevent abnormalities throughout development and adult homeostasis.
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Affiliation(s)
- Kanako Matsumoto
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Suita, Osaka, Japan
| | - Yuki Akieda
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Yukinari Haraoka
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Naoki Hirono
- Laboratory for Embryogenesis, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Hiroshi Sasaki
- Laboratory for Embryogenesis, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
- Department of Biological Sciences, Graduate School of Science, Osaka University, Suita, Osaka, Japan.
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, Japan.
- Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan.
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Konopka A, Gawin K, Barszcz M. Hedgehog Signalling Pathway and Its Role in Shaping the Architecture of Intestinal Epithelium. Int J Mol Sci 2024; 25:12007. [PMID: 39596072 PMCID: PMC11593361 DOI: 10.3390/ijms252212007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
The hedgehog (Hh) signalling pathway plays a key role in both embryonic and postnatal development of the intestine and is responsible for gut homeostasis. It regulates stem cell renewal, formation of the villous-crypt axis, differentiation of goblet and Paneth cells, the cell cycle, apoptosis, development of gut innervation, and lipid metabolism. Ligands of the Hh pathway, i.e., Indian hedgehog (Ihh) and Sonic hedgehog (Shh), are expressed by superficial enterocytes but act in the mesenchyme, where they are bound by a Patched receptor localised on myofibroblasts and smooth muscle cells. This activates a cascade leading to the transcription of target genes, including those encoding G1/S-specific cyclin-D2 and -E1, B-cell lymphoma 2, fibroblast growth factor 4, and bone morphogenetic protein 4. The Hh pathway is tightly connected to Wnt signalling. Ihh is the major ligand in the Hh pathway. Its activation inhibits proliferation, while its blocking induces hyperproliferation and triggers a wound-healing response. Thus, Ihh is a negative feedback regulator of cell proliferation. There are data indicating that diet composition may affect the expression of the Hh pathway genes and proteins, which in turn, induces changes in mucosal architecture. This was shown for fat, vitamin A, haem, berberine, and ovotransferrin. The Hh signalling is also affected by the intestinal microbiota, which affects the intestinal barrier integrity. This review highlights the critical importance of the Hh pathway in shaping the intestinal mucosa and summarises the results obtained so far in research on the effect of dietary constituents on the activity of this pathway.
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Affiliation(s)
- Adrianna Konopka
- Laboratory of Analysis of Gastrointestinal Tract Protective Barrier, Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
| | - Kamil Gawin
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
| | - Marcin Barszcz
- Laboratory of Analysis of Gastrointestinal Tract Protective Barrier, Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
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Kim BR, Kim DY, Tran NL, Kim BG, Lee SI, Kang SH, Min BY, Hur W, Oh SC. Daunorubicin induces GLI1‑dependent apoptosis in colorectal cancer cell lines. Int J Oncol 2024; 64:66. [PMID: 38757343 PMCID: PMC11095621 DOI: 10.3892/ijo.2024.5654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Daunorubicin, also known as daunomycin, is a DNA‑targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to have anticancer effects in monotherapy or combination therapy in solid tumors, but at present it has not been adequately studied in colorectal cancer (CRC). In the present study, from a screening using an FDA‑approved drug library, it was found that daunorubicin suppresses GLI‑dependent luciferase reporter activity. Daunorubicin also increased p53 levels, which contributed to both GLI1 suppression and apoptosis. The current detailed investigation showed that daunorubicin promoted the β‑TrCP‑mediated ubiquitination and proteasomal degradation of GLI1. Moreover, a competition experiment using BODIPY‑cyclopamine, a well‑known Smo inhibitor, suggested that daunorubicin does not bind to Smo in HCT116 cells. Administration of daunorubicin (2 mg/kg, ip, qod, 15 days) into HCT116 xenograft mice profoundly suppressed tumor progress and the GLI1 level in tumor tissues. Taken together, the present results revealed that daunorubicin suppresses canonical Hedgehog pathways in CRC. Ultimately, the present study discloses a new mechanism of daunorubicin's anticancer effect and might provide a rationale for expanding the clinical application of daunorubicin.
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Affiliation(s)
- Bo Ram Kim
- Division of Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Republic of Korea
- Institute of Convergence New Drug Development, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Dae Yeong Kim
- Division of Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Republic of Korea
- Institute of Convergence New Drug Development, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Na Ly Tran
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Bu Gyeom Kim
- Division of Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Republic of Korea
- Institute of Convergence New Drug Development, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Sun Il Lee
- Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - Sang Hee Kang
- Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - Byung Yook Min
- Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - Wooyoung Hur
- Medicinal Materials Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea
| | - Sang Cheul Oh
- Division of Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Republic of Korea
- Institute of Convergence New Drug Development, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Das P, Battu S, Mehra L, Singh A, Ahmad M, Agarwal A, Chauhan A, Ahmad A, Vishnubhatla S, Gupta SD, Ahuja V, Makharia G. Correlation between intestinal stem cell niche changes and small bowel crypt failure in patients with treatment-naïve celiac disease. INDIAN J PATHOL MICR 2024; 67:259-266. [PMID: 38427764 DOI: 10.4103/ijpm.ijpm_760_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/27/2023] [Indexed: 03/03/2024] Open
Abstract
OBJECTIVES We hypothesized that crypt failure in the small bowel results in villous flattening in patients with celiac disease (CeD). We investigated whether alterations in the stem cell niche (ISC) are responsible for this phenomenon. MATERIALS AND METHODS We included 92 duodenal (D2/3) biopsies from treatment-naive patients of CeD and 37 controls. All underwent screening for serum anti-tissue transglutaminase and endoscopic upper small bowel biopsy. Immunohistochemical markers were used to investigate ISC niche alterations, including LGR5 for crypt basal cells (CBC), Bmi1 for position 4+ cells, β-Defensin for Paneth cells, R-spondin1 as WNT activator, transcription factor-4 as WNT transcription factor, BMP receptor1A as WNT inhibitor, fibronectin-1 as periepithelial stromal cell marker, H2AX as apoptosis marker, and Ki67 as proliferation marker. We also analyzed IgA anti-tTG2 antibody deposits by using dual-color immunofluorescence staining. RESULTS We found that in biopsies from patients with treatment-naive CeD with modified Marsh grade 3a-3c changes, the epithelial H2AX apoptotic index was upregulated than in controls. LGR5+ crypt basal cells were upregulated in all modified Marsh grades compared to controls. However, the Ki67 proliferation index, expressions of WNT-activator RSPO1, and position-4 cell marker Bmi1 did not significantly alter in patients' biopsies as compared to controls ( P = 0.001). We also observed depletion of pericrypt stromal fibronectin-1 in patients with CeD compared to controls. In addition, we identified IgA anti-TG2 antibody deposits in pericrypt stroma. CONCLUSIONS Our data suggests that ISC niche failure is a plausible hypothesis for villous flattening in patients with CeD, resulting from pericrypt IgA anti-TG2 antibody complex-mediated stromal depletion.
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Affiliation(s)
- Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Sudha Battu
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Lalita Mehra
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Alka Singh
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Muzaffar Ahmad
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Agarwal
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Chauhan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Anam Ahmad
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Thazhackavayal Baby B, Kulkarni AM, Gayam PKR, Harikumar KB, Aranjani JM. Beyond cyclopamine: Targeting Hedgehog signaling for cancer intervention. Arch Biochem Biophys 2024; 754:109952. [PMID: 38432565 DOI: 10.1016/j.abb.2024.109952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/05/2024]
Abstract
Hedgehog (Hh) signaling plays a significant role in embryogenesis and several physiological processes, such as wound healing and organ homeostasis. In a pathological setting, it is associated with oncogenesis and is responsible for disease progression and poor clinical outcomes. Hedgehog signaling mediates downstream actions via Glioma Associated Oncogene Homolog (GLI) transcription factors. Inhibiting Hh signaling is an important oncological strategy in which inhibitors of the ligands SMO or GLI have been looked at. This review briefly narrates the Hh ligands, signal transduction, the target genes involved and comprehensively describes the numerous inhibitors that have been evaluated for use in various neoplastic settings.
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Affiliation(s)
- Beena Thazhackavayal Baby
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India
| | - Aniruddha Murahar Kulkarni
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India
| | - Prasanna Kumar Reddy Gayam
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, 695014, Kerala State, India
| | - Jesil Mathew Aranjani
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India.
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10
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Pope HF, Pilmane M, Junga A, Pētersons A. The Assessment of CDX1, IHH, SHH, GATA4, FOXA2, FOXF1 in Congenital Intra-Abdominal Adhesions. Acta Med Litu 2024; 31:109-121. [PMID: 38978864 PMCID: PMC11227690 DOI: 10.15388/amed.2024.31.1.15] [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: 12/19/2023] [Revised: 03/17/2024] [Accepted: 03/25/2024] [Indexed: 07/10/2024] Open
Abstract
Congenital abdominal adhesions are a rare condition that can result in a small bowel obstruction at any age, more frequently in pediatric populations. The cause remains unknown, and the importance of aberrant congenital bands is related to the difficulty of diagnosis, and cases of death with late detection have been documented. This research examines the expression of Caudal Type Homeobox 1 (CDX1), Indian Hedgehog (IHH), Sonic Hedgehog (SHH), GATA Binding Protein 4 (GATA4), Forkhead Box A2 (FOXA2) and Forkhead Box F1 (FOXF1) gene expression in human abdominal congenital adhesion fibroblast and endothelium cells by chromogenic in situ hybridization, with the aim of elucidating their potential association with the etiology of congenital intra-abdominal adhesion band development. The potential genes' signals were examined using a semi-quantitative approach. Significant correlations were observed between the expression of CDX1 (p <.001) and SHH (p=0.032) genes in fibroblasts from congenital intra-abdominal adhesions compared to fibroblasts from control peritoneal tissue. Statistically significant very strong correlations were found between the CDX1 and IHH comparing endothelium and fibroblast cells in congenital abdominal adhesion bands. There was no statistically significant difference found in the distribution of IHH, FOXA2, GATA4, and FOXF1 between the fibroblasts and endothelium of the patients compared to the control group. The presence of notable distinctions and diverse associations suggests the potential involvement of numerous morpho-pathogenetic processes in the development of intraabdominal adhesions.
