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Gu T, Raval R, Bashkin Z, Zhou C, Ko S, Kong N, Hong S, Bhaskara A, Shah S, Joshi A, Thellakal S, Rim K, Marimuthu A, Venkatesan S, Wang E, Li S, Jayabalan A, Tao A, Fang Y, Xia L, Chui A, Shu E, Zhang T, Chen Z, Njoo E. Synthesis, antiproliferative activity, and biological profiling of C-19 trityl and silyl ether andrographolide analogs in colon cancer and breast cancer cells. Bioorg Med Chem Lett 2025; 121:130163. [PMID: 40043819 DOI: 10.1016/j.bmcl.2025.130163] [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: 10/14/2024] [Revised: 02/08/2025] [Accepted: 02/28/2025] [Indexed: 03/10/2025]
Abstract
Andrographolide, a labdane diterpenoid isolated from Andrographis paniculata, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through in vitro TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.
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Affiliation(s)
- Tiffany Gu
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Rushika Raval
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Zachary Bashkin
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Carina Zhou
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Sanghyuk Ko
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Natalie Kong
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Seoyeon Hong
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Aditya Bhaskara
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Samarth Shah
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Aditi Joshi
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Samahith Thellakal
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Kaitlyn Rim
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Anushree Marimuthu
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Srishti Venkatesan
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Emma Wang
- Department of Computer Science & Engineering, Aspiring Scholars Directed Research Program, USA
| | - Sophia Li
- Department of Computer Science & Engineering, Aspiring Scholars Directed Research Program, USA
| | - Aditi Jayabalan
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Alice Tao
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Yilin Fang
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Lorelei Xia
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Aidan Chui
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Emily Shu
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA
| | - Tracy Zhang
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Zhan Chen
- Department of Biological and Life Sciences, Aspiring Scholars Directed Research Program, USA
| | - Edward Njoo
- Department of Chemistry, Aspiring Scholars Directed Research Program, USA.
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McDermott A, Juárez M, Wade MG, Patten SA, Plante I. Exposure to brominated flame retardants during pregnancy and lactation increases the prevalence of breast lesions and cancer-associated pathways in sprague-dawley rats. Reprod Toxicol 2025; 135:108928. [PMID: 40316034 DOI: 10.1016/j.reprotox.2025.108928] [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: 11/29/2024] [Revised: 04/01/2025] [Accepted: 04/21/2025] [Indexed: 05/04/2025]
Abstract
The mammary gland undergoes significant changes during pregnancy, lactation, and involution, making it highly susceptible to endocrine-disrupting chemicals such as brominated flame retardants (BFRs). Despite being restricted in many countries, some BFRs persist in the environment and accumulate in human tissues, including the mammary gland and human milk. This study investigates the effects of BFRs exposure during pregnancy and lactation on mammary gland development and breast cancer risk in a rat model. Dams were exposed to a mixture of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), formulated based on relative congener levels found in house dust. Post-weaning, dams were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate tumor formation. The results revealed that both low and high doses of BFRs induced lesions in mammary epithelium, with an increase in total lesion number in low dose. Molecular analysis revealed disruptions in the Wnt/β-catenin signaling pathway, leading to an increase in oncogene expression, including c-Myc and c-Jun. RNA sequencing also indicated dysregulation in calcium signaling and glucose metabolism pathways. Our findings suggest that BFR exposure during the critical window of mammary gland involution compromises the cancer-protective effects of pregnancy and lactation. These effects are particularly significant at low exposure levels, demonstrating a non-monotonic dose-response. The study underscores the potential long-term health risks associated with environmental BFR exposure and highlights the need for further research on its implications on the risks of developing breast cancer later in life.
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Affiliation(s)
- Alec McDermott
- INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada
| | - Melany Juárez
- INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada
| | - Michael G Wade
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada
| | | | - Isabelle Plante
- INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada.
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Wang Y, Yao Y, Kou S, Wang S, Song J, Yang S, Wang H, Wang Y. SIK2 promotes malignant features of human osteosarcoma via up-regulating MMP2 and β-catenin expression. Genes Dis 2025; 12:101325. [PMID: 39634133 PMCID: PMC11616025 DOI: 10.1016/j.gendis.2024.101325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/20/2024] [Accepted: 03/31/2024] [Indexed: 12/07/2024] Open
Affiliation(s)
- Yutong Wang
- School of Public Health and Laboratory of Qilu Medical University, Zibo, Shandong 255300, China
| | - Yulan Yao
- Department of Neurology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, China
| | - Sen Kou
- Department of Neurology, Zibo 148 Hospital, Zibo, Shandong 255300, China
| | - Shanshan Wang
- Department of Neurology, Zibo 148 Hospital, Zibo, Shandong 255300, China
| | - Juntao Song
- Department of Oncology and Hematology, Zibo 148 Hospital, Zibo, Shandong 255300, China
| | - Siqi Yang
- Department of Neurology, Zibo 148 Hospital, Zibo, Shandong 255300, China
| | - Hongwei Wang
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yunliang Wang
- Department of Neurology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, China
- Department of Neurology, Zibo 148 Hospital, Zibo, Shandong 255300, China
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Rida Zainab S, Zeb Khan J, Khalid Tipu M, Jahan F, Irshad N. A review on multiple sclerosis: Unravelling the complexities of pathogenesis, progression, mechanisms and therapeutic innovations. Neuroscience 2025; 567:133-149. [PMID: 39709058 DOI: 10.1016/j.neuroscience.2024.12.029] [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: 10/24/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 12/23/2024]
Abstract
Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) targeting myelinated axons. Pathogenesis of MS entails an intricate genetic, environmental, and immunological interaction. Dysregulation of immune response i.e. autoreactive T & B-Cells and macrophage infiltration into the CNS leads to inflammation, demyelination, and neurodegeneration. Disease progression of MS varies among individuals transitioning from one form of relapsing-remitting to secondary progressive MS (SPMS). Research advances have unfolded various molecular targets involved in MS from oxidative stress to blood-brain barrier (BBB) disruption. Different pathways are being targeted so far such as inflammatory and cytokine signaling pathways to overcome disease progression. Therapeutic innovations have significantly transformed the management of MS, especially the use of disease-modifying therapies (DMTs) to reduce relapse rates and control disease progression. Advancements in research, neuroprotective strategies, and remyelination strategies hold promising results in reversing CNS damage. Various mice models are being adopted for testing new entities in MS research.
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Affiliation(s)
- Syeda Rida Zainab
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Jehan Zeb Khan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Muhammad Khalid Tipu
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Faryal Jahan
- Shifa College of Pharmaceutical Sciences, STMU, Islamabad, Pakistan.
| | - Nadeem Irshad
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Juarez MN, McDermott A, Wade MG, Plante I. Exposure to brominated flame retardants in utero and through lactation delays the development of DMBA-induced mammary cancer: potential effects on subtypes? Front Endocrinol (Lausanne) 2024; 15:1429142. [PMID: 39610845 PMCID: PMC11602300 DOI: 10.3389/fendo.2024.1429142] [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: 05/07/2024] [Accepted: 10/21/2024] [Indexed: 11/30/2024] Open
Abstract
Introduction Brominated flame retardants (BFRs) are chemical compounds used to reduce the flammability of various products; some BFRs exhibit endocrine-disrupting properties and can leach into the environment leading to human and wildlife exposure. The mammary gland has specific vulnerability windows during which it is more sensitive to the effects of endocrine disrupting compounds (EDCs), such as the in utero life, puberty and pregnancy. Our previous studies revealed precocious mammary gland development, disruptions in junctional proteins, and altered proliferation-apoptosis balance during puberty in rats exposed to BFRs in utero and through lactation. Such effects have been associated with increased mammary cancer risk. Objective The current study aimed to determine if in utero and lactational exposure to BFRs renders the mammary gland more susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancer. Methods Dams were exposed to a BFRs mixture (0. 0.06 or 60 mg/kg/day), and mammary cancer was induced in pups using DMBA at post-natal day 46. Tumors onset and growth were monitored, and tumors were characterized using histology and molecular biology. Results Although BFRs exposure did not significantly affect mammary tumor number or burden, it showed significant delay in mammary tumor onset and growth in BFR-exposed animal. These effects could potentially be due to BFRs' impact on cellular responses, DMBA metabolism, or mammary gland shift of the sensitivity window. Molecular analysis of mammary tumors showed a shift in the ratio of luminal A, luminal B, and (HER2)-enriched tumors, and an increase in triple-negative breast cancer (TNBC) subtypes in BFR-exposed animals. Additionally, BFRs exposure showed lung lesions indicative of inflammation, independent of mammary cancer development. Conclusion Our study highlights the complex relationship between BFRs exposure and mammary cancer risk, emphasizing the need for further investigation into underlying mechanisms and long-term effects of BFRs on mammary gland development and carcinogenesis.
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MESH Headings
- Animals
- Female
- Flame Retardants/toxicity
- 9,10-Dimethyl-1,2-benzanthracene/toxicity
- Pregnancy
- Lactation
- Rats
- Prenatal Exposure Delayed Effects/chemically induced
- Prenatal Exposure Delayed Effects/pathology
- Mammary Neoplasms, Experimental/chemically induced
- Mammary Neoplasms, Experimental/pathology
- Mammary Neoplasms, Experimental/metabolism
- Rats, Sprague-Dawley
- Mammary Glands, Animal/drug effects
- Mammary Glands, Animal/pathology
- Mammary Glands, Animal/growth & development
- Mammary Glands, Animal/metabolism
- Endocrine Disruptors/toxicity
- Carcinogens/toxicity
- Halogenated Diphenyl Ethers/toxicity
- Maternal Exposure/adverse effects
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Affiliation(s)
- Melany N. Juarez
- INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada
| | - Alec McDermott
- INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada
| | - Michael G. Wade
- Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada
| | - Isabelle Plante
- INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada
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Amin MN, Abdelmohsen UR, Samra YA. Turkish coffee has an antitumor effect on breast cancer cells in vitro and in vivo. Nutr Metab (Lond) 2024; 21:73. [PMID: 39272080 PMCID: PMC11396339 DOI: 10.1186/s12986-024-00846-4] [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: 03/26/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Breast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo. METHODS In our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. β-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry. RESULTS Both coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in β- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density. CONCLUSION These findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer.
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Affiliation(s)
- Mohamed N Amin
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Usama Ramadan Abdelmohsen
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia City, 61111, Egypt
| | - Yara A Samra
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
- Department of Basic Medical Sciences, Faculty of Oral and Dental Medicine, Ahram Canadian University, Giza, 12566, Egypt
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Li H, Yuan C, Wang H, Cui L, Liu K, Guo L, Li J, Dong J. The Effect of Selenium on Endometrial Repair in Goats with Endometritis at High Cortisol Levels. Biol Trace Elem Res 2024; 202:2564-2576. [PMID: 37814171 DOI: 10.1007/s12011-023-03866-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/12/2023] [Indexed: 10/11/2023]
Abstract
Endometritis is a common postpartum disease of female animals that causes significant losses to the goat industry. High levels of cortisol induced by various stresses after delivery severely inhibit innate immunity and tissue repair. The repair ability of the endometrium is closely related to the reproductive performance of goats. Selenium (Se) is an essential trace element in animals that has powerful antioxidant and immunity-enhancing functions. In this study, we established a goat model of endometritis at high cortisol (Hydrocortisone) levels to investigate the effect of Se (supplement additive) on endometrial repair. The results showed that the clinical symptoms, %PMN in uterine secretions, morphological endometrial damage, and the gene expression of BAX were reduced in the goats with Se supplementation compared with those in the model group. Se increased the gene expression of BCL2, VEGFA, TGFB1, and PCNA and activated the PI3K/AKT and Wnt/β-catenin signaling pathways in goats with Se supplementation. In conclusion, Se reduced the inflammatory response, increased the proliferation, and decreased the apoptosis of endometrial cells to promote endometrial tissue repair in goats with endometritis at high cortisol levels. It probably achieved this effect of promoting repair by activating the Wnt/β-catenin and PI3K/AKT pathways and affecting the gene expression of VEGFA, TGFB1, PCNA, BCL2, and BAX.
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Affiliation(s)
- Hanqing Li
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China
| | - Changning Yuan
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China
| | - Heng Wang
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China
| | - Luying Cui
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China
| | - Kangjun Liu
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China
| | - Long Guo
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China
| | - Jianji Li
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China.
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China.
| | - Junsheng Dong
- College of Veterinary Medicine, Yangzhou University, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou, 225009, China.
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, 225009, China.
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Gadwal A, Purohit P, Khokhar M, Vishnoi JR, Pareek P, Choudhary R, Elhence P, Banerjee M, Sharma P. GALNT6, GALNT14, and Gal-3 in association with GDF-15 promotes drug resistance and stemness of breast cancer via β-catenin axis. Growth Factors 2024; 42:84-100. [PMID: 38889447 DOI: 10.1080/08977194.2024.2368907] [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: 06/26/2023] [Accepted: 06/12/2024] [Indexed: 06/20/2024]
Abstract
N-acetylgalactosaminyltransferases (GALNTs) are a polypeptide responsible for aberrant glycosylation in breast cancer (BC), but the mechanism is unclear. In this study, expression levels of GALNT6, GALNT14, and Gal-3 were assessed in BC, and their association with GDF-15, β-catenin, stemness (SOX2 and OCT4), and drug resistance marker (ABCC5) was evaluated. Gene expression of GALNT6, GALNT14, Gal-3, GDF-15, OCT4, SOX2, ABCC5, and β-catenin in tumor and adjacent non-tumor tissues (n = 30) was determined. The same was compared with GEO-microarray datasets. A significant increase in the expression of candidate genes was observed in BC tumor compared to adjacent non-tumor tissue; and in pre-therapeutic patients compared to post-therapeutic. GALNT6, GALNT14, Gal-3, and GDF-15 showed positive association with β-catenin, SOX2, OCT4, and ABCC5 and were significantly associated with poor Overall Survival. Our findings were also validated via in silico analysis. Our study suggests that GALNT6, GALNT14, and Gal-3 in association with GDF-15 promote stemness and intrinsic drug resistance in BC, possibly by β-catenin signaling pathway.
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Affiliation(s)
- Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Jeewan Ram Vishnoi
- Department of Oncosurgery, All India Institute of Medical Sciences, Jodhpur, India
| | - Puneet Pareek
- Department of Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, India
| | - Ramkaran Choudhary
- Department of General Surgery, All India Institute of Medical Sciences, Jodhpur, India
| | - Poonam Elhence
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
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9
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Kong L, Jin X. Dysregulation of deubiquitination in breast cancer. Gene 2024; 902:148175. [PMID: 38242375 DOI: 10.1016/j.gene.2024.148175] [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: 10/25/2023] [Revised: 12/04/2023] [Accepted: 01/16/2024] [Indexed: 01/21/2024]
Abstract
Breast cancer (BC) is a highly frequent malignant tumor that poses a serious threat to women's health and has different molecular subtypes, histological subtypes, and biological features, which act by activating oncogenic factors and suppressing cancer inhibitors. The ubiquitin-proteasome system (UPS) is the main process contributing to protein degradation, and deubiquitinases (DUBs) are reverse enzymes that counteract this process. There is growing evidence that dysregulation of DUBs is involved in the occurrence of BC. Herein, we review recent research findings in BC-associated DUBs, describe their nature, classification, and functions, and discuss the potential mechanisms of DUB-related dysregulation in BC. Furthermore, we present the successful treatment of malignant cancer with DUB inhibitors, as well as analyzing the status of targeting aberrant DUBs in BC.
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Affiliation(s)
- Lili Kong
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo 315211, Zhejiang, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo 315211, Zhejiang, China.
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10
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Ren W, Wang J, Zeng Y, Wang T, Meng J, Yao X. Differential age-related transcriptomic analysis of ovarian granulosa cells in Kazakh horses. Front Endocrinol (Lausanne) 2024; 15:1346260. [PMID: 38352714 PMCID: PMC10863452 DOI: 10.3389/fendo.2024.1346260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/13/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction The Kazakh horse, renowned for its excellence as a breed, exhibits distinctive reproductive traits characterized by early maturity and seasonal estrus. While normal reproductive function is crucial for ensuring the breeding and expansion of the Kazakh horse population, a noteworthy decline in reproductive capabilities is observed after reaching 14 years of age. Methods In this study, ovarian granulosa cells (GCs) were meticulously collected from Kazakh horses aged 1, 2, 7, and above 15 years old (excluding 15 years old) for whole transcriptome sequencing. Results The analysis identified and selected differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs for each age group, followed by a thorough examination through GO enrichment analysis. The study uncovered significant variations in the expression profiles of mRNAs, lncRNAs, miRNAs, and circRNAs within GCs at different stages of maturity. Notably, eca-miR-486-3p and miR-486-y exhibited the highest degree of connectivity. Subsequent GO, KEGG, PPI, and ceRNA network analyses elucidated that the differentially expressed target genes actively participate in signaling pathways associated with cell proliferation, apoptosis, and hormonal regulation. These pathways include but are not limited to the MAPK signaling pathway, Hippo signaling pathway, Wnt signaling pathway, Calcium signaling pathway, Aldosterone synthesis and secretion, Cellular senescence, and NF-kappa B signaling pathway-essentially encompassing signal transduction pathways crucial to reproductive processes. Discussion This research significantly contributes to unraveling the molecular mechanisms governing follicular development in Kazakh horses. It establishes and preliminarily validates a differential regulatory network involving lncRNA-miRNA-mRNA, intricately associated with processes such as cell proliferation, differentiation, and apoptosis and integral to the developmental intricacies of stromal follicles. The findings of this study provide a solid theoretical foundation for delving deeper into the realm of reproductive aging in Kazakh mares, presenting itself as a pivotal regulatory pathway in the context of horse ovarian development.
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Affiliation(s)
- Wanlu Ren
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China
| | - Jianwen Wang
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China
- Xinjiang Agricultural University, Xinjiang Key Laboratory of Equine Breeding and Exercise Physiology, Urumqi, China
| | - Yaqi Zeng
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China
| | - Tongliang Wang
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China
| | - Jun Meng
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China
- Xinjiang Agricultural University, Xinjiang Key Laboratory of Equine Breeding and Exercise Physiology, Urumqi, China
| | - Xinkui Yao
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China
- Xinjiang Agricultural University, Xinjiang Key Laboratory of Equine Breeding and Exercise Physiology, Urumqi, China
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11
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Hemida AS, Shabaan MI, Taha MA, Abdou AG. Impact of immunohistochemical expression of kinesin family member 18A (Kif18A) and β-catenin in infiltrating breast carcinoma of no special type. World J Surg Oncol 2024; 22:15. [PMID: 38195458 PMCID: PMC10777553 DOI: 10.1186/s12957-023-03276-3] [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: 10/04/2023] [Accepted: 12/09/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND KIF18A is a regulator of the cell cycle that stimulates the proliferation of cancer cells. The Wnt/β-catenin pathway is involved in different issues' carcinogenesis and is being examined as a therapeutic target. The relationship between KIF18A and β-catenin in breast cancer was not previously investigated. Therefore, this work aims to study the immunohistochemical expression and correlation of KIF18A and β-catenin in breast-infiltrating duct carcinoma (IDC) and their relation to prognosis. MATERIAL AND METHODS Slides cut from paraffin blocks of 135 IDC and 40 normal breast tissues were stained by KIF18A and β-catenin antibodies. KIF18A cytoplasmic or nucleocytoplasmic staining and β-catenin aberrant expression either nucleo-cytoplasmic or cytoplasmic staining were considered. RESULTS Normal breast tissue and IDC showed a significant difference regarding KIF18A and aberrant β-catenin expression. High KIF18A and β-catenin H score values were associated with poor prognostic factors such as high grade, advanced stage, distant metastasis, high Ki67 status, and Her2neu-enriched subtype. There was a significant direct correlation between KIF18A and β-catenin as regards percent and H score values. Prolonged overall survival (OS) was significantly associated with mild intensity and low H score of KIF18A, and low β-catenin H score. CONCLUSIONS KIF18A could be involved in breast carcinogenesis by activating β-catenin. Overexpression of KIF18A and aberrant expression of β-catenin are considered proto-oncogenes of breast cancer development. KIF18A and β-catenin could be poor prognostic markers and predictors of aggressive behavior of breast cancer.
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Affiliation(s)
- Aiat Shaban Hemida
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt.
| | - Mohammed Ibrahim Shabaan
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt
| | - Mennatallah Ahmed Taha
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt
| | - Asmaa Gaber Abdou
- Pathology Department, Faculty of Medicine, Menoufia University, Yassin Abd Elghafar Street, Shebin El Kom, 32511, Egypt
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12
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Elgun T, Yurttas AG, Cinar K, Ozcelik S, Gul A. Effect of aza-BODIPY-photodynamic therapy on the expression of carcinoma-associated genes and cell death mode. Photodiagnosis Photodyn Ther 2023; 44:103849. [PMID: 37863378 DOI: 10.1016/j.pdpdt.2023.103849] [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: 08/18/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/22/2023]
Abstract
BACKGROUND Breast cancer is the most common cancer affecting women worldwide.Photodynamic therapy(PDT) has now proven to be a promising form of cancer therapy due to its targeted and low cytotoxicity to healthy cells and tissues.PDT is a technique used to create cell death localized by light after application of a light-sensitive agent.Aza-BODIPY is a promising photosensitizer for use in PDT. Our results showed that aza-BODIPY-PDT induced apoptosis, probably through p53 and caspase3 in MCF-7 cells. Future studies should delineate the molecular mechanisms underlying aza-BODIPY-PDT-induced cell death for a better understanding of the signaling pathways modulated by the therapy so that this novel technology could be implemented in the clinic for treating breast cancer. AIM In this study,we aimed to determine the change in the expression levels of 88 carcinoma-associated genes induced by aza-BODIPY-PDT were analyzed so as to understand the specific pathways that are modulated by aza-BODIPY-PDT. MATERIAL METHOD In this study,the molecular basis of the anti-cancer activity of aza-BODIPY-PDT was investigated.Induction of apoptosis and necrosis in MCF-7 breast cancer cells after treatment with aza- BODIPY derivative with phthalonitrile substituents (aza-BODIPY) followed by light exposure was evaluated by Annexin V 7- Aminoactinomycin D (7-AAD) flow cytometry. RESULTS Aza-BODIPY-PDT induced cell death in MCF-7 cells treated with aza-BODIPY-PDT; flow cytometry revealed that 28 % of the cells died by apoptosis. Seven of the 88 carcinoma-associated genes that were assayed were differentially expressed -EGF, LEF1, WNT1, TCF7, and TGFBR2 were downregulated, and CASP3 and TP53 were upregulated - in cells subjected to aza-BODIPY-PDT.This made us think that the aza-BODIPY-PDT induced caspase 3 and p53-mediated apoptosis in MCF7 cells. CONCLUSION In our study,it was determined that the application of aza-BODIPY-PDT to MCF7 cells had a negative effect on cell connectivity and cell cycle.The fact that the same effect was not observed in control cells and MCF7 cells in the dark field of aza-BODIPY indicates that aza-BODIPY has a strong phodynamic anticancer effect.
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Affiliation(s)
- Tugba Elgun
- Department of Medical Biology, Faculty of Medicine, Biruni University, Istanbul, Turkey
| | - Asiye Gok Yurttas
- Department of Biochemistry, Faculty of Pharmacy, Istanbul Health and Technology University, Istanbul, Turkey.
| | - Kamil Cinar
- Department of Physics, Faculty of Basic Sciences, Gebze Technical University, Istanbul, Turkey
| | - Sennur Ozcelik
- Department of Chemistry, Istanbul Technical University, Istanbul, Turkey
| | - Ahmet Gul
- Department of Chemistry, Istanbul Technical University, Istanbul, Turkey
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13
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Liu Y, Lei P, Samuel RZ, Kashyap AM, Groth T, Bshara W, Neelamegham S, Andreadis ST. Cadherin-11 increases tumor cell proliferation and metastatic potential via Wnt pathway activation. Mol Oncol 2023; 17:2056-2073. [PMID: 37558205 PMCID: PMC10552893 DOI: 10.1002/1878-0261.13507] [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: 09/16/2022] [Revised: 06/23/2023] [Accepted: 07/08/2023] [Indexed: 08/11/2023] Open
Abstract
During epithelial-mesenchymal transition (EMT) in cancer progression, tumor cells switch cadherin profile from E-cadherin to cadherin-11 (CDH11), which is accompanied by increased invasiveness and metastatic activity. However, the mechanism through which CDH11 may affect tumor growth and metastasis remains elusive. Here, we report that CDH11 was highly expressed in multiple human tumors and was localized on the membrane, in the cytoplasm and, surprisingly, also in the nucleus. Interestingly, β-catenin remained bound to carboxy-terminal fragments (CTFs) of CDH11, the products of CDH11 cleavage, and co-localized with CTFs in the nucleus in the majority of breast cancer samples. Binding of β-catenin to CTFs preserved β-catenin activity, whereas inhibiting CDH11 cleavage led to β-catenin phosphorylation and diminished Wnt signaling, similar to CDH11 knockout. Our data elucidate a previously unknown role of CDH11, which serves to stabilize β-catenin in the cytoplasm and facilitates its translocation to the nucleus, resulting in activation of Wnt signaling, with subsequent increased proliferation, migration and invasion potential.
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Affiliation(s)
- Yayu Liu
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Pedro Lei
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Ronel Z. Samuel
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Anagha M. Kashyap
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Theodore Groth
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Wiam Bshara
- Roswell Park Comprehensive Cancer Center Pathology Resource NetworkBuffaloNYUSA
| | - Sriram Neelamegham
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- Department of Biomedical Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- New York State Center of Excellence in Bioinformatics and Life SciencesBuffaloNYUSA
- Center for Cell, Gene and Tissue Engineering (CGTE), University at BuffaloThe State University of New YorkAmherstNYUSA
| | - Stelios T. Andreadis
- Department of Chemical and Biological Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- Department of Biomedical Engineering, University at BuffaloThe State University of New YorkAmherstNYUSA
- New York State Center of Excellence in Bioinformatics and Life SciencesBuffaloNYUSA
- Center for Cell, Gene and Tissue Engineering (CGTE), University at BuffaloThe State University of New YorkAmherstNYUSA
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14
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Anand AA, Khan M, V M, Kar D. The Molecular Basis of Wnt/ β-Catenin Signaling Pathways in Neurodegenerative Diseases. Int J Cell Biol 2023; 2023:9296092. [PMID: 37780577 PMCID: PMC10539095 DOI: 10.1155/2023/9296092] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 10/03/2023] Open
Abstract
Defective Wnt signaling is found to be associated with various neurodegenerative diseases. In the canonical pathway, the Frizzled receptor (Fzd) and the lipoprotein receptor-related proteins 5/6 (LRP5/LRP6) create a seven-pass transmembrane receptor complex to which the Wnt ligands bind. This interaction causes the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and GSK-3β (glycogen synthase kinase-3 beta) to be recruited by the scaffold protein Dishevelled (Dvl), which in turn deactivates the β-catenin destruction complex. This inactivation stops the destruction complex from phosphorylating β-catenin. As a result, β-catenin first builds up in the cytoplasm and then migrates into the nucleus, where it binds to the Lef/Tcf transcription factor to activate the transcription of more than 50 Wnt target genes, including those involved in cell growth, survival, differentiation, neurogenesis, and inflammation. The treatments that are currently available for neurodegenerative illnesses are most commonly not curative in nature but are only symptomatic. According to all available research, restoring Wnt/β-catenin signaling in the brains of patients with neurodegenerative disorders, particularly Alzheimer's and Parkinson's disease, would improve the condition of several patients with neurological disorders. The importance of Wnt activators and modulators in patients with such illnesses is to mainly restore rather than overstimulate the Wnt/β-catenin signaling, thereby reestablishing the equilibrium between Wnt-OFF and Wnt-ON states. In this review, we have tried to summarize the significance of the Wnt canonical pathway in the pathophysiology of certain neurodegenerative diseases, such as Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis, and other similar diseases, and as to how can it be restored in these patients.
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Affiliation(s)
- Ananya Anurag Anand
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad 211012, India
| | - Misbah Khan
- Department of Biotechnology, Ramaiah University of Applied Sciences, Bengaluru 560054, India
| | - Monica V
- Department of Biotechnology, Ramaiah University of Applied Sciences, Bengaluru 560054, India
| | - Debasish Kar
- Department of Biotechnology, Ramaiah University of Applied Sciences, Bengaluru 560054, India
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15
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Dai Y, Zhang X, Ou Y, Zou L, Zhang D, Yang Q, Qin Y, Du X, Li W, Yuan Z, Xiao Z, Wen Q. Anoikis resistance--protagonists of breast cancer cells survive and metastasize after ECM detachment. Cell Commun Signal 2023; 21:190. [PMID: 37537585 PMCID: PMC10399053 DOI: 10.1186/s12964-023-01183-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/04/2023] [Indexed: 08/05/2023] Open
Abstract
Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.
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Affiliation(s)
- Yalan Dai
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Oncology, Garze Tibetan Autonomous Prefecture People's Hospital, Kangding, China
| | - Xinyi Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shenzhen, China
| | - Yingjun Ou
- Clinical Medicine School, Southwest Medicial Univercity, Luzhou, China
- Orthopaedics, Garze Tibetan Autonomous Prefecture People's Hospital, Kangding, China
| | - Linglin Zou
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Duoli Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qingfan Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Qin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiuju Du
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wei Li
- Southwest Medical University, Luzhou, China
| | | | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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16
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Wu D, Zhang Z, Sun W, Yan Y, Jing M, Ma S. The effect of G0S2 on insulin sensitivity: A proteomic analysis in a G0S2-overexpressed high-fat diet mouse model. Front Endocrinol (Lausanne) 2023; 14:1130350. [PMID: 37033250 PMCID: PMC10076770 DOI: 10.3389/fendo.2023.1130350] [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: 12/23/2022] [Accepted: 03/07/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND Previous research has shown a tight relationship between the G0/G1 switch gene 2 (G0S2) and metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and obesity and diabetes, and insulin resistance has been shown as the major risk factor for both NAFLD and T2DM. However, the mechanisms underlying the relationship between G0S2 and insulin resistance remain incompletely understood. Our study aimed to confirm the effect of G0S2 on insulin resistance, and determine whether the insulin resistance in mice fed a high-fat diet (HFD) results from G0S2 elevation. METHODS In this study, we extracted livers from mice that consumed HFD and received tail vein injections of AD-G0S2/Ad-LacZ, and performed a proteomics analysis. RESULTS Proteomic analysis revealed that there was a total of 125 differentially expressed proteins (DEPs) (56 increased and 69 decreased proteins) among the identified 3583 proteins. Functional enrichment analysis revealed that four insulin signaling pathway-associated proteins were significantly upregulated and five insulin signaling pathway -associated proteins were significantly downregulated. CONCLUSION These findings show that the DEPs, which were associated with insulin resistance, are generally consistent with enhanced insulin resistance in G0S2 overexpression mice. Collectively, this study demonstrates that G0S2 may be a potential target gene for the treatment of obesity, NAFLD, and diabetes.
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Affiliation(s)
- Dongming Wu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhenyuan Zhang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, China
| | - Wenxiu Sun
- Department of Nursing, Taishan Vocational College of Nursing, Taian, China
| | - Yong Yan
- Department of Transfusion Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Mengzhe Jing
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, China
| | - Shizhan Ma
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, China
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17
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Spina E, Simundza J, Incassati A, Chandramouli A, Kugler MC, Lin Z, Khodadadi-Jamayran A, Watson CJ, Cowin P. Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency. Nat Commun 2022; 13:1421. [PMID: 35302059 PMCID: PMC8931046 DOI: 10.1038/s41467-022-28937-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 02/16/2022] [Indexed: 12/15/2022] Open
Abstract
Gpr125 is an orphan G-protein coupled receptor, with homology to cell adhesion and axonal guidance factors, that is implicated in planar polarity and control of cell movements. By lineage tracing we demonstrate that Gpr125 is a highly specific marker of bipotent mammary stem cells in the embryo and of multiple long-lived unipotent basal mammary progenitors in perinatal and postnatal glands. Nipple-proximal Gpr125+ cells express a transcriptomic profile indicative of chemo-repulsion and cell movement, whereas Gpr125+ cells concentrated at invasive ductal tips display a hybrid epithelial-mesenchymal phenotype and are equipped to bind chemokine and growth factors and secrete a promigratory matrix. Gpr125 progenitors acquire bipotency in the context of transplantation and cancer and are greatly expanded and massed at the pushing margins of short latency MMTV-Wnt1 tumors. High Gpr125 expression identifies patients with particularly poor outcome within the basal breast cancer subtype highlighting its potential utility as a factor to stratify risk. Gpr125 has emerged as a specific marker of mammary stem cells and basal progenitors. Here they show that Gpr125 cells congregate at ductal tips during morphogenesis and amass at tumor margins, and that high Gpr125 predicts early tumor onset and poor outcome in basal breast cancer.
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Affiliation(s)
- Elena Spina
- Department of Cell Biology, New York University School of Medicine, New York, USA.
| | - Julia Simundza
- Department of Cell Biology, New York University School of Medicine, New York, USA
| | - Angela Incassati
- Department of Cell Biology, New York University School of Medicine, New York, USA
| | - Anupama Chandramouli
- Department of Cell Biology, New York University School of Medicine, New York, USA.,Department of Dermatology, New York University School of Medicine, New York, USA
| | - Matthias C Kugler
- Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, USA
| | - Ziyan Lin
- Department of Applied Bioinformatics, New York University School of Medicine, New York, USA
| | | | | | - Pamela Cowin
- Department of Cell Biology, New York University School of Medicine, New York, USA. .,Department of Dermatology, New York University School of Medicine, New York, USA.
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18
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Haręża DA, Wilczyński JR, Paradowska E. Human Papillomaviruses as Infectious Agents in Gynecological Cancers. Oncogenic Properties of Viral Proteins. Int J Mol Sci 2022; 23:1818. [PMID: 35163748 PMCID: PMC8836588 DOI: 10.3390/ijms23031818] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/29/2022] [Accepted: 02/03/2022] [Indexed: 01/25/2023] Open
Abstract
Human papillomaviruses (HPVs), which belong to the Papillomaviridae family, constitute a group of small nonenveloped double-stranded DNA viruses. HPV has a small genome that only encodes a few proteins, and it is also responsible for 5% of all human cancers, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. HPV types may be classified as high- and low-risk genotypes (HR-HPVs and LR-HPVs, respectively) according to their oncogenic potential. HR-HPV 16 and 18 are the most common types worldwide and are the primary types that are responsible for most HPV-related cancers. The activity of the viral E6 and E7 oncoproteins, which interfere with critical cell cycle points such as suppressive tumor protein p53 (p53) and retinoblastoma protein (pRB), is the major contributor to HPV-induced neoplastic initiation and progression of carcinogenesis. In addition, the E5 protein might also play a significant role in tumorigenesis. The role of HPV in the pathogenesis of gynecological cancers is still not fully understood, which indicates a wide spectrum of potential research areas. This review focuses on HPV biology, the distribution of HPVs in gynecological cancers, the properties of viral oncoproteins, and the molecular mechanisms of carcinogenesis.
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Affiliation(s)
- Daria A. Haręża
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 93-232 Lodz, Poland;
- BioMedChem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, 90-237 Lodz, Poland
| | - Jacek R. Wilczyński
- Department of Surgical and Oncological Gynecology, Medical University of Lodz, 90-419 Lodz, Poland;
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 93-232 Lodz, Poland;
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Tu JJ, Ou-Yang L, Zhu Y, Yan H, Qin H, Zhang XF. Differential network analysis by simultaneously considering changes in gene interactions and gene expression. Bioinformatics 2021; 37:4414-4423. [PMID: 34245246 DOI: 10.1093/bioinformatics/btab502] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 06/13/2021] [Accepted: 07/05/2021] [Indexed: 11/14/2022] Open
Abstract
MOTIVATION Differential network analysis is an important tool to investigate the rewiring of gene interactions under different conditions. Several computational methods have been developed to estimate differential networks from gene expression data, but most of them do not consider that gene network rewiring may be driven by the differential expression of individual genes. New differential network analysis methods that simultaneously take account of the changes in gene interactions and changes in expression levels are needed. RESULTS In this paper, we propose a differential network analysis method that considers the differential expression of individual genes when identifying differential edges. First, two hypothesis test statistics are used to quantify changes in partial correlations between gene pairs and changes in expression levels for individual genes. Then, an optimization framework is proposed to combine the two test statistics so that the resulting differential network has a hierarchical property, where a differential edge can be considered only if at least one of the two involved genes is differentially expressed. Simulation results indicate that our method outperforms current state-of-the-art methods. We apply our method to identify the differential networks between the luminal A and basal-like subtypes of breast cancer and those between acute myeloid leukemia and normal samples. Hub nodes in the differential networks estimated by our method, including both differentially and non-differentially expressed genes, have important biological functions. AVAILABILITY The source code is available at https://github.com/Zhangxf-ccnu/chNet. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Jia-Juan Tu
- School of Mathematics and Statistics & Hubei Key Laboratory of Mathematical Sciences, Central China Normal University, Wuhan, 430079, China
| | - Le Ou-Yang
- College of Electronics and Information Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Yuan Zhu
- School of Automation, China University of Geosciences, Wuhan, 430074, China.,Hubei Key Laboratory of Advanced Control and Intelligent Automation for Complex Systems, China University of Geosciences, Wuhan, 430074, China
| | - Hong Yan
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong, China
| | - Hong Qin
- Department of Statistics, Zhongnan University of Economics and Law, Wuhan, 430073, China
| | - Xiao-Fei Zhang
- School of Mathematics and Statistics & Hubei Key Laboratory of Mathematical Sciences, Central China Normal University, Wuhan, 430079, China
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20
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Abstract
Every year, over 2 million women are diagnosed with breast cancer. Although considerable progress was made within the last years in cancer prevention, diagnosis and treatment, breast cancer is still responsible for over 600,000 of deaths per year. Over the years, numerous mouse models have been developed to understand breast cancer etiology and progression. Among those, mammary carcinomas induced by carcinogen, such as 7,12-dimethylbenz[a]anthracene (DMBA), has been widely used. Generally, 30-70% of mice exposed to 4-6 weekly doses of 1mg of DMBA during the peripubertal period (4-10 weeks of age) will develop mammary tumors within 150-200 days after the first exposure, that sometime metastasize to the lungs. As a result, DMBA-induced tumorigenesis is thought to be an accurate and relevant model to study breast cancer as it closely mimics this multistep process. This chapter presents the typical protocol used in mice to induce mammary gland tumors using DMBA. The influence of the number of doses and the total burden of DMBA given, as well as of the age and strain of the mice on mammary gland incident and on tumor onset are discussed. The current knowledge regarding mechanisms involved in DMBA-induced tumorigenesis is also presented.
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Schupbach D, Comeau-Gauthier M, Harvey E, Merle G. Wnt modulation in bone healing. Bone 2020; 138:115491. [PMID: 32569871 DOI: 10.1016/j.bone.2020.115491] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 12/31/2022]
Abstract
Genetic studies have been instrumental in the field of orthopaedics for finding tools to improve the standard management of fractures and delayed unions. The Wnt signaling pathway that is crucial for development and maintenance of many organs also has a very promising pathway for enhancement of bone regeneration. The Wnt pathway has been shown to have a direct effect on stem cells during bone regeneration, making Wnt a potential target to stimulate bone repair after trauma. A more complete view of how Wnt influences animal bone regeneration has slowly come to light. This review article provides an overview of studies done investigating the modulation of the canonical Wnt pathway in animal bone regeneration models. This not only includes a summary of the recent work done elucidating the roles of Wnt and β-catenin in fracture healing, but also the results of thirty transgenic studies, and thirty-eight pharmacological studies. Finally, we discuss the discontinuation of sclerostin clinical trials, ongoing clinical trials with lithium, the results of Dkk antibody clinical trials, the shift into combination therapies and the future opportunities to enhance bone repair and regeneration through the modulation of the Wnt signaling pathway.
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Affiliation(s)
- Drew Schupbach
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada; Experimental Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A7-117, Montreal, Québec H3G 1A4, Canada.
| | - Marianne Comeau-Gauthier
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada; Experimental Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A7-117, Montreal, Québec H3G 1A4, Canada.
| | - Edward Harvey
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada.
| | - Geraldine Merle
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada; Department of Chemical Engineering, Polytechnique Montreal, 2500, chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
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Systematic analysis of breast atypical hyperplasia-associated hub genes and pathways based on text mining. Eur J Cancer Prev 2020; 28:507-514. [PMID: 30394935 PMCID: PMC6784767 DOI: 10.1097/cej.0000000000000494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The purpose of this study was to describe breast atypical hyperplasia (BAH)-related gene expression and to systematically analyze the functions, pathways, and networks of BAH-related hub genes. On the basis of natural language processing, gene data for BAH were extracted from the PubMed database using text mining. The enriched Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were obtained using DAVID (http://david.abcc.ncifcrf.gov/). A protein–protein interaction network was constructed using the STRING database. Hub genes were identified as genes that interact with at least 10 other genes within the BAH-related gene network. In total, 138 BAH-associated genes were identified as significant (P < 0.05), and 133 pathways were identified as significant (P < 0.05, false discovery rate < 0.05). A BAH-related protein network that included 81 interactions was constructed. Twenty genes were determined to interact with at least 10 others (P < 0.05, false discovery rate < 0.05) and were identified as the BAH-related hub genes of this protein–protein interaction network. These 20 genes are TP53, PIK3CA, JUN, MYC, EGFR, CCND1, AKT1, ERBB2, CTNN1B, ESR1, IGF-1, VEGFA, HRAS, CDKN1B, CDKN1A, PCNA, HGF, HIF1A, RB1, and STAT5A. This study may help to disclose the molecular mechanisms of BAH development and provide implications for BAH-targeted therapy or even breast cancer prevention. Nevertheless, connections between certain genes and BAH require further exploration.
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Piperine suppresses the Wnt/β-catenin pathway and has anti-cancer effects on colorectal cancer cells. Sci Rep 2020; 10:11681. [PMID: 32669593 PMCID: PMC7363889 DOI: 10.1038/s41598-020-68574-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 12/08/2019] [Indexed: 01/12/2023] Open
Abstract
More than 94% of colorectal cancer cases have mutations in one or more Wnt/β-catenin signaling pathway components. Inactivating mutations in APC or activating mutations in β-catenin (CTNNB1) lead to signaling overactivation and subsequent intestinal hyperplasia. Numerous classes of medicines derived from synthetic or natural small molecules, including alkaloids, have benefited the treatment of different diseases, including cancer, Piperine is a true alkaloid, derived from lysine, responsible for the spicy taste of black pepper (Piper nigrum) and long pepper (Piper longum). Studies have shown that piperine has a wide range of pharmacological properties; however, piperine molecular mechanisms of action are still not fully understood. By using Wnt/β-catenin pathway epistasis experiment we show that piperine inhibits the canonical Wnt pathway induced by overexpression of β-catenin, β-catenin S33A or dnTCF4 VP16, while also suppressing β-catenin nuclear localization in HCT116 cell line. Additionally, piperine impairs cell proliferation and migration in HCT116, SW480 and DLD-1 colorectal tumor cell lines, while not affecting the non-tumoral cell line IEC-6. In summary, piperine inhibits the canonical Wnt signaling pathway and displays anti-cancer effects on colorectal cancer cell lines.
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Identifying Dysregulated lncRNA-Associated ceRNA Network Biomarkers in CML Based on Dynamical Network Biomarkers. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5189549. [PMID: 32149112 PMCID: PMC7049421 DOI: 10.1155/2020/5189549] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/04/2020] [Indexed: 11/17/2022]
Abstract
The incidence of chronic myeloid leukemia (CML) is increasing year by year, which is a serious threat to human health. Early diagnosis can reduce mortality and improve prognosis. LncRNAs have been shown to be effective biomarkers for a variety of diseases and can act as competitive endogenous RNA (ceRNA). In this study, the dysregulated lncRNA-associated ceRNA networks (DLCN) of the chronic phase (CP), accelerated phase (AP), and blastic crisis (BC) for CML are constructed. Then, based on dynamic network biomarkers (DNB), some dysregulated lncRNA-associated ceRNA network biomarkers of CP, AP, and BC for CML are identified according to DNB criteria. Thus, a lncRNA (SNHG5) is identified from DLCN_CP, a lncRNA (DLEU2) is identified from DLCN_AP, and two lncRNAs (SNHG3, SNHG5) are identified from DLCN_BC. In addition, the critical index (CI) used to detect disease outbreaks shows that CML occurs in CP, which is consistent with clinical medicine. By analyzing the functions of the identified ceRNA network biomarkers, it has been found that they are effective lncRNA biomarkers directly or indirectly related to CML. The result of this study will help deepen the understanding of CML pathology from the perspective of ceRNA and help discover the effective biomarkers of CP, AP, and BC for CML in the future, so as to help patients get timely treatment and reduce the mortality of CML.
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Eugenol restricts Cancer Stem Cell population by degradation of β-catenin via N-terminal Ser37 phosphorylation-an in vivo and in vitro experimental evaluation. Chem Biol Interact 2020; 316:108938. [PMID: 31926151 DOI: 10.1016/j.cbi.2020.108938] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/11/2019] [Accepted: 01/06/2020] [Indexed: 11/24/2022]
Abstract
Eugenol a phenylpropanoid, predominantly found in clove is a very common spice in daily cuisine. It already reported to have anti-breast cancer activity. In this study, the effect of eugenol on CSC (Cancer Stem Cell) markers and its main regulator β-catenin both in vivo Ehrlich Ascites Carcinoma (EAC) cell line and in vitro MCF-7 cell line was investigated with that of the untreated group. The therapeutic doses were found to significantly induce apoptosis leaving normal mice and cells unaffected. The in-depth analysis revealed the downregulation of β-catenin thereby facilitating its degradation by N-terminal phosphorylation of Ser37 residue. Significant downregulation of various CSC markers was also observed in vivo after eugenol treatment those are regulated by the intracellular status of β-catenin. These findings were validated by the effect of eugenol on the formation of the secondary sphere in vitro. Notable downregulation of the enriched stemness of secondary mammosphere was detected by the significantly decreased percentage of CD44+/CD24-/low population after eugenol treatment along with their distorted morphology and smaller the number of spheres. The underlying mechanism revealed significant downregulation of β-catenin and the set of CSC markers along with their reduced mRNA expression in secondary sphere culture. Therefore, it can be concluded from the study that eugenol exerts its chemotherapeutic potential by impeding β-catenin nuclear translocation thereby promoting its cytoplasmic degradation as a result stemness is being suppressed potentially even if in the enriched state. Therefore the study contributes to reduce the cancer-induced complications associated with the CSC population. This will ultimately confer the longer and improved patient's life.
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Dong J, Li J, Li J, Cui L, Meng X, Qu Y, Wang H. The proliferative effect of cortisol on bovine endometrial epithelial cells. Reprod Biol Endocrinol 2019; 17:97. [PMID: 31757215 PMCID: PMC6873581 DOI: 10.1186/s12958-019-0544-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 11/13/2019] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Bovine endometrial epithelial cells (BEECs) undergo regular regeneration after calving. Elevated cortisol concentrations have been reported in postpartum cattle due to various stresses. However, the effects of the physiological level of cortisol on proliferation in BEECs have not been reported. The aim of this study was to investigate whether cortisol can influence the proliferation properties of BEECs and to clarify the possible underlying mechanism. METHODS BEECs were treated with different concentrations of cortisol (5, 15 and 30 ng/mL). The mRNA expression of various growth factors was detected by quantitative reverse transcription-polymerase chain reaction (qPCR), progression of the cell cycle in BEECs was measured using flow cytometric analysis, and the activation of the Wnt/β-catenin and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways was detected with Western blot and immunofluorescence. RESULTS Cortisol treatment resulted in upregulated mRNA levels of vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF); however, it had no influence on transforming growth factor-beta1 (TGF-β1). Cortisol (15 ng/mL) accelerated the cell cycle transition from the G0/G1 to the S phase. Cortisol upregulated the expression of β-catenin, c-Myc, and cyclinD1 and promoted the phosphorylation of PI3K and AKT. CONCLUSIONS These results demonstrated that cortisol may promote proliferation in BEECs by increasing the expression of some growth factors and activating the Wnt/β-catenin and PI3K/AKT signaling pathways.
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Affiliation(s)
- Junsheng Dong
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
| | - Jun Li
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
| | - Jianji Li
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
| | - Luying Cui
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
| | - Xia Meng
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
| | - Yang Qu
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
| | - Heng Wang
- grid.268415.cCollege of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu China
- Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu China
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Cho E, Kwon YJ, Ye DJ, Baek HS, Kwon TU, Choi HK, Chun YJ. G0/G1 Switch 2 Induces Cell Survival and Metastasis through Integrin-Mediated Signal Transduction in Human Invasive Breast Cancer Cells. Biomol Ther (Seoul) 2019; 27:591-602. [PMID: 31272137 PMCID: PMC6824625 DOI: 10.4062/biomolther.2019.063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/24/2019] [Accepted: 06/04/2019] [Indexed: 12/25/2022] Open
Abstract
Human breast cancer cell line, MDA-MB-231, is highly invasive and aggressive, compared to less invasive cell line, MCF-7. To explore the genes that might influence the malignancy of MDA-MB-231, DNA microarray analysis was performed. The results showed that G0/G1 switch 2 (G0S2) was one of the most highly expressed genes among the genes upregulated in MDA-MB-231. Although G0S2 acts as a direct inhibitor of adipose triglyceride lipase, action of G0S2 in cancer progression is not yet understood. To investigate whether G0S2 affects invasiveness of MDA-MB-231 cells, G0S2 expression was inhibited using siRNA, which led to decreased cell proliferation, migration, and invasion of MDA-MB-231 cells. Consequently, G0S2 inhibition inactivated integrinregulated FAK-Src signaling, which promoted Hippo signaling and inactivated ERK1/2 signaling. In addition, G0S2 downregulation decreased β-catenin expression, while E-cadherin expression was increased. It was demonstrated for the first time that G0S2 mediates the Hippo pathway and induces epithelial to mesenchymal transition (EMT). Taken together, our results suggest that G0S2 is a major factor contributing to cell survival and metastasis of MDA-MB-231 cells.
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Affiliation(s)
- Eunah Cho
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Yeo-Jung Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Dong-Jin Ye
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Hyoung-Seok Baek
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Tae-Uk Kwon
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Hyung-Kyoon Choi
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974,
Republic of Korea
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Jagannathan NR. Application of in vivo MR methods in the study of breast cancer metabolism. NMR IN BIOMEDICINE 2019; 32:e4032. [PMID: 30456917 DOI: 10.1002/nbm.4032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 08/25/2018] [Accepted: 09/26/2018] [Indexed: 06/09/2023]
Abstract
In the last two decades, various in vivo MR methodologies have been evaluated for their potential in the study of cancer metabolism. During malignant transformation, metabolic alterations occur, leading to morphological and functional changes. Among various MR methods, in vivo MRS has been extensively used in breast cancer to study the metabolism of cells, tissues or whole organs. It provides biochemical information at the metabolite level. Altered choline, phospholipid and energy metabolism has been documented using proton (1 H), phosphorus (31 P) and carbon (13 C) isotopes. Increased levels of choline-containing compounds, phosphomonoesters and phosphodiesters in breast cancer, which are indicative of altered choline and phospholipid metabolism, have been reported using in vivo, in vitro and ex vivo NMR studies. These changes are reversed on successful therapy, which depends on the treatment regimen given. Monitoring the various tumor intermediary metabolic pathways using nuclear spin hyperpolarization of 13 C-labeled substrates by dynamic nuclear polarization has also been recently reported. Furthermore, the utility of various methods such as diffusion, dynamic contrast and perfusion MRI have also been evaluated to study breast tumor metabolism. Parameters such as tumor volume, apparent diffusion coefficient, volume transfer coefficient and extracellular volume ratio are estimated. These parameters provide information on the changes in tumor microstructure, microenvironment, abnormal vasculature, permeability and grade of the tumor. Such changes seen during cancer progression are due to alterations in the tumor metabolism, leading to changes in cell architecture. Due to architectural changes, the tissue mechanical properties are altered; this can be studied using magnetic resonance elastography, which measures the elastic properties of tissues. Moreover, these structural MRI methods can be used to investigate the effect of therapy-induced changes in tumor characteristics. This review discusses the potential of various in vivo MR methodologies in the study of breast cancer metabolism.
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Nigjeh SE, Yeap SK, Nordin N, Rahman H, Rosli R. In Vivo Anti-Tumor Effects of Citral on 4T1 Breast Cancer Cells via Induction of Apoptosis and Downregulation of Aldehyde Dehydrogenase Activity. Molecules 2019; 24:molecules24183241. [PMID: 31492037 PMCID: PMC6767168 DOI: 10.3390/molecules24183241] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/14/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among females globally. The tumorigenic activities of cancer cells such as aldehyde dehydrogenase (ALDH) activity and differentiation have contributed to relapse and eventual mortality in breast cancer. Thus, current drug discovery research is focused on targeting breast cancer cells with ALDH activity and their capacity to form secondary tumors. Citral (3,7-dimethyl-2,6-octadienal), from lemon grass (Cymbopogoncitrates), has been previously reported to have a cytotoxic effect on breast cancer cells. Hence, this study was conducted to evaluate the in vivo effect of citral in targeting ALDH activity of breast cancer cells. BALB/c mice were challenged with 4T1 breast cancer cells followed by daily oral feeding of 50 mg/kg citral or distilled water for two weeks. The population of ALDH+ tumor cells and their capacity to form secondary tumors in both untreated and citral treated 4T1 challenged mice were assessed by Aldefluor assay and tumor growth upon cell reimplantation in normal mice, respectively. Citral treatment reduced the size and number of cells with ALDH+ activity of the tumors in 4T1-challenged BALB/c mice. Moreover, citral-treated mice were also observed with smaller tumor size and delayed tumorigenicity after reimplantation of the primary tumor cells into normal mice. These findings support the antitumor effect of citral in targeting ALDH+ cells and tumor recurrence in breast cancer cells.
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Affiliation(s)
- Siyamak Ebrahimi Nigjeh
- Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Daneshjou Boulevard, Tehran 1983969411, Iran
- Department of Medical Genetics, Tehran University of Medical Sciences, Poursina street, Tehran 1366736511, Iran
| | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Jalan Sunsuria, Bandar Sunsuria, Sepang 43900, Selangor, Malaysia
| | - Norshariza Nordin
- Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
| | - Heshu Rahman
- Department of Medical Laboratory Sciences and Technology, College of Health Sciences, Komar University of Science and Technology, Chaq Chaq Qularaese, Sarchinar District, Sulaimani 334, Iraq
- Department of Clinical and Internal Medicine, College of Veterinary Medicine, University of Sulaimani, Sulaimani 334, Iraq
| | - Rozita Rosli
- Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
- Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia.
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Song T, Yang J, Zhou J, Chen Z, Yuan X. A Review of the Mechanisms of Wnt7b in the Process of Malignant Tumor Invasion and Metastasis. INT J PHARMACOL 2019. [DOI: 10.3923/ijp.2019.523.532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Gupta SM, Mania-Pramanik J. Molecular mechanisms in progression of HPV-associated cervical carcinogenesis. J Biomed Sci 2019; 26:28. [PMID: 31014351 PMCID: PMC6477741 DOI: 10.1186/s12929-019-0520-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 04/11/2019] [Indexed: 12/13/2022] Open
Abstract
Cervical cancer is the fourth most frequent cancer in women worldwide and a major cause of mortality in developing countries. Persistent infection with high-risk human papillomavirus (HPV) is a necessary cause for the development of cervical cancer. In addition, genetic and epigenetic alterations in host cell genes are crucial for progression of cervical precancerous lesions to invasive cancer. Although much progress has been made in understanding the life cycle of HPV and it’s role in the development of cervical cancer, there is still a critical need for accurate surveillance strategies and targeted therapeutic options to eradicate these cancers in patients. Given the widespread nature of HPV infection and the type specificity of currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of viral oncoproteins be elucidated. A better understanding of the mechanisms involved in oncogenesis can provide novel insights and opportunities for designing effective therapeutic approaches against HPV-associated malignancies. In this review, we briefly summarize epigenetic alterations and events that cause alterations in host genomes inducing cell cycle deregulation, aberrant proliferation and genomic instability contributing to tumorigenesis.
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Affiliation(s)
- Sadhana M Gupta
- Department of Infectious Diseases Biology, National Institute for Research in Reproductive Health, J.M. Street, Parel, Mumbai, 400012, India.
| | - Jayanti Mania-Pramanik
- Department of Infectious Diseases Biology, National Institute for Research in Reproductive Health, J.M. Street, Parel, Mumbai, 400012, India
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Jiang J, Wang J, He X, Ma W, Sun L, Zhou Q, Li M, Yu S. High expression of
SPAG
5 sustains the malignant growth and invasion of breast cancer cells through the activation of Wnt/β‐catenin signalling. Clin Exp Pharmacol Physiol 2019; 46:597-606. [PMID: 30854682 DOI: 10.1111/1440-1681.13082] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 03/03/2019] [Accepted: 03/04/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Jue Jiang
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Juan Wang
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Xin He
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Wenqi Ma
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Lei Sun
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Qi Zhou
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Miao Li
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
| | - Shanshan Yu
- Department of Ultrasound The Second Affiliated Hospital Medical School of Xi'an Jiaotong University Xi'an China
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Rajabi P, Heydarpoor M, Maghsoudi A, Mohaghegh F, Dehghani Mobarakeh M. The Study for Diagnostic Value of β-Catenin Immunohistochemistry Marker in Distinction of Aggressive and Non-Aggressive Basal Cell Carcinoma. IRANIAN JOURNAL OF PATHOLOGY 2018; 14:52-60. [PMID: 31531101 PMCID: PMC6708562 DOI: 10.30699/ijp.14.1.52] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 12/24/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND & OBJECTIVE Basal cell carcinoma (BCC) is a common skin cancer arising from the basal layer of the epidermis and its appendages. They are locally invasive, aggressive, and destructive of skin and the surrounding struc- tures. β-Catenin is a multifunctional protein located to the intracellular side of the cytoplasmic membrane coded by the CTNNB1 gene, which maps to chromosome 3p22.1. It has a critical role in cell-to-cell adhesion by linking cadherins to the actin cytoskeleton and has a central role in transcriptional regulation in the Wnt signaling pathway. We evaluated the diagnostic value of the Beta catenin immunohistochemistry marker in distinction of aggressive and non-aggressive Basal cell carcinoma. METHODS This cross sectional and descriptive-analytical study was done on archived formalin fixed, paraffin embed- ded tissue blocks in pathology library of Al-Zahra hospital in Isfahan city. We used immunochemistry to determinate the role of β-Catenin in aggressiveness in BCC with higher rate of relapse. RESULTS A total of 76 samples were evaluated in two groups (aggressive &none aggressive). The mean percentage of cytoplasmic β-Catenin staining in aggressive group was more significant than the other group (sensitivity: 86.8% specificity: 81.6%, PPV: 81.5% and NPV: 86.1%) and the mean percentage of membranous β-Catenin staining in non- aggressive group were significant more than the aggressive group. Intensity of membranous staining in both groups significant less than normal epithelium. CONCLUSION Cytoplasmic β-Catenin staining in aggressive BCC is more significant than non-aggressive subtypes, so this indicates that the use of β-Catenin IHC marker maybe helpful in the diagnosis of aggressive BCC.
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Affiliation(s)
- Parvin Rajabi
- Dept. of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mitra Heydarpoor
- Dept. of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmadreza Maghsoudi
- Internal Medicine Dept., Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Mohaghegh
- Dept of Dermatology, Medicine School, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Dehghani Mobarakeh
- Resident of Pathology, Dept. of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Lu Y, Cao J, Napoli M, Xia Z, Zhao N, Creighton CJ, Li W, Chen X, Flores ER, McManus MT, Rosen JM. miR-205 Regulates Basal Cell Identity and Stem Cell Regenerative Potential During Mammary Reconstitution. Stem Cells 2018; 36:1875-1889. [PMID: 30267595 PMCID: PMC6379077 DOI: 10.1002/stem.2914] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 08/20/2018] [Accepted: 08/28/2018] [Indexed: 02/05/2023]
Abstract
Mammary gland development is fueled by stem cell self-renewal and differentiation. External cues from the microenvironment coupled with internal cues such as post-transcriptional regulation exerted by microRNAs regulate stem cell behavior and fate. Here, we have identified a miR-205 regulatory network required for mammary gland ductal development and stem cell regeneration following transplantation into the cleared mammary fat pad. In the postnatal mammary gland, miR-205 is predominantly expressed in the basal/stem cell enriched population. Conditional deletion of miR-205 in mammary epithelial cells impairs stem cell self-renewal and mammary regenerative potential in the in vitro mammosphere formation assay and in vivo mammary reconstitution. miR-205 null transplants display significant changes in basal cells, basement membrane, and stroma. NKD1 and PTPA, which inhibit the Wnt signaling pathway, and AMOT, which causes YAP cytoplasmic retention and inactivation were identified as miR-205 downstream mediators. These studies also confirmed that miR-205 is a direct ΔNp63 target gene that is critical for the regulation of basal cell identity. Stem Cells 2018;36:1875-15.
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Affiliation(s)
- Yang Lu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX
| | - Jin Cao
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Marco Napoli
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Zheng Xia
- Department of Molecular Microbiology & Immunology, Computational Biology Program, Oregon Health & Science University, Portland, Oregon
| | - Na Zhao
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Chad J Creighton
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Wei Li
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Xi Chen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Elsa R Flores
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Michael T McManus
- Department of Microbiology and Immunology, UCSF Diabetes Center and the WM Keck Center for Noncoding RNAs at UCSF, San Francisco, California
| | - Jeffrey M Rosen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
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35
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Dianati E, Wade MG, Hales BF, Robaire B, Plante I. From the Cover: Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants Decreased p-β-Cateninser675 Expression and Its Interaction With E-Cadherin in the Mammary Glands of Lactating Rats. Toxicol Sci 2018; 159:114-123. [PMID: 28903489 DOI: 10.1093/toxsci/kfx123] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Proper mammary gland development and function require precise hormonal regulation and bidirectional cross talk between cells provided by means of paracrine factors as well as intercellular junctions; exposure to environmental endocrine disruptors can disturb these processes. Exposure to one such family of chemicals, the brominated flame retardants (BFRs), is ubiquitous. Here, we tested the hypothesis that BFR exposures disrupt signaling pathways and intercellular junctions that control mammary gland development. Before mating, during pregnancy and throughout lactation, female Sprague-Dawley rats were fed diets containing that BFR mixture based on house dust, delivering nominal exposures of BFR of 0 (control), 0.06, 20, or 60 mg/kg/d. Dams were euthanized and mammary glands collected on postnatal day 21. BFR exposure had no significant effects on mammary gland/body weight ratios or the levels of proteins involved in milk synthesis, epithelial-mesenchymal transition, cell-cell interactions, or hormone signalling. However, BFR exposure (0.06 mg/kg/d) down-regulated phospho-ser675 β-catenin (p-β-catSer675) levels in the absence of any effect on total β-catenin levels. Levels of p-CREB were also down-regulated, suggesting that PKA inhibition plays a role. p-β-catSer675 co-localized with β-catenin at the mammary epithelial cell membrane, and its expression was decreased in animals from the 0.06 and 20 mg/kg/d BFR treatment groups. Although β-Catenin signaling was not affected by BFR exposure, the interaction between p-β-catSer675 and E-cadherin was significantly reduced. Together, our results demonstrate that exposure to an environmentally relevant mixture of BFR during pregnancy and lactation decreases p-β-catser675 at cell adhesion sites, likely in a PKA-dependant manner, altering mammary gland signaling.
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Affiliation(s)
- Elham Dianati
- INRS, Institut Armand-Frappier, Laval, Québec, Canada.,Centre de Recherche Biomed, Université du Québec à Montréal, Montréal, Québec, Canada
| | - Michael G Wade
- Health Canada, Environmental Health Science and Research Bureau, Ottawa, Ontario, Canada
| | | | - Bernard Robaire
- Department of Pharmacology and Therapeutics.,Department of Obstetrics and Gynecology, Faculty of Medicine, McGill University, Montreal, Québec, Canada
| | - Isabelle Plante
- INRS, Institut Armand-Frappier, Laval, Québec, Canada.,Centre de Recherche Biomed, Université du Québec à Montréal, Montréal, Québec, Canada
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36
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Affiliation(s)
- Isabella Albanese
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Kashif Khan
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Bianca Barratt
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Hamood Al-Kindi
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Adel Schwertani
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
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37
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Liu T, Yu T, Hu H, He K. Knockdown of the long non-coding RNA HOTTIP inhibits colorectal cancer cell proliferation and migration and induces apoptosis by targeting SGK1. Biomed Pharmacother 2017; 98:286-296. [PMID: 29274585 DOI: 10.1016/j.biopha.2017.12.064] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 12/03/2017] [Accepted: 12/14/2017] [Indexed: 12/13/2022] Open
Abstract
More and more long non-coding RNA (lncRNA) might be serve as molecular biomarkers for tumor cell progression. HOTTIP has been recently revealed as oncogenic regulator in several cancers. However, it remains unclear about whether and how HOTTIP regulates Colorectal cancer (CRC). In the present study, we assayed the expression of HOTTIP in CRC tissues and cell lines, and detected CRC cells (HCT-116 and SW620) proliferation, migration, and apoptosis when HOTTIP was knocked down. Furthermore, we discovered the underlying mechanism. The level of HOTTIP was higher in CRC tissues and in CRC cells compared with adjacent normal tissues and normal colon tissue cell. Knockdown of HOTTIP inhibited the cell proliferation migration and induced apoptosis in HCT-116 and SW620 cell lines. In addition, luciferase reporter assay suggested that knockdown of HOTTIP could target decreasing the expression of Serum- and glucocorticoid-inducible kinase 1 (SGK1) gene, and we subsequently verified that up-regulation of the SGK1 gene promoted cell proliferation and migration and inhibited cell apoptosis in HCT-116 and SW620 cell lines. Furthermore, Knockdown of HOTTIP significantly suppressed the expression of GSK3β, β-catenin, c-myc, Vimentin and MMP-7, and increased the expression of E-cadherin, FoxO3a, p27 and Bim proteins in HCT-116 and SW620 cell lines, and up-regulation of the SGK1 emerged the opposite effect with knockdown of HOTTIP. The data described in this study suggest that HOTTIP may be an oncogene and a potential target in CRC.
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Affiliation(s)
- Tianyou Liu
- Ultrasonography Department, Huai'an Second People's Hospital, The Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Tao Yu
- Medical Oncology, Xuzhou First People's Hospital, Xuzhou, Jiangsu, China
| | - Haiying Hu
- Department of General Surgery, Affiliated AoYang Hospital of Jiangsu University, Zhangjiagang, Suzhou, 215600 China
| | - Keping He
- Ultrasonography Department, Huai'an Huaiyin Hospital, Huaian, Jiangsu, 223300 China.
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38
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Siddique A, Yu B, Khan K, Buyting R, Al-Kindi H, Alaws H, Rhéaume E, Tardif JC, Cecere R, Schwertani A. Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves. Can J Physiol Pharmacol 2017; 96:208-214. [PMID: 29244962 DOI: 10.1139/cjpp-2017-0577] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co-receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis.
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Affiliation(s)
- Ateeque Siddique
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Bin Yu
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Kashif Khan
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Ryan Buyting
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Hamood Al-Kindi
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Hossny Alaws
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Eric Rhéaume
- b Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | | | - Renzo Cecere
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Adel Schwertani
- a Cardiology, Cardiac Surgery and Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
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39
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Arnold KM, Pohlig RT, Sims-Mourtada J. Co-activation of Hedgehog and Wnt signaling pathways is associated with poor outcomes in triple negative breast cancer. Oncol Lett 2017; 14:5285-5292. [PMID: 29142600 PMCID: PMC5666657 DOI: 10.3892/ol.2017.6874] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 08/03/2017] [Indexed: 12/21/2022] Open
Abstract
Hedgehog (HH) and Wnt pathway activation have been implicated in poor prognosis of breast cancer. Crosstalk between these two pathways has been demonstrated to be important in breast cancer progression, however the association between these two pathways and breast cancer survival rate is unknown. The present study comprised a cohort of 36 patients with triple negative breast cancer (TNBC) to investigate co-activation of HH and canonical Wnt pathway in association to patient outcome. All patients had varying degrees of cytoplasmic sonic HH and glioma-associated oncogene homolog (Gli)-1 staining, which positively correlated with tumor stage. Nuclear β-catenin was additionally correlated to tumor stage. A significant association was observed between nuclear Gli-1 and nuclear β-catenin. Co-activation of HH and Wnt pathways was associated with poorer prognosis in TNBC patients resulting in a greater risk of early recurrence and decreased overall survival rate compared with patients with only one pathway activated. Therefore, the combined activation status of the HH and Wnt pathways may be a useful prognostic marker for TNBC patients at risk for early recurrence.
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Affiliation(s)
- Kimberly M Arnold
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA.,Department of Medical Laboratory Sciences, University of Delaware, Newark, DE 19716, USA
| | - Ryan T Pohlig
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA
| | - Jennifer Sims-Mourtada
- Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, DE 19713, USA.,Department of Medical Laboratory Sciences, University of Delaware, Newark, DE 19716, USA.,Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
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40
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Anbalagan M, Sheng M, Fleischer B, Zhang Y, Gao Y, Hoang V, Matossian M, Burks HE, Burow ME, Collins-Burow BM, Hangauer D, Rowan BG. Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression. Mol Cancer Res 2017; 15:1491-1502. [PMID: 28751463 DOI: 10.1158/1541-7786.mcr-16-0297-t] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 02/22/2017] [Accepted: 07/19/2017] [Indexed: 12/20/2022]
Abstract
Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01-treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERα promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERα expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen.Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ERα expression in ERα- breast tumors, a novel treatment strategy to treat triple-negative breast cancer. Mol Cancer Res; 15(11); 1491-502. ©2017 AACR.
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Affiliation(s)
- Muralidharan Anbalagan
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Mei Sheng
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Brian Fleischer
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Yifang Zhang
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.,Department of Obstetrics and Gynecology, Affiliated Hospital of Taishan Medical University, Taishan, Shandong, China
| | - Yuanjun Gao
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.,Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Van Hoang
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Margarite Matossian
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Hope E Burks
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Matthew E Burow
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bridgette M Collins-Burow
- Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana
| | - David Hangauer
- Athenex Pharmaceuticals LLC, New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York
| | - Brian G Rowan
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.
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41
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Is there an association between enhanced choline and β-catenin pathway in breast cancer? A pilot study by MR Spectroscopy and ELISA. Sci Rep 2017; 7:2221. [PMID: 28533512 PMCID: PMC5440410 DOI: 10.1038/s41598-017-01459-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 03/30/2017] [Indexed: 12/19/2022] Open
Abstract
Total choline (tCho) was documented as a biomarker for breast cancer diagnosis by in vivo MRS. To understand the molecular mechanisms behind elevated tCho in breast cancer, an association of tCho with β-catenin and cyclin D1 was evaluated. Hundred fractions from 20 malignant, 10 benign and 20 non-involved breast tissues were isolated. Cytosolic and nuclear expressions of β-catenin and cyclin D1 were estimated using ELISA. Higher tCho was seen in malignant compared to benign tissues. Malignant tissues showed higher cytosolic and nuclear β-catenin expressions than benign and non-involved tissues. Within malignant tissues, β-catenin and cyclin D1 expressions were higher in the nucleus than cytosol. Cyclin D1 expression was higher in the cytosolic fractions of benign and non-involved than malignant tissues. Furthermore, in malignant tissues, tCho showed a positive correlation with the cytosolic and nuclear expression of β-catenin and cyclin D1 and also a correlation between nuclear expressions of both these proteins was seen. Higher cytosolic β-catenin expression was seen in progesterone receptor negative than positive patients. Results provide an evidence of correlation between non-invasive biomarker, tCho and the Wnt/β-catenin pathway. The findings explain the molecular mechanism of tCho elevation which may facilitate exploration of additional therapeutic targets for breast cancer.
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42
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Bahrami A, Hasanzadeh M, ShahidSales S, Yousefi Z, Kadkhodayan S, Farazestanian M, Joudi Mashhad M, Gharib M, Mahdi Hassanian S, Avan A. Clinical Significance and Prognosis Value of Wnt Signaling Pathway in Cervical Cancer. J Cell Biochem 2017; 118:3028-3033. [DOI: 10.1002/jcb.25992] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 03/14/2017] [Indexed: 12/23/2022]
Affiliation(s)
- Afsane Bahrami
- Department of Modern Sciences and Technologies, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Malihe Hasanzadeh
- Department of Gynecology Oncology, Woman Health Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | | | - Zohre Yousefi
- Department of Gynecology Oncology, Woman Health Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Sima Kadkhodayan
- Department of Gynecology Oncology, Woman Health Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Marjaneh Farazestanian
- Department of Gynecology Oncology, Woman Health Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | | | - Masoumeh Gharib
- Department of Pathology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Seyed Mahdi Hassanian
- Department of Medical Biochemistry, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
- Metabolic syndrome Research centerMashhad University of Medical SciencesMashhadIran
| | - Amir Avan
- Metabolic syndrome Research centerMashhad University of Medical SciencesMashhadIran
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43
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Cellular transformation of human mammary epithelial cells by SATB2. Stem Cell Res 2017; 19:139-147. [PMID: 28167342 DOI: 10.1016/j.scr.2017.01.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 01/04/2017] [Accepted: 01/30/2017] [Indexed: 12/19/2022] Open
Abstract
Breast tumors are heterogeneous and carry a small population of progenitor cells that can produce various subtypes of breast cancer. SATB2 (special AT-rich binding protein-2) is a newly identified transcription factor and epigenetic regulator. It is highly expressed in embryonic stem cells, but not in adult tissues, and regulates pluripotency-maintaining factors. However, the molecular mechanisms by which SATB2 induces transformation of human mammary epithelial cells (HMECs) leading to malignant phenotype are unknown. The main goal of this paper is to examine the molecular mechanisms by which SATB2 induces cellular transformation of HMECs into cells that are capable of self-renewal. SATB2-transformed HMECs gain the phenotype of breast progenitor cells by expressing markers of stem cells, pluripotency-maintaining factor, and epithelial to mesenchymal transition. SATB2 is highly expressed in human breast cancer cell lines, primary mammary tissues and cancer stem cells (CSCs), but not in HMECs and normal breast tissues. Chromatin Immunoprecipitation assays demonstrate that SATB2 can directly bind to promoters of Bcl-2, c-Myc, Nanog, Klf4, and XIAP, suggesting a role of SATB2 in regulation of pluripotency, cell survival and proliferation. Furthermore, inhibition of SATB2 by shRNA in breast cancer cell lines and CSCs attenuates cell proliferation and EMT phenotype. Our results suggest that SATB2 induces dedifferentiation/transformation of mature HMECs into progenitor-like cells.
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44
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Pakula H, Xiang D, Li Z. A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland. Cancers (Basel) 2017; 9:E14. [PMID: 28134791 PMCID: PMC5332937 DOI: 10.3390/cancers9020014] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 01/19/2017] [Accepted: 01/24/2017] [Indexed: 12/13/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR). Androgen deprivation therapy (ADT) is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC) after a period of ADT. A variety of mechanisms of progression from androgen-dependent PCa to CRPC under ADT have been postulated, but it remains largely unclear as to when and how castration resistance arises within prostate tumors. In addition, AR signaling may be modulated by extracellular factors among which are the cysteine-rich glycoproteins WNTs. The WNTs are capable of signaling through several pathways, the best-characterized being the canonical WNT/β-catenin/TCF-mediated canonical pathway. Recent studies from sequencing PCa genomes revealed that CRPC cells frequently harbor mutations in major components of the WNT/β-catenin pathway. Moreover, the finding of an interaction between β-catenin and AR suggests a possible mechanism of cross talk between WNT and androgen/AR signaling pathways. In this review, we discuss the current knowledge of both AR and WNT pathways in prostate development and tumorigenesis, and their interaction during development of CRPC. We also review the possible therapeutic application of drugs that target both AR and WNT/β-catenin pathways. Finally, we extend our review of AR and WNT signaling to the mammary gland system and breast cancer. We highlight that the role of AR signaling and its interaction with WNT signaling in these two hormone-related cancer types are highly context-dependent.
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Affiliation(s)
- Hubert Pakula
- Division of Genetics, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Room 466, Boston, MA 02115, USA.
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
| | - Dongxi Xiang
- Division of Genetics, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Room 466, Boston, MA 02115, USA.
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
| | - Zhe Li
- Division of Genetics, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Room 466, Boston, MA 02115, USA.
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
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45
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Jin Y, Cui D, Ren J, Wang K, Zeng T, Gao L. CACNA2D3 is downregulated in gliomas and functions as a tumor suppressor. Mol Carcinog 2016; 56:945-959. [PMID: 27583705 DOI: 10.1002/mc.22548] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 08/22/2016] [Accepted: 08/29/2016] [Indexed: 01/08/2023]
Abstract
CACNA2D3, an auxiliary member of the alpha-2/delta subunit three family of the voltage-dependent calcium channel complex, plays a critical role in tumor suppression. However, its role in glioma carcinogenesis remains largely unknown. Here, we investigated the putative tumor suppressive role of CACNA2D3 in gliomas. Downregulation of CACNA2D3 was frequently detected in glioma tissues and cells compared with their non-tumorigenic counterparts, and correlated with poor survival. To investigate the underlying mechanism of CACNA2D3 in the development and progression of glioma, we performed CACNA2D3 ectopic expression in glioma cells (U87 and U251) and knockdown of CACNA2D3 in LN229 cells and conducted in vitro and in vivo functional assays. Our findings showed that increased intracellular calcium (Ca2+ ) mediated by overexpression of CACNA2D3 induced mitochondrial-mediated apoptosis, upregulation of NLK (through the Wnt/Ca2+ pathway) and inhibition of the epithelial-to-mesenchymal transition. Ectopic expression of CACNA2D3 inhibited cell proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas CACNA2D3 depletion inhibited cell viability and invasion. Furthermore, we confirmed that CACNA2D3 increased NLK expression in vitro by immunostaining and found that downregulation of CACNA2D3 in glioma cells and high-grade glioma tissue was accompanied by increased methylation. A reporter assay showed increased luciferase activity in NLK knockdown glioma cells and transcriptional activity of β-cantenin/TCF was remarkably enhanced, which further confirmed that NLK antagonizes Wnt signaling-mediated anchorage-dependent and independent cell proliferation and invasion. This mechanism may contribute to a better understanding of glioma cancer pathogenesis and facilitate the development of new therapeutic strategies for the treatment of this disease. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Yi Jin
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Daming Cui
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jie Ren
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Ke Wang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Tao Zeng
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Liang Gao
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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Sun H, Luo G, Chen D, Xiang Z. A Comprehensive and System Review for the Pharmacological Mechanism of Action of Rhein, an Active Anthraquinone Ingredient. Front Pharmacol 2016; 7:247. [PMID: 27582705 PMCID: PMC4987408 DOI: 10.3389/fphar.2016.00247] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 07/27/2016] [Indexed: 11/30/2022] Open
Abstract
Rhein is a major medicinal ingredient isolated from several traditional Chinese medicines, including Rheum palmatum L., Aloe barbadensis Miller, Cassia angustifolia Vahl., and Polygonum multiflorum Thunb. Rhein has various pharmacological activities, such as anti-inflammatory, antitumor, antioxidant, antifibrosis, hepatoprotective, and nephroprotective activities. Although more than 100 articles in PubMed are involved in the pharmacological mechanism of action of rhein, only a few focus on the relationship of crosstalk among multiple pharmacological mechanisms. The mechanism of rhein involves multiple pathways which contain close interactions. From the overall perspective, the pathways which are related to the targets of rhein, are initiated by the membrane receptor. Then, MAPK and PI3K-AKT parallel signaling pathways are activated, and several downstream pathways are affected, thereby eventually regulating cell cycle and apoptosis. The therapeutic effect of rhein, as a multitarget molecule, is the synergistic and comprehensive result of the involvement of multiple pathways rather than the blocking or activation of a single signaling pathway. We review the pharmacological mechanisms of action of rhein by consulting literature published in the last 100 years in PubMed. We then summarize these pharmacological mechanisms from a comprehensive, interactive, and crosstalk perspective. In general, the molecular mechanism of action of drug must be understood from a systematic and holistic perspective, which can provide a theoretical basis for precise treatment and rational drug use.
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Affiliation(s)
- Hao Sun
- School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China
| | - Guangwen Luo
- School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China
| | - Dahui Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China
| | - Zheng Xiang
- School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China
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Proteomic Analysis of Stage-II Breast Cancer from Formalin-Fixed Paraffin-Embedded Tissues. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3071013. [PMID: 27110560 PMCID: PMC4823502 DOI: 10.1155/2016/3071013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 02/22/2016] [Accepted: 03/07/2016] [Indexed: 01/25/2023]
Abstract
Breast cancer is the most frequently occurring disease among women worldwide. The early stage of breast cancer identification is the key challenge in cancer control and prevention procedures. Although gene expression profiling helps to understand the molecular mechanism of diseases or disorder in the living system, gene expression pattern alone is not sufficient to predict the exact mechanisms. Current proteomics tools hold great application for analysis of cancerous conditions. Hence, the generation of differential protein expression profiles has been optimized for breast cancer and normal tissue samples in our organization. Normal and tumor tissues were collected from 20 people from a local hospital. Proteins from the diseased and normal tissues have been investigated by 2D gel electrophoresis and MALDI-TOF-MS. The peptide mass fingerprint data were fed into various public domains like Mascot, MS-Fit, and Pept-ident against Swiss-Prot protein database and the proteins of interest were identified. Some of the differentially expressed proteins identified were human annexin, glutathione S-transferase, vimentin, enolase-1, dihydrolipoamide dehydrogenase, glutamate dehydrogenase, Cyclin A1, hormone sensitive lipase, beta catenin, and so forth. Many types of proteins were identified as fundamental steps for developing molecular markers for diagnosis of human breast cancer as well as making a new proteomic database for future research.
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Weivoda MM, Ruan M, Hachfeld CM, Pederson L, Howe A, Davey RA, Zajac JD, Kobayashi Y, Williams BO, Westendorf JJ, Khosla S, Oursler MJ. Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. J Bone Miner Res 2016; 31:65-75. [PMID: 26189772 PMCID: PMC4758681 DOI: 10.1002/jbmr.2599] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Although there has been extensive characterization of the Wnt signaling pathway in the osteoblast lineage, the effects of Wnt proteins on the osteoclast lineage are less well studied. We found that osteoclast lineage cells express canonical Wnt receptors. Wnt3a reduced osteoclast formation when applied to early bone-marrow macrophage (BMM) osteoclast differentiation cultures, whereas late addition did not suppress osteoclast formation. Early Wnt3a treatment inactivated the crucial transcription factor NFATc1 in osteoclast progenitors. Wnt3a led to the accumulation of nuclear β-catenin, confirming activation of canonical Wnt signaling. Reducing low-density lipoprotein receptor-related proteins (Lrp) 5 and Lrp6 protein expression prevented Wnt3a-induced inactivation of NFATc1; however, deletion of β-catenin did not block Wnt3a inactivation of NFATc1, suggesting that this effect was mediated by a noncanonical pathway. Wnt3a rapidly activated the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and pharmacological stimulation of cAMP/PKA signaling suppressed osteoclast differentiation; Wnt3a-induced NFATc1 phosphorylation was blocked by inhibiting interactions between PKA and A-kinase anchoring proteins (AKAPs). These data indicate that Wnt3a directly suppresses osteoclast differentiation through both canonical (β-catenin) and noncanonical (cAMP/PKA) pathways in osteoclast precursors. In vivo reduction of Lrp5 and Lrp6 expressions in the early osteoclast lineage via Rank promoter Cre recombination reduced trabecular bone mass, whereas disruption of Lrp5/6 expression in late osteoclast precursors via cathepsin K (Ctsk) promoter Cre recombination did not alter the skeletal phenotype. Surprisingly, reduction of Lrp5/6 in the early osteoclast lineage decreased osteoclast numbers, as well as osteoblast numbers. Published studies have previously noted that β-catenin signaling is required for osteoclast progenitor proliferation. Our in vivo data suggest that Rank promoter Cre-mediated deletion of Lrp5/6 may similarly impair osteoclast progenitor proliferation.
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Affiliation(s)
- Megan M Weivoda
- Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Ming Ruan
- Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Christine M Hachfeld
- Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Larry Pederson
- Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Alan Howe
- Department of Pharmacology, University of Vermont College of Medicine, Burlington, VT, USA
| | - Rachel A Davey
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
| | - Jeffrey D Zajac
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
| | - Yasuhiro Kobayashi
- Institute for Oral Science, Matsumoto Dental University, Shiojiri, Nagano, Japan
| | - Bart O Williams
- Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA
| | | | - Sundeep Khosla
- Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Merry Jo Oursler
- Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
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The Wnt inhibitor dickkopf-1: a link between breast cancer and bone metastases. Clin Exp Metastasis 2015; 32:857-66. [DOI: 10.1007/s10585-015-9750-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 09/18/2015] [Indexed: 12/17/2022]
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50
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Abedi N, Mohammadi-Yeganeh S, Koochaki A, Karami F, Paryan M. miR-141 as potential suppressor of β-catenin in breast cancer. Tumour Biol 2015; 36:9895-901. [PMID: 26164002 DOI: 10.1007/s13277-015-3738-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Accepted: 06/29/2015] [Indexed: 12/14/2022] Open
Abstract
Triple negative breast cancer (TNBC) is well known for its heterogeneous features and lack of targeted therapy. A variety of cell signaling pathways have been linked to the initiation and progression of these tumors where canonical Wnt signaling is one of the main candidate pathways. Considering past literatures on this matter and negative reports regarding mutations in β-catenin gene (CTNNB1), we focus our attention to another level of gene expression control level, microRNAs (miRNAs). For proper miRNA target detection, we utilized bioinformatics as a relatively new and reliable tool for miRNA: mRNA prediction. MDA-MB-231 (invasive breast cancer) and MCF-10A (normal breast) cell lines were chosen as models. We used different bioinformatic tools such as TargetScan, miRanda, etc. For miRNA targeting CTNNB1-3´UTR confirmation, luciferase assay was carried out. miRNA expression was induced in cell lines through viral constructs expressing desired miRNA. Quantitative real-time PCR was performed for the measurement of expression levels of selected miRNA and target gene. miR-141 was selected via expanded search among various bioinformatic tools. miR-141 expression level was downregulated in MDA-MB-231 cell line, and CTNNB1 gene expression was upregulated. After transduction with viral construct, miR-141 expression was elevated in both cell lines, and gene expression was notably decreased. β-Catenin can be considered as one of the main players in these tumors' pathogenesis. Also, it is the potential target of miR-141, in which its downregulation was detected in cell lines, and can be considered as a promising new targeted approach toward TNBC.
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Affiliation(s)
- Nairi Abedi
- Department of New Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Samira Mohammadi-Yeganeh
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ameneh Koochaki
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Karami
- Department of New Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Mahdi Paryan
- Department of Research and Development, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran.
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