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Silveira FM, Schuch LF, Pereira-Prado V, Molina-Frechero N, Lopez-Verdin S, Gómez Palacio-Gastélum M, Arocena M, Niklander S, Sicco E, Bologna-Molina R. Hypoxia-inducible factor-1α at the invasive tumor front in oral squamous cell carcinoma. World J Exp Med 2025; 15:102175. [DOI: 10.5493/wjem.v15.i2.102175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/02/2025] [Accepted: 02/28/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition, leading to aggressive tumor progression.
AIM To characterize the expression of hypoxia-inducible factor 1-alpha (HIF-1α) at the invasive tumor front (ITF) in comparison to tumor islands (TI) in oral squamous cell carcinoma (OSCC) and to explore its relationship with E-cadherin and Vimentin expression.
METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa (NOM) were included in this study. The ITF was identified based on the region and immune expression of AE1/AE3. Immunohistochemistry was performed to assess the expression of HIF-1α, Vimentin, and E-cadherin. The immunostaining was analyzed using an immunoreactive score, and the results were illustrated using immunofluorescence.
RESULTS HIF-1α expression was significantly higher in the TI region compared to the ITF region (P = 0.0134). Additionally, a significant difference was observed between TI and NOM (P = 0.0115). In the ITF regions, HIF-1α expression showed a significant correlation with Vimentin expression, with higher levels of HIF-1α associated with increased Vimentin expression (P = 0.017).
CONCLUSION Based on the results of this study, HIF-1α appears to play a distinct role in OSCC tumor progression, underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC. Further research is needed to better understand their impact on OSCC prognosis.
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Affiliation(s)
- Felipe Martins Silveira
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Lauren Frenzel Schuch
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Vanesa Pereira-Prado
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Nelly Molina-Frechero
- Division of Biological and Health Sciences, Autonomous Metropolitan University, Coyoacan 04960, Mexico
| | - Sandra Lopez-Verdin
- Health Science Center, Research Institute of Dentistry, Universidad de Guadalajara, Guadalajara 44100, Jalisco, Mexico
| | | | - Miguel Arocena
- Departamento de Biología Odontológica, Facultad de Odontología, Universidad de la República, Montevideo 11600, Uruguay
| | - Sven Niklander
- Unit of Oral Pathology and Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar 2520000, Chile
| | - Estefania Sicco
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Ronell Bologna-Molina
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
- Department of Research, Universidad Juarez del Estado de Durango, Durango 34000, Mexico
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Lu Q, Liu J, Xiong Y, Jian J, Wang J, Chen Z, Wan S, Liu X, Wang L. Cyanidin-3-glucoside upregulated NDRG2 through the PI3K/AKT pathway to alleviate EMT and ECM in renal fibrosis. Sci Rep 2025; 15:10695. [PMID: 40155416 PMCID: PMC11953473 DOI: 10.1038/s41598-025-94918-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/18/2025] [Indexed: 04/01/2025] Open
Abstract
Renal fibrosis is a critical progression of chronic kidney disease, and epithelial-to-mesenchymal transition (EMT) and extracellular matrix(ECM) deposition are crucial pathologic change of renal fibrosis, which still lacks of effective treatment. In this study, it was found that cyanidin-3-O-glucoside (C3G) could inhibit EMT and ECM activated by unilateral ureteral obstruction (UUO) and transforming growth factor-β1 (TGF-β1) stimulation. Moreover, N-Myc downstream-regulated gene 2(NDRG2), which involved in the progression of renal fibrosis, was down-regulated in vivo and in vitro model. However, C3G pretreatment could reverse the reductive expression of NDRG2. Furthermore, we found that the combined treatment of C3G and si-NDRG2 could reverse the decreased EMT and ECM, which induced by C3G treatment only. And the activation of Phosphatidylinositol 3-kinase (PI3K)/ Protein Kinase B (AKT) pathway significantly enhanced EMT and ECM, which was decreased by C3G treatment only in TGF-β1 induced Human Kidney 2 (HK-2) cells. In conclusion, our results demonstrated that C3G alleviated EMT and ECM by elevating NDRG2 expression through the PI3K/AKT pathway, indicating that C3G could be a potential treatment against renal fibrosis.
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Affiliation(s)
- Qianxue Lu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jin Liu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Yufeng Xiong
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jun Jian
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jingsong Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Shanshan Wan
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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Gottumukkala SB, Palanisamy A. Non-small cell lung cancer map and analysis: exploring interconnected oncogenic signal integrators. Mamm Genome 2025:10.1007/s00335-025-10110-6. [PMID: 39939487 DOI: 10.1007/s00335-025-10110-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025]
Abstract
Non-Small Cell lung cancer (NSCLC) is known for its fast progression, metastatic potency, and a leading cause of mortality globally. At diagnosis, approximately 30-40% of NSCLC patients already present with metastasis. Epithelial to mesenchymal transition (EMT) is a developmental program implicated in cancer progression and metastasis. Transforming Growth Factor-β (TGFβ) and its signalling plays a prominent role in orchestrating the process of EMT and cancer metastasis. In present study, a comprehensive molecular interaction map of TGFβ induced EMT in NSCLC was developed through an extensive literature survey. The map encompasses 394 species interconnected through 554 reactions, representing the relationship and complex interplay between TGFβ induced SMAD dependent and independent signalling pathways (PI3K/Akt, Wnt, EGFR, JAK/STAT, p38 MAPK, NOTCH, Hypoxia). The map, built using Cell Designer and compliant with SBGN and SBML standards, was subsequently translated into a logical modelling framework using CaSQ and dynamically analysed with Cell Collective. These analyses illustrated the complex regulatory dynamics, capturing the known experimental outcomes of TGFβ induced EMT in NSCLC including the co-existence of hybrid EM phenotype during transition. Hybrid EM phenotype is known to contribute for the phenotypic plasticity during metastasis. Network-based analysis identified the crucial network level properties and hub regulators, while the transcriptome-based analysis cross validated the prognostic significance and clinical relevance of key regulators. Overall, the map developed and the subsequent analyses offer deeper understanding of the complex regulatory network governing the process of EMT in NSCLC.
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Affiliation(s)
- Sai Bhavani Gottumukkala
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana, India
| | - Anbumathi Palanisamy
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana, India.
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4
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Li Q, Zhang H, He Y, Zhang H, Han C. Inhibition of Colorectal Cancer Metastasis by Total Flavones of Abelmoschus manihot via LncRNA AL137782-mediated STAT3/EMT Pathway Regulation. Curr Pharm Des 2025; 31:219-232. [PMID: 39289944 DOI: 10.2174/0113816128298998240828060306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) ranks among the most lethal malignancies globally, particularly following metastasis which results in poor prognosis. In recent years, CRC incidence in China has persistently increased. Total flavonoids (TFA) from Abelmoschus manihot, a natural compound, are recognized for their anti-inflammatory, analgesic, and antioxidant properties. However, despite extensive research into the therapeutic potential of TFA, coverage of its role in cancer treatment is notably lacking. To address this research void, our study aims to unveil the role and potential mechanisms of TFA in treating CRC. METHODS We conducted a series of experiments to assess the impact of TFA on CRC cells. Two specific CRC cell lines, DLD-1 and HCT116, were employed in cell proliferation, colony formation, flow cytometry, and cell migration assays. Additionally, to test the in vivo effects of TFA, we developed a nude mouse xenograft tumor model to assess TFA's impact on tumor growth and liver metastasis. Furthermore, we meticulously analyzed the gene expression differences between CRC cells pretreated with TGF-β and those treated with TFA using RNA-seq technology. We also examined the molecular mechanisms of TFA and assessed the expression of proteins related to the STAT3/EMT signaling pathway through Western blotting and siRNA technology. RESULTS Our research findings reveal for the first time the effect of TFA on CRC cells. Result shows that TFA could suppress cell proliferation, migration, and induce apoptosis. In vivo results showed that TFA inhibited tumor growth and liver metastasis. Molecular mechanism studies have shown that TFA exerts these effects by upregulating the expression of non-coding RNA AL137782, inhibiting the EMT/STAT3 signaling pathway. These results suggest that TFA is a potential candidate for mitigating CRC metastasis. CONCLUSION However, further research is needed to comprehensively evaluate the efficacy and safety of TFA in animal models and clinical settings. These findings bring great hope for the development of innovative CRC treatment methods.
