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Schachtschneider KM, Redlon LN, Lokken RP, Huang YH, Guzman G, Schook LB, Gaba RC. Epigenetic regulation of individual components of combined hepatocellular-cholangiocarcinoma. PLoS One 2025; 20:e0324145. [PMID: 40424447 PMCID: PMC12112136 DOI: 10.1371/journal.pone.0324145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
Combined hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) is a rare liver tumor comprising histologic features of both HCC and CCA. Due to its heterogeneous nature, treatment of combined HCC-CCA is a significant clinical challenge and prognosis remains poor. Therefore, further understanding of the tumor biology underlying the individual subtypes of this mixed tumor is required to improve treatment stratification and optimize treatment strategies. This study sought to identify altered epigenetic regulation and gene expression patterns in the individual components of combined HCC-CCA. Formalin fixed paraffin embedded (FFPE) tumor specimens from 9 patients diagnosed with combined HCC-CCA were utilized in this study. Hematoxylin and eosin (H&E) staining was performed for each sample, and regions representative of the individual HCC and CCA components were delineated. Adjacent unstained slides were cut and dissected to separate HCC and CCA components. DNA and RNA extraction was performed for each sample for DNA methylation (n = 7 HCC and 7 CCA) and gene expression (n = 7 HCC and 8 CCA) profiling via reduced representation bisulfite sequencing (RRBS) and RNA-seq, respectively. Samples did not cluster by tumor type when comparing genome-wide DNA methylation or gene expression patterns. Of the 5 patients with DNA methylation data available for both subtypes, 4 clustered by patient as opposed to cancer subtype, suggesting similar epigenetic regulatory patterns arising from development in the same microenvironment and genetic background. Differential analysis resulted in the identification of 57 differentially expressed genes (DEGs) and 808 differentially methylated regions (DMRs) between the HCC and CCA subtypes. Genes associated with DMRs were associated with Wnt signaling, voltage-gated channels, metal binding, and cellular regulation. Finally, increased expression of several genes previously implicated in tumor aggressiveness, prognosis, and treatment responses were identified. These results highlight the potential importance of accounting for underlying HCC and CCA tumor biology when determining the optimal course of treatment for this deadly disease.
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Affiliation(s)
- Kyle M. Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Luke N. Redlon
- College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Ryan Peter Lokken
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America
| | - Yu-Hui Huang
- Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Lawrence B. Schook
- Department of Radiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
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Jomova K, Alomar SY, Valko R, Liska J, Nepovimova E, Kuca K, Valko M. Flavonoids and their role in oxidative stress, inflammation, and human diseases. Chem Biol Interact 2025; 413:111489. [PMID: 40147618 DOI: 10.1016/j.cbi.2025.111489] [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: 06/02/2024] [Revised: 02/23/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Richard Valko
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Jan Liska
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University, 811 08, Bratislava, Slovakia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50003, Hradec Kralove, Czech Republic; Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic
| | - Kamil Kuca
- Center of Advanced Innovation Technologies, VSB-Technical University of Ostrava, Ostrava-Poruba, 708 00, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, 5005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
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Liu Y, Ma Y, Zhou B, Bian B, Zhou Y, Chen S, Zhang P, Shen L, Chen H. Clofoctol impairs the stemness of gastric cancer and induces TNF-mediated necroptosis by directly binding to RanBP2. Cell Mol Life Sci 2025; 82:194. [PMID: 40325218 PMCID: PMC12052660 DOI: 10.1007/s00018-025-05723-8] [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: 12/04/2024] [Revised: 04/10/2025] [Accepted: 04/21/2025] [Indexed: 05/07/2025]
Abstract
Gastric cancer stem cells (GCSCs) play a crucial role in the initiation, progression, recurrence and therapeutic resistance, contributing to a poor prognosis. Consequently, GCSCs are deemed to be a potential therapeutic target for gastric cancer (GC). Although β-catenin is a well-recognized therapeutic target for GC and several inhibitors have demonstrated potent anti-tumor effects, there is a dearth of therapeutic agents targeting β-catenin for clinical therapy. In this study, we carried out high-throughput screening of clinically approved drugs to identify effective inhibitors of β-catenin. The results revealed that the antibiotic drug, clofoctol (CFT) effectively reduced the β-catenin level, attenuated stemness traits both in vitro and in vivo, and induced necroptosis of GCSCs. Further analyzing of downstream genes and targeted proteins, we found that CFT inhibited GCSCs viability by binding to the SUMO E3 ligase RanBP2, thereby suppressing the SerpinE1/β-catenin axis and activating TNF-mediated necroptosis. These results indicate that CFT may exert potent therapeutic effects against GC by targeting β-catenin and inhibiting the viability of GCSCs.
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Affiliation(s)
- Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhui Ma
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingqian Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Bingxian Bian
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yunlan Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Shiyu Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Peng Zhang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Stokes AE, Clark HM, Edwards JL, Payton RR, Beever JE, Freeman TF, Hessock EA, Schrick FN, Moorey SE. Transcriptome profiles of blastocysts originating from oocytes matured in follicular fluid from preovulatory follicles of greater or lesser maturity. BMC Genomics 2025; 26:339. [PMID: 40186098 PMCID: PMC11969919 DOI: 10.1186/s12864-025-11521-0] [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: 09/11/2024] [Accepted: 03/24/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Oocyte competence for early embryo development relies on intercellular communication between the maturing oocyte and preovulatory follicle. Preovulatory follicle maturity, as indicated by serum estradiol concentration or follicle diameter, has previously been linked to pregnancy, follicular fluid metabolites, cumulus-oocyte metabolism, and oocyte competency for embryo development. Such relationships indicate metabolic and developmental programming of the oocyte based on the preovulatory follicle's physiological status, but downstream impacts on the molecular signature of blastocysts have not been examined. We hypothesized that supplementing maturing oocytes with follicular fluid originating from preovulatory follicles of greater or lesser maturity would impact the transcriptome of resulting blastocysts and indicate metabolic programming of the embryo that originated from the oocyte's maturation environment. The objective was to investigate the effect of follicle maturity on the oocyte by examining the transcriptome of blastocysts originating from oocytes matured in the presence of follicular fluid from preovulatory follicles of greater or lesser maturity. RESULTS In vitro maturing oocytes were supplemented with follicular fluid collected from preovulatory follicles of greater or lesser maturity. Following identical embryo culture procedures, RNA-sequencing was performed on pools of 2 blastocysts (Greater, n = 12; Lesser, n = 15; all with stage code = 7 and quality code = 1). A total of 12,310 genes were identified in blastocysts after filtering to remove lowly abundant genes. There were 113 genes that differed in expression between blastocysts originating from oocytes matured in greater versus lesser maturity follicular fluid (eFDR < 0.01). Although no pathways were significantly enriched with differentially expressed genes, transcriptome profiles suggested improved Wnt/β-catenin signaling, metabolism, and protection from oxidative stress in blastocysts derived from oocytes matured in greater maturity follicular fluid, while potential unregulated cell growth presented in blastocysts resulting from the lesser follicle maturity treatment. CONCLUSIONS Follicular fluid from preovulatory follicles of greater physiological maturity may better prepare maturing oocytes for early embryo development. Furthermore, oocytes matured in follicular fluid from preovulatory follicles of lesser maturity may attempt to overcompensate for nutrient deficit during oocyte maturation, leading to uncontrolled cellular growth and increased oxidative stress.
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Affiliation(s)
- Allyson E Stokes
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - Hannah M Clark
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - J Lannett Edwards
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - Rebecca R Payton
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - Jon E Beever
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - Trevor F Freeman
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - Emma A Hessock
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - F Neal Schrick
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA
| | - Sarah E Moorey
- Department of Animal Science, University of Tennessee Institute of Agriculture and AgResearch, 2506 River Drive, Knoxville, TN, 37996, USA.
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Boudná M, Blavet N, Samoilenko T, Macháčková T, Jugas R, Vychytilová-Faltejsková P, Boudný M, Bartošová R, Kotouček J, Bystrý V, Koželková K, Slabý O, Součková K. Analysis of extracellular vesicles of frequently used colorectal cancer cell lines. BMC Cancer 2025; 25:555. [PMID: 40148827 PMCID: PMC11951637 DOI: 10.1186/s12885-025-13936-0] [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: 07/07/2024] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks as the second most prevalent malignancy globally, highlighting the urgent need for more effective diagnostic and therapeutic strategies, as well as a deeper understanding of its molecular basis. Extensive research has demonstrated that cells actively secrete extracellular vesicles (EVs) to mediate intercellular communication at both proximal and distal sites. In this study, we conducted a comprehensive analysis of the RNA content of small extracellular vesicles (sEVs) secreted into the culture media of five frequently utilised CRC cell lines (RKO, HCT116, HCT15, HT29, and DLD1). RNA sequencing data revealed significant insights into the RNA profiles of these sEVs, identifying nine protein-coding genes and fourteen long non-coding RNA (lncRNA) genes that consistently ranked among the top 30 most abundant across all cell lines. Notably, the genes found in sEVs were highly similar among the cell lines, indicating a conserved molecular signature. Several of these genes have been previously documented in the context of cancer biology, while others represent novel discoveries. These findings provide valuable insights into the molecular cargo of sEVs in CRC, potentially unveiling novel biomarkers and therapeutic targets.
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Affiliation(s)
- Marie Boudná
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Nicolas Blavet
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Tetiana Samoilenko
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Táňa Macháčková
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Robin Jugas
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Petra Vychytilová-Faltejsková
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Miroslav Boudný
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Renata Bartošová
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Jan Kotouček
- Department of Pharmacology and Toxicology, Veterinary Research Institute, Brno, Czech Republic
| | - Vojtěch Bystrý
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Kateřina Koželková
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Ondřej Slabý
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
- Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
| | - Kamila Součková
- Centre for Molecular Medicine, Central European Institute of Technology, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
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Imtiaz I, Schloss J, Bugarcic A. Interplay Between Traditional and Scientific Knowledge: Phytoconstituents and Their Roles in Lung and Colorectal Cancer Signaling Pathways. Biomolecules 2025; 15:380. [PMID: 40149916 PMCID: PMC11940637 DOI: 10.3390/biom15030380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/27/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Natural plant products have been used for cancer treatment since ancient times and continue to play a vital role in modern anticancer drug development. However, only a small fraction of identified medicinal plants has been thoroughly investigated, particularly for their effects on cellular pathways in lung and colorectal cancers, two under-researched cancers with poor prognostic outcomes (lung cancers). This review focuses on the lung and colorectal cancer signaling pathways modulated by bioactive compounds from eleven traditional medicinal plants: Curcuma longa, Astragalus membranaceus, Glycyrrhiza glabra, Althaea officinalis, Echinacea purpurea, Sanguinaria canadensis, Codonopsis pilosula, Hydrastis canadensis, Lobelia inflata, Scutellaria baicalensis, and Zingiber officinale. These plants were selected based on their documented use in traditional medicine and modern clinical practice. Selection criteria involved cross-referencing herbs identified in a scoping review of traditional cancer treatments and findings from an international survey on herbal medicine currently used for lung and colorectal cancer management by our research group and the availability of existing literature on their anticancer properties. The review identifies several isolated phytoconstituents from these plants that exhibit anticancer properties by modulating key signaling pathways such as PI3K/Akt/mTOR, RAS/RAF/MAPK, Wnt/β-catenin, and TGF-β in vitro. Notable constituents include sanguinarine, berberine, hydrastine, lobeline, curcumin, gingerol, shogaol, caffeic acid, echinacoside, cichoric acid, glycyrrhizin, 18-β-glycyrrhetinic acid, astragaloside IV, lobetyolin, licochalcone A, baicalein, baicalin, wogonin, and glycyrol. Curcumin and baicalin show preclinical effectiveness but face bioavailability challenges, which may be overcome by combining them with piperine or using oral extracts to enhance gut microbiome conversion, integrating traditional knowledge with modern strategies for improved outcomes. Furthermore, herbal extracts from Echinacea, Glycyrrhiza, and Codonopsis, identified in traditional knowledge, are currently in clinical trials. Notably, curcumin and baicalin also modulate miRNA pathways, highlighting a promising intersection of modern science and traditional medicine. Thus, the development of anticancer therapeutics continues to benefit from the synergy of traditional knowledge, scientific innovation, and technological advancements.