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Affiliation(s)
| | - Māra Pilmane
- Institute of Anatomy and Anthropology, Riga Stradiņš University, Riga, Latvia
| | - Anna Junga
- Institute of Anatomy and Anthropology, Riga Stradiņš University, Riga, Latvia
| | - Aigars Pētersons
- Children’s Clinical University Hospital, Riga Stradiņš University, Riga, Latvia
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11
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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.
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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.
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12
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Gall L, Duckworth C, Jardi F, Lammens L, Parker A, Bianco A, Kimko H, Pritchard DM, Pin C. Homeostasis, injury, and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt. eLife 2023; 12:e85478. [PMID: 38063302 PMCID: PMC10789491 DOI: 10.7554/elife.85478] [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: 12/09/2022] [Accepted: 12/07/2023] [Indexed: 01/16/2024] Open
Abstract
The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration, and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43, and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms, and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation, and migration and leads to loss of barrier integrity. During recovery, our in silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.
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Affiliation(s)
- Louis Gall
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - Carrie Duckworth
- Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUnited Kingdom
| | - Ferran Jardi
- Preclinical Sciences and Translational Safety, JanssenBeerseBelgium
| | - Lieve Lammens
- Preclinical Sciences and Translational Safety, JanssenBeerseBelgium
| | - Aimee Parker
- Gut Microbes and Health Programme, Quadram InstituteNorwichUnited Kingdom
| | - Ambra Bianco
- Clinical Pharmacology and Safety Sciences, AstraZenecaCambridgeUnited Kingdom
| | - Holly Kimko
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - David Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUnited Kingdom
| | - Carmen Pin
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
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13
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Pontarollo G, Kollar B, Mann A, Khuu MP, Kiouptsi K, Bayer F, Brandão I, Zinina VV, Hahlbrock J, Malinarich F, Mimmler M, Bhushan S, Marini F, Ruf W, Belheouane M, Baines JF, Endres K, Reba SM, Raker VK, Deppermann C, Welsch C, Bosmann M, Soshnikova N, Chassaing B, Bergentall M, Sommer F, Bäckhed F, Reinhardt C. Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling. Nat Metab 2023; 5:1174-1187. [PMID: 37414930 PMCID: PMC10365997 DOI: 10.1038/s42255-023-00828-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 05/24/2023] [Indexed: 07/08/2023]
Abstract
The gut microbiota influences intestinal barrier integrity through mechanisms that are incompletely understood. Here we show that the commensal microbiota weakens the intestinal barrier by suppressing epithelial neuropilin-1 (NRP1) and Hedgehog (Hh) signaling. Microbial colonization of germ-free mice dampens signaling of the intestinal Hh pathway through epithelial Toll-like receptor (TLR)-2, resulting in decreased epithelial NRP1 protein levels. Following activation via TLR2/TLR6, epithelial NRP1, a positive-feedback regulator of Hh signaling, is lysosomally degraded. Conversely, elevated epithelial NRP1 levels in germ-free mice are associated with a strengthened gut barrier. Functionally, intestinal epithelial cell-specific Nrp1 deficiency (Nrp1ΔIEC) results in decreased Hh pathway activity and a weakened gut barrier. In addition, Nrp1ΔIEC mice have a reduced density of capillary networks in their small intestinal villus structures. Collectively, our results reveal a role for the commensal microbiota and epithelial NRP1 signaling in the regulation of intestinal barrier function through postnatal control of Hh signaling.
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Affiliation(s)
- Giulia Pontarollo
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Bettina Kollar
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Department of Chemistry, Biochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Amrit Mann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - My Phung Khuu
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Klytaimnistra Kiouptsi
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany
| | - Franziska Bayer
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Inês Brandão
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Valeriya V Zinina
- Institute of Molecular Medicine, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Jennifer Hahlbrock
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Frano Malinarich
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Maximilian Mimmler
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Department of Chemistry, Biochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Sudhanshu Bhushan
- Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University of Giessen, Giessen, Germany
| | - Federico Marini
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany
| | - Meriem Belheouane
- Institute for Experimental Medicine, Kiel University and Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - John F Baines
- Institute for Experimental Medicine, Kiel University and Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Scott M Reba
- Department of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Verena K Raker
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany
| | - Christoph Welsch
- Department of Internal Medicine 1, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Markus Bosmann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Natalia Soshnikova
- Institute of Molecular Medicine, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Benoit Chassaing
- INSERM U1016, Team 'Mucosal microbiota in chronic inflammatory diseases', CNRS UMR 8104, Université de Paris, Paris, France
| | - Mattias Bergentall
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Felix Sommer
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Fredrik Bäckhed
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Physiology, Region Västra Götland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany.
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14
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Wu H, Zhang L, Chen B, Ou B, Xu J, Tian N, Yang D, Ai Y, Chen Q, Quan D, Zhang T, Lv L, Tian Y, Zhang J, Wu S. B13, a well-tolerated inhibitor of hedgehog pathway, exhibited potent anti-tumor effects against colorectal carcinoma in vitro and in vivo. Bioorg Chem 2023; 135:106488. [PMID: 36989734 DOI: 10.1016/j.bioorg.2023.106488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/02/2023] [Accepted: 03/18/2023] [Indexed: 03/29/2023]
Abstract
Abnormal activation of Hedgehog (Hh) signaling pathway mediates the genesis and progression of various tumors [1]. Currently, three drugs targeting the Hh signaling component Smoothened (Smo) have been marketed for the clinical treatment of basal cell tumors or acute myeloid leukemia. However, drug resistance is a common problem in those drugs, so the study of Smo inhibitors that can overcome drug resistance has important guiding significance for clinical adjuvant drugs. MTT assay, clone formation assay and EdU assay were used to detect the proliferation inhibitory activity of the drugs on tumor cells. The effect of B13 on cell cycle and apoptosis were detected by flow cytometry. An acute toxicity test was used to detect the toxicity of B13 in vivo, and xenograft tumor model was used to detect the efficacy of B13 in vivo. The binding of B13 to Smo was studied by BODIPY-cyclopamine competitive binding assay and molecular docking. The effect of B13 on the expression and localization of downstream target gene Gli1/2 of Smo was investigated by Western Blot and immunofluorescence assay. SmoD473H mutant cell line was constructed to study the effect of B13 against drug resistance. (1) B13 had the strongest inhibitory activity against colorectal cancer cells. (2) B13 can effectively inhibit the clone formation and EdU positive rate of colon cancer cells. (3) B13 can block the cell cycle in the G2/M phase and cell apoptosis. (4) B13 has low toxicity in vivo, and its efficacy in vivo is better than that of the Vismodegib. (5) Molecular docking and BODIPY-cyclopamine experiments showed that B13 could bind to Smo protein. (6) B13 can inhibit the protein expression of Gli1, the downstream of Smo, and inhibit its entry into the nucleus. (7) B13 could inhibit the expression of Gli1 in the HEK293 cells with SmoD473H, and the molecular docking results showed that B13 could bind SmoD473H protein. B13 with the best anti-tumor activity was screened out by MTT assay. In vitro, pharmacodynamics experiments showed that B13 could effectively inhibit the proliferation and metastasis of colorectal cancer cells, induce cell cycle arrest, and induce cell apoptosis. In vivo pharmacodynamics experiments showed that B13 was superior to Vismodegib in antitumor activity and had low toxicity in vivo. Mechanism studies have shown that B13 can bind Smo protein, inhibit the expression of downstream Gli1 and its entry into the nucleus. Notably, B13 overcomes resistance caused by SmoD473H mutations.
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15
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Melo US, Jatzlau J, Prada-Medina CA, Flex E, Hartmann S, Ali S, Schöpflin R, Bernardini L, Ciolfi A, Moeinzadeh MH, Klever MK, Altay A, Vallecillo-García P, Carpentieri G, Delledonne M, Ort MJ, Schwestka M, Ferrero GB, Tartaglia M, Brusco A, Gossen M, Strunk D, Geißler S, Mundlos S, Stricker S, Knaus P, Giorgio E, Spielmann M. Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation. Nat Commun 2023; 14:2034. [PMID: 37041138 PMCID: PMC10090176 DOI: 10.1038/s41467-023-37585-8] [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: 06/08/2022] [Accepted: 03/21/2023] [Indexed: 04/13/2023] Open
Abstract
Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.
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Affiliation(s)
- Uirá Souto Melo
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany.
- Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, 13353, Berlin, Germany.
| | - Jerome Jatzlau
- Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195, Berlin, Germany
| | - Cesar A Prada-Medina
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany
| | - Elisabetta Flex
- Istituto Superiore di Sanità, Department of Oncology and Molecular Medicine, 00161, Rome, Italy
| | - Sunhild Hartmann
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany
| | - Salaheddine Ali
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany
| | - Robert Schöpflin
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany
| | - Laura Bernardini
- Cytogenetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, 71013, San Giovanni Rotondo, Foggia, Italy
| | - Andrea Ciolfi
- Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy
| | - M-Hossein Moeinzadeh
- Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, 14195, Berlin, Germany
| | - Marius-Konstantin Klever
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany
- Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, 13353, Berlin, Germany
| | - Aybuge Altay
- Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology, 14195, Berlin, Germany
| | | | - Giovanna Carpentieri
- Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy
| | | | - Melanie-Jasmin Ort
- Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195, Berlin, Germany
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany
| | - Marko Schwestka
- Institute of Active Polymers, Helmholtz-Zentrum Hereon, 14513, Teltow, Germany
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), 13353, Berlin, Germany
| | | | - Marco Tartaglia
- Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy
| | - Alfredo Brusco
- Department of Medical Sciences, University of Torino, 10126, Torino, Italy
- Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy
| | - Manfred Gossen
- Institute of Active Polymers, Helmholtz-Zentrum Hereon, 14513, Teltow, Germany
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), 13353, Berlin, Germany
| | - Dirk Strunk
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020, Salzburg, Austria
| | - Sven Geißler
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), 13353, Berlin, Germany
| | - Stefan Mundlos
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany
- Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, 13353, Berlin, Germany
| | - Sigmar Stricker
- Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195, Berlin, Germany
| | - Petra Knaus
- Freie Universität Berlin, Institute for Chemistry and Biochemistry, 14195, Berlin, Germany
| | - Elisa Giorgio
- Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
- Medical Genetics Unit, IRCCS Mondino Foundation, 27100, Pavia, Italy.
| | - Malte Spielmann
- Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195, Berlin, Germany.
- Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and University of Kiel, Lübeck, 23562, Germany.
- DZHK (German Centre for Cardiovascular Research) Germany, partner site Hamburg, Lübeck, Kiel, Lübeck, 23562, Germany.
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16
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Harishankar A, Viswanathan VK. Attaching and effacing pathogens modulate host mitochondrial structure and function. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 377:65-86. [PMID: 37268351 PMCID: PMC11321239 DOI: 10.1016/bs.ircmb.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are human enteric pathogens that contribute significantly to morbidity and mortality worldwide. These extracellular pathogens attach intimately to intestinal epithelial cells and cause signature lesions by effacing the brush border microvilli, a property they share with other "attaching and effacing" (A/E) bacteria, including the murine pathogen Citrobacter rodentium. A/E pathogens use a specialized apparatus called a type III secretion system (T3SS) to deliver specific proteins directly into the host cytosol and modify host cell behavior. The T3SS is essential for colonization and pathogenesis, and mutants lacking this apparatus fail to cause disease. Thus, deciphering effector-induced host cell modifications is critical for understanding A/E bacterial pathogenesis. Several of the ∼20-45 effector proteins delivered into the host cell modify disparate mitochondrial properties, some via direct interactions with the mitochondria and/or mitochondrial proteins. In vitro studies have uncovered the mechanistic basis for the actions of some of these effectors, including their mitochondrial targeting, interaction partners, and consequent impacts on mitochondrial morphology, oxidative phosphorylation and ROS production, disruption of membrane potential, and intrinsic apoptosis. In vivo studies, mostly relying on the C. rodentium/mouse model, have been used to validate a subset of the in vitro observations; additionally, animal studies reveal broad changes to intestinal physiology that are likely accompanied by mitochondrial alterations, but the mechanistic underpinnings remain undefined. This chapter provides an overview of A/E pathogen-induced host alterations and pathogenesis, specifically focusing on mitochondria-targeted effects.
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Affiliation(s)
- Anusha Harishankar
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, United States
| | - V K Viswanathan
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ, United States; The BIO5 Institute for Collaborative Research, The University of Arizona, Tucson, AZ, United States; Department of Immunobiology, The University of Arizona, Tucson, AZ, United States.
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17
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Li R, Cai Y, Lin H, Dong L, Tang M, Lang Y, Qi Y, Peng Y, Zhou B, Yang G, Teng Y, Yang X. Generation of an Ihh-mKate2-Dre knock-in mouse line. Genesis 2022; 60:e23488. [PMID: 35765931 DOI: 10.1002/dvg.23488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 05/16/2022] [Accepted: 05/25/2022] [Indexed: 11/06/2022]
Abstract
Indian hedgehog (Ihh), a member of the Hh family, plays important roles in vertebrate development and homeostasis. To improve our understanding of the function of Ihh-expressing cells and their progeny as well, we generate an Ihh-mKate2tomm20 -Dre knock-in mouse line that can label Ihh-positive cells with a fluorescence protein mKate2 and trace Ihh-positive cells and their progeny via Dre-mediated recombination. Consistent with previous reports, we verified Ihh expression in hypertrophic chondrocytes of growth plate and granulosa cells of ovarian follicles by mKate2 immunostaining, and meanwhile confirmed Dre activity in these cells via a Dre reporter mouse line Rosa26-confetti2. We also found, for the first time, that Ihh can mark some cell types, including retinal ganglion cells, Purkinje cells, and gallbladder epithelial cells. Taken together, the Ihh-mKate2tomm20 -Dre mouse is a genetic tool for examining the precise expression profile of Ihh and tracing Ihh-expressing cells and their progeny.
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Affiliation(s)
- Rongyu Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yunting Cai
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Huisang Lin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Lei Dong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Mingchuan Tang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yiming Lang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yini Qi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yanli Peng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Bin Zhou
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Guan Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yan Teng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xiao Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
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18
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Fischer MM, Herzel H, Blüthgen N. Mathematical modelling identifies conditions for maintaining and escaping feedback control in the intestinal epithelium. Sci Rep 2022; 12:5569. [PMID: 35368028 PMCID: PMC8976856 DOI: 10.1038/s41598-022-09202-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/17/2022] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium is one of the fastest renewing tissues in mammals. It shows a hierarchical organisation, where intestinal stem cells at the base of crypts give rise to rapidly dividing transit amplifying cells that in turn renew the pool of short-lived differentiated cells. Upon injury and stem-cell loss, cells can also de-differentiate. Tissue homeostasis requires a tightly regulated balance of differentiation and stem cell proliferation, and failure can lead to tissue extinction or to unbounded growth and cancerous lesions. Here, we present a two-compartment mathematical model of intestinal epithelium population dynamics that includes a known feedback inhibition of stem cell differentiation by differentiated cells. The model shows that feedback regulation stabilises the number of differentiated cells as these become invariant to changes in their apoptosis rate. Stability of the system is largely independent of feedback strength and shape, but specific thresholds exist which if bypassed cause unbounded growth. When dedifferentiation is added to the model, we find that the system can recover faster after certain external perturbations. However, dedifferentiation makes the system more prone to losing homeostasis. Taken together, our mathematical model shows how a feedback-controlled hierarchical tissue can maintain homeostasis and can be robust to many external perturbations.
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Affiliation(s)
- Matthias M Fischer
- Institute for Theoretical Biology, Charité Universitätsmedizin Berlin and Humboldt Universität zu Berlin, Berlin, 10115, Germany
- Institute of Pathology, Charité Universitätsmedizin Berlinn, Berlin, 10117, Germany
| | - Hanspeter Herzel
- Institute for Theoretical Biology, Charité Universitätsmedizin Berlin and Humboldt Universität zu Berlin, Berlin, 10115, Germany
| | - Nils Blüthgen
- Institute for Theoretical Biology, Charité Universitätsmedizin Berlin and Humboldt Universität zu Berlin, Berlin, 10115, Germany.
- Institute of Pathology, Charité Universitätsmedizin Berlinn, Berlin, 10117, Germany.
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19
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Danesh Pouya F, Rasmi Y, Nemati M. Signaling Pathways Involved in 5-FU Drug Resistance in Cancer. Cancer Invest 2022; 40:516-543. [PMID: 35320055 DOI: 10.1080/07357907.2022.2055050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Anti-metabolite drugs prevent the synthesis of essential cell growth compounds. 5-fluorouracil is used as an anti-metabolic drug in various cancers in the first stage of treatment. Unfortunately, in some cancers, 5-fluorouracil has low effectiveness because of its drug resistance. Studies have shown that drug resistance to 5-fluorouracil is due to the activation of specific signaling pathways and increased expressions of enzymes involved in drug metabolites. However, when 5-fluorouracil is used in combination with other drugs, the sensitivity of cancer cells to 5-fluorouracil increases, and the effect of drug resistance is reversed. This study discusses how the function of 5-fluorouracil in JAK/STAT, Wnt, Notch, NF-κB, and hedgehogs in some cancers.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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20
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Yin W, Liontos A, Koepke J, Ghoul M, Mazzocchi L, Liu X, Lu C, Wu H, Fysikopoulos A, Sountoulidis A, Seeger W, Ruppert C, Günther A, Stainier DYR, Samakovlis C. An essential function for autocrine hedgehog signaling in epithelial proliferation and differentiation in the trachea. Development 2022; 149:274222. [PMID: 35112129 PMCID: PMC8918789 DOI: 10.1242/dev.199804] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 12/07/2021] [Indexed: 12/12/2022]
Abstract
The tracheal epithelium is a primary target for pulmonary diseases as it provides a conduit for air flow between the environment and the lung lobes. The cellular and molecular mechanisms underlying airway epithelial cell proliferation and differentiation remain poorly understood. Hedgehog (HH) signaling orchestrates communication between epithelial and mesenchymal cells in the lung, where it modulates stromal cell proliferation, differentiation and signaling back to the epithelium. Here, we reveal a previously unreported autocrine function of HH signaling in airway epithelial cells. Epithelial cell depletion of the ligand sonic hedgehog (SHH) or its effector smoothened (SMO) causes defects in both epithelial cell proliferation and differentiation. In cultured primary human airway epithelial cells, HH signaling inhibition also hampers cell proliferation and differentiation. Epithelial HH function is mediated, at least in part, through transcriptional activation, as HH signaling inhibition leads to downregulation of cell type-specific transcription factor genes in both the mouse trachea and human airway epithelial cells. These results provide new insights into the role of HH signaling in epithelial cell proliferation and differentiation during airway development. Summary: A conserved autocrine role for HH signaling in tracheal epithelial cell proliferation and differentiation is revealed, suggesting potential new interventions for airway epithelial proliferation and differentiation defects.