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Affiliation(s)
- Qian Li
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, PR China
- Department of Proctology, Xinyi Hospital of Traditional Chinese Medicine, Xinyi, Jiangsu 221400, PR China
| | - Hui Zhang
- Department of Ultrasound, Xu Zhou Hospital of Traditional Chinese Medicine, Zhongshan South Road 169, Yunlong District, Xu Zhou, Jiangsu 221000, PR China
| | - Yongshan He
- Department of Colorectal Surgery, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Kongjiang Road 1665, Yangpu District, Shanghai 200092, PR China
| | - Hao Zhang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Daxue Road 4655, Changqing District, Jinan, Shandong, PR China
| | - Conghui Han
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, 221000, PR China
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5
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Yang H, Zhang X, Xue B. New insights into the role of cellular senescence and chronic wounds. Front Endocrinol (Lausanne) 2024; 15:1400462. [PMID: 39558972 PMCID: PMC11570929 DOI: 10.3389/fendo.2024.1400462] [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: 03/13/2024] [Accepted: 10/16/2024] [Indexed: 11/20/2024] Open
Abstract
Chronic or non-healing wounds, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers (PUs) and wounds in the elderly etc., impose significant biological, social, and financial burdens on patients and their families. Despite ongoing efforts, effective treatments for these wounds remain elusive, costing the United States over US$25 billion annually. The wound healing process is notably slower in the elderly, partly due to cellular senescence, which plays a complex role in wound repair. High glucose levels, reactive oxygen species, and persistent inflammation are key factors that induce cellular senescence, contributing to chronic wound failure. This suggests that cellular senescence may not only drive age-related phenotypes and pathology but also be a key mediator of the decreased capacity for trauma repair. This review analyzes four aspects: characteristics of cellular senescence; cytotoxic stressors and related signaling pathways; the relationship between cellular senescence and typical chronic non-healing wounds; and current and future treatment strategies. In theory, anti-aging therapy may influence the process of chronic wound healing. However, the underlying molecular mechanism is not well understood. This review summarizes the relationship between cellular senescence and chronic wound healing to contribute to a better understanding of the mechanisms of chronic wound healing.
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Affiliation(s)
- Huiqing Yang
- Institute of Evolution and Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Xin Zhang
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Bo Xue
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
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6
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Chen RY, Ding LJ, Liu YJ, Shi JJ, Yu J, Li CY, Lu JF, Yang GJ, Chen J. Marine Staurosporine Analogues: Activity and Target Identification in Triple-Negative Breast Cancer. Mar Drugs 2024; 22:459. [PMID: 39452867 PMCID: PMC11509616 DOI: 10.3390/md22100459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/28/2024] [Accepted: 10/03/2024] [Indexed: 10/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and drug resistance and no targeted drug available at present. Compound 4, a staurosporine alkaloid derived from Streptomyces sp. NBU3142 in a marine sponge, exhibits potent anti-TNBC activity. This research investigated its impact on MDA-MB-231 cells and their drug-resistant variants. The findings highlighted that compound 4 inhibits breast cancer cell migration, induces apoptosis, arrests the cell cycle, and promotes cellular senescence in both regular and paclitaxel-resistant MDA-MB-231 cells. Additionally, this study identified mitogen-activated protein kinase kinase kinase 11 (MAP3K11) as a target of compound 4, implicating its role in breast tumorigenesis by affecting cell proliferation, migration, and cell cycle progression.
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Affiliation(s)
- Ru-Yi Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Li-Jian Ding
- School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China;
| | - Yan-Jun Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Jin-Jin Shi
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Jing Yu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Chang-Yun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Jian-Fei Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China; (R.-Y.C.); (Y.-J.L.); (J.-J.S.); (J.Y.); (C.-Y.L.); (J.-F.L.)
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7
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Cai W, Xiao C, Fan T, Deng Z, Wang D, Liu Y, Li C, He J. Targeting LSD1 in cancer: Molecular elucidation and recent advances. Cancer Lett 2024; 598:217093. [PMID: 38969160 DOI: 10.1016/j.canlet.2024.217093] [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: 05/09/2024] [Revised: 06/18/2024] [Accepted: 06/27/2024] [Indexed: 07/07/2024]
Abstract
Histones are the main components of chromatin, functioning as an instructive scaffold to maintain chromosome structure and regulate gene expression. The dysregulation of histone modification is associated with various pathological processes, especially cancer initiation and development, and histone methylation plays a critical role. However, the specific mechanisms and potential therapeutic targets of histone methylation in cancer are not elucidated. Lys-specific demethylase 1A (LSD1) was the first identified demethylase that specifically removes methyl groups from histone 3 at lysine 4 or lysine 9, acting as a repressor or activator of gene expression. Recent studies have shown that LSD1 promotes cancer progression in multiple epigenetic regulation or non-epigenetic manners. Notably, LSD1 dysfunction is correlated with repressive cancer immunity. Many LSD1 inhibitors have been developed and clinical trials are exploring their efficacy in monotherapy, or combined with other therapies. In this review, we summarize the oncogenic mechanisms of LSD1 and the current applications of LSD1 inhibitors. We highlight that LSD1 is a promising target for cancer treatment. This review will provide the latest theoretical references for further understanding the research progress of oncology and epigenetics, deepening the updated appreciation of epigenetics in cancer.
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Affiliation(s)
- Wenpeng Cai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Di Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yixiao Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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8
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Chowdhury D, Mistry A, Maity D, Bhatia R, Priyadarshi S, Wadan S, Chakraborty S, Haldar S. Pan-cancer analyses suggest kindlin-associated global mechanochemical alterations. Commun Biol 2024; 7:372. [PMID: 38548811 PMCID: PMC10978987 DOI: 10.1038/s42003-024-06044-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/11/2024] [Indexed: 04/01/2024] Open
Abstract
Kindlins serve as mechanosensitive adapters, transducing extracellular mechanical cues to intracellular biochemical signals and thus, their perturbations potentially lead to cancer progressions. Despite the kindlin involvement in tumor development, understanding their genetic and mechanochemical characteristics across different cancers remains elusive. Here, we thoroughly examined genetic alterations in kindlins across more than 10,000 patients with 33 cancer types. Our findings reveal cancer-specific alterations, particularly prevalent in advanced tumor stage and during metastatic onset. We observed a significant co-alteration between kindlins and mechanochemical proteome in various tumors through the activation of cancer-related pathways and adverse survival outcomes. Leveraging normal mode analysis, we predicted structural consequences of cancer-specific kindlin mutations, highlighting potential impacts on stability and downstream signaling pathways. Our study unraveled alterations in epithelial-mesenchymal transition markers associated with kindlin activity. This comprehensive analysis provides a resource for guiding future mechanistic investigations and therapeutic strategies targeting the roles of kindlins in cancer treatment.