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Affiliation(s)
| | | | - Andrea Bugarcic
- National Centre for Naturopathic Medicine, Faculty of Health, Southern Cross University, Military Road, Lismore, NSW 2480, Australia; (I.I.); (J.S.)
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Mizoo T, Oka T, Sugahara O, Minato T, Higa T, Nakayama KI. GPLD1+ cancer stem cells contribute to chemotherapy resistance and tumour relapse in intestinal cancer. J Biochem 2025; 177:105-119. [PMID: 39743241 DOI: 10.1093/jb/mvae082] [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: 11/05/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 01/04/2025] Open
Abstract
Cancer stem cells (CSCs) play a central role in cancer progression, therapy resistance, and disease recurrence. With the use of a quadruple-mutant mouse intestinal cancer organoid model and single-cell RNA-sequencing analysis, we have now identified glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), an enzyme that catalyzes the cleavage of glycosylphosphatidylinositol (GPI) anchors of membrane proteins, as a marker of slowly cycling CSCs. Ablation of Gpld1+ cells in combination with 5-fluorouracil treatment greatly attenuated cell viability in and regrowth of the intestinal cancer organoids. In addition, we identified serine protease 8 (PRSS8) as a key substrate of GPLD1 in human colorectal cancer cells. GPLD1 cleaves the GPI anchor of PRSS8 and thereby mediates release of the protease from the plasma membrane, resulting in the activation of Wnt signalling and promotion of the epithelial-mesenchymal transition (EMT) in the cancer cells. Pharmacological inhibition of GPLD1 suppressed Wnt signalling activity and EMT in association with upregulation of the amount of functional PRSS8 at the plasma membrane. Our findings suggest that targeting of GPLD1 in colorectal cancer might contribute to a new therapeutic strategy that is based on suppression of Wnt signalling and EMT-related cancer progression driven by CSCs.
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Affiliation(s)
- Taisuke Mizoo
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Takeru Oka
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Osamu Sugahara
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Takafumi Minato
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Tsunaki Higa
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Keiichi I Nakayama
- Laboratory of Anticancer Strategies, Advanced Research Initiative, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
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8
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Kim J, Jeon YJ, Chang IY, Lee JH, You HJ. Disruption of the β-catenin destruction complex via Ephexin1-Axin1 interaction promotes colorectal cancer proliferation. Exp Mol Med 2025; 57:151-166. [PMID: 39741188 PMCID: PMC11799323 DOI: 10.1038/s12276-024-01381-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/16/2024] [Accepted: 10/20/2024] [Indexed: 01/02/2025] Open
Abstract
Wnt signaling is essential for cell growth and tumor formation and is abnormally activated in colorectal cancer (CRC), contributing to tumor progression; however, the specific role and regulatory mechanisms involved in tumor development remain unclear. Here, we show that Ephexin1, a guanine nucleotide exchange factor, is significantly overexpressed in CRC and is correlated with increased Wnt/β-catenin pathway activity. Through comprehensive analysis, including RNA sequencing data from TCGA and functional assays, we observed that Ephexin1 promotes tumor proliferation and migration by activating the Wnt/β-catenin pathway. This effect was mediated by the interaction of Ephexin1 with Axin1, a critical component of the β-catenin destruction complex, which in turn enhanced the stability and activity of β-catenin in signaling pathways critical for tumor development. Importantly, our findings also suggest that targeting Ephexin1 may increase the efficacy of Wnt/β-catenin pathway inhibitors in CRC treatment. These findings highlight the potential of targeting Ephexin1 as a strategy for developing effective treatments for CRC, suggesting a novel and promising approach to therapy aimed at inhibiting cancer progression.
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Affiliation(s)
- Jeeho Kim
- Laboratory of Genomic Instability and Cancer Therapeutics, Gwangju, South Korea
- Department of Pharmacology, Gwangju, South Korea
| | | | | | - Jung-Hee Lee
- Laboratory of Genomic Instability and Cancer Therapeutics, Gwangju, South Korea.
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju, 501-759, South Korea.
| | - Ho Jin You
- Laboratory of Genomic Instability and Cancer Therapeutics, Gwangju, South Korea.
- Department of Pharmacology, Gwangju, South Korea.
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9
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Jang JH, Jung J, Kang HG, Kim W, Kim WJ, Lee H, Cho JY, Hong R, Kim JW, Chung JY, Chun KH, Kim SJ. Kindlin-1 promotes gastric cancer cell motility through the Wnt/β-catenin signaling pathway. Sci Rep 2025; 15:2481. [PMID: 39833319 PMCID: PMC11756408 DOI: 10.1038/s41598-025-86220-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025] Open
Abstract
Despite advances in gastric cancer diagnosis and treatment, its prognosis remains poor owing to aggressive tumor progression and metastasis. As understanding the relevant molecular mechanisms is essential to effectively improve patient outcomes, we elucidated the role of Kindlin-1 in gastric cancer progression and metastasis. Kindlin-1 expression was analyzed in 359 gastric cancer tissue samples provided by Kangnam Sacred Heart Hospital and publicly available GSE datasets. Kindlin-1 showed significantly higher expression in gastric cancer tissues than that in normal tissues, and high Kindlin-1 expression was associated with poor prognosis. Further, the mRNA and protein expression of Kindlin-1 were high in gastric cancer cell lines, where they were associated with increased proliferation, migration, and invasion. Our findings demonstrated that Kindlin-1 regulated epithelial-mesenchymal transition-related genes through interaction with activated Wnt/β-catenin signaling. Notably, Kindlin-1 enhanced β-catenin expression and promoted its nuclear translocation from the cytoplasm, increasing TCF4 transcriptional activity and inducing gastric cancer progression and metastasis. Overall, these findings demonstrate that Kindlin-1 is upregulated in gastric cancer and activates Wnt/β-catenin signaling to promote cell proliferation and motility.
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Affiliation(s)
- Jun-Ho Jang
- Department of Integrative Biological Sciences and BK21 FOUR Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jiyoon Jung
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 07441, Republic of Korea
| | - Hyeon-Gu Kang
- Department of Integrative Biological Sciences and BK21 FOUR Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju, 61452, Republic of Korea
- Institute of Well-Aging Medicare and Chosun University G-LAMP Project Group, Chosun University, Gwangju, 61452, Republic of Korea
| | - Woong Kim
- Institute of Well-Aging Medicare and Chosun University G-LAMP Project Group, Chosun University, Gwangju, 61452, Republic of Korea
| | - Won-Jin Kim
- Department of Integrative Biological Sciences and BK21 FOUR Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju, 61452, Republic of Korea
- Institute of Well-Aging Medicare and Chosun University G-LAMP Project Group, Chosun University, Gwangju, 61452, Republic of Korea
| | - Hana Lee
- Department of Integrative Biological Sciences and BK21 FOUR Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju, 61452, Republic of Korea
- Institute of Well-Aging Medicare and Chosun University G-LAMP Project Group, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ju Yeon Cho
- Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ran Hong
- Department of Pathology, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jeong Won Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 07441, Republic of Korea
| | - Joon-Yong Chung
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Kyung-Hee Chun
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Seok-Jun Kim
- Department of Integrative Biological Sciences and BK21 FOUR Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju, 61452, Republic of Korea.
- Institute of Well-Aging Medicare and Chosun University G-LAMP Project Group, Chosun University, Gwangju, 61452, Republic of Korea.
- Department of Biomedical Science, Chosun University, Gwangju, 61452, Republic of Korea.
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10
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Tehrani HA, Zangi M, Fathi M, Vakili K, Hassan M, Rismani E, Hossein-Khannazer N, Vosough M. GPC-3 in hepatocellular carcinoma; A novel biomarker and molecular target. Exp Cell Res 2025; 444:114391. [PMID: 39725192 DOI: 10.1016/j.yexcr.2024.114391] [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: 10/21/2024] [Revised: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
Hepatocellular carcinoma (HCC) is a global health issue due to its late diagnosis and high recurrence rate. The early detection and diagnosis of HCC with specific and sensitive biomarkers and using novel treatment approaches to improve patient outcomes are essential. Glypican-3 (GPC-3) is a cell surface proteoglycan that is overexpressed in many tumors, including HCC. GPC-3 could be used as a specific biomarker for HCC early detection and could be a potential target for precise therapeutic strategies. Effective identification of GPC-3 could improve both diagnosis and targeted therapy of HCC. Moreover, targeted therapy using GPC-3 could result in a better treatment outcome. Recently, GPC3-targeted therapies have been used in different investigational therapeutic approaches like bi-specific/monoclonal antibodies, peptide vaccines, and CAR T cell therapies. This study aims to highlight the theranostic potential of GPC-3 as a novel biomarker for early detection and as a potential molecular target for HCC treatment as well.
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Affiliation(s)
- Hamed Azhdari Tehrani
- Department of Hematology-Medical Oncology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masood Zangi
- Critical Care Quality Improvement Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Elham Rismani
- Molecular Medicine Department, Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Massoud Vosough
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Cellular and Molecular Biology, Faculty of Sciences and Advanced Technology in Biology, University of Science and Culture, Tehran, Iran.
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11
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Wang W, Liu X, Zhao L, Jiang K, Yu Z, Yang R, Zhou W, Cui J, Liang T. FBXW7 in gastrointestinal cancers: from molecular mechanisms to therapeutic prospects. Front Pharmacol 2024; 15:1505027. [PMID: 39749199 PMCID: PMC11694028 DOI: 10.3389/fphar.2024.1505027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 11/28/2024] [Indexed: 01/04/2025] Open
Abstract
F-box and WD repeat domain-containing 7 (FBXW7), formerly known as hCdc4, hAGO Fbw7, or SEL10, plays a specific recognition function in SCF-type E3 ubiquitin ligases. FBXW7 is a well-established cancer suppressor gene that specifically controls proteasomal degradation and destruction of many key oncogenic substrates. The FBXW7 gene is frequently abnormal in human malignancies especially in gastrointestinal cancers. Accumulating evidence reveals that mutations and deletions of FBXW7 are participating in the occurrence, progression and treatment resistance of human gastrointestinal cancers. Considering the current therapeutic challenges faced by gastrointestinal cancers, elucidating the biological function and molecular mechanism of FBXW7 can provide new perspectives and references for future personalized treatment strategies. In this review, we elucidate the key molecular mechanisms by which FBXW7 and its substrates are involved in gastrointestinal cancers. Furthermore, we discuss the consequences of FBXW7 loss or dysfunction in tumor progression and underscore its potential as a prognostic and therapeutic biomarker. Lastly, we propose potential therapeutic strategies targeting FBXW7 to guide the precision treatment of gastrointestinal cancers.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Tingting Liang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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12
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Weng C, Jin R, Jin X, Yang Z, He C, Zhang Q, Xu J, Lv B. Exploring the Mechanisms, Biomarkers, and Therapeutic Targets of TRIM Family in Gastrointestinal Cancer. Drug Des Devel Ther 2024; 18:5615-5639. [PMID: 39654601 PMCID: PMC11626976 DOI: 10.2147/dddt.s482340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024] Open
Abstract
Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates. As E3 ubiquitin ligases, proteins of tripartite motif (TRIM) family play a role in cancer signaling, development, apoptosis, and formation. These proteins regulate diverse biological activities and signaling pathways. This study comprehensively outlines the functions of TRIM proteins in gastrointestinal physiology, contributing to our knowledge of the molecular pathways involved in gastrointestinal tumors. Gastrointestinal region (GI) cancers are closely linked to the ubiquitination system, with the E3 ubiquitin ligase playing a crucial role by targeting various substrates.