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Affiliation(s)
- Wenguang Yin
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany.,State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, People's Republic of China.,Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim 61231, Germany
| | - Andreas Liontos
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.,Science for Life Laboratory, Stockholm University, Solna 171 21, Sweden
| | - Janine Koepke
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany
| | - Maroua Ghoul
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany
| | - Luciana Mazzocchi
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany
| | - Xinyuan Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, People's Republic of China
| | - Chunyan Lu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, People's Republic of China
| | - Haoyu Wu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, People's Republic of China
| | - Athanasios Fysikopoulos
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany
| | - Alexandros Sountoulidis
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.,Science for Life Laboratory, Stockholm University, Solna 171 21, Sweden
| | - Werner Seeger
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany.,Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
| | - Clemens Ruppert
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany
| | - Andreas Günther
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany
| | - Didier Y R Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim 61231, Germany
| | - Christos Samakovlis
- Cardio-Pulmonary Institute, Member of the German Center for Lung Research (DZL), University of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University of Giessen, Giessen 35392, Germany.,Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden.,Science for Life Laboratory, Stockholm University, Solna 171 21, Sweden.,Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany
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21
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Akhshi T, Shannon R, Trimble WS. The complex web of canonical and non-canonical Hedgehog signaling. Bioessays 2022; 44:e2100183. [PMID: 35001404 DOI: 10.1002/bies.202100183] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022]
Abstract
Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non-canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia - microtubule-based signaling hubs - an extensive list of crucial functions mediated by non-canonical Hh signaling has emerged. Moreover, amounting evidence indicates that canonical and non-canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non-canonical signaling and discuss new evidence indicating inter-relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics.
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Affiliation(s)
- Tara Akhshi
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Rachel Shannon
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - William S Trimble
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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22
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Khan I. Understanding and Targeting the Colon Cancer Pathogenesis: A Molecular Perspective. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Imran Khan
- Bezmialem Vakif University, Turkey; Integral University, India
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23
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Helal MG, Abd Elhameed AG. Graviola mitigates acetic acid-induced ulcerative colitis in rats: insight on apoptosis and Wnt/Hh signaling crosstalk. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:29615-29628. [PMID: 33559079 DOI: 10.1007/s11356-021-12716-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 01/26/2021] [Indexed: 06/12/2023]
Abstract
In this study, we elucidated the potential protective effects of graviola leaves, compared with sulfasalazine, against acetic acid (AA)-induced ulcerative colitis (UC) in rats. Twenty-eight mature male rats were divided into four groups, Sham, Colitis, Colitis/Sulfa, and Colitis/Graviola, and were treated orally with either saline, saline, sulfasalazine (100 mg/kg/day), or graviola (100 mg/kg/day), respectively, for 7 days. On the 4th day, UC was induced by transrectal administration of 4% AA. Colon tissues were excised for macroscopic and histopathological evaluation and immunohistochemical analysis of caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax). Also, levels of oxidative mediators, Wnt family member1 (Wnt1), smoothened (Smo), and glioblastoma-1 (Gli1) were evaluated. Macroscopic and histopathological examination revealed that both graviola and sulfasalazine significantly mitigated colonic damage. Besides, both treatments significantly alleviated AA-induced oxidative stress, as evidenced by reduced nitric oxide (No) and malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity and raised reduced glutathione (GSH) content. Both treatments significantly attenuated AA-induced apoptosis via downregulating the expression of Bax and caspase-3 and upregulating the expression of the anti-apoptotic protein, Bcl-2. Furthermore, downregulation of mRNA expression of Wnt1 with concomitant upregulation of Smo and Gli1 was observed in rats treated with either sulfasalazine or graviola. Based on these observations, graviola may attenuate AA-induced UC, at least partially, by modulating apoptosis and Wingless/Int1 (Wnt) and hedgehog (Hh) signaling crosstalk.
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Affiliation(s)
- Manar G Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Ahmed G Abd Elhameed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
- Department of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt
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24
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Avery JT, Zhang R, Boohaker RJ. GLI1: A Therapeutic Target for Cancer. Front Oncol 2021; 11:673154. [PMID: 34113570 PMCID: PMC8186314 DOI: 10.3389/fonc.2021.673154] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022] Open
Abstract
GLI1 is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway and is tightly regulated during embryonic development and tissue patterning/differentiation. GLI1 has low-level expression in differentiated tissues, however, in certain cancers, aberrant activation of GLI1 has been linked to the promotion of numerous hallmarks of cancer, such as proliferation, survival, angiogenesis, metastasis, metabolic rewiring, and chemotherapeutic resistance. All of these are driven, in part, by GLI1’s role in regulating cell cycle, DNA replication and DNA damage repair processes. The consequences of GLI1 oncogenic activity, specifically the activity surrounding DNA damage repair proteins, such as NBS1, and cell cycle proteins, such as CDK1, can be linked to tumorigenesis and chemoresistance. Therefore, understanding the underlying mechanisms driving GLI1 dysregulation can provide prognostic and diagnostic biomarkers to identify a patient population that would derive therapeutic benefit from either direct inhibition of GLI1 or targeted therapy towards proteins downstream of GLI1 regulation.
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Affiliation(s)
- Justin T Avery
- Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States
| | - Ruowen Zhang
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Rebecca J Boohaker
- Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States
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25
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Su J, Wang Y, Zhang X, Ma M, Xie Z, Pan Q, Ma Z, Peppelenbosch MP. Remodeling of the gut microbiome during Ramadan-associated intermittent fasting. Am J Clin Nutr 2021; 113:1332-1342. [PMID: 33842951 PMCID: PMC8106760 DOI: 10.1093/ajcn/nqaa388] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/23/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Intermittent fasting is a popular dietary intervention with perceived relatively easy compliance and is linked to various health benefits, including weight loss and improvement in blood glucose concentrations. The mechanistic explanations underlying the beneficial effects of intermittent fasting remain largely obscure but may involve alterations in the gut microbiota. OBJECTIVES We sought to establish the effects of 1 mo of intermittent fasting on the gut microbiome. METHODS We took advantage of intermittent fasting being voluntarily observed during the Islamic faith-associated Ramadan and sampled feces and blood, as well as collected longitudinal physiologic data in 2 cohorts, sampled in 2 different years. The fecal microbiome was determined by 16S sequencing. Results were contrasted to age- and body weight-matched controls and correlated to physiologic parameters (e.g., body mass and calorie intake). RESULTS We observed that Ramadan-associated intermittent fasting increased microbiome diversity and was specifically associated with upregulation of the Clostridiales order-derived Lachnospiraceae [no fasting 24.6 ± 13.67 compared with fasting 39.7 ± 15.9 in relative abundance (%); linear discriminant analysis = 4.9, P < 0.001 by linear discriminant analysis coupled with effect size measurements] and Ruminococcaceae [no fasting 13.4 ± 6.9 compared with fasting 23.2 ± 12.9 in relative abundance (%); linear discriminant analysis = 4.7, P < 0.001 by linear discriminant analysis coupled with effect size measurements] bacterial families. Microbiome composition returned to baseline upon cessation of intermittent feeding. Furthermore, changes in Lachnospiraceae concentrations mirrored intermittent fasting-provoked changes in physiologic parameters. CONCLUSIONS Intermittent fasting provokes substantial remodeling of the gut microbiome. The intermittent fasting-provoked upregulation of butyric acid-producing Lachnospiraceae provides an obvious possible mechanistic explanation for health effects associated with intermittent fasting.
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Affiliation(s)
- Junhong Su
- Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Basic Medicine, Medical School, Kunming University of Science and Technology, Kunming, China
| | - Yueying Wang
- China-Malaysia National Joint Laboratory, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Xiaofang Zhang
- Department of Basic Medicine, Medical School, Kunming University of Science and Technology, Kunming, China
| | - Mingfu Ma
- The Fifth People's Hospital of Qinghai (Qinghai Tumor Hospital), Xining, China
| | - Zhenrong Xie
- The Medical Biobank, the First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Zhongren Ma
- China-Malaysia National Joint Laboratory, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
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26
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Krishnan M, Kumar S, Kangale LJ, Ghigo E, Abnave P. The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models. Biomolecules 2021; 11:biom11050667. [PMID: 33946143 PMCID: PMC8144950 DOI: 10.3390/biom11050667] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/02/2021] [Accepted: 04/09/2021] [Indexed: 12/12/2022] Open
Abstract
Adult stem cells (ASCs) are the undifferentiated cells that possess self-renewal and differentiation abilities. They are present in all major organ systems of the body and are uniquely reserved there during development for tissue maintenance during homeostasis, injury, and infection. They do so by promptly modulating the dynamics of proliferation, differentiation, survival, and migration. Any imbalance in these processes may result in regeneration failure or developing cancer. Hence, the dynamics of these various behaviors of ASCs need to always be precisely controlled. Several genetic and epigenetic factors have been demonstrated to be involved in tightly regulating the proliferation, differentiation, and self-renewal of ASCs. Understanding these mechanisms is of great importance, given the role of stem cells in regenerative medicine. Investigations on various animal models have played a significant part in enriching our knowledge and giving In Vivo in-sight into such ASCs regulatory mechanisms. In this review, we have discussed the recent In Vivo studies demonstrating the role of various genetic factors in regulating dynamics of different ASCs viz. intestinal stem cells (ISCs), neural stem cells (NSCs), hematopoietic stem cells (HSCs), and epidermal stem cells (Ep-SCs).
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Affiliation(s)
- Meera Krishnan
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Gurgaon-Faridabad Ex-pressway, Faridabad 121001, India; (M.K.); (S.K.)
| | - Sahil Kumar
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Gurgaon-Faridabad Ex-pressway, Faridabad 121001, India; (M.K.); (S.K.)
| | - Luis Johnson Kangale
- IRD, AP-HM, SSA, VITROME, Aix-Marseille University, 13385 Marseille, France;
- Institut Hospitalo Universitaire Méditerranée Infection, 13385 Marseille, France;
| | - Eric Ghigo
- Institut Hospitalo Universitaire Méditerranée Infection, 13385 Marseille, France;
- TechnoJouvence, 13385 Marseille, France
| | - Prasad Abnave
- Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Gurgaon-Faridabad Ex-pressway, Faridabad 121001, India; (M.K.); (S.K.)