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Affiliation(s)
- Debojyoti Chowdhury
- Department of Chemical and Biological Sciences, S.N. Bose National Centre for Basic Sciences, Kolkata, West Bengal, 700106, India.
| | - Ayush Mistry
- Department of Biology, Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, 131029, India
| | - Debashruti Maity
- Department of Chemical and Biological Sciences, S.N. Bose National Centre for Basic Sciences, Kolkata, West Bengal, 700106, India
| | - Riti Bhatia
- Department of Biology, Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, 131029, India
| | - Shreyansh Priyadarshi
- Department of Biology, Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, 131029, India
| | - Simran Wadan
- Department of Biology, Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, 131029, India
| | - Soham Chakraborty
- Department of Biology, Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, 131029, India
| | - Shubhasis Haldar
- Department of Chemical and Biological Sciences, S.N. Bose National Centre for Basic Sciences, Kolkata, West Bengal, 700106, India.
- Department of Biology, Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, 131029, India.
- Technical Research Centre, S.N. Bose National Centre for Basic Sciences, Kolkata, West Bengal, 700106, India.
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9
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Wang JD, Zhang JS, Li XX, Wang KJ, Li M, Mao YY, Wan XH. Knockout of TGF-β receptor II by CRISPR/Cas9 delays mesenchymal transition of Lens epithelium and posterior capsule opacification. Int J Biol Macromol 2024; 259:129290. [PMID: 38199534 DOI: 10.1016/j.ijbiomac.2024.129290] [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: 09/07/2022] [Revised: 12/16/2023] [Accepted: 01/04/2024] [Indexed: 01/12/2024]
Abstract
Posterior capsule opacification (PCO) is the most common postoperative complication of cataract surgery. Transforming growth factor-β (TGF-β) is related to epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) that is proven to induce PCO formation in clinical and experimental studies. In this study, CRISPR sequences targeting exon of TGF-βRII were knocked out with lentiviral transfection in LECs. Rabbits' PCO model was established and recombinant adeno-associated virus (AAV) for transferring the gRNA of TGF βRII were intravitreally injected. SgRNA inhibited TGF-βRII expression and human LECs proliferation. In TGF-βRII knockout group, LECs motility and migration were suppressed, N-cadherin and vimentin expressions were significantly decreased, whereas E-cadherin was increased. The animal model showed that TGF-βRII knockout in vivo was effective in suppressing PCO. The current study suggested that the CRISPR/Cas9 endonuclease system could suppress TGF-βRII secretion, which participates in the EMT procedure of LECs in vitro and PCO in vivo. These findings might provide a new gene-editing approach and insight into a novel therapeutic strategy for PCO.
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Affiliation(s)
- Jin Da Wang
- Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100730, China
| | - Jing Shang Zhang
- Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100730, China
| | - Xiao Xia Li
- Department of Ophthalmology, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China
| | - Kai Jie Wang
- Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100730, China
| | - Meng Li
- Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100730, China
| | - Ying Yan Mao
- Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China
| | - Xiu Hua Wan
- Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100730, China.
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10
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Xie X, Chauhan GB, Edupuganti R, Kogawa T, Park J, Tacam M, Tan AW, Mughees M, Vidhu F, Liu DD, Taliaferro JM, Pitner MK, Browning LS, Lee JH, Bertucci F, Shen Y, Wang J, Ueno NT, Krishnamurthy S, Hortobagyi GN, Tripathy D, Van Laere SJ, Bartholomeusz G, Dalby KN, Bartholomeusz C. Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer. CANCER RESEARCH COMMUNICATIONS 2023; 3:1078-1092. [PMID: 37377604 PMCID: PMC10281291 DOI: 10.1158/2767-9764.crc-22-0330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 03/21/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023]
Abstract
Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that MELK mRNA levels were higher in TNBC tumors [8.11 (3.79-10.95)] than in HR+HER2- tumors [6.54 (2.90-9.26)]; P < 0.001]. In univariate analysis, patients with breast cancer with high-MELK-expressing tumors had worse overall survival (P < 0.001) and distant metastasis-free survival (P < 0.01) than patients with low-MELK-expressing tumors. In a multicovariate Cox regression model, high MELK expression was associated with shorter overall survival after adjusting for other baseline risk factors. MELK knockdown using siRNA or MELK inhibition using the MELK inhibitor MELK-In-17 significantly reduced invasiveness, reversed epithelial-to-mesenchymal transition, and reduced CSC self-renewal and maintenance in TNBC cells. Nude mice injected with CRISPR MELK-knockout MDA-MB-231 cells exhibited suppression of lung metastasis and improved overall survival compared with mice injected with control cells (P < 0.05). Furthermore, MELK-In-17 suppressed 4T1 tumor growth in syngeneic BALB/c mice (P < 0.001). Our findings indicate that MELK supports metastasis by promoting epithelial-to-mesenchymal transition and the CSC phenotype in TNBC. Significance These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.
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Affiliation(s)
- Xuemei Xie
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Current Institution: Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA
| | - Gaurav B. Chauhan
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ramakrishna Edupuganti
- Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Takahiro Kogawa
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jihyun Park
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Moises Tacam
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alex W. Tan
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mohd Mughees
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fnu Vidhu
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Diane D. Liu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Juliana M. Taliaferro
- Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Mary Kathryn Pitner
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Luke S. Browning
- Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Ju-Hyeon Lee
- Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - François Bertucci
- Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France
| | - Yu Shen
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jian Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naoto T. Ueno
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Current Institution: Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA
| | - Savitri Krishnamurthy
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
- Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gabriel N. Hortobagyi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Debu Tripathy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Steven J. Van Laere
- Center for Oncological Research, Integrated Personalized and Precision Oncology Network, University of Antwerp, Antwerp, Wilrijk
- Department Oncology, KU Leuven, Leuven, Belgium
| | - Geoffrey Bartholomeusz
- Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kevin N. Dalby
- Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Chandra Bartholomeusz
- Section of Translational Breast Cancer Research, Houston, Texas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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11
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Ponomartsev N, Zilov D, Gushcha E, Travina A, Sergeev A, Enukashvily N. Overexpression of Pericentromeric HSAT2 DNA Increases Expression of EMT Markers in Human Epithelial Cancer Cell Lines. Int J Mol Sci 2023; 24:ijms24086918. [PMID: 37108080 PMCID: PMC10138405 DOI: 10.3390/ijms24086918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/02/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Pericentromeric tandemly repeated DNA of human satellites 1, 2, and 3 (HS1, HS2, and HS3) is actively transcribed in some cells. However, the functionality of the transcription remains obscure. Studies in this area have been hampered by the absence of a gapless genome assembly. The aim of our study was to map a transcript that we have previously described as HS2/HS3 on chromosomes using a newly published gapless genome assembly T2T-CHM13, and create a plasmid overexpressing the transcript to assess the influence of HS2/HS3 transcription on cancer cells. We report here that the sequence of the transcript is tandemly repeated on nine chromosomes (1, 2, 7, 9, 10, 16, 17, 22, and Y). A detailed analysis of its genomic localization and annotation in the T2T-CHM13 assembly revealed that the sequence belonged to HSAT2 (HS2) but not to the HS3 family of tandemly repeated DNA. The transcript was found on both strands of HSAT2 arrays. The overexpression of the HSAT2 transcript increased the transcription of the genes encoding the proteins involved in the epithelial-to-mesenchymal transition, EMT (SNAI1, ZEB1, and SNAI2), and the genes that mark cancer-associated fibroblasts (VIM, COL1A1, COL11A1, and ACTA2) in cancer cell lines A549 and HeLa. Co-transfection of the overexpression plasmid and antisense nucleotides eliminated the transcription of EMT genes observed after HSAT2 overexpression. Antisense oligonucleotides also decreased transcription of the EMT genes induced by tumor growth factor beta 1 (TGFβ1). Thus, our study suggests HSAT2 lncRNA transcribed from the pericentromeric tandemly repeated DNA is involved in EMT regulation in cancer cells.