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Affiliation(s)
- Chunyan Weng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Rijuan Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Xiaoliang Jin
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Zimei Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Chenghai He
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
- Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Qiuhua Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
| | - Jingli Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Bin Lv
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, People’s Republic of China
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13
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Copeland SE, Snow SM, Wan J, Matkowskyj KA, Halberg RB, Weaver BA. MAD1 upregulation sensitizes to inflammation-mediated tumor formation. PLoS Genet 2024; 20:e1011437. [PMID: 39374311 PMCID: PMC11486420 DOI: 10.1371/journal.pgen.1011437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 10/17/2024] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells-low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA). A modest 2-fold overexpression of MAD1 in murine colon resulted in decreased p53 expression and increased mitotic defects consistent with CIN. After exposure to the colon-specific inflammatory agent dextran sulfate sodium (DSS), 31% of mice developed colon lesions, including a mucinous adenocarcinoma, while none formed in control animals. Lesion incidence was particularly high in male mice, 57% of which developed at least one hyperplastic polyp, adenoma or adenocarcinoma in the colon. Notably, mice expressing HA-MAD1 also developed lesions in tissues in which DSS is not expected to induce inflammation. These findings demonstrate that MAD1 upregulation is sufficient to promote colon tumorigenesis in the context of inflammation in immune-competent mice.
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Affiliation(s)
- Sarah E. Copeland
- Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Santina M. Snow
- Cancer Biology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Jun Wan
- Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Kristina A. Matkowskyj
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Richard B. Halberg
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Beth A. Weaver
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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14
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Kamal R, Awasthi A, Paul P, Mir MS, Singh SK, Dua K. Novel drug delivery systems in colorectal cancer: Advances and future prospects. Pathol Res Pract 2024; 262:155546. [PMID: 39191194 DOI: 10.1016/j.prp.2024.155546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 08/10/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
Colorectal cancer (CRC) is an abnormal proliferation of cells within the colon and rectum, leading to the formation of polyps and disruption of mucosal functions. The disease development is influenced by a combination of factors, including inflammation, exposure to environmental mutagens, genetic alterations, and impairment in signaling pathways. Traditional treatments such as surgery, radiation, and chemotherapy are often used but have limitations, including poor solubility and permeability, treatment resistance, side effects, and post-surgery issues. Novel Drug Delivery Systems (NDDS) have emerged as a superior alternative, offering enhanced drug solubility, precision in targeting cancer cells, and regulated drug release. Thereby addressing the shortcomings of conventional therapies and showing promise for more effective CRC management. The present review sheds light on the pathogenesis, signaling pathways, biomarkers, conventional treatments, need for NDDS, and application of NDDS against CRC. Additionally, clinical trials, ongoing clinical trials, marketed formulations, and patents on CRC are also covered in the present review.
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Affiliation(s)
- Raj Kamal
- Department of Quality Assurance, ISF College of Pharmacy, Moga, Punjab 142001, India; School of Pharmacy, Desh Bhagat University, Mandi Gobindgarh, Punjab 147301, India
| | - Ankit Awasthi
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab 142001, India; Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Priyanka Paul
- Department of Pharmaceutical Science, PCTE Group of Institute, Ludhiana, Punjab, India
| | - Mohammad Shabab Mir
- School of Pharmacy, Desh Bhagat University, Mandi Gobindgarh, Punjab 147301, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
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15
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Zha P, Liu W, Zhou Y, Chen Y. Protective effects of chlorogenic acid on the intestinal barrier of broiler chickens: an immunological stress model study. Poult Sci 2024; 103:103949. [PMID: 38917604 PMCID: PMC11251075 DOI: 10.1016/j.psj.2024.103949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 06/01/2024] [Accepted: 06/03/2024] [Indexed: 06/27/2024] Open
Abstract
This study was conducted to investigate the protective effects of chlorogenic acid (CGA) on inflammatory responses and intestinal health of lipopolysaccharide (LPS)-challenged broilers. One hundred and forty-four 1-day-old male broiler chicks were divided into 3 groups with 6 replicates of 8 birds each. The groups were as follows: 1) Control group: birds fed a basal diet; 2) LPS group: LPS-challenged birds fed a basal diet; 3) CGA group: LPS-challenged birds fed a CGA-supplemented diet. The LPS was intraperitoneally administered at a dose of 1 mg/kg of body weight. CGA increased the weight gain and feed intake of LPS-challenged birds by 37.05% and 24.29%, respectively (P < 0.05). CGA also alleviated LPS-induced inflammation, as evidenced by lower levels of pro-inflammatory cytokines in the serum and jejunum (tumor necrosis factor-α, interferon-γ, interleukin-1β, and interleukin-6), and the decreased myeloperoxidase activity in the jejunum (P < 0.05). These effects were accompanied by a decrease in the mRNA abundance of toll-like receptor 4 and myeloid differentiation factor 88 and an inhibition of nuclear factor kappa-B translocation in the jejunum (P < 0.05). CGA reduced circulating diamine oxidase activity and levels of D-lactate and endotoxin, and positively regulated the expression of jejunal claudin-3 and zonula occludens-1 in LPS-challenged broilers (P < 0.05). Compared to the LPS group, CGA reduced the apoptotic rate of epithelial cells and cytochrome c concentration in the jejunum, and normalized the expression of genes responsible for proliferation and apoptosis in jejunal epithelial cells, including cysteine aspartate-specific protease-9, B cell lymphoma-2, and proliferating cell nuclear antigen (P < 0.05). Furthermore, CGA normalized the altered phosphorylation of protein kinase B and glycogen synthase kinase-3β, as well as the translocation of nuclear β-catenin in the jejunum of LPS-challenged broilers (P < 0.05). These results suggested that CGA supplementation improved growth performance, alleviated inflammation, and helped maintain intestinal integrity and barrier function in LPS-challenged broilers, possibly through the regulation of the toll-like receptor 4/nuclear factor kappa-B and protein kinase B/Wnt/β-catenin pathways.
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Affiliation(s)
- Pingping Zha
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China
| | - Wenhan Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China
| | - Yanmin Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China
| | - Yueping Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China.
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16
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Golivi Y, Kumari S, Farran B, Alam A, Peela S, Nagaraju GP. Small molecular inhibitors: Therapeutic strategies for pancreatic cancer. Drug Discov Today 2024; 29:104053. [PMID: 38849028 DOI: 10.1016/j.drudis.2024.104053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/09/2024]
Abstract
Pancreatic cancer (PC), a disease with high heterogeneity and a dense stromal microenvironment, presents significant challenges and a bleak prognosis. Recent breakthroughs have illuminated the crucial interplay among RAS, epidermal growth factor receptor (EGFR), and hedgehog pathways in PC progression. Small molecular inhibitors have emerged as a potential solution with their advantages of oral administration and the ability to target intracellular and extracellular sites effectively. However, despite the US FDA approving over 100 small-molecule targeted antitumor drugs, challenges such as low response rates and drug resistance persist. This review delves into the possibility of using small molecules to treat persistent or spreading PC, highlighting the challenges and the urgent need for a diverse selection of inhibitors to develop more effective treatment strategies.
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Affiliation(s)
- Yuvasri Golivi
- Department of Bioscience and Biotechnology, Banasthali University, Banasthali, RJ 304 022, India
| | - Seema Kumari
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GIS, GITAM, Visakhapatnam, Andhra Pradesh 530045, India
| | - Batoul Farran
- Department of Hematology and Oncology, Henry Ford Health, Detroit, MI 48202, USA
| | - Afroz Alam
- Department of Bioscience and Biotechnology, Banasthali University, Banasthali, RJ 304 022, India
| | - Sujatha Peela
- Department of Biotechnology, Dr. B. R. Ambedkar University, Srikakulam, Andhra Pradesh, 532001, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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17
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Romdhoni AC, Rajanagara AS, Albab CF, Waskito LA, Wibowo IN, Mohamad Yunus MR. The Role of Cyclin d1 in Radiotherapy Resistance of Advance Stage Nasopharyngeal Carcinoma: A Systematic Review. Asian Pac J Cancer Prev 2024; 25:2211-2218. [PMID: 39068551 PMCID: PMC11480630 DOI: 10.31557/apjcp.2024.25.7.2211] [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: 11/13/2023] [Indexed: 07/30/2024] Open
Abstract
OBJECTIVE One of the biggest therapy challenges for nasopharyngeal cancer (NPC) is still radioresistance. The radioresistance in NPC is thought to be caused by cyclin D1 overexpression. The purpose of this study was to determine how cyclin D1 contributes to radiation resistance in NPC. METHODS Adhering to the PRISMA guidelines, we systematically reviewed studies on cyclin D1-associated radioresistance in NPC from 2012 until 2023. From our search, 15 studies were included. RESULTS Cyclin D1's role in radiotherapy resistance is elucidated through several mechanisms, notably SHP-1 and B-catenin. Overexpression of SHP-1 led to an increase in cyclin D1, a higher proportion of cells in the S-phase, and radioresistance. Conversely, inhibiting β-catenin and cyclin D1 expression enhances radiation sensitivity. CONCLUSION In conclusion, Cyclin D1 has a strong correlation with radiation resistance; downregulation of the protein increases radiosensitivity, while overexpression of the protein promotes radioresistance.
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Affiliation(s)
- Achmad Chusnu Romdhoni
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine, Universitas Airlangga, Indonesia.
| | | | | | - Langgeng Agung Waskito
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, 60286, Indonesia.
- Otorhinolaryngologist Head and Neck Surgeon, Faculty of Medicine, Univerisiti Kebangsaan, Malaysia.
| | | | - Mohd Razif Mohamad Yunus
- Otorhinolaryngologist Head and Neck Surgeon, Faculty of Medicine, Univerisiti Kebangsaan, Malaysia.
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18
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Zhou Y, He Z, Li T, Choppavarapu L, Hu X, Cao R, Leone GW, Kahn M, Jin VX. 3D Chromatin Alteration by Disrupting β-Catenin/CBP Interaction Is Enriched with Insulin Signaling in Pancreatic Cancer. Cancers (Basel) 2024; 16:2202. [PMID: 38927910 PMCID: PMC11201718 DOI: 10.3390/cancers16122202] [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: 03/28/2024] [Revised: 06/02/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of how the functional crosstalk between the antagonist and the β-catenin/CBP interaction affects changes in 3D chromatin architecture and, thereby, gene expression and downstream effects remains to be elucidated. Here, we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate that the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1-a key insulin signaling gene-significantly impeding pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
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Affiliation(s)
- Yufan Zhou
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (Z.H.); (T.L.)
| | - Zhijing He
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (Z.H.); (T.L.)