- Correspondence:
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27
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Ma G, Yang Y, Chen Y, Wei X, Ding J, Zhou RP, Hu W. Blockade of TRPM7 Alleviates Chondrocyte Apoptosis and Articular Cartilage Damage in the Adjuvant Arthritis Rat Model Through Regulation of the Indian Hedgehog Signaling Pathway. Front Pharmacol 2021; 12:655551. [PMID: 33927631 PMCID: PMC8076952 DOI: 10.3389/fphar.2021.655551] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/26/2021] [Indexed: 12/15/2022] Open
Abstract
Articular cartilage damage with subsequent impairment of joint function is a common feature of articular diseases, in particular, rheumatoid arthritis and osteoarthritis. While articular cartilage injury mediated by chondrocyte apoptosis is a known major pathological feature of arthritis, the specific mechanisms remain unclear at present. Transient receptor potential melastatin-like seven channel (TRPM7) is reported to play an important regulatory role in apoptosis. This study focused on the effects of TRPM7 on arthritic chondrocyte injury and its underlying mechanisms of action. Sodium nitroprusside (SNP)-induced rat primary chondrocyte apoptosis and rat adjuvant arthritis (AA) were used as in vitro and in vivo models, respectively. Blockage of TRPM7 with 2-APB or specific siRNA resulted in increased chondrocyte viability and reduced toxicity of SNP. Moreover, treatment with 2-APB enhanced the Bcl-2/Bax ratio and reduced cleaved PARP and IL-6, MMP-13 and ADAMTS-5 expression in SNP-treated chondrocytes. Activation of Indian Hedgehog with purmorphamine reversed the protective effects of 2-APB on SNP-induced chondrocyte apoptosis. Blockage of TRPM7 with 2-APB relieved the clinical signs of AA in the rat model and reduced the arthritis score and paw swelling. Similar to findings in SNP-treated chondrocytes, 2-APB treatment increased the Bcl-2/Bax ratio and suppressed cleaved PARP, IL-6, MMP-13, ADAMTS-5, TRPM7, and Indian hedgehog expression in articular cartilage of AA rats. Our collective findings suggest that blockade of TRPM7 could effectively reduce chondrocyte apoptosis and articular cartilage damage in rats with adjuvant arthritis through regulation of the Indian Hedgehog signaling pathway.
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Affiliation(s)
- Ganggang Ma
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Yang Yang
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Yong Chen
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Xin Wei
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Jie Ding
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Ren-Peng Zhou
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, China
| | - Wei Hu
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, China
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28
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Fattahi S, Nikbakhsh N, Ranaei M, Sabour D, Akhavan-Niaki H. Association of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stage. Sci Rep 2021; 11:7471. [PMID: 33811245 PMCID: PMC8018955 DOI: 10.1038/s41598-021-86946-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the leading cause of cancer-related mortality worldwide. Given the importance of gastric cancer in public health, identifying biomarkers associated with disease onset is an important part of precision medicine. The hedgehog signaling pathway is considered as one of the most significant widespread pathways of intracellular signaling in the early events of embryonic development. This pathway contributes also to the maintenance of pluripotency of cancer stem cells pluripotency. In this study, we analyzed the expression levels of sonic hedgehog (Shh) signaling pathway genes IHH, BOC, RAB23a and their regulatory miRNAs including MIR-195-5p, MIR-509-3-5p, MIR-6738-3p in gastric cancer patients. In addition, the impact of infection status on the expression level of those genes and their regulatory miRNAs was investigated. One hundred samples taken from 50 gastric cancer patients (50 tumoral tissues and their adjacent non-tumoral counterparts) were included in this study. There was a significant difference in all studied genes and miRNAs in tumoral tissues in comparison with their adjacent non-tumoral counterparts. The lower expression of IHH, BOC, RAB23, miR-195-5p, and miR-6738-3p was significantly associated with more advanced cancer stage. Additionally, IHH upregulation was significantly associated with CMV infection (P < 0.001). Also, receiver operating characteristic (ROC) curve analysis indicated that mir-195 was significantly related to several clinicopathological features including tumor stage, grade, age, gender, and infection status of gastric cancer and can be considered as a potential diagnostic biomarker for gastric cancer. This study confirms the important role of Shh signaling pathway genes in gastric cancer tumorigenesis and their potential as novel molecular biomarkers and therapeutic targets.
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Affiliation(s)
- Sadegh Fattahi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Novin Nikbakhsh
- Department of Surgery, Rouhani Hospital Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Ranaei
- Department of Pathology, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Davood Sabour
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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29
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New insights into the GDF9-Hedgehog-GLI signaling pathway in human ovaries: from fetus to postmenopause. J Assist Reprod Genet 2021; 38:1387-1403. [PMID: 33772413 DOI: 10.1007/s10815-021-02161-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/18/2021] [Indexed: 10/21/2022] Open
Abstract
RESEARCH QUESTION Are glioma-associated oncogene homolog 1, 2, and 3 (GLI1, 2, and 3) and protein patched homolog 1 (PTCH1) specific markers for precursor theca cells in human ovaries as in mouse ovaries? DESIGN To study the GDF9-HH-GLI pathway and assess whether GLI1 and 3 and PTCH1 are specific markers for precursor theca cells in the human ovary, growth differentiation factor 9 (GDF9), Indian Hedgehog (IHH), Desert Hedgehog (DHH), Sonic Hedgehog (SHH), PTCH1 and GLI1, 2 and 3 were investigated in fetal (n=9), prepubertal (n=9), reproductive-age (n=15), and postmenopausal (n=8) human ovarian tissue. Immunohistochemistry against GDF9, IHH, DHH, SHH, PTCH1, GLI1, GLI2, and GLI3 was performed on human ovarian tissue sections fixed in 4% formaldehyde and embedded in paraffin. Western blotting was carried out on extracted proteins from the same samples used in the previous step to prove the antibodies' specificity. The quantitative real-time polymerase chain reaction was performed to identify mRNA levels for Gdf9, Ihh, Gli1, Gli2, and Gli3 in menopausal ovaries. RESULTS Our results showed that, in contrast to mice, all studied proteins were expressed in primordial follicles of fetal, prepubertal, and reproductive-age human ovaries and stromal cells of reproductive-age and postmenopausal ovaries. Intriguingly, Gdf9, Ihh, and Gli3 mRNA, but not Gli1 and 2, was detected in postmenopausal ovaries. Moreover, GLI1, GLI3, and PTCH1 are not limited to a specific population of cells. They were spread throughout the organ, which means they are not specific markers for precursor theca cells in human ovaries. CONCLUSION These results could provide a basis for understanding how this pathway modulates follicle development and ovarian cell steroidogenesis in human ovaries.
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Cui H, Yu W, Yu M, Luo Y, Yang M, Cong R, Chu X, Gao G, Zhong M. GPR126 regulates colorectal cancer cell proliferation by mediating HDAC2 and GLI2 expression. Cancer Sci 2021; 112:1798-1810. [PMID: 33629464 PMCID: PMC8088945 DOI: 10.1111/cas.14868] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/20/2021] [Accepted: 02/20/2021] [Indexed: 12/15/2022] Open
Abstract
The G‐protein‐coupled receptor 126 (GPR126) may play an important role in tumor development, although its role remains poorly understood. We found that GPR126 had higher expression in most colorectal cancer cell lines than in normal colon epithelial cell lines, and higher expression levels in colorectal cancer tissues than in normal adjacent colon tissues. GPR126 knockdown induced by shRNA inhibited cell viability and colony formation in HT‐29, HCT116, and LoVo cells, decreased BrdU incorporation into newly synthesized proliferating HT‐29 cells, led to an arrest of cell cycle progression at the G1 phase in HCT‐116 and HT‐29 cells, and suppressed tumorigenesis of HT‐29, HCT116, and LoVo cells in nude mouse xenograft models. GPR126 knockdown engendered decreased transcription and translation of histone deacetylase 2 (HDAC2), previously implicated in the activation of GLI1 and GLI2 in the Hedgehog signaling pathway. Ectopic expression of HDAC2 in GPR126‐silenced cells restored cell viability and proliferation, GLI2 luciferase reporter activity, partially recovered GLI2 expression, and reduced the cell cycle arrest. HDAC2 regulated GLI2 expression and, along with GLI2, it bound to the PTCH1 promoter, as evidenced by a chip assay with HT‐29 cells. Purmorphamine, a hedgehog agonist, largely restored the cell viability and expression of GLI2 proteins in GPR126‐silenced HT‐29 cells, whereas GANT61, a hedgehog inhibitor, further enhanced the GPR126 knockdown‐induced inhibitory effects. Our findings demonstrate that GPR126 regulates colorectal cancer cell proliferation by mediating the expression of HDAC2 and GLI2, therefore it may represent a suitable therapeutic target for colorectal cancer treatment.
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Affiliation(s)
- Hengxiang Cui
- Medical Research Center, Second Affiliated Hospital of Nantong University, Nantong, China.,Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
| | - Wenjie Yu
- Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
| | - Minhao Yu
- Department of Gastrointestinal Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Luo
- Department of Gastrointestinal Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mingming Yang
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China
| | - Ruochen Cong
- Medical Research Center, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xin Chu
- Medical Research Center, Second Affiliated Hospital of Nantong University, Nantong, China
| | - Ganglong Gao
- Department of Gastrointestinal Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhong
- Department of Gastrointestinal Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
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Abstract
The hedgehog (Hh) signaling pathway plays several diverse regulatory and patterning roles during organogenesis of the intestine and in the regulation of adult intestinal homeostasis. In the embryo, fetus, and adult, intestinal Hh signaling is paracrine: Hh ligands are expressed in the endodermally derived epithelium, while signal transduction is confined to the mesenchymal compartment, where at least a dozen distinct cell types are capable of responding to Hh signals. Epithelial Hh ligands not only regulate a variety of mesenchymal cell behaviors, but they also direct these mesenchymal cells to secrete additional soluble factors (e.g., Wnts, Bmps, inflammatory mediators) that feed back to regulate the epithelial cells themselves. Evolutionary conservation of the core Hh signaling pathway, as well as conservation of epithelial/mesenchymal cross talk in the intestine, has meant that work in many diverse model systems has contributed to our current understanding of the role of this pathway in intestinal organogenesis, which is reviewed here.
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Affiliation(s)
- Katherine D Walton
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; ,
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Deborah L Gumucio
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; ,
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32
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Epithelium-derived Indian Hedgehog restricts stromal expression of ErbB family members that drive colonic tumor cell proliferation. Oncogene 2021; 40:1628-1643. [PMID: 33479497 DOI: 10.1038/s41388-020-01633-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 12/15/2020] [Accepted: 12/17/2020] [Indexed: 02/04/2023]
Abstract
Indian Hedgehog (Ihh) is a morphogen expressed by epithelial cells in the small intestine and colon that signals in a paracrine manner to gp38+ stromal cells. The loss of Ihh signaling results in increased epithelial proliferation, lengthening and multiplication of intestinal crypts and the activation of a stromal cell immune response. How Ihh controls epithelial proliferation through the stroma and how it affects colorectal cancer development remains poorly defined. To study the influence of Ihh signaling on the earliest stage of colorectal carcinogenesis, we used a well characterized mouse model in which both alleles of the Adenoma Polyposis Coli (Apc) gene could be inducibly deleted, leading to instant transformation of the colonic epithelium to an adenomatous phenotype. Concurrent deletion of Ihh from the adenomatous colonic epithelium of Apc inducible double mutant mice resulted in a remarkable increase in the hyperproliferative epithelial phenotype and increased accumulation of Lgr5+ stem cells. Transcriptional profiling of sorted colonic gp38+ fibroblasts showed upregulation of three ErbB pathway ligands (EREG, BTC, and NRG1) in Apc-/-Ihh-/- double mutant mice. We found that recombinant EREG, BTC, and NRG1 but not Lgr5 ligand R-Spondin promoted growth and proliferation of Apc double mutant colonic organoids. Thus, the loss of Ihh enhances Apc-driven colonic adenomagenesis via upregulation of ErbB pathway family members in colonic stromal cells. Our findings highlight the critical role of epithelium-derived Indian Hedgehog as a stromal tumor suppressor in the intestine.
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Geyer N, Gerling M. Hedgehog Signaling in Colorectal Cancer: All in the Stroma? Int J Mol Sci 2021; 22:ijms22031025. [PMID: 33498528 PMCID: PMC7864206 DOI: 10.3390/ijms22031025] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/18/2021] [Accepted: 01/18/2021] [Indexed: 12/13/2022] Open
Abstract
Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.
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Affiliation(s)
- Natalie Geyer
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden;
| | - Marco Gerling
- Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden;
- Theme Cancer, Oncology, Karolinska University Hospital, 17176 Solna, Sweden
- Correspondence:
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Nisar S, Hashem S, Macha MA, Yadav SK, Muralitharan S, Therachiyil L, Sageena G, Al-Naemi H, Haris M, Bhat AA. Exploring Dysregulated Signaling Pathways in Cancer. Curr Pharm Des 2020; 26:429-445. [PMID: 31939726 DOI: 10.2174/1381612826666200115095937] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023]
Abstract
Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.
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Affiliation(s)
- Sabah Nisar
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Sheema Hashem
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States.,Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India
| | - Santosh K Yadav
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | | | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Hamda Al-Naemi
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
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In JG, Yin J, Atanga R, Doucet M, Cole RN, DeVine L, Donowitz M, Zachos NC, Blutt SE, Estes MK, Kovbasnjuk O. Epithelial WNT2B and Desert Hedgehog Are Necessary for Human Colonoid Regeneration after Bacterial Cytotoxin Injury. iScience 2020; 23:101618. [PMID: 33089106 PMCID: PMC7559866 DOI: 10.1016/j.isci.2020.101618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/03/2020] [Accepted: 09/24/2020] [Indexed: 01/09/2023] Open
Abstract
Intestinal regeneration and crypt hyperplasia after radiation or pathogen injury relies on Wnt signaling to stimulate stem cell proliferation. Mesenchymal Wnts are essential for homeostasis and regeneration in mice, but the role of epithelial Wnts remains largely uncharacterized. Using the enterohemorrhagic E. coli-secreted cytotoxin EspP to induce injury to human colonoids, we evaluated a simplified, epithelial regeneration model that lacks mesenchymal Wnts. Here, we demonstrate that epithelial-produced WNT2B is upregulated following injury and essential for regeneration. Hedgehog signaling, specifically activation via the ligand Desert Hedgehog (DHH), but not Indian or Sonic Hedgehog, is another driver of regeneration and modulates WNT2B expression. These findings highlight the importance of epithelial WNT2B and DHH in regulating human colonic regeneration after injury.
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Affiliation(s)
- Julie G. In
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jianyi Yin
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Roger Atanga
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Michele Doucet
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Robert N. Cole
- Department of Biological Chemistry, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lauren DeVine
- Department of Biological Chemistry, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nicholas C. Zachos
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sarah E. Blutt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mary K. Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Olga Kovbasnjuk
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Kolbe E, Aleithe S, Rennert C, Spormann L, Ott F, Meierhofer D, Gajowski R, Stöpel C, Hoehme S, Kücken M, Brusch L, Seifert M, von Schoenfels W, Schafmayer C, Brosch M, Hofmann U, Damm G, Seehofer D, Hampe J, Gebhardt R, Matz-Soja M. Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human. Cell Rep 2020; 29:4553-4567.e7. [PMID: 31875560 DOI: 10.1016/j.celrep.2019.11.104] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/14/2019] [Accepted: 11/25/2019] [Indexed: 12/12/2022] Open
Abstract
The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.
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Affiliation(s)
- Erik Kolbe
- Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany
| | - Susanne Aleithe
- Department of Neurology, Leipzig University, Leipzig 04103, Germany
| | - Christiane Rennert
- Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany; Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Leipzig 04103, Germany
| | - Luise Spormann
- Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany
| | - Fritzi Ott
- Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Faculty, Berlin 14195, Germany
| | - Robert Gajowski
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Faculty, Berlin 14195, Germany
| | - Claus Stöpel
- Institute for Computer Science, Leipzig University, Leipzig 04103, Germany
| | - Stefan Hoehme
- Institute for Computer Science, Leipzig University, Leipzig 04103, Germany
| | - Michael Kücken
- Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden 01069, Germany
| | - Lutz Brusch
- Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden 01069, Germany
| | - Michael Seifert
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden 01307, Germany
| | - Witigo von Schoenfels
- Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel 24105, Germany
| | - Clemens Schafmayer
- Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel 24105, Germany
| | - Mario Brosch
- Medical Department 1, University Hospital Dresden, Technical University Dresden, Dresden 01069, Germany
| | - Ute Hofmann
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart 70376, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Leipzig 04103, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Leipzig 04103, Germany
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technical University Dresden, Dresden 01069, Germany
| | - Rolf Gebhardt
- Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany
| | - Madlen Matz-Soja
- Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany.
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Baulies A, Angelis N, Li VSW. Hallmarks of intestinal stem cells. Development 2020; 147:147/15/dev182675. [PMID: 32747330 DOI: 10.1242/dev.182675] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Intestinal stem cells (ISCs) are highly proliferative cells that fuel the continuous renewal of the intestinal epithelium. Understanding their regulatory mechanisms during tissue homeostasis is key to delineating their roles in development and regeneration, as well as diseases such as bowel cancer and inflammatory bowel disease. Previous studies of ISCs focused mainly on the position of these cells along the intestinal crypt and their capacity for multipotency. However, evidence increasingly suggests that ISCs also exist in distinct cellular states, which can be an acquired rather than a hardwired intrinsic property. In this Review, we summarise the recent findings into how ISC identity can be defined by proliferation state, signalling crosstalk, epigenetics and metabolism, and propose an update on the hallmarks of ISCs. We further discuss how these properties contribute to intestinal development and the dynamics of injury-induced regeneration.
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Affiliation(s)
- Anna Baulies
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Nikolaos Angelis
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Vivian S W Li
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Hemagglutinating Virus of Japan Envelope (HVJ-E)-Guided Gene Transfer to the Intestinal Epithelium. Methods Mol Biol 2020. [PMID: 32705650 DOI: 10.1007/978-1-0716-0747-3_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The rapidly self-renewing epithelium of the small intestine represents an exquisite model for the stem cell-driven tissue renewal and tumorigenesis. Intestinal stem cells (ISCs) are located in the crypt base, where they produce rapidly dividing progenitors that undergo cell-cycle arrest and terminal differentiation upon several rounds of cell division. So far, genetic studies in mice have played a central role in analyzing function of genes during the stem cell-driven renewal of the intestinal epithelium. However, generation and maintenance of genetically engineered mice are a time-consuming endeavor, which limits the progress in intestinal biology. Recently, we have established a novel method that serves as an alternative to mouse genetics in intestinal biology. The method, termed intestine-specific gene transfer (iGT), enables rapid and efficient delivery of small molecules, such as siRNAs and plasmids, into the intestinal epithelium of living mice by utilizing the hemagglutinating virus of Japan envelope (HVJ-E). Here, we describe a detailed protocol for iGT and discuss how this method can accelerate progress in intestinal biology and elucidate the mechanisms of intestinal epithelium self-renewal.
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Badgery H, Chong L, Iich E, Huang Q, Georgy SR, Wang DH, Read M. Recent insights into the biology of Barrett's esophagus. Ann N Y Acad Sci 2020; 1481:198-209. [PMID: 32681541 DOI: 10.1111/nyas.14432] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/04/2020] [Accepted: 06/17/2020] [Indexed: 12/21/2022]
Abstract
Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), an aggressive cancer with a poor prognosis. Our understanding of the pathogenesis and Barrett's metaplasia is incomplete, and this has limited the development of new therapeutic targets and agents, risk stratification ability, and management strategies. This review outlines current insights into the biology of BE and addresses controversies surrounding cell of origin, cellular reprogramming theories, updates on esophageal epithelial barrier function, and the significance of goblet cell metaplasia and its association with malignant change. Further research into the basic biology of BE is vital as it will underpin novel therapies and improve our ability to predict malignant progression and help identify the minority of patients who will develop EAC.
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Affiliation(s)
- Henry Badgery
- Department of Upper Gastrointestinal Surgery, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Lynn Chong
- Department of Upper Gastrointestinal Surgery, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Elhadi Iich
- Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Qin Huang
- Department of Pathology and Laboratory Medicine, Veterans Affairs Boston Healthcare System and Harvard Medical School, West Roxbury, Massachusetts
| | - Smitha Rose Georgy
- Department of Anatomic Pathology, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - David H Wang
- Department of Hematology and Oncology, UT Southwestern Medical Centre and VA North Texas Health Care System, Dallas, Texas
| | - Matthew Read
- Department of Upper Gastrointestinal Surgery, St Vincent's Hospital, Melbourne, Victoria, Australia.,Department of Surgery, The University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia
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40
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Wan ML, Wang Y, Zeng Z, Deng B, Zhu BS, Cao T, Li YK, Xiao J, Han Q, Wu Q. Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways. Biosci Rep 2020; 40:BSR20200265. [PMID: 32149326 PMCID: PMC7087324 DOI: 10.1042/bsr20200265] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/21/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related death among men worldwide. CRC is a multifactor digestive pathology, which is a huge problem faced not only by clinicians but also by researchers. Importantly, a unique feature of CRC is the dysregulation of molecular signaling pathways. To date, a series of reviews have indicated that different signaling pathways are disordered and have potential as therapeutic targets in CRC. Nevertheless, an overview of the function and interaction of multiple signaling pathways in CRC is needed. Therefore, we summarized the pathways, biological functions and important interactions involved in CRC. First, we investigated the involvement of signaling pathways, including Wnt, PI3K/Akt, Hedgehog, ErbB, RHOA, Notch, BMP, Hippo, AMPK, NF-κB, MAPK and JNK. Subsequently, we discussed the biological function of these pathways in pathophysiological aspects of CRC, such as proliferation, apoptosis and metastasis. Finally, we summarized important interactions among these pathways in CRC. We believe that the interaction of these pathways could provide new strategies for the treatment of CRC.
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Affiliation(s)
- Mao-lin Wan
- Department of Hepatobiliary and Pancreatic Surgery, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Yu Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of University of South China, Hengyang, 421001, P.R. China
| | - Zhi Zeng
- Department of Pathology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Bo Deng
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Bi-sheng Zhu
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Ting Cao
- Department of Digestive Medical, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
| | - Yu-kun Li
- Key Laboratory of Tumor Cellular and Molecular Pathology, College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan, 421001, P.R. China
| | - Jiao Xiao
- Department of Endocrinology, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
| | - Qi Han
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Qing Wu
- Department of Digestive Medical, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
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Discrete Hedgehog Factor Expression and Action in the Developing Phallus. Int J Mol Sci 2020; 21:ijms21041237. [PMID: 32059607 PMCID: PMC7072906 DOI: 10.3390/ijms21041237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/10/2020] [Accepted: 02/10/2020] [Indexed: 01/02/2023] Open
Abstract
Hypospadias is a failure of urethral closure within the penis occurring in 1 in 125 boys at birth and is increasing in frequency. While paracrine hedgehog signalling is implicated in the process of urethral closure, how these factors act on a tissue level to execute closure itself is unknown. This study aimed to understand the role of different hedgehog signalling members in urethral closure. The tammar wallaby (Macropus eugenii) provides a unique system to understand urethral closure as it allows direct treatment of developing offspring because mothers give birth to young before urethral closure begins. Wallaby pouch young were treated with vehicle or oestradiol (known to induce hypospadias in males) and samples subjected to RNAseq for differential expression and gene ontology analyses. Localisation of Sonic Hedgehog (SHH) and Indian Hedgehog (IHH), as well as the transcription factor SOX9, were assessed in normal phallus tissue using immunofluorescence. Normal tissue culture explants were treated with SHH or IHH and analysed for AR, ESR1, PTCH1, GLI2, SOX9, IHH and SHH expression by qPCR. Gene ontology analysis showed enrichment for bone differentiation terms in male samples compared with either female samples or males treated with oestradiol. Expression of SHH and IHH localised to specific tissue areas during development, akin to their compartmentalised expression in developing bone. Treatment of phallus explants with SHH or IHH induced factor-specific expression of genes associated with bone differentiation. This reveals a potential developmental interaction involved in urethral closure that mimics bone differentiation and incorporates discrete hedgehog activity within the developing phallus and phallic urethra.
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Yuan J, Xie A, Cao Q, Li X, Chen J. INHBB Is a Novel Prognostic Biomarker Associated with Cancer-Promoting Pathways in Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6909672. [PMID: 33083477 PMCID: PMC7563060 DOI: 10.1155/2020/6909672] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 09/05/2020] [Accepted: 09/15/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Inhibin subunit beta B (INHBB) is a protein-coding gene that participated in the synthesis of the transforming growth factor-β (TGF-β) family members. The study is aimed at exploring the clinical significance of INHBB in patients with colorectal cancer (CRC) by bioinformatics analysis. METHODS Real-time PCR and analyses of Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases were utilized to evaluate the INHBB gene transcription level of colorectal cancer (CRC) tissue. We evaluated the INHBB methylation level and the relationship between expression and methylation levels of CpG islands in CRC tissue. The corresponding clinical data were obtained to further explore the association of INHBB with clinical and survival features. In addition, Gene Set Enrichment Analysis (GSEA) was performed to explore the gene ontology and signaling pathways of INHBB involved. RESULTS INHBB expression was elevated in CRC tissue. Although the promoter of INHBB was hypermethylated in CRC, methylation did not ultimately correlate with the expression of INHBB. Overexpression of INHBB was significantly and positively associated with invasion depth, distant metastasis, and TNM stage. Cox regression analyses and Kaplan-Meier survival analysis indicated that high expression of INHBB was correlated with worse overall survival (OS) and disease-free survival (DFS). GSEA showed that INHBB was closely correlated with 5 cancer-promoting signaling pathways including the Hedgehog signaling pathway, ECM receptor interaction, TGF-β signaling pathway, focal adhesion, and pathway in cancer. INHBB expression significantly promoted macrophage infiltration and inhibited memory T cell, mast cell, and dendritic cell infiltration. INHBB expression was positively correlated with stromal and immune scores of CRC samples. CONCLUSION INHBB might be a potential prognostic biomarker and a novel therapeutic target for CRC.
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Affiliation(s)
- Jinpeng Yuan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041 Guangdong, China
- Shantou University Medical College, China
| | - Aosi Xie
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041 Guangdong, China
| | - Qiangjian Cao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041 Guangdong, China
| | - Xinxin Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041 Guangdong, China
| | - Juntian Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041 Guangdong, China
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Zheng L, Rui C, Zhang H, Chen J, Jia X, Xiao Y. Sonic hedgehog signaling in epithelial tissue development. Regen Med Res 2019; 7:3. [PMID: 31898580 PMCID: PMC6941452 DOI: 10.1051/rmr/190004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 12/09/2019] [Indexed: 12/16/2022] Open
Abstract
The Sonic hedgehog (SHH) signaling pathway is essential for embryonic development and tissue regeneration. The dysfunction of SHH pathway is involved in a variety of diseases, including cancer, birth defects, and other diseases. Here we reviewed recent studies on main molecules involved in the SHH signaling pathway, specifically focused on their function in epithelial tissue and appendages development, including epidermis, touch dome, hair, sebaceous gland, mammary gland, tooth, nail, gastric epithelium, and intestinal epithelium. The advance in understanding the SHH signaling pathway will give us more clues to the mechanisms of tissue repair and regeneration, as well as the development of new treatment for diseases related to dysregulation of SHH signaling pathway.
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Affiliation(s)
- Lu Zheng
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Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University Hangzhou PR China
| | - Chen Rui
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Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University Hangzhou PR China
| | - Hao Zhang
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Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University Hangzhou PR China
| | - Jing Chen
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Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University Hangzhou PR China
| | - Xiuzhi Jia
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Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University Hangzhou PR China
| | - Ying Xiao
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Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University Hangzhou PR China
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Iyer DN, Sin WY, Ng L. Linking stemness with colorectal cancer initiation, progression, and therapy. World J Stem Cells 2019; 11:519-534. [PMID: 31523371 PMCID: PMC6716088 DOI: 10.4252/wjsc.v11.i8.519] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/12/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023] Open
Abstract
The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the cause or an effect of the disease? How do cancer stem cells assist in colorectal tumor dissemination to distant organs? What are the molecular or environmental factors affecting the roles of these cells in colorectal cancer? Through this review, we investigate the key findings until now and attempt to elucidate the origins, physical properties, microenvironmental niches, as well as the molecular signaling network that support the existence, self-renewal, plasticity, quiescence, and the overall maintenance of cancer stem cells in colorectal cancer. Increasing data show that the cancer stem cells play a crucial role not only in the establishment of the primary colorectal tumor but also in the distant spread of the disease. Hence, we will also look at the mechanisms adopted by cancer stem cells to influence the development of metastasis and evade therapeutic targeting and its role in the overall disease prognosis. Finally, we will illustrate the importance of understanding the biology of these cells to develop improved clinical strategies to tackle colorectal cancer.
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Affiliation(s)
- Deepak Narayanan Iyer
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai-Yan Sin
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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45
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Pelullo M, Zema S, Nardozza F, Checquolo S, Screpanti I, Bellavia D. Wnt, Notch, and TGF-β Pathways Impinge on Hedgehog Signaling Complexity: An Open Window on Cancer. Front Genet 2019; 10:711. [PMID: 31552081 PMCID: PMC6736567 DOI: 10.3389/fgene.2019.00711] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 07/05/2019] [Indexed: 12/22/2022] Open
Abstract
Constitutive activation of the Hedgehog (Hh) signaling pathway is associated with increased risk of developing several malignancies. The biological and pathogenic importance of Hh signaling emphasizes the need to control its action tightly, both physiologically and therapeutically. Evidence of crosstalk between Hh and other signaling pathways is reported in many tumor types. Here, we provide an overview of the current knowledge about the communication between Hh and major signaling pathways, such as Notch, Wnt, and transforming growth factor β (TGF-β), which play critical roles in both embryonic and adult life. When these pathways are unbalanced, impaired crosstalk contributes to disease development. It is reported that more than one of these pathways are active in different type of tumors, at the same time. Therefore, starting from a plethora of stimuli that activate multiple signaling pathways, we describe the signals that preferentially converge on the Hh signaling cascade that influence its activity. Moreover, we highlight several connection points between Hh and Notch, Wnt, or TGF-β pathways, showing a reciprocal synergism that contributes to tumorigenesis, supporting a more malignant behavior by tumor cells, such as in leukemia and brain tumors. Understanding the importance of these molecular interlinking networks will provide a rational basis for combined anticancer drug development.