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Affiliation(s)
- Nikita Ponomartsev
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | - Danil Zilov
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
- Applied Genomics Laboratory, SCAMT Institute, ITMO University, Saint Petersburg 191002, Russia
| | - Ekaterina Gushcha
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | - Alexandra Travina
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | - Alexander Sergeev
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
| | - Natella Enukashvily
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia
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12
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Kim TU, Lee SW, Baek SM, Yim JH, Lee YJ, Son JH, Park SJ, Park JK. Apocrine cystomatosis: From the aspect of epithelial-mesenchymal transition. VET MED-CZECH 2023; 68:33-37. [PMID: 38384992 PMCID: PMC10878258 DOI: 10.17221/77/2022-vetmed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/02/2022] [Indexed: 02/23/2024] Open
Abstract
Apocrine cystomatosis, also called epitrichial sweat gland cystomatosis, is a non-neoplastic condition characterised by multiple dilated cysts of sweat gland origin. Histopathologically, these cysts comprise two layers of cells: an inner layer of glandular epithelial cells and an outer layer of myoepithelial cells. A case of apocrine cystomatosis was admitted to a local hospital. The microscopic investigation revealed that some enlarged cysts showed the transition of glandular epithelial cells into a spindle, mesenchymal cell-like morphology. The epithelial-to-mesenchymal transition (EMT) has long been studied as a pathway for embryogenesis, organ development, and carcinogenesis. While various molecular factors, including cytokines and growth factors, are known to induce EMT, mechanical forces have also been proposed to initiate EMT. The present case describes a possible relationship between EMT occurring in a cystic condition and further pathological inspection.
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Affiliation(s)
- Tae-Un Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Seoung-Woo Lee
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Su-Min Baek
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Hyuk Yim
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Young-Jin Lee
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jun-Hyeok Son
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sang-Joon Park
- Laboratory of Veterinary Histology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jin-Kyu Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
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13
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Connecting multiple microenvironment proteomes uncovers the biology in head and neck cancer. Nat Commun 2022; 13:6725. [PMID: 36344512 PMCID: PMC9640649 DOI: 10.1038/s41467-022-34407-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022] Open
Abstract
The poor prognosis of head and neck cancer (HNC) is associated with metastasis within the lymph nodes (LNs). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN-negative or -positive tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision-making. Protein profiles are strictly associated with immune modulation across datasets, and this provides the basis for investigating immune markers associated with metastasis. The proteome of LN metastatic cells recapitulates the proteome of the primary tumor sites. Conversely, the LN microenvironment proteome highlights the candidate prognostic markers. By integrating prioritized peptide, protein, and transcript levels with machine learning models, we identify nodal metastasis signatures in blood and saliva. We present a proteomic characterization wiring multiple sites in HNC, thus providing a promising basis for understanding tumoral biology and identifying metastasis-associated signatures.
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14
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Regulation of Semaphorin3A in the process of cutaneous wound healing. Cell Death Differ 2022; 29:1941-1954. [PMID: 35347234 PMCID: PMC9525670 DOI: 10.1038/s41418-022-00981-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
Semaphorin 3A (Sema3A) has been recognized as a crucial regulator of morphogenesis and homeostasis over a wide range of organ systems. However, its function in cutaneous wound healing is poorly understood. In our study, we demonstrated that Sema3A adenovirus plasmids transfection limited keratinocyte proliferation and decreased migrative capacity as assessed by in vitro wound healing assay. Sema3A transduction inhibited TGF-β1-mediated keratinocyte migration and EMT process. Besides, we applied mice with K14-Cre-mediated deletion of Sema3A and found that Sema3A depletion postponed wound closure with decreased re-epithelialization and matrix growth. Contrary to the results obtained with full-length Sema3A plasmids transfection, increased keratinocyte migration with recombinant Sema3A proteins resulted in quicker closure of the wounding area after a scratch. Further, exogenously applied recombinant Sema3A worked with EGF to maintain the activation of EGFR by interacting with NRP1 and thereby regulated the internalization of the EGFR-NRP1 complex. Taken together, these results indicated a paradoxical role of autonomous and non-autonomous Sema3A expression during wound healing. Combined administration of recombinant EGF and Sema3A proteins could accelerate the process of wound repair, thus providing promising treatment prospects in the future.
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15
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Ahmad M, Sun Y, Jia X, Li J, Zhang L, Yang Z, Lin Y, Zhang X, Khan ZA, Qian J, Luo Y. Therapeutic values of chick early amniotic fluid (ceAF) that facilitates wound healing via potentiating a SASP-mediated transient senescence. Genes Dis 2022; 9:1345-1356. [PMID: 35873014 PMCID: PMC9293714 DOI: 10.1016/j.gendis.2021.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/24/2021] [Accepted: 03/12/2021] [Indexed: 12/17/2022] Open
Abstract
Inflammatory, proliferative and remodeling phases constitute a cutaneous wound healing program. Therapeutic applications and medication are available; however, they commonly are comprised of fortified preservatives that might prolong the healing process. Chick early amniotic fluids (ceAF) contain native therapeutic factors with balanced chemokines, cytokines and growth-related factors; their origins in principle dictate no existence of harmful agents that would otherwise hamper embryo development. Instead, they possess a spectrum of molecules driving expeditious mitotic divisions and possibly exerting other functions. Employing both in vitro and in vivo models, we examined ceAF's therapeutic potentials in wound healing and found intriguing involvement of transient senescence, known to be intimately intermingled with Senescence Associated Secretory Phenotypes (SASP) that function in addition to or in conjunction with ceAF to facilitate wound healing. In our cutaneous wound healing models, a low dose of ceAF exhibited the best efficacies; however, higher doses attenuated the wound healing presumably by inducing p16 expression over a threshold. Our studies thus link an INK4/ARF locus-mediated signaling cascade to cutaneous wound healing, suggesting therapeutic potentials of ceAF exerting functions likely by driving transient senescence, expediting cellular proliferation, migration, and describing a homeostatic and balanced dosage strategy in medical intervention.
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Affiliation(s)
- Mashaal Ahmad
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Yandi Sun
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Xueyao Jia
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Jingjia Li
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Lihong Zhang
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Ze Yang
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Yindan Lin
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Xueyun Zhang
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
| | - Zara Ahmad Khan
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Jin Qian
- Zhejiang HygeianCells BioMedical Co. Ltd., Hangzhou, Zhejiang 310000, PR China
| | - Yan Luo
- Department of Biochemistry and Cancer Institute of the Second Affiliated Hospital, Key Laboratory of Cancer Prevention and Intervention of China National MOE, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China
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16
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The Function of N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Negative Regulator in Tumor Cell Metastasis. Int J Mol Sci 2022; 23:ijms23169365. [PMID: 36012631 PMCID: PMC9408851 DOI: 10.3390/ijms23169365] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/18/2022] [Accepted: 08/18/2022] [Indexed: 11/23/2022] Open
Abstract
N-myc downstream-regulated gene 2 (NDRG2) is a tumor-suppressor gene that suppresses tumorigenesis and metastasis of tumors and increases sensitivity to anti-cancer drugs. In this review, we summarize information on the clinicopathological characteristics of tumor patients according to NDRG2 expression in various tumor tissues and provide information on the metastasis inhibition-related cell signaling modulation by NDRG2. Loss of NDRG2 expression is a prognostic factor that correlates with TNM grade and tumor metastasis and has an inverse relationship with patient survival in various tumor patients. NDRG2 inhibits cell signaling, such as AKT-, NF-κB-, STAT3-, and TGF-β-mediated signaling, to induce tumor metastasis, and induces activation of GSK-3β which has anti-tumor effects. Although NDRG2 operates as an adaptor protein to mediate the interaction between kinases and phosphatases, which is essential in regulating cell signaling related to tumor metastasis, the molecular mechanism of NDRG2 as an adapter protein does not seem to be fully elucidated. This review aims to assist the research design regarding NDRG2 function as an adaptor protein and suggests NDRG2 as a molecular target to inhibit tumor metastasis and improve the prognosis in tumor patients.