- Department of Stomatology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Tian Li
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (Z.H.); (T.L.)
| | - Lavanya Choppavarapu
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Xiaohui Hu
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China;
| | - Ruifeng Cao
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, The State University of New Jersey, Piscataway, NJ 08854, USA;
| | - Gustavo W. Leone
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;
| | - Victor X. Jin
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Burgos-Molina AM, Téllez Santana T, Redondo M, Bravo Romero MJ. The Crucial Role of Inflammation and the Immune System in Colorectal Cancer Carcinogenesis: A Comprehensive Perspective. Int J Mol Sci 2024; 25:6188. [PMID: 38892375 PMCID: PMC11172443 DOI: 10.3390/ijms25116188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively 'cloaking' themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer.
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Affiliation(s)
- Antonio Manuel Burgos-Molina
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
| | - Teresa Téllez Santana
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
- Research Network on Chronic Diseases, Primary Care, and Health Promotion (RICAPPS), Carlos III Health Institute (Instituto de Salud Carlos III), Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
- Málaga Biomedical Research Institute (Instituto de Investigación Biomédica de Málaga, IBIMA), Calle Doctor Miguel Díaz Recio, 28, 29010 Málaga, Spain
| | - Maximino Redondo
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
- Research Network on Chronic Diseases, Primary Care, and Health Promotion (RICAPPS), Carlos III Health Institute (Instituto de Salud Carlos III), Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
- Málaga Biomedical Research Institute (Instituto de Investigación Biomédica de Málaga, IBIMA), Calle Doctor Miguel Díaz Recio, 28, 29010 Málaga, Spain
- Research Unit, Hospital Costa del Sol, Autovía A-7, km 187, 29603 Marbella, Spain
| | - María José Bravo Romero
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
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20
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Szilveszter RM, Muntean M, Florea A. Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments-An Overview. Biomolecules 2024; 14:656. [PMID: 38927059 PMCID: PMC11201617 DOI: 10.3390/biom14060656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial-mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages-predominantly with a pro-tumoral role-hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines.
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Affiliation(s)
- Raluca-Margit Szilveszter
- Department of Pathology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400340 Cluj-Napoca, Romania
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
- Cluj County Emergency Clinical Hospital, 400340 Cluj-Napoca, Romania
| | - Mara Muntean
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
| | - Adrian Florea
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
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21
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Yamaguchi J, Kokuryo T, Yokoyama Y, Oishi S, Sunagawa M, Mizuno T, Onoe S, Watanabe N, Ogura A, Ebata T. Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer. Cancer Med 2024; 13:e7395. [PMID: 38872370 PMCID: PMC11176577 DOI: 10.1002/cam4.7395] [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: 11/12/2023] [Revised: 05/30/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND AND AIMS Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. METHODS To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1-/-) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. RESULTS The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. CONCLUSION These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.
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Affiliation(s)
- Junpei Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toshio Kokuryo
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shunsuke Oishi
- Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan
| | - Masaki Sunagawa
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Mizuno
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shunsuke Onoe
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuyuki Watanabe
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Ogura
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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22
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Wang Z, Chang Y, Sun H, Li Y, Tang T. Advances in molecular mechanisms of inflammatory bowel disease‑associated colorectal cancer (Review). Oncol Lett 2024; 27:257. [PMID: 38646499 PMCID: PMC11027113 DOI: 10.3892/ol.2024.14390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 03/15/2024] [Indexed: 04/23/2024] Open
Abstract
The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.
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Affiliation(s)
- Zhi Wang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yu Chang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Haibo Sun
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yuqin Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Tongyu Tang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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23
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de Brot S, Cobb J, Alibhai AA, Jackson-Oxley J, Haque M, Patke R, Harris AE, Woodcock CL, Lothion-Roy J, Varun D, Thompson R, Gomes C, Kubale V, Dunning MD, Jeyapalan JN, Mongan NP, Rutland CS. Immunohistochemical Investigation into Protein Expression Patterns of FOXO4, IRF8 and LEF1 in Canine Osteosarcoma. Cancers (Basel) 2024; 16:1945. [PMID: 38792023 PMCID: PMC11120020 DOI: 10.3390/cancers16101945] [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: 04/30/2024] [Revised: 05/16/2024] [Accepted: 05/18/2024] [Indexed: 05/26/2024] Open
Abstract
Osteosarcoma (OSA) is the most common type of primary bone malignancy in people and dogs. Our previous molecular comparisons of canine OSA against healthy bone resulted in the identification of differentially expressed protein-expressing genes (forkhead box protein O4 (FOXO4), interferon regulatory factor 8 (IRF8), and lymphoid enhancer binding factor 1 (LEF1)). Immunohistochemistry (IHC) and H-scoring provided semi-quantitative assessment of nuclear and cytoplasmic staining alongside qualitative data to contextualise staining (n = 26 patients). FOXO4 was expressed predominantly in the cytoplasm with significantly lower nuclear H-scores. IRF8 H-scores ranged from 0 to 3 throughout the cohort in the nucleus and cytoplasm. LEF1 was expressed in all patients with significantly lower cytoplasmic staining compared to nuclear. No sex or anatomical location differences were observed. While reduced levels of FOXO4 might indicate malignancy, the weak or absent protein expression limits its primary use as diagnostic tumour marker. IRF8 and LEF1 have more potential for prognostic and diagnostic uses and facilitate further understanding of their roles within their respective molecular pathways, including Wnt/beta-catenin/LEF1 signalling and differential regulation of tumour suppressor genes. Deeper understanding of the mechanisms involved in OSA are essential contributions towards the development of novel diagnostic, prognostic, and treatment options in human and veterinary medicine contexts.
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Affiliation(s)
- Simone de Brot
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Comparative Pathology Platform of the University of Bern (COMPATH), Institute of Animal Pathology, University of Bern, 3012 Bern, Switzerland
| | - Jack Cobb
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Aziza A. Alibhai
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Jorja Jackson-Oxley
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Maria Haque
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Rodhan Patke
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Anna E. Harris
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Corinne L. Woodcock
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Jennifer Lothion-Roy
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Dhruvika Varun
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Rachel Thompson
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Claudia Gomes
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Valentina Kubale
- Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Mark D. Dunning
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Willows Veterinary Centre and Referral Service, Solihull B90 4NH, UK
| | - Jennie N. Jeyapalan
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Faculty of Medicine and Health Science, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Nigel P. Mongan
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Willows Veterinary Centre and Referral Service, Solihull B90 4NH, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10075, USA
| | - Catrin S. Rutland
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Faculty of Medicine and Health Science, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
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24
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Helderman NC, van Leerdam ME, Kloor M, Ahadova A, Nielsen M. Emerge of colorectal cancer in Lynch syndrome despite colonoscopy surveillance: A challenge of hide and seek. Crit Rev Oncol Hematol 2024; 197:104331. [PMID: 38521284 DOI: 10.1016/j.critrevonc.2024.104331] [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: 01/13/2024] [Revised: 03/09/2024] [Accepted: 03/20/2024] [Indexed: 03/25/2024] Open
Abstract
Even with colonoscopy surveillance, Lynch syndromes (LS) carriers still develop colorectal cancer (CRC). The cumulative incidence of CRCs under colonoscopy surveillance varies depending on the affected mismatch repair (MMR) gene. However, the precise mechanisms driving these epidemiological patterns remain incompletely understood. In recent years, several potential mechanisms explaining the occurrence of CRCs during colonoscopy surveillance have been proposed in individuals with and without LS. These encompass biological factors like concealed/accelerated carcinogenesis through a bypassed adenoma stage and accelerated progression from adenomas. Alongside these, various colonoscopy-related factors may contribute to formation of CRCs under colonoscopy surveillance, like missed yet detectable (pre)cancerous lesions, detected yet incompletely removed (pre)cancerous lesions, and colonoscopy-induced carcinogenesis due to tumor cell reimplantation. In this comprehensive literature update, we reviewed these potential factors and evaluated their relevance to each MMR group in an attempt to raise further awareness and stimulate research regarding this conflicting phenomenon.
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Affiliation(s)
- Noah C Helderman
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Matthias Kloor
- Department of Applied Tumor Biology, Heidelberg University Hospital, Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Heidelberg University Hospital, Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
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25
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Bhat AA, Kukreti N, Afzal M, Goyal A, Thapa R, Ali H, Shahwan M, Almalki WH, Kazmi I, Alzarea SI, Singh SK, Dua K, Gupta G. Ferroptosis and circular RNAs: new horizons in cancer therapy. EXCLI JOURNAL 2024; 23:570-599. [PMID: 38887390 PMCID: PMC11180955 DOI: 10.17179/excli2024-7005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 04/09/2024] [Indexed: 06/20/2024]
Abstract
Cancer poses intricate challenges to treatment due to its complexity and diversity. Ferroptosis and circular RNAs (circRNAs) are emerging as innovative therapeutic avenues amid the evolving landscape of cancer therapy. Extensive investigations into circRNAs reveal their diverse roles, ranging from molecular regulators to pivotal influencers of ferroptosis in cancer cell lines. The results underscore the significance of circRNAs in modulating molecular pathways that impact crucial aspects of cancer development, including cell survival, proliferation, and metastasis. A detailed analysis delineates these pathways, shedding light on the molecular mechanisms through which circRNAs influence ferroptosis. Building upon recent experimental findings, the study evaluates the therapeutic potential of targeting circRNAs to induce ferroptosis. By identifying specific circRNAs associated with the etiology of cancer, this analysis paves the way for the development of targeted therapeutics that exploit vulnerabilities in cancer cells. This review consolidates the existing understanding of ferroptosis and circRNAs, emphasizing their role in cancer therapy and providing impetus for ongoing research in this dynamic field. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Asif Ahmad Bhat
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, U. P., India
| | - Riya Thapa
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Haider Ali
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
- Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Moyad Shahwan
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, 346, United Arab Emirates
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, Ajman, 346, United Arab Emirates
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I. Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Al-Jouf, Saudi Arabia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, India
- Faculty of Health, Australian Research Center in Complementary and Integrative Medicine, University of Technology, Sydney, Ultimo-NSW 2007, Australia
- School of Medical and Life Sciences, Sunway University, Sunway, Malaysia
| | - Kamal Dua
- Faculty of Health, Australian Research Center in Complementary and Integrative Medicine, University of Technology, Sydney, Ultimo-NSW 2007, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology, Sydney, Ultimo-NSW 2007, Australia
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, Ajman, 346, United Arab Emirates
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26
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Ilhan M, Hastar N, Kampfrath B, Spierling DN, Jatzlau J, Knaus P. BMP Stimulation Differentially Affects Phosphorylation and Protein Stability of β-Catenin in Breast Cancer Cell Lines. Int J Mol Sci 2024; 25:4593. [PMID: 38731813 PMCID: PMC11083028 DOI: 10.3390/ijms25094593] [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: 02/19/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Increased expression and nuclear translocation of β-CATENIN is frequently observed in breast cancer, and it correlates with poor prognosis. Current treatment strategies targeting β-CATENIN are not as efficient as desired. Therefore, detailed understanding of β-CATENIN regulation is crucial. Bone morphogenetic proteins (BMP) and Wingless/Integrated (WNT) pathway crosstalk is well-studied for many cancer types including colorectal cancer, whereas it is still poorly understood for breast cancer. Analysis of breast cancer patient data revealed that BMP2 and BMP6 were significantly downregulated in tumors. Since mutation frequency in genes enhancing β-CATENIN protein stability is relatively low in breast cancer, we aimed to investigate whether decreased BMP ligand expression could contribute to a high protein level of β-CATENIN in breast cancer cells. We demonstrated that downstream of BMP stimulation, SMAD4 is required to reduce β-CATENIN protein stability through the phosphorylation in MCF7 and T47D cells. Consequently, BMP stimulation reduces β-CATENIN levels and prevents its nuclear translocation and target gene expression in MCF7 cells. Conversely, BMP stimulation has no effect on β-CATENIN phosphorylation or stability in MDA-MB-231 and MDA-MB-468 cells. Likewise, SMAD4 modulation does not alter the response of those cells, indicating that SMAD4 alone is insufficient for BMP-induced β-CATENIN phosphorylation. While our data suggest that considering BMP activity may serve as a prognostic marker for understanding β-CATENIN accumulation risk, further investigation is needed to elucidate the differential responsiveness of breast cancer cell lines.
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Affiliation(s)
- Mustafa Ilhan
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nurcan Hastar
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Branka Kampfrath
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
| | - Deniz Neslihan Spierling
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
| | - Jerome Jatzlau
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Petra Knaus
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
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Ma Y, Song Y, Wang J, Shi X, Yuan Z, Li S, Li H, Chen Z, Li S. Discovery of novel covalent inhibitors of DJ-1 through hybrid virtual screening. Future Med Chem 2024; 16:665-677. [PMID: 38390730 DOI: 10.4155/fmc-2023-0301] [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: 10/16/2023] [Accepted: 01/26/2024] [Indexed: 02/24/2024] Open
Abstract
Background: DJ-1 is a ubiquitously expressed protein with multiple functions. Its overexpression has been associated with the occurrence of several cancers, positioning DJ-1 as a promising therapeutic target for cancer treatment. Methods: To find novel inhibitors of DJ-1, we employed a hybrid virtual screening strategy that combines structure-based and ligand-based virtual screening on a comprehensive compound library. Results: In silico study identified six hit compounds as potential DJ-1 inhibitors that were assessed in vitro at the cellular level. Compound 797780-71-3 exhibited antiproliferation activity in ACHN cells with an IC50 value of 12.18 μM and was able to inhibit the Wnt signaling pathway. This study discovers a novel covalent inhibitor for DJ-1 and paves the way for further optimization.
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Affiliation(s)
- Yanyu Ma
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Yidan Song
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Junyi Wang
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Xiayu Shi
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Zhen Yuan
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Shuang Li
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Honglin Li
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
- Innovation Center for AI & Drug Discovery, East China Normal University, Shanghai, 200062, China
- Lingang Laboratory, Shanghai, 200031, China
| | - Zhuo Chen
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
| | - Shiliang Li
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China
- Innovation Center for AI & Drug Discovery, East China Normal University, Shanghai, 200062, China
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Wang J, Zhang J, Liu H, Meng L, Gao X, Zhao Y, Wang C, Gao X, Fan A, Cao T, Fan D, Zhao X, Lu Y. N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer. Cancer Commun (Lond) 2024; 44:469-490. [PMID: 38512764 PMCID: PMC11024687 DOI: 10.1002/cac2.12534] [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: 08/18/2023] [Revised: 02/29/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. METHODS The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. RESULTS Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders. CONCLUSION Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC.
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Affiliation(s)
- Jiayao Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
- The Air Force Hospital of Southern Theater CommandGuangzhouGuangdongP. R. China
| | - Jiehao Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
- The Air Force Hospital of Southern Theater CommandGuangzhouGuangdongP. R. China
| | - Hao Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Lingnan Meng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
- National Center for International Research of Bio‐targeting TheranosticsGuangxi Key Laboratory of Bio‐targeting TheranosticsGuangxi Medical UniversityNanningGuangxiP. R. China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Yihan Zhao
- Second Clinical CollegeShaanxi University of Traditional Chinese MedicineXianyangShaanxiP. R. China
| | - Chen Wang
- College of Life SciencesNorthwest UniversityXi'anShaanxiP. R. China
| | - Xiaoliang Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Ahui Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Tianyu Cao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Xiaodi Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Yuanyuan Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
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Sini MC, Doro MG, Frogheri L, Zinellu A, Paliogiannis P, Porcu A, Scognamillo F, Delogu D, Santeufemia DA, Persico I, Palomba G, Maestrale GB, Cossu A, Palmieri G. Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population. J Transl Med 2024; 22:108. [PMID: 38280995 PMCID: PMC10821545 DOI: 10.1186/s12967-024-04923-3] [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: 12/28/2023] [Accepted: 01/22/2024] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia. METHODS A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms. RESULTS Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival. CONCLUSIONS The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.
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Affiliation(s)
- Maria Cristina Sini
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Maria Grazia Doro
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Laura Frogheri
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Panagiotis Paliogiannis
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Traversa La Crucca 3, 07100, Sassari, Italy
| | - Alberto Porcu
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Traversa La Crucca 3, 07100, Sassari, Italy
| | - Fabrizio Scognamillo
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Traversa La Crucca 3, 07100, Sassari, Italy
| | - Daniele Delogu
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Traversa La Crucca 3, 07100, Sassari, Italy
| | | | - Ivana Persico
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Grazia Palomba
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Giovanni Battista Maestrale
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Antonio Cossu
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Traversa La Crucca 3, 07100, Sassari, Italy
| | - Giuseppe Palmieri
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy.
- Immuno-Oncology & Targeted Cancer Biotherapies, University of Sassari, Sassari, Italy.
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Meng F, Ai C, Yan G, Wang G. Tumor-suppressive zinc finger protein 24 (ZNF24) sensitizes colorectal cancer cells to 5-fluorouracil by inhibiting the Wnt pathway and activating the p53 signaling. Exp Cell Res 2023; 433:113796. [PMID: 37774763 DOI: 10.1016/j.yexcr.2023.113796] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 08/16/2023] [Accepted: 09/22/2023] [Indexed: 10/01/2023]
Abstract
Carcinogenesis and colorectal cancer (CRC) development are associated with dysregulation of various pathways, including Wnt and p53. 5-fluorouracil (5-FU) is a common chemotherapeutic agent for CRC treatment, but its efficacy is restricted by drug resistance. Doxycycline is an orally active tetracycline antibiotic known for its antimicrobial and anticancer cell proliferation activities. This study intends to delineate the potential role of bioinformatically predicted ZNF24 in the 5-FU resistance of CRC cells. The expression of ZNF24 was measured in clinically collected CRC tissues and cells. Afterward, ectopic ZNF24 expression was induced by DOX to evaluate the viability, colony-forming ability and sphere-forming ability of CRC cells. It was found that ZNF24 was validated to be poorly expressed in CRC tissues, and ectopic expression of ZNF24 was revealed to restrict the malignant phenotypes of CRC cells. In addition, restored ZNF24 attenuated 5-FU resistance of CRC cells by inhibiting the Wnt pathway and activating p53 signaling. Furthermore, an inhibitor of Wnt production 2 (IWP-2) treatment was an alternative to ZNF24 up-regulation in sensitizing CRC cells to 5-FU treatment. In conclusion, our results indicate that ZNF24 inhibits 5-FU resistance of CRC cells by suppressing the Wnt pathway and activating p53 signaling, which offers a potential strategy for managing chemoresistance in CRC.
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Affiliation(s)
- Fanqi Meng
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Chunlong Ai
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Guoqiang Yan
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Guangyi Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, PR China.
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Huang L, Liu Y, Pan Y, Liu C, Gao H, Ren Q, Wang J, Wang H, Zhang Y, Wu A. Elaiophylin Elicits Robust Anti-Tumor Responses via Apoptosis Induction and Attenuation of Proliferation, Migration, Invasion, and Angiogenesis in Pancreatic Cancer Cells. Molecules 2023; 28:7205. [PMID: 37894684 PMCID: PMC10608934 DOI: 10.3390/molecules28207205] [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: 08/08/2023] [Revised: 10/11/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. In this study, we investigate the potential therapeutic efficacy of elaiophylin, a novel compound, in targeting BxPC-3 and PANC-1 pancreatic cancer cells. We comprehensively explore elaiophylin's impact on apoptosis induction, proliferation inhibition, migration suppression, invasion attenuation, and angiogenesis inhibition, key processes contributing to cancer progression and metastasis. The results demonstrate that elaiophylin exerts potent pro-apoptotic effects, inducing a substantial increase in apoptotic cells. Additionally, elaiophylin significantly inhibits proliferation, migration, and invasion of BxPC-3 and PANC-1 cells. Furthermore, elaiophylin exhibits remarkable anti-angiogenic activity, effectively disrupting tube formation in HUVECs. Moreover, elaiophylin significantly inhibits the Wnt/β-Catenin signaling pathway. Our findings collectively demonstrate the multifaceted potential of elaiophylin as a promising therapeutic agent against pancreatic cancer via inhibition of the Wnt/β-Catenin signaling pathway. By targeting diverse cellular processes crucial for cancer progression, elaiophylin emerges as a prospective candidate for future targeted therapies. Further investigation of the in vivo efficacy of elaiophylin is warranted, potentially paving the way for novel and effective treatment approaches in pancreatic cancer management.
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Affiliation(s)
- Lufen Huang
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Yufeng Liu
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Yiru Pan
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou 646000, China;
| | - Chao Liu
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Huijie Gao
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Qiang Ren
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Jianan Wang
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Huiyun Wang
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Yuntao Zhang
- Department of Pharmacy, Jining Medical University, Rizhao 276500, China; (L.H.); (Y.L.); (C.L.); (H.G.); (Q.R.); (J.W.); (H.W.)
| | - Anguo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou 646000, China;
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Chen X, Zhang L, He L, Zheng L, Tuo B. Potassium channels as novel molecular targets in hepatocellular carcinoma (Review). Oncol Rep 2023; 50:185. [PMID: 37654193 PMCID: PMC10485806 DOI: 10.3892/or.2023.8622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/31/2023] [Indexed: 09/02/2023] Open
Abstract
Hepatocellular carcinoma (HCC) poses a serious health burden worldwide. It is often not diagnosed until the patient is at an advanced stage of the disease, when treatment options are limited and the prognosis is poor. Therefore, novel treatment strategies are urgently required. Potassium (K+) channels have an important role in HCC, including regulating the proliferation, migration, invasion and drug resistance of HCC cells. The aim of the present review was therefore to survey the relevant publications that have investigated K+ channels not only as markers for the early diagnosis of HCC, but also as potential therapeutic targets for the treatment of HCC. Several of these channels have been indicated to be the sites of action for natural products previously known to inhibit HCC; however, more systematic studies are required to determine which K+ channels may be utilized for the clinical treatment of HCC, particularly in the advanced stages of the disease and in cases where patients are resistant to the existing drugs.
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Affiliation(s)
- Xingyue Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Ling He
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Liming Zheng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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Chen X, Liu X, Li QH, Lu BF, Xie BM, Ji YM, Zhao Y. A patient-derived organoid-based study identified an ASO targeting SNORD14E for endometrial cancer through reducing aberrant FOXM1 Expression and β-catenin nuclear accumulation. J Exp Clin Cancer Res 2023; 42:230. [PMID: 37667311 PMCID: PMC10478245 DOI: 10.1186/s13046-023-02801-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 08/16/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Most of the endometrial cancer (EC) patients are diagnosis in early stage with a good prognosis while the patients with locally advanced recurrent or metastatic result in a poor prognosis. Adjuvant therapy could benefit the prognosis of patients with high-risk factors. Unfortunately, the molecular classification of great prognostic value has not yet reached an agreement and need to be further refined. The present study aims to identify new targets that have prognostic value in EC based on the method of EC patient-derived organ-like organs (PDOs), and further investigate their efficacy and mechanism. METHODS The Cancer Genome Atlas (TCGA) database was used to determine SNORD14E expression. The effects of SNORD14E were investigated using CCK8, Transwell, wound-healing assays, and a xenograft model experiment; apoptosis was measured by flow cytometry. Antisense oligonucleotide (ASO) targeting SNORD14E was designed and patient-derived organoids (PDO) models in EC patients was established. A xenograft mouse and PDO model were employed to evaluate the effects of ASO targeting SNORD14E. RNA-seq, Nm-seq, and RNA immunoprecipitation (RIP) experiments were employed to confirm the alternative splicing (AS) and modification induced by SNORD14E. A minigene reporter gene assay was conducted to confirm AS and splicing factors on a variable exon. Actinomycin-d (Act-D) and Reverse Transcription at Low deoxy-ribonucleoside triphosphate concentrations followed by PCR (RTL-P) were utilized to confirm the effects of 2'-O methylation modification on FOXM1. RESULTS We found that SNORD14E was overexpressed in EC tissues and patients with high expressed SNORD14E were distributed in the TCGA biomolecular classification subgroups without difference. Further, SNORD14E could reduce disease-free survival (DFS) and recurrence free survival (RFS) of EC patients. SNORD14E promoted proliferation, migration, and invasion and inhibited the apoptosis of EC cells in vitro. ASOs targeting SNORD14E inhibited cell proliferation, migration, invasion while promoted cell apoptosis. ASOs targeting SNORD14E inhibited tumor growth in the xenograft mouse model. TCGA-UCEC database showed that the proportion of patients with high expression of SNORD14E in middle-high risk and high-risk patients recommended by EMSO-ESGO-ESTRO guidelines for adjuvant therapy is more than 50%. Next, we enrolled 8 cases of high-risk and high-risk EC patients according to EMSO-ESGO-ESTRO guidelines and successfully constructed EC-PDOs. ASOs targeting SNORD14E inhibited the EC-PDO growth. Mechanistically, SNORD14E could recognize the mRNA of FOXM1 and recruit SRSF1 to promote the shearing of the variable exon VIIa of FOXM1, resulting in the overexpression of the FOXM1 malignant subtypes FOXM1b and FOXM1c. In addition, SNORD14E modified FOXM1 mRNA with 2`-O-methylation, which prolonged the half-life of FOXM1 mRNA. The nucleus accumulation of β-catenin caused by aberrant FOXM1 expression led to EC progression. CONCLUSIONS ASO targeting SNORD14E can be an effective treatment for EC.
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Affiliation(s)
- Xi Chen
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China
| | - Xin Liu
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China
| | - Qian-Hui Li
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China
| | - Bing-Feng Lu
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China
| | - Bu-Min Xie
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China
| | - Yu-Meng Ji
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China
| | - Yang Zhao
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, PR China.
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Zhang H, Li Z, Jiang J, Lei Y, Xie J, Liu Y, Yi B. SNTB1 regulates colorectal cancer cell proliferation and metastasis through YAP1 and the WNT/β-catenin pathway. Cell Cycle 2023; 22:1865-1883. [PMID: 37592763 PMCID: PMC10599191 DOI: 10.1080/15384101.2023.2244778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 08/19/2023] Open
Abstract
Colorectal cancer is a common type of digestive tract cancer with a significant morbidity and death rate across the world, partially attributing to the metastasis-associated problems. In this study, integrative bioinformatics analyses were performed to identify genes that might contribute to colorectal cancer metastasis, and 293 genes were dramatically increased and 369 genes were decreased within colon cancer samples. Among up-regulated genes, top five genes correlated with colorectal cancer patient's prognosis were verified for expression in clinical samples and syntrophin beta 1 (SNTB1) was the most up-regulated. In vitro, SNTB1 knockdown suppresses the malignant behaviors of colorectal cancer cells, including cell viability, colony formation capacity, as well as the abilities to migrate and invade. Furthermore, SNTB1 knockdown decreased the levels of Wnt1, C-Jun, C-Myc, TCF7, and cyclin D1, and inhibited EMT in both cell lines. In vivo, SNTB1 knockdown inhibited tumor growth and metastasis in nude mice models. SNTB1 positively regulated Yes1 associated transcriptional regulator (YAP1) expression; YAP1 partially reversed the effects of SNTB1 on colorectal cancer cell phenotypes and the Wnt/β-catenin/MYC signaling. In conclusion, SNTB1 knockdown inhibits colorectal cancer cell aggressiveness in vitro and tumor growth and metastasis in vivo through the Wnt/β-catenin/MYC signaling; YAP1 might mediate SNTB1 functions on colorectal cancer.
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Affiliation(s)
- Hao Zhang
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Zheng Li
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Juan Jiang
- Department of Nephrology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Yang Lei
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Jingmao Xie
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Yihui Liu
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Bo Yi
- Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, China
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Xue W, Cai L, Li S, Hou Y, Wang YD, Yang D, Xia Y, Nie X. WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice. Discov Oncol 2023; 14:136. [PMID: 37486552 PMCID: PMC10366069 DOI: 10.1007/s12672-023-00739-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/26/2023] [Indexed: 07/25/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and leading cause of death worldwide, whereas its pathogenesis has not been fully elucidated. Although mutations in some crucial genes in WNT pathways such as β-catenin and APC are not common in NSCLC, the abnormal signal transduction of WNT pathways is still closely related to the occurrence and progression of NSCLC. WNT ligands (WNTs) are a class of secreted glycoproteins that activate WNT pathways through binding to their receptors and play important regulatory roles in embryonic development, cell differentiation, and tissue regeneration. Therefore, the abnormal expression or dysfunction of WNTs undoubtedly affects WNT pathways and thus participates in the pathogenesis of diseases. There are 19 members of human WNTs, WNT1, WNT2, WNT2b, WNT3, WNT3a, WNT4, WNT5a, WNT5b, WNT6, WNT7a, WNT7b, WNT8a, WNT8b, WNT9a, WNT9b, WNT10a, WNT10b, WNT11 and WNT16. The expression levels of WNTs, binding receptors, and activated WNT pathways are diverse in different tissue types, which endows the complexity of WNT pathways and multifarious biological effects. Although abundant studies have reported the role of WNTs in the pathogenesis of NSCLC, it still needs further study as therapeutic targets for lung cancer. This review will systematically summarize current research on human WNTs in NSCLC, from molecular pathogenesis to potential clinical practice.
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Affiliation(s)
- Wanting Xue
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China
| | - Lihong Cai
- Kaifeng Key Laboratory of Radiation Oncology, Kaifeng Cancer Hospital, Kaifeng University, Kaifeng, 475003, China
| | - Su Li
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China
| | - Yujia Hou
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Dongbin Yang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China.
- Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Hebi, 458030, China.
| | - Yubing Xia
- Kaifeng Key Laboratory of Radiation Oncology, Kaifeng Cancer Hospital, Kaifeng University, Kaifeng, 475003, China.
| | - Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China.
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
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Song H, Sontz RA, Vance MJ, Morris JM, Sheriff S, Zhu S, Duan S, Zeng J, Koeppe E, Pandey R, Thorne CA, Stoffel EM, Merchant JL. High-fat diet plus HNF1A variant promotes polyps by activating β-catenin in early-onset colorectal cancer. JCI Insight 2023; 8:e167163. [PMID: 37219942 PMCID: PMC10371337 DOI: 10.1172/jci.insight.167163] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 05/19/2023] [Indexed: 05/24/2023] Open
Abstract
The incidence of early-onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here, we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 α (HNF1AA98V, rs1800574). The HNF1AA98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9, and the mice were placed on either a high-fat diet (HFD) or high-sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however, 19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes, and Wnt/β-catenin signaling components in the HNF1A mutant relative to the WT mice. Mouse polyps and colon cancers from participants carrying the HNF1AA98V variant exhibited reduced CDX2 and elevated β-catenin proteins. We further demonstrated decreased occupancy of HNF1AA98V at the Cdx2 locus and reduced Cdx2 promoter activity compared with WT HNF1A. Collectively, our study shows that the HNF1AA98V variant plus a HFD promotes the formation of colonic polyps by activating β-catenin via decreasing Cdx2 expression.
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Affiliation(s)
- Heyu Song
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, and
| | - Ricky A. Sontz
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, and
| | - Matthew J. Vance
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, and
| | - Julia M. Morris
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA
| | - Sulaiman Sheriff
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, and
| | - Songli Zhu
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Suzann Duan
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, and
| | - Jiping Zeng
- Department of Urology, University of Arizona College of Medicine, Tucson, Arizona, USA
| | | | - Ritu Pandey
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA
| | - Curtis A. Thorne
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA
| | - Elena M. Stoffel
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Juanita L. Merchant
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, and
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Ahmed EM, Farag AS, Abdelwahed MS, Hanbazazh M, Samman A, Ashmawy D, Abd-Elhameed NR, Tharwat M, Othman AE, Shawky TA, Attia RM, Ibrahim AA, Azzam S, Elhussiny MEA, Nasr M, Naeem SA, Abd-Elhay WM, Ali Alfaifi AM, Hasan A. The Expression of Stem Cell Marker LGR5 and Its Coexpression with Β-Catenin in Sporadic Colorectal Carcinoma and Adenoma: A Comparative Immunohistochemical Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1233. [PMID: 37512045 PMCID: PMC10383310 DOI: 10.3390/medicina59071233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 06/24/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023]
Abstract
Background: LGR5 is one of the most important stem cell markers for colorectal cancer (CRC), as it potentiates Wnt/Β-catenin signaling. The well-characterized deregulation of Wnt/Β-catenin signaling that occurs during adenoma/carcinoma sequence in CRC renders LGR5 a hopeful therapeutic target. We assessed the immunohistochemical expression of LGR5 and Β-catenin in normal colonic and tumorous lesions with a clinicopathological correlation. Methods: Tissue blocks and clinical data of 50 selected cases were included: 8 from normal mucosa, 12 cases of adenoma, and 30 cases of CRC, where sections were cut and re-examined and the immunohistochemical technique was conducted using anti-LGR5 and anti-Β-catenin to measure the staining density. Results: There was no expression of LGR5 in normal mucosa compared to samples of adenoma and CRC samples. The association analysis showed that CRC specimens were more likely to have strong LGR5 and Β-catenin expressions than the other two groups (p = 0.048 and p < 0.001, respectively). Specimens with high-grade dysplastic adenoma were more likely to express moderate-to-strong expression of LGR5 and Β-catenin (p = 0.013 and p = 0.036, respectively). In contrast, there were no statistically significant associations between LGR5 and Β-catenin expression with grade and stage. Conclusion: These results suggest and support the possible role of LGR5 as a potential marker of cancer stem cells in sporadic colorectal carcinogenesis in addition to a prognostic value for LGR5 and Β-catenin in adenomatous lesions according to immunohistochemical expression density. A potential therapeutic role of LGR5 in CRC is suggested for future studies based on its role in pathogenesis.
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Affiliation(s)
- Eman Mohamed Ahmed
- Pathology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11884, Egypt
| | - Abeer Said Farag
- Pathology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11884, Egypt
| | - Mohammed S Abdelwahed
- Pathology Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
- Pathology Department, Faculty of Medicine, University of Jeddah, Jeddah 23218, Saudi Arabia
| | - Mehenaz Hanbazazh
- Pathology Department, Faculty of Medicine, University of Jeddah, Jeddah 23218, Saudi Arabia
| | - Abdulhadi Samman
- Pathology Department, Faculty of Medicine, University of Jeddah, Jeddah 23218, Saudi Arabia
| | - Diaa Ashmawy
- Pathology Department, Faculty of Medicine, Al-Azhar University, Damietta 34517, Egypt
| | | | - Mohamed Tharwat
- Pathology Department, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt
| | - Alyaa E Othman
- Infectious Diseases Department, Faculty of Medicine, Suez Canal University, Ismailia 41552, Egypt
| | - Taiseer Ahmed Shawky
- Internal Medicine Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Radwa Mohamed Attia
- General Surgery Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11884, Egypt
| | | | - Sherif Azzam
- Clinical Oncology Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | | | - Mohamed Nasr
- Histology Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Suhaib Alsayed Naeem
- Histology Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Wagih M Abd-Elhay
- Histology Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | | | - Abdulkarim Hasan
- Pathology Department, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
- Prince Mishari bin Saud Hospital, Ministry of Health, Albahah 22888, Saudi Arabia
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Haraoka Y, Miyake M, Ishitani T. Zebrafish imaging reveals hidden oncogenic-normal cell communication during primary tumorigenesis. Cell Struct Funct 2023; 48:113-121. [PMID: 37164759 PMCID: PMC10721949 DOI: 10.1247/csf.23026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/08/2023] [Indexed: 05/12/2023] Open
Abstract
Oncogenic mutations drive tumorigenesis, and single cells with oncogenic mutations act as the tumor seeds that gradually evolve into fully transformed tumors. However, oncogenic cell behavior and communication with neighboring cells during primary tumorigenesis remain poorly understood. We used the zebrafish, a small vertebrate model suitable for in vivo cell biology, to address these issues. We describe the cooperative and competitive communication between oncogenic cells and neighboring cells, as revealed by our recent zebrafish imaging studies. Newly generated oncogenic cells are actively eliminated by neighboring cells in healthy epithelia, whereas oncogenic cells cooperate with their neighbors to prime tumorigenesis in unhealthy epithelia via additional mutations or inflammation. In addition, we discuss the potential of zebrafish in vivo imaging to determine the initial steps of human tumorigenesis.Key words: zebrafish, imaging, cell-cell communication, cell competition, EDAC, senescence, primary tumorigenesis.
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Affiliation(s)
- Yukinari Haraoka
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Mai Miyake
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan
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Dawoud MM, Salah M, Mohamed ASED. Clinical significance of immunohistochemical expression of DDR1 and β-catenin in colorectal carcinoma. World J Surg Oncol 2023; 21:168. [PMID: 37271822 DOI: 10.1186/s12957-023-03041-6] [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: 03/24/2023] [Accepted: 05/19/2023] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND Despite recent advances in therapy modalities of colorectal cancer (CRC), it is still the third cause of cancer-related deaths worldwide. Thus, the search for new target therapies became mandatory. DDR1 is a collagen receptor that has a suggested role in cellular proliferation, tumor invasion, and metastasis. MATERIAL AND METHODS Forty-eight cases of CRC, 20 of CR adenoma, and 8 cases of non-tumoral colonic tissue were subjected to immunohistochemistry by DDR1 and β-catenin antibodies. Results were compared among the different studied groups and correlated with clinicopathologic data and available survival data. Also, the expression of both proteins was compared versus each other. Results were compared among the 3 studied groups and correlated with clinicopathologic and survival data. RESULTS It revealed a stepwise increase of DDR1 expression among studied groups toward carcinoma (P = 0.006). DDR1 expression showed a direct association with stage D in the modified Dukes' staging system (P = 0.013), higher-grade histologic types (P = 0.008), and lymph node invasion (P = 0.028) but inverse correlation with the presence of intratumoral inflammatory response (TIR) (P = 0.001). The shortest OS was associated with strong intensity of DDR1 (P = 0.012). The DDR1 and β-catenin expressions were significantly correlated (P = 0.028), and the combined expression of both was correlated with TNM staging (P = 0.017). CONCLUSION DDR1 overexpression is a frequent feature in CRC and CR adenoma. DDR1 is a poor prognostic factor and a suppressor of the TIR. DDR1 and β-catenin seem to have a synergistic action.
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Affiliation(s)
- Marwa Mohammed Dawoud
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Marwa Salah
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
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Lee M, Kim YS, Lim S, Shin SH, Kim I, Kim J, Choi M, Kim JH, Koh SJ, Park JW, Shin HW. Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development. Nat Commun 2023; 14:2363. [PMID: 37185280 PMCID: PMC10130090 DOI: 10.1038/s41467-023-38080-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.
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Affiliation(s)
- Mingyu Lee
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, USA
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yi-Sook Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Suha Lim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Hyun Shin
- Hanmi Research Center, Hanmi Pharmaceutical Co. Ltd., 550 Dongtangiheung-ro, Hwaseong-si, 18469, Gyeonggi-do, South Korea
| | - Iljin Kim
- Department of Pharmacology, Inha University College of Medicine, Incheon, South Korea
| | - Jiyoung Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Min Choi
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Seong-Joon Koh
- Liver Research Institute and Seoul National University College of Medicine, Seoul, South Korea
| | - Jong-Wan Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyun-Woo Shin
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea.
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea.
- Sensory Organ Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
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Kramer ED, Tzetzo SL, Colligan SH, Hensen ML, Brackett CM, Clausen BE, Taketo MM, Abrams SI. β-Catenin signaling in alveolar macrophages enhances lung metastasis through a TNF-dependent mechanism. JCI Insight 2023; 8:e160978. [PMID: 37092550 PMCID: PMC10243816 DOI: 10.1172/jci.insight.160978] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 03/08/2023] [Indexed: 04/25/2023] Open
Abstract
The main cause of malignancy-related mortality is metastasis. Although metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment, especially macrophages, which correlate with poor clinical outcomes. Macrophages consist of bone marrow-derived and tissue-resident populations. In contrast to bone marrow-derived macrophages, the transcriptional pathways that govern the pro-metastatic activities of tissue-resident macrophages (TRMs) remain less clear. Alveolar macrophages (AMs) are a TRM population with critical roles in tissue homeostasis and metastasis. Wnt/β-catenin signaling is a hallmark of cancer and has been identified as a pathologic regulator of AMs in infection. We tested the hypothesis that β-catenin expression in AMs enhances metastasis in solid tumor models. Using a genetic β-catenin gain-of-function approach, we demonstrated that (a) enhanced β-catenin in AMs heightened lung metastasis; (b) β-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and (c) localized TNF-α blockade abrogated this metastatic outcome. Last, β-catenin gene CTNNB1 and TNF expression levels were positively correlated in AMs of patients with lung cancer. Overall, our findings revealed a Wnt/β-catenin/TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to the antineoplastic actions of TNF-α.
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Affiliation(s)
| | | | | | | | - Craig M. Brackett
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Björn E. Clausen
- Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Makoto M. Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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Gu S, Liu F, Xie X, Ding M, Wang Z, Xing X, Xiao T, Sun X. β-Sitosterol blocks the LEF-1-mediated Wnt/β-catenin pathway to inhibit proliferation of human colon cancer cells. Cell Signal 2023; 104:110585. [PMID: 36603684 DOI: 10.1016/j.cellsig.2022.110585] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/15/2022] [Accepted: 12/31/2022] [Indexed: 01/04/2023]
Abstract
OBJECTIVES This study aimed to investigate the LEF-1-mediated Wnt/β-catenin pathway for its biological functions and prognostic value in colon cancer (CC). Furthermore, the potential molecular mechanism of β-sitosterol in CC was investigated in vitro. METHODS Clinical information and gene expression profiles from CC patients were obtained based on Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In addition, we applied R software "Limma" package for the differential analysis of LEF-1 between cancer and para-carcinoma tissue samples. Kaplan-Meier (KM) survival analysis was adopted for analyzing whether LEF-1 was of prognostic significance. Moreover, gene set enrichment analysis (GSEA) was adopted for pathway enrichment analysis and visualization. In addition, CCK8, plate cloning, scratch and high-content screening (HCS) imaging assays were performed to examine the therapeutic efficacy of β-sitosterol in human CC HCT116 cells. siRNA technology was employed to knock down LEF1 expression in HCT116 cells. qRT-PCR and Western-blot (WB) analysis were carried out to analyze the HCT-116 mRNA and protein expression levels, respectively. RESULTS LEF-1 was up-regulated within CC and acted as an oncogenic gene. LEF-1 up-regulation predicted the dismal prognostic outcome and activated the Wnt/β-catenin pathway. β-sitosterol effectively suppressed HCT116 cells proliferation and invasion. For the mechanism underlying β-sitosterol, β-sitosterol was found to significantly down-regulate LEF-1 gene and protein expression and disrupt Wnt/β-catenin pathway transmission in HCT116 cells. After suppressing LEF-1 expression, its downstream targets including C-myc, Survivin and CCND1 were also down-regulated. CONCLUSION According to our results, LEF-1 down-regulation can effectively block Wnt/β-catenin pathway, inhibit CC cell growth and migration. Collectively, β-sitosterol can be used to treat CC, which can provide anti-tumor activity by targeting LEF-1.
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Affiliation(s)
- Shengliang Gu
- Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China
| | - Fahui Liu
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Xueheng Xie
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China; Key Laboratory of efficacy evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China
| | - Meng Ding
- Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China
| | - Zhen Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China; Key Laboratory of efficacy evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China
| | - Xiaoyan Xing
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China; Key Laboratory of efficacy evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China.
| | - Tianbao Xiao
- Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China; Key Laboratory of efficacy evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China.
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Brown AD, Cranstone C, Dupré DJ, Langelaan DN. β-Catenin interacts with the TAZ1 and TAZ2 domains of CBP/p300 to activate gene transcription. Int J Biol Macromol 2023; 238:124155. [PMID: 36963539 DOI: 10.1016/j.ijbiomac.2023.124155] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
The transcriptional co-regulator β-catenin is a critical member of the canonical Wnt signaling pathway, which plays an important role in regulating cell fate. Deregulation of the Wnt/β-catenin pathway is characteristic in the development of major types of cancer, where accumulation of β-catenin promotes cancer cell proliferation and renewal. β-catenin gene expression is facilitated through recruitment of co-activators such as histone acetyltransferases CBP/p300; however, the mechanism of their interaction is not fully understood. Here we investigate the interaction between the C-terminal transactivation domain of β-catenin and CBP/p300. Using a combination of pulldown assays, isothermal titration calorimetry, and nuclear resonance spectroscopy we determine the disordered C-terminal region of β-catenin binds promiscuously to the TAZ1 and TAZ2 domains of CBP/p300. We then map the interaction site of the C-terminal β-catenin transactivation domain onto TAZ1 and TAZ2 using chemical-shift perturbation studies. Luciferase-based gene reporter assays indicate Asp750-Leu781 is critical to β-catenin gene activation, and mutagenesis revealed that acidic and hydrophobic residues within this region are necessary to maintain TAZ1 binding. These results outline a mechanism of Wnt/β-catenin gene regulation that underlies cell development and provides a framework to develop methods to block β-catenin dependent signaling.
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Affiliation(s)
- Alexandra D Brown
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Connor Cranstone
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Denis J Dupré
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - David N Langelaan
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
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Bakulina NV, Tikhonov SV, Okovityi SV, Lutaenko EA, Bolshakov AO, Prikhodko VA, Nekrasova AS. [Pharmacokinetics and pharmacodynamics of rebamipide. New possibilities of therapy: A review]. TERAPEVT ARKH 2023; 94:1431-1437. [PMID: 37167190 DOI: 10.26442/00403660.2022.12.202000] [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: 01/15/2023] [Accepted: 01/15/2023] [Indexed: 01/18/2023]
Abstract
The MedLine database contains 570 publications, including 71 randomized clinical trials and 6 meta-analyses on the rebamipide molecule in 2022. Indications for the use of rebamipide are gastric ulcer, chronic gastritis with hyperacidityin the acute stage, erosive gastritis, prevention of damage to the gastrointestinal mucosa while taking non-steroidal anti-inflammatory drugs, eradication of Helicobacter pylori. Currently trials are studying the efficacy and safety of the drug in gouty and rheumatoid arthritis, osteoarthritis, Sjögren's syndrome, bronchial asthma, vitiligo, atherosclerosis, diseases of the kidneys and liver; using in traumatology to accelerate bone regeneration; in ophthalmology to improve the regeneration of corneal epithelium; in oncology to reduce inflammatory changes in the oral mucosa after chemoradiotherapy. The review article is about the main pharmacokinetic and pharmacodynamic characteristics of rebamipide. A detailed understanding of pharmacodynamics and pharmacokinetics allows for individual selection of therapy based on the characteristics of the patient's body - gender, age, comorbidities; choose the optimal route of administration and dosing regimen; predict adverse effects and drug interactions; be determined with new clinical indications.
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Affiliation(s)
- N V Bakulina
- Mechnikov North-Western State Medical University
| | - S V Tikhonov
- Mechnikov North-Western State Medical University
| | - S V Okovityi
- Saint Petersburg State Chemical Pharmaceutical University
| | - E A Lutaenko
- Mechnikov North-Western State Medical University
| | | | - V A Prikhodko
- Saint Petersburg State Chemical Pharmaceutical University
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Mokgautsi N, Kuo YC, Huang YJ, Chen CH, Mukhopadhyay D, Wu ATH, Huang HS. Preclinical Evaluation of a Novel Small Molecule LCC-21 to Suppress Colorectal Cancer Malignancy by Inhibiting Angiogenic and Metastatic Signatures. Cells 2023; 12:cells12020266. [PMID: 36672201 PMCID: PMC9856425 DOI: 10.3390/cells12020266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/06/2022] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers, and it frequently metastasizes to the liver and lymph nodes. Despite major advances in treatment modalities, CRC remains a poorly characterized biological malignancy, with high reported cases of deaths globally. Moreover, cancer stem cells (CSCs) and their microenvironment have been widely shown to promote colon cancer development, progression, and metastasis. Therefore, an understanding of the underlying mechanisms that contribute to the maintenance of CSCs and their markers in CRC is crucial in efforts to treat cancer metastasis and develop specific therapeutic targets for augmenting current standard treatments. Herein, we applied computational simulations using bioinformatics to identify potential theranostic markers for CRC. We identified the overexpression of vascular endothelial growth factor-α (VEGFA)/β-catenin/matrix metalloproteinase (MMP)-7/Cluster of Differentiation 44 (CD44) in CRC to be associated with cancer progression, stemness, resistance to therapy, metastasis, and poor clinical outcomes. To further investigate, we explored in silico molecular docking, which revealed potential inhibitory activities of LCC-21 as a potential multitarget small molecule for VEGF-A/CTNNB1/MMP7/CD44 oncogenic signatures, with the highest binding affinities displayed. We validated these finding in vitro and demonstrated that LCC-21 inhibited colony and sphere formation, migration, and invasion, and these results were further confirmed by a Western blot analysis in HCT116 and DLD-1 cells. Thus, the inhibitory effects of LCC-21 on these angiogenic and onco-immunogenic signatures could be of translational relevance as potential CRC biomarkers for early diagnosis.
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Affiliation(s)
- Ntlotlang Mokgautsi
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Cheng Kuo
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Yan-Jiun Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chien-Hsin Chen
- Division of Colorectal Surgery, Department of Surgery, WanFang Hospital, Taipei Medical University, No. 111 Sec. 3 Xinglong Rd., Wenshan Dist., Taipei 11031, Taiwan
| | | | - Alexander T. H. Wu
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- The Ph.D. Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11031, Taiwan
- Correspondence: (A.T.H.W.); (H.-S.H.); Tel.: +886-2-2697-2035 (ext. 112) (A.T.H.W.); +886-2-6638-2736 (ext. 1377) (H.-S.H.)
| | - Hsu-Shan Huang
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei 11031, Taiwan
- Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (A.T.H.W.); (H.-S.H.); Tel.: +886-2-2697-2035 (ext. 112) (A.T.H.W.); +886-2-6638-2736 (ext. 1377) (H.-S.H.)
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Ko YL, Kumar V, Lippert J, Diaz-Cano S, Skordilis K, Kimpel O, Kircher S, Asia M, Elhassan YS, Altieri B, Ronchi CL. Coincidence of primary adrenocortical carcinoma and melanoma: three CASE reports. BMC Endocr Disord 2023; 23:4. [PMID: 36604647 PMCID: PMC9817389 DOI: 10.1186/s12902-022-01253-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 12/15/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a heterogeneous prognosis, while adrenal metastasis from other primary cancers, including melanoma, may occur more frequently. ACC may rarely occur as part of familial cancer syndromes, but even in sporadic cases, a significant proportion of patients had other malignancies before or after diagnosis of ACC. Herein we present three cases where sporadic ACC was identified in patients with coexistent or previous history of melanoma. CASE DESCRIPTION Patient 1 - A 37-yr-old man with a superficial spreading BRAF-positive melanoma was found to harbour a progressively growing left adrenal mass. Initially, he was suspected of having adrenal metastasis, but the histology after adrenalectomy confirmed ACC. Patient 2 - A 68-year-old man with a history of recurrent BRAF-positive melanoma was diagnosed with disseminated metastatic melanoma recurrence, including a rapidly enlarging left adrenal mass. Consequently, he underwent left adrenalectomy, and histology again confirmed ACC. Patient 3 - A 50-yr-old man was referred with histological diagnosis of metastatic ACC. He had a background history of pT1 melanoma. We undertook targeted sequencing of ACC tissue samples in all cases. Somatic variants were observed in the known driver genes CTNNB1 (Patient 1), APC and KMT2D (Patient 2), and APC and TP53 (Patient 3). Germline TP53 variants (Li-Fraumeni syndrome) were excluded in all cases. Retrospective review of our patient cohort in the last 21 years revealed a frequency of 0.5% of histologically diagnosed melanoma metastasis among patients referred for adrenal masses. On the other hand, 1.6% of patients with histologically confirmed ACC had a previous history of melanoma. CONCLUSION Sporadic ACC can occur in the background of melanoma, even if adrenal metastasis might appear to be the most likely diagnosis. Coexistent primary adrenal malignancy should be considered and investigated for in all patients with a history of melanoma with suspicious adrenal lesions.
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Affiliation(s)
- Ye Lynn Ko
- Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vaishnavi Kumar
- Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Juliane Lippert
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
| | - Salvador Diaz-Cano
- Department of Histopathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Kassiani Skordilis
- Department of Histopathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Otilia Kimpel
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
| | - Stefan Kircher
- Institute for Pathology, University of Würzburg, Würzburg, Germany
| | - Miriam Asia
- Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Yasir S Elhassan
- Institute of Metabolism and System Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT, UK
- Centre for Endocrinology, Diabetes, and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK
| | - Barbara Altieri
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
| | - Cristina L Ronchi
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany.
- Institute of Metabolism and System Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, B15 2TT, UK.
- Centre for Endocrinology, Diabetes, and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK.
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Gong H, Chen K, Zhou L, Jin Y, Chen W. Deleted in liver cancer 1 suppresses the growth of prostate cancer cells through inhibiting Rho-associated protein kinase pathway. Asian J Urol 2023; 10:50-57. [PMID: 36721699 PMCID: PMC9875144 DOI: 10.1016/j.ajur.2021.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 09/24/2021] [Accepted: 10/13/2021] [Indexed: 02/03/2023] Open
Abstract
Objective Deleted in liver cancer 1 (DLC1) is a GTPase-activating protein that is reported as a suppressor in certain human cancers. However, the detailed biological function of DLC1 is still unclear in human prostate cancer (PCa). In the present study, we aimed to explore the function of DLC1 in PCa cells. Methods Silencing and overexpression of DLC1 were induced in an androgen-sensitive PCa cell line (LNCaP) using RNA interference and lentiviral vector transduction. The Cell Counting Kit-8 assay was performed to determine cell proliferation. The cell cycle was examined by performing a propidium iodide staining assay. Results Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of LNCaP cells. Moreover, DLC1 expression was negatively correlated with Rho-associated protein kinase (ROCK) expression in LNCaP cells. Importantly, this study showed that the ROCK inhibitor Y27632 restored the function of DLC1 in LNCaP cells and reduced the tumorigenicity of LNCaP cells in vivo. Conclusion Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of PCa cells and negatively correlated with ROCK expression in PCa cells and tissue.
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Affiliation(s)
- Hua Gong
- Department of Urology, Zhoupu Hospital, Medicine and Health Sciences, Shanghai University, Shanghai, China
| | - Kang Chen
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lan Zhou
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yongchao Jin
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Weihua Chen
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China,Corresponding author.
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Behrouj H, Mokarram P. BAMLET (Bovine α-lactalbumin made lethal to tumor cells) inhibits autophagy flux and induces apoptosis via down-regulation of protein kinase CK1α and attenuation of the AKT/p-ß-catenin (S552) pathway in RAS-mutated human colorectal HCT 116 cells. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:1212-1219. [PMID: 37736507 PMCID: PMC10510486 DOI: 10.22038/ijbms.2023.69343.15114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 06/06/2023] [Indexed: 09/23/2023]
Abstract
Objectives Oncogenic RAS mutations occur in nearly 50% of colorectal cancer cases and are usually dependent on the autophagy mechanism to maintain tumorigenesis. We have recently demonstrated that CK1α controls autophagy machinery possibly through the AKT/p-ß-catenin (S552) signaling in colorectal cancer cells harboring RAS mutation. It has been found that a lipid-protein complex comprising oleic acid binds to human α-lactalbumin, known as HAMLET (human α -lactalbumin made lethal to tumor cells), targets a broad range of kinases including CK1α. Therefore, this study was designed to investigate the effects of BAMLET (bovine α -lactalbumin made lethal to tumor cells, the bovine counterpart of HAMLET) on CK1α expression, AKT/Phospho-ß-catenin (S552) pathway, and autophagy flux in RAS-mutated human colorectal HCT 116 cells. Materials and Methods For this purpose, HCT116 cells were treated with BAMLET and casein kinase 1 inhibitor (D4476), and quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis were used to measure the proteins and genes of the AKT/Phospho-ß-catenin (S552) pathway and autophagy. Apoptosis was measured by flow-cytometry. Results We found that BAMLET significantly reduced cell viability and decreased the expression of CK1α. Additionally, BAMLET inhibited autophagy flux and enhanced the ability of CK1α inhibitor D4476 to impair autophagy flux, which was accompanied by an increase in the apoptosis percentage. We also observed that BAMLET empowered D4476 to down-regulate the AKT/Phospho-ß-catenin (S552) axis. Conclusion BAMLET hampers autophagy flux and leads to apoptosis induction, possibly, by reducing the expression of CK1α and attenuation of the AKT/Phospho-ß-catenin (S552) axis.
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Affiliation(s)
- Hamid Behrouj
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Behbahan Faculty of Medical Sciences, Behbahan, Iran
| | - Pooneh Mokarram
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Wang H, Zhao M, Shi F, Zheng S, Xiong L, Zheng L. A review of signal pathway induced by virulent protein CagA of Helicobacter pylori. Front Cell Infect Microbiol 2023; 13:1062803. [PMID: 37124036 PMCID: PMC10140366 DOI: 10.3389/fcimb.2023.1062803] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and Helicobacter pylori (H. pylori) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of H. pylori, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of H. pylori-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the H. pylori infection and treatment of GC in the future.
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Affiliation(s)
- Haiqiang Wang
- Department of Internal Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Li Xiong
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Internal Medicine, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
- *Correspondence: Lihong Zheng,
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