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Affiliation(s)
- Maria Pelullo
- Center of Life Nano Science Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Sabrina Zema
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | | | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy
| | | | - Diana Bellavia
- Department of Molecular Medicine, Sapienza University, Rome, Italy
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46
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RUNX3 suppresses metastasis and stemness by inhibiting Hedgehog signaling in colorectal cancer. Cell Death Differ 2019; 27:676-694. [PMID: 31278361 DOI: 10.1038/s41418-019-0379-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 05/29/2019] [Accepted: 06/18/2019] [Indexed: 12/24/2022] Open
Abstract
Disabled tumor suppressor genes and hyperactive oncogenes greatly contribute to cell fates during cancer development because of their genetic alterations such as somatic mutations. However, little is known about how tumor suppressor genes react to diverse oncogenes during tumor progression. Our previous study showed that RUNX3 inhibits invasiveness by preventing vascular endothelial growth factor secretion and suppressed endothelial cell growth and tube formation in colorectal cancer (CRC). Hedgehog signaling is crucial for the physiological maintenance and self-renewal of stem cells, and its deregulation is responsible for their tumor development. The mechanisms that inhibit this pathway during proliferation remain poorly understood. Here, we found that the tumor suppressor RUNX3 modulates tumorigenesis in response to cancer cells induced by inhibiting oncogene GLI1 ubiquitination. Moreover, we demonstrated that RUNX3 and GLI1 expression were inversely correlated in CRC cells and tissues. We observed a direct interaction between RUNX3 and GLI1, promoting ubiquitination of GLI1 at the intracellular level. Increased ubiquitination of GLI1 was induced by the E3 ligase β-TrCP. This novel RUNX3-dependent regulatory loop may limit the extent and duration of Hedgehog signaling during extension of the tumor initiation capacity. On the basis of our results, identification of agents that induce RUNX3 may be useful for developing new and effective therapies for CRC.
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47
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Faria AVDS, Akyala AI, Parikh K, Brüggemann LW, Spek CA, Cao W, Bruno MJ, Bijlsma MF, Fuhler GM, Peppelenbosch MP. Smoothened-dependent and -independent pathways in mammalian noncanonical Hedgehog signaling. J Biol Chem 2019; 294:9787-9798. [PMID: 30992365 DOI: 10.1074/jbc.ra119.007956] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/10/2019] [Indexed: 12/16/2022] Open
Abstract
Hedgehog proteins are pivotal morphogens acting through a canonical pathway involving first activation of ligand binding to Patched followed by alleviation of Smoothened receptor inhibition, leading to activation of Gli transcription factors. Noncanonical Hedgehog signaling remains poorly characterized but is thought to be mainly dependent on Smoothened. However, Smoothened inhibitors have yielded only partial success in combating Hedgehog signal transduction-dependent cancer, suggesting that noncanonical Smoothened-independent pathways also are clinically relevant. Moreover, several Smoothened-dependent effects (e.g. neurite projection) do not require transcriptional activation, further suggesting biological importance of noncanonical Smoothened-dependent pathways. We comprehensively characterized the cellular kinome in Hedgehog-challenged murine WT and Smoothened-/- fibroblasts as well as Smoothened agonist-stimulated cells. A peptide assay-based kinome analysis (in which cell lysates are used to phosphorylate specific kinase substrates), along with endocytosis, Lucifer Yellow-based, and immunoblotting assays, identified an elaborate signaling network of both Smoothened-dependent and -independent pathways that mediates actin reorganization through Src-like kinases, activates various proinflammatory signaling cascades, and concomitantly stimulates Wnt and Notch signaling while suppressing bone morphogenetic protein (BMP) signaling. The contribution of noncanonical Smoothened-independent signaling to the overall effects of Hedgehog on cellular physiology appears to be much larger than previously envisioned and may explain the transcriptionally independent effects of Hedgehog signaling on cytoskeleton. The observation that Patched-dependent, Smoothened-independent, noncanonical Hedgehog signaling increases Wnt/Notch signaling provides a possible explanation for the failure of Smoothened antagonists in combating Hedgehog-dependent but Smoothened inhibitor-resistant cancer. Our findings suggest that inhibiting Hedgehog-Patched interaction could result in more effective therapies as compared with conventional Smoothened-directed therapies.
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Affiliation(s)
- Alessandra V de S Faria
- From the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.,the Department of Biochemistry and Tissue Biology, Biology Institute, University of Campinas, Campinas, São Paulo 13083-862, Brazil
| | - Adamu Ishaku Akyala
- From the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands.,the Department of Microbiology, Faculty of Natural and Applied Sciences, Nasarawa State University, Keffi, Nasarawa State, Nigeria
| | - Kaushal Parikh
- the Department of Cell Biology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands, and
| | - Lois W Brüggemann
- the Center for Experimental and Molecular Medicine, Academic Medical Center, Room H2-257, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - C Arnold Spek
- the Center for Experimental and Molecular Medicine, Academic Medical Center, Room H2-257, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Wanlu Cao
- From the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands
| | - Marco J Bruno
- From the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands
| | - Maarten F Bijlsma
- the Center for Experimental and Molecular Medicine, Academic Medical Center, Room H2-257, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Gwenny M Fuhler
- From the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- From the Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, NL-3000 CA Rotterdam, The Netherlands, .,the Department of Cell Biology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands, and
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48
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Lima-Fernandes E, Murison A, da Silva Medina T, Wang Y, Ma A, Leung C, Luciani GM, Haynes J, Pollett A, Zeller C, Duan S, Kreso A, Barsyte-Lovejoy D, Wouters BG, Jin J, Carvalho DDD, Lupien M, Arrowsmith CH, O'Brien CA. Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells. Nat Commun 2019; 10:1436. [PMID: 30926792 PMCID: PMC6441108 DOI: 10.1038/s41467-019-09309-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 02/27/2019] [Indexed: 12/21/2022] Open
Abstract
In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog (IHH), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.
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Affiliation(s)
- Evelyne Lima-Fernandes
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G1L7, Canada.,Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Alex Murison
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Tiago da Silva Medina
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Yadong Wang
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Anqi Ma
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Cherry Leung
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Genna M Luciani
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G1L7, Canada.,Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Jennifer Haynes
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Aaron Pollett
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S1A8, Canada.,Lunenfeld-Tanenbaum Research Institute Toronto, Toronto, ON, M5G1X5, Canada
| | - Constanze Zeller
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | - Shili Duan
- Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada
| | - Antonija Kreso
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada
| | | | - Bradly G Wouters
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, ON, M5G1L7, Canada
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Daniel D De Carvalho
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada
| | - Mathieu Lupien
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada.,Ontario Institute for Cancer Research, Toronto, ON, M5G1L7, Canada
| | - Cheryl H Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G1L7, Canada. .,Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada.
| | - Catherine A O'Brien
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G1L7, Canada. .,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S1A8, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada. .,Department of Physiology, University of Toronto, Toronto, ON, M5G1L7, Canada. .,Department of Surgery, Toronto General Hospital, Toronto, ON, M5G2C4, Canada.
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Salaritabar A, Berindan-Neagoe I, Darvish B, Hadjiakhoondi F, Manayi A, Devi KP, Barreca D, Orhan IE, Süntar I, Farooqi AA, Gulei D, Nabavi SF, Sureda A, Daglia M, Dehpour AR, Nabavi SM, Shirooie S. Targeting Hedgehog signaling pathway: Paving the road for cancer therapy. Pharmacol Res 2019; 141:466-480. [DOI: 10.1016/j.phrs.2019.01.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 11/24/2018] [Accepted: 01/08/2019] [Indexed: 02/08/2023]
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50
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Pedone E, Marucci L. Role of β-Catenin Activation Levels and Fluctuations in Controlling Cell Fate. Genes (Basel) 2019; 10:genes10020176. [PMID: 30823613 PMCID: PMC6410200 DOI: 10.3390/genes10020176] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 02/18/2019] [Indexed: 12/12/2022] Open
Abstract
Cells have developed numerous adaptation mechanisms to external cues by controlling signaling-pathway activity, both qualitatively and quantitatively. The Wnt/β-catenin pathway is a highly conserved signaling pathway involved in many biological processes, including cell proliferation, differentiation, somatic cell reprogramming, development, and cancer. The activity of the Wnt/β-catenin pathway and the temporal dynamics of its effector β-catenin are tightly controlled by complex regulations. The latter encompass feedback loops within the pathway (e.g., a negative feedback loop involving Axin2, a β-catenin transcriptional target) and crosstalk interactions with other signaling pathways. Here, we provide a review shedding light on the coupling between Wnt/β-catenin activation levels and fluctuations across processes and cellular systems; in particular, we focus on development, in vitro pluripotency maintenance, and cancer. Possible mechanisms originating Wnt/β-catenin dynamic behaviors and consequently driving different cellular responses are also reviewed, and new avenues for future research are suggested.
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Affiliation(s)
- Elisa Pedone
- Department of Engineering Mathematics, University of Bristol, Bristol, BS8 1UB, UK.
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
| | - Lucia Marucci
- Department of Engineering Mathematics, University of Bristol, Bristol, BS8 1UB, UK.
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
- BrisSynBio, Bristol, BS8 1TQ, UK.
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