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17
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Chen XL, Xu YM, Lau ATY. Toxic metals in the regulation of epithelial-mesenchymal plasticity: demons or angels? Cancer Cell Int 2022; 22:237. [PMID: 35897065 PMCID: PMC9327425 DOI: 10.1186/s12935-022-02638-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 06/21/2022] [Indexed: 02/08/2023] Open
Abstract
Epithelial cells can trans-differentiate into motile mesenchymal cells through a dynamic process known as epithelial-mesenchymal transition (EMT). EMT is crucial in embryonic development and wound healing but also contributes to human diseases such as organ fibrosis and cancer progression. Heavy metals are environmental pollutants that can affect human health in various ways, including causing cancers. The cytotoxicity and carcinogenicity of heavy metals are complex, and studies have demonstrated that some of these metals can affect the progress of EMT. Here, we focus on reviewing the roles of six environmentally common toxic metals concerning EMT: arsenic (AS), cadmium (Cd), cobalt (Co), chromium (Cr), nickel (Ni), and copper (Cu). Noteworthily, the effects of these elements on EMT may vary according to the form, dose, and exposure time; the dual role of heavy metals (e.g., AS, Cd, and Cu) on EMT is also observed, in which, sometimes they can promote while sometimes inhibit the EMT process. Given the vast number of toxicologically relevant metals that exist in nature, we believe a comprehensive understanding of their effects on EMT is required to dictate in what circumstances these metals act more likely as demons or angels.
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Affiliation(s)
- Xu-Li Chen
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 People’s Republic of China
| | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 People’s Republic of China
| | - Andy T. Y. Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041 People’s Republic of China
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18
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Pouliquen DL, Boissard A, Henry C, Coqueret O, Guette C. Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies. Front Pharmacol 2022; 13:934534. [PMID: 35873564 PMCID: PMC9304619 DOI: 10.3389/fphar.2022.934534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/15/2022] [Indexed: 11/21/2022] Open
Abstract
Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.
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Affiliation(s)
- Daniel L. Pouliquen
- Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
- *Correspondence: Daniel L. Pouliquen,
| | - Alice Boissard
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Cécile Henry
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Olivier Coqueret
- Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Catherine Guette
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
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19
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GBA1-dependent membrane glucosylceramide reprogramming promotes liver cancer metastasis via activation of the Wnt/β-catenin signalling pathway. Cell Death Dis 2022; 13:508. [PMID: 35637196 PMCID: PMC9151913 DOI: 10.1038/s41419-022-04968-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 05/15/2022] [Accepted: 05/23/2022] [Indexed: 12/14/2022]
Abstract
The effect of glucosylceramide (GlcCer) reprogramming on liver cancer metastasis remains poorly understood. In this study, we demonstrated that the protein expression of GBA1, which catalyses the conversion of GlcCer to ceramide, was downregulated in liver cancer tissue. A clinical relevance analysis revealed that low expression of GBA1 was associated with the metastatic potential of liver cancer cells. Furthermore, loss- and gain-of-function studies confirmed that low expression of GBA1 promoted metastasis of liver cancer both in vitro and in vivo. Mechanistic studies indicated that low expression of GBA1 enhanced the metastatic ability of liver cancer by promoting the epithelial-mesenchymal transition (EMT), in which Wnt signalling pathway is involved. In the plasma membrane (PM), GBA1-dependent GlcCer reprogramming increased LRP6 location in the PM leading to an interaction between GlcCer and LRP6, subsequently promoting LRP6 phosphorylation at Ser1490, and finally activating the Wnt/β-catenin signalling pathway. To our knowledge, this is the first time to be found that GlcCer interacted with a protein. In addition, the results of mass spectrometry indicated that GlcCer d18:1/18:0 was the most notably increased studied species in the PM when GBA1 was downregulated, suggesting that GlcCer d18:1/18:0 may be the major functional lipid that promotes GBA1-dependent liver cancer metastasis. Thus, GBA1-mediated GlcCer reprogramming in the PM promotes metastasis of liver cancer via activation of the Wnt/β-catenin signalling pathway, upregulation of GBA1 may be a potential therapeutic strategy to combat liver cancer metastasis.
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20
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He J, Shan S, Li Q, Fang B, Xie Y. Mechanical Stretch Triggers Epithelial-Mesenchymal Transition in Keratinocytes Through Piezo1 Channel. Front Physiol 2022; 13:745572. [PMID: 35615675 PMCID: PMC9124769 DOI: 10.3389/fphys.2022.745572] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) process has emerged as a central regulator of embryonic development, tissue repair and tumor malignancy. In recent years, researchers have specifically focused on how mechanical signals drive the EMT program in epithelial cells. However, how epithelial cells specifically leverage mechanical force to control the EMT process remains unclear. Here, we show that the bona fide mechanically activated cation channel Piezo1 plays a critical role in the EMT. The Piezo1 is expressed in human primary epidermal keratinocytes (HEKs) and is responsible for the mechanical stretch-induced Ca2+ concentration. Inhibition of Piezo1 activation by the inhibitor GsMTx4 or by siRNA-mediated Piezo1 knockdown influenced the morphology and migration of HEKs. Moreover, Piezo1 activity also altered EMT-correlated markers expression in response to mechanical stretch. We propose that the mechanically activated cation channel Piezo1 is an important determinant of mechanical force-induced EMT in keratinocytes and might play similar roles in other epithelial cells.
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Affiliation(s)
| | | | | | - Bin Fang
- *Correspondence: Yun Xie, ; Bin Fang,
| | - Yun Xie
- *Correspondence: Yun Xie, ; Bin Fang,
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21
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Shen L, Gu P, Qiu C, Ding WT, Zhang L, Cao WY, Li ZY, Yan B, Sun X. Lysophosphatidylcholine acyltransferase 1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma via the Wnt/β-catenin signaling pathway. Ann Hepatol 2022; 27:100680. [PMID: 35108614 DOI: 10.1016/j.aohep.2022.100680] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Hepatocellular carcinoma (HCC) is one of the most malignant digestive tumors, and its insidious onset and rapid progression are the main reasons for the difficulty in effective treatment. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that regulates phospholipid metabolism of the cell membrane. However, the mechanism by which LPCAT1 regulates HCC metastasis remains unknown. This study aimed to explore its biological function and potential mechanisms concerning migration and invasion in HCC. MATERIALS AND METHODS LPCAT1 expression in HCC tissues and its association with clinical outcomes were investigated by western blotting and bioinformatic methods, respectively. The role of LPCAT1 in migration and invasion was assessed via Transwell assays. The expression pattern of epithelial-mesenchymal transition (EMT) markers was quantified by western blotting. The biological behaviors of LPCAT1 in vivo were evaluated using xenograft tumor models and caudal vein metastatic models. Signaling pathways related to LPCAT1 were predicted using gene set enrichment analysis (GSEA) and further confirmed by western blotting. RESULTS LPCAT1 expression was significantly upregulated in HCC tissues and indicated a poor prognosis of HCC patients. Several EMT-related markers were found to be regulated by LPCAT1. HCC cells overexpressing LPCAT1 exhibited remarkably high migration and invasion capacities, upregulated expression of mesenchymal markers and reduced E-cadherin expression. In vivo, LPCAT1 promoted HCC pulmonary metastasis. Furthermore, the Wnt/β-catenin signaling pathway was confirmed to be activated by LPCAT1. CONCLUSIONS LPCAT1 could serve as a promising biomarker of HCC and as a novel therapeutic target for the treatment of metastatic HCC.
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Affiliation(s)
- Ling Shen
- Clinical Medical School, Shanghai General Hospital of Nanjing Medical University, Shanghai, China; Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peng Gu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Qiu
- Institute of Gallstone Disease, Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen-Tao Ding
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Zhang
- Intervention Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wan-Yue Cao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zu-Yin Li
- Department of Hepatobiliary Surgery, Peking University Organ Transplantation Institute, Peking University People's Hospital, Beijing, China
| | - Bin Yan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xing Sun
- Clinical Medical School, Shanghai General Hospital of Nanjing Medical University, Shanghai, China; Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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22
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Ma X, Wang D, Feng X, Liu Y, Li J, Yang W. Huangqin Tang Interference With Colitis Associated Colorectal Cancer Through Regulation of Epithelial Mesenchymal Transition and Cell Cycle. Front Pharmacol 2022; 13:837217. [PMID: 35462890 PMCID: PMC9020878 DOI: 10.3389/fphar.2022.837217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/01/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Although the exact molecular mechanisms of colitis-associated colorectal cancer are not fully understood, the chronic inflammation was positively correlated with tumorigenesis. The traditional Chinese medicine botanical formulation Huangqin Tang has significant anti-inflammatory effects. We investigated whether HQT can ameliorate the progression of inflammation to cancer through its anti-inflammatory effects by using relevant predictions and experiments. Methods: We used the azoxymethane/dextran sodium sulfate method to induce the mice colitis-associated colorectal cancer model. After preventive administration of Huangqin Tang to the mice model, colonic tissues were taken for quantitative proteomic analysis of tandem mass tags, and the proteomic results were then experimentally validated using the molecular biology approach. Results: Proteomic screening revealed that the effect of the mechanism of Huangqin-Tang on the colitis-associated colorectal cancer mice model may be related to infinite replication which demonstrated abnormal G1/S checkpoint and epithelial mesenchymal transition acceleration. The levels of inflammatory factors such as interleukin-1α, interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly reduced in colitis-associated colorectal cancer mice treated with Huangqin Tang; the aberrant expression of G1/S checkpoint-associated sites of cell cycle protein-dependent kinase 4, D1-type cyclins, and dysregulation of related sites of the WNT pathway which are most related to the acceleration of the epithelial mesenchymal transition process including WNT3A, β-catenin, E-cadherin, and glycogen synthase kinase 3β has been improved. Conclusion: Reducing inflammation and thus inhibiting the progression of colitis-associated colorectal cancer by using Huangqin-Tang is effective, and the mechanism of action may be related to the inhibition of uncontrolled proliferation during tumorigenesis. In the follow-up, we will conduct a more in-depth study on the relevant mechanism of action.
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Affiliation(s)
- Xuran Ma
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dunfang Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xue Feng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yaqing Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jia Li
- School hospital, Tsinghua University, Beijing, China
| | - Weipeng Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Weipeng Yang,
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miR-4731-5p Enhances Apoptosis and Alleviates Epithelial-Mesenchymal Transition through Targeting RPLP0 in Non-Small-Cell Lung Cancer. JOURNAL OF ONCOLOGY 2022; 2022:3793318. [PMID: 35342398 PMCID: PMC8947863 DOI: 10.1155/2022/3793318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/20/2022] [Accepted: 01/22/2022] [Indexed: 02/07/2023]
Abstract
Background/Aim. MircoRNA-4731-5p (miR-4731-5p) is a new miRNA involved in different human cancers, but its function has not been clarified in non-small-cell lung cancer (NSCLC). The present study attended to resolve the role of miR-4731-5p in NSCLC. Materials and Methods. The expression level of miR-4731-5p or ribosomal protein large P0 (RPLP0) and NSCLC clinicopathologic characteristics were analyzed. The binding between miR-4731-5p and RPLP0 was confirmed by TargetScan prediction and luciferase reporter experiment. Also, the probable role of miR-4731-5p in NSCLC via RPLP0 was elaborated by the MTT, western blotting, immunofluorescence, transwell, flow cytometry, and TUNEL assays. Moreover, in vivo verification was conducted in xenografted nude mice. Results. The level of miR-4731-5p was notably declined in vivo and in vitro, which was involved in the prognosis of lung cancer patients. The miR-4731-5p mimic could remarkably restrain cell viability, invasion, and the translational expression level of vimentin and e-cadherin, with promoted cell apoptosis in NSCLC, which were notably reversed by RPLP0 overexpression. Conclusion. miR-4731-5p/RPLP0 axis might be an underlying therapeutic target for NSCLC.
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Abstract
The inflammation is an important biological response induced by various harmful stimuli, like viruses, bacterial infections, toxins, toxic compounds, tissue injury. During inflammation inflammatory cytokines and reactive oxygen species are produced. Inflammatory cytokines act on various receptors present on the plasma membrane of target cells. To initiate signaling cascade, and activate transcription factors, receptors should be internalized and enter the early endosomes, where the members of the signaling cascade can meet. The further cytoplasmic fate of the receptor plays crucial role in the progression and the course of inflammation. Usually acute inflammation removes injurious stimuli and helps to regain the normal healthy status of the organism. In contrast to this the uncontrolled chronic inflammation—stimulating other than immune cells, inducing transdifferentiation—can provide base of various serious diseases. This paper draws the attention of the long-lasting consequence of chronic inflammation, pointing out that one of the most important step in medication is to identify in time the factors initiating and maintaining inflammation.
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Affiliation(s)
- Anna L Kiss
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
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25
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Ahram M, Abdullah MS, Mustafa SA, Alsafadi DB, Battah AH. Androgen down-regulates desmocollin 2 in association with induction of mesenchymal transition of breast MDA-MB-453 cancer cells. Cytoskeleton (Hoboken) 2022; 78:391-399. [PMID: 35023302 DOI: 10.1002/cm.21691] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 01/06/2022] [Accepted: 01/08/2022] [Indexed: 11/06/2022]
Abstract
Desmosomes are cellular structures that are critical in cell-cell adhesion and in maintaining tissue architecture. Changes in the expression of desmocollin-2 (DSC2) have been noted during tumor progression into an invasive phenotype and as cells undergo epithelial-mesenchymal transition. We have previously reported that breast MDA-MB-453 cancer cells, a luminal androgen receptor model of triple-negative breast cancer, acquire mesenchymal features when treated with the androgen receptor (AR) agonist, dihydrotestosterone (DHT). We have therefore investigated androgen regulation of the expression and cellular localization of DSC2 in MDA-MB-453 cells. Treatment of the cells with DHT resulted in a dose-dependent reduction in DSC2 protein levels and dispersion of its membrane localization concomitant with AR- and β-catenin-mediated mesenchymal transition of cells. A significant correlation was revealed between decreased expression of AR and increased expression of DSC2 in patient samples. In addition, whereas lower expression of AR was associated with a reduced overall and recurrence-free survival of breast cancer patients, higher expression of DSC2 was found in invasive breast tumors than in normal breast cells and was correlated with lower patient survival. Upon knocking down DSC2, the cells became elongated, mesenchymal-like, and slightly, but insignificantly, more migratory. The addition of DHT further stimulated cell elongation and migration. DSC2 siRNA-transfected cells reverted to a normal epithelial morphology upon inhibition of β-catenin. These results highlight the role of DSC2 in maintaining the epithelial morphology of MDA-MB-453 cells and the negative regulation of the desmosomal protein by DHT during stimulation of the androgen-induced, β-catenin-mediated mesenchymal transition of the cells. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Mamoun Ahram
- Department of Physiology and Biochemistry, School of Medicine, The University of Jordan, Amman, Jordan
| | - Mohammad S Abdullah
- Department of Physiology and Biochemistry, School of Medicine, The University of Jordan, Amman, Jordan
| | - Shahed A Mustafa
- Department of Microbiology, Pathology, and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
| | - Dana B Alsafadi
- Department of Physiology and Biochemistry, School of Medicine, The University of Jordan, Amman, Jordan
| | - Abdelkader H Battah
- Department of Microbiology, Pathology, and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
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OUP accepted manuscript. Glycobiology 2022; 32:556-579. [DOI: 10.1093/glycob/cwac014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/22/2022] [Accepted: 03/09/2022] [Indexed: 11/12/2022] Open
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27
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Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, Qian X. Emerging mechanisms progress of colorectal cancer liver metastasis. Front Endocrinol (Lausanne) 2022; 13:1081585. [PMID: 36568117 PMCID: PMC9772455 DOI: 10.3389/fendo.2022.1081585] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastasis. The hepatic portal venous system, responsible for collecting most intestinal blood, makes the liver the most common site of CRC metastasis. The formation of liver metastases from colorectal cancer is a long and complex process. It involves the maintenance of primary tumors, vasculature invasion, distant colonization, and metastasis formation. In this review, we serve on how the CRC cells acquire stemness, invade the vascular, and colonize the liver. In addition, we highlight how the resident cells of the liver and immune cells interact with CRC cells. We also discuss the current immunotherapy approaches and challenges we face, and finally, we look forward to finding new therapeutic targets based on novel sequencing technologies.
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28
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Sun W, Byon CH, Kim DH, Choi HI, Park JS, Joo SY, Kim IJ, Jung I, Bae EH, Ma SK, Kim SW. Renoprotective Effects of Maslinic Acid on Experimental Renal Fibrosis in Unilateral Ureteral Obstruction Model via Targeting MyD88. Front Pharmacol 2021; 12:708575. [PMID: 34588982 PMCID: PMC8475766 DOI: 10.3389/fphar.2021.708575] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022] Open
Abstract
Maslinic acid (MA), also named crategolic acid, is a pentacyclic triterpene extracted from fruits and vegetables. Although various beneficial pharmacological effects of MA have been revealed, its effect on renal fibrosis remains unclear. This study was designed to clarify whether MA could attenuate renal fibrosis and determine the putative underlying molecular mechanisms. We demonstrated that MA-treated mice with unilateral ureteral obstruction (UUO) developed a histological injury of low severity and exhibited downregulated expression of fibrotic markers, including α-smooth muscle actin (α-SMA), vimentin, and fibronectin by 38, 44 and 40%, and upregulated expression of E-cadherin by 70% as compared with untreated UUO mice. Moreover, MA treatment restored the expression levels of α-SMA, connective tissue growth factor, and vimentin to 10, 7.8 and 38% of those induced by transforming growth factor (TGF)-β in NRK49F cells. MA decreased expression of Smad2/3 phosphorylation and Smad4 in UUO kidneys and TGF-β treated NRK49F cells (p < 0.05, respectively). Notably, MA specifically interferes with MyD88, an adaptor protein, thereby mitigating Smad4 nuclear expression (p < 0.01 compared to TGF-β treated group) and ameliorating renal fibrotic changes (p < 0.01 for each fibrotic markers compared to TGF-β induced cells). In addition, in the UUO model and lipopolysaccharide-induced NRK49F cells, MA treatment decreased the expression of IL-1β, TGF-α and MCP-1, ICAM-1, associated with the suppression of NF-κB signaling. These findings suggest that MA is a potential agent that can reduce renal interstitial fibrosis, to some extent, via targeting TGF-β/Smad and MyD88 signaling.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, South Korea
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Kumar V, Panda A, Dash KC, Bhuyan L, Mahapatra N, Mishra P. Immunohistochemical Expression of the Epithelial to Mesenchymal Transition Proteins E-cadherin and ß-catenin in Grades of Oral Squamous Cell Carcinoma. J Pharm Bioallied Sci 2021; 13:S555-S560. [PMID: 34447152 PMCID: PMC8375807 DOI: 10.4103/jpbs.jpbs_562_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/10/2020] [Accepted: 11/18/2020] [Indexed: 12/09/2022] Open
Abstract
Background E-Cadherin/β-Catenin protein complexes play a major role in epithelial to mesenchymal transition (EMT) and vice versa. Such types of EMT are implicated physiologically during embryonic development and pathologically in tissue fibrosis and tumorigenesis. Aims The aim was the evaluation of E-Cadherin and β-Catenin immunoreactivity in various grades of oral squamous cell carcinoma (OSCC) and to correlate their pattern of expression. Materials and Methods Immunohistochemical expression of E-Cadherin/β-Catenin was evaluated in a total n = 30 tissue samples comprising of n = 10 well-differentiated squamous cell carcinoma (WDSCC), n = 10 moderately differentiated squamous cell carcinoma (MDSCC), and n = 10 poorly differentiated squamous cell carcinoma (PDSCC). Based on the intensity of staining, an immunoreactivity scoring was calculated. Statistical Analysis The scorings obtained were subjected to independent t-test, paired t-test, Chi-square test, and ANOVA test using SPSS version 20.0 statistical analysis software. P < 0.05 was considered statistically significant. Results A significant difference was observed in the expression of β-Catenin between normal mucosa and WDSCC; normal mucosa and MDSCC. A gradual decrease in the immunoreactivity score of E-Cadherin is seen in WDSCC, MDSCC, and PDSCC. Conclusion Therefore, dysregulation of these proteins can lead to tumor progression, invasion, and metastasis. Further studies are warranted to specify the role of these EMT proteins as prognostic/therapeutic markers in patients suffering from OSCC.
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Affiliation(s)
- Vijay Kumar
- Department of Oral and Maxillofacial Pathology and Microbiology, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, India
| | - Abikshyeet Panda
- Department of Oral and Maxillofacial Pathology and Microbiology, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, India
| | - Kailash Chandra Dash
- Department of Oral and Maxillofacial Pathology and Microbiology, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, India
| | - Lipsa Bhuyan
- Department of Oral and Maxillofacial Pathology and Microbiology, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, India
| | - Niva Mahapatra
- Department of Oral and Maxillofacial Pathology and Microbiology, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, India
| | - Pallavi Mishra
- Department of Oral and Maxillofacial Pathology and Microbiology, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, India
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Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression. Breast Cancer Res Treat 2021; 189:333-345. [PMID: 34241740 PMCID: PMC8357760 DOI: 10.1007/s10549-021-06316-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 06/24/2021] [Indexed: 11/05/2022]
Abstract
Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. Methods We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. Results We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. Conclusions Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15’s dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-021-06316-2.
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Font-Noguera M, Montemurro M, Benassayag C, Monier B, Suzanne M. Getting started for migration: A focus on EMT cellular dynamics and mechanics in developmental models. Cells Dev 2021; 168:203717. [PMID: 34245942 DOI: 10.1016/j.cdev.2021.203717] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/11/2021] [Accepted: 06/28/2021] [Indexed: 12/27/2022]
Abstract
The conversion of epithelial cells into mesenchymal ones, through a process known as epithelial-mesenchymal transition (or EMT) is a reversible process involved in critical steps of animal development as early as gastrulation and throughout organogenesis. In pathological conditions such as aggressive cancers, EMT is often associated with increased drug resistance, motility and invasiveness. The characterisation of the upstream signals and main decision takers, such as the EMT-transcription factors, has led to the identification of a core molecular machinery controlling the specification towards EMT. However, the cellular execution steps of this fundamental shift are poorly described, especially in cancerous cells. Here we review our current knowledge regarding the stepwise nature of EMT in model organisms as diverse as sea urchin, Drosophila, zebrafish, mouse or chicken. We focus on the cellular dynamics and mechanics of the transitional stages by which epithelial cells progressively become mesenchymal and leave the epithelium. We gather the currently available pieces of the puzzle, including the overlooked property of EMT cells to produce mechanical forces along their apico-basal axis before detaching from their neighbours. We discuss the interplay between EMT and the surrounding tissue. Finally, we propose a conceptual framework of EMT cell dynamics from the very first hint of epithelial cell reorganisation to the successful exit from the epithelial sheet.
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Affiliation(s)
- Meritxell Font-Noguera
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
| | - Marianne Montemurro
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
| | - Corinne Benassayag
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
| | - Bruno Monier
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
| | - Magali Suzanne
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France.
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COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6648078. [PMID: 33824874 PMCID: PMC8007342 DOI: 10.1155/2021/6648078] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/04/2021] [Accepted: 03/06/2021] [Indexed: 12/12/2022]
Abstract
Purpose This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). Methods HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan–Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. Results COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio (OR) = 1.616, >20 vs. ≤20, p < 0.05), stage (OR = 1.744, III vs. I, p < 0.05), and grade (OR = 1.746, G4+G3 vs. G2+G1, p < 0.05). Kaplan–Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression (p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio (HR) = 1.068, p < 0.0001) and multivariate Cox (HR = 2.011, p < 0.05) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. Conclusion COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.
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Ben Brahim C, Courageux C, Jolly A, Ouine B, Cartier A, de la Grange P, de Koning L, Leroy P. Proliferation Genes Repressed by TGF-β Are Downstream of Slug/Snail2 in Normal Bronchial Epithelial Progenitors and Are Deregulated in COPD. Stem Cell Rev Rep 2021; 17:703-718. [PMID: 33495975 DOI: 10.1007/s12015-021-10123-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2021] [Indexed: 12/16/2022]
Abstract
Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-β in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-β, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-β are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-β,we show that there is positive correlations between the effect of differentiation and TGF-β on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and β-Catenin, two molecules from TGF-βsignaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-β-induced mechanisms.
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Affiliation(s)
- Chamseddine Ben Brahim
- INSERM UMR1152, Physiopathology and Epidemiology of Respiratory Diseases, Paris, France
- Faculty of Medicine, Paris Diderot University, Bichat Campus, Paris, France
| | - Charlotte Courageux
- INSERM UMR1152, Physiopathology and Epidemiology of Respiratory Diseases, Paris, France
- Faculty of Medicine, Paris Diderot University, Bichat Campus, Paris, France
| | | | - Bérengère Ouine
- Institut Curie, Department of Translational Research, RPPA platform, PSL Research University, Paris, France
| | - Aurélie Cartier
- Institut Curie, Department of Translational Research, RPPA platform, PSL Research University, Paris, France
| | | | - Leanne de Koning
- Institut Curie, Department of Translational Research, RPPA platform, PSL Research University, Paris, France
| | - Pascale Leroy
- INSERM UMR1152, Physiopathology and Epidemiology of Respiratory Diseases, Paris, France.
- Faculty of Medicine, Paris Diderot University, Bichat Campus, Paris, France.
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Xu X, Liu M, Yang Y, Wei C, Zhang X, Song H, Wang Y, Duan X. VSP‑17 suppresses the migration and invasion of triple‑negative breast cancer cells through inhibition of the EMT process via the PPARγ/AMPK signaling pathway. Oncol Rep 2020; 45:975-986. [PMID: 33650675 PMCID: PMC7859999 DOI: 10.3892/or.2020.7916] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/03/2020] [Indexed: 01/10/2023] Open
Abstract
VSP-17, a novel peroxisome proliferator-activated receptor γ (PPARγ) agonist, has been previously demonstrated to suppress the metastasis of triple-negative breast cancer (TNBC) by upregulating the expression levels of E-cadherin, which is a key marker of epithelial-mesenchymal transition (EMT). However, the mechanism of action of VSP-17, in particular whether it may be associated with the EMT process, remains unknown. The present study investigated the ability of VSP-17 to inhibit the invasiveness and migratory ability of TNBC cell lines (MDA-MB-231 and MDA-MB-453) performed in in vitro experiments. including cell migration assay, cell invasion assay, cell transfection, RT-qPCR, western blot (WB) analysis and immunofluorescence. The present study aimed to ascertain whether and how the PPARγ/AMP-activated protein kinase (AMPK) signaling pathway serves a role in the inhibitory effects of VSP-17 on cell migration and invasion. The results revealed that both treatment with compound C (an AMPK inhibitor) and transfection with small interfering RNA (si)AMPK notably diminished the inhibitory effect of VSP-17 treatment on the migration and invasion of MDA-MB-231 and MDA-MB-453 cells, indicating that VSP-17 may, at least partly, exert its effects via AMPK. Furthermore, both compound C and siAMPK markedly diminished the VSP-17-induced downregulation of vimentin expression levels and upregulation of E-cadherin expression levels, further indicating that the VSP-17-induced inhibition of the EMT process may be dependent on AMPK. The combination of GW9662 (a PPARγ antagonist) or siPPARγ diminished the inhibitory effect of VSP-17 treatment on the migration and invasion of the TNBC cells, indicating that PPARγ may serve an important role in the VSP-17-induced inhibition of the migration and invasion of TNBC cells. In addition, both GW9662 and siPPARγ significantly reversed the VSP-17-induced downregulation of vimentin expression levels and upregulation of E-cadherin expression levels, implying that the VSP-17-induced inhibition of the EMT process may be dependent on PPARγ. VSP-17 treatment also upregulated the expression levels of p-AMPK, which could be reversed by either GW9662 or siPPARγ, indicating that the VSP-17-induced activation of the AMPK signaling pathway was PPARγ-dependent. In conclusion, the findings of the present study indicated that VSP-17 treatment may inhibit the migration and invasion of TNBC cells by suppressing the EMT process via the PPARγ/AMPK signaling pathway.
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Affiliation(s)
- Xiaotian Xu
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Meng Liu
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yingying Yang
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Chengqiong Wei
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Xiyang Zhang
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Hengzhi Song
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yuhui Wang
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Xiaoqun Duan
- Guangxi Colleges and Universities Key Laboratory of Pharmacology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
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Pantazi P, Carollo E, Carter DRF, Brooks SA. A practical toolkit to study aspects of the metastatic cascade in vitro. Acta Histochem 2020; 122:151654. [PMID: 33157489 DOI: 10.1016/j.acthis.2020.151654] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/23/2020] [Accepted: 10/28/2020] [Indexed: 12/30/2022]
Abstract
While metastasis - the spread of cancer from the primary location to distant sites in the body - remains the principle cause of cancer death, it is incompletely understood. It is a complex process, requiring the metastatically successful cancer cell to negotiate a formidable series of interconnected steps, which are described in this paper. For each step, we review the range of in vitro assays that may be used to study them. We also provide a range of detailed, step-by-step protocols that can be undertaken in most modestly-equipped laboratories, including methods for converting qualitative observations into quantitative data for analysis. Assays include: (1) a gelatin degradation assay to study the ability of endothelial cells to degrade extracellular matrix during tumour angiogenesis; (2) the morphological characterisation of cells undergoing epithelial-mesenchymal transition (EMT) as they acquire motility; (3) a 'scratch' or 'wound-healing' assay to study cancer cell migration; (4) a transwell assay to study cancer cell invasion through extracellular matrix; and (5) a static adhesion assay to examine cancer cell interactions with, and adhesion to, endothelial monolayers. This toolkit of protocols will enable researchers who are interested in metastasis to begin to focus on defined aspects of the process. It is only by further understanding this complex, fascinating and clinically relevant series of events that we may ultimately devise ways of better treating, or even preventing, cancer metastasis. The assays may also be of more broad interest to researchers interested in studying aspects of cellular behaviour in relation to other developmental and disease processes.
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Cellular and molecular events of inflammation induced transdifferentiation (EMT) and regeneration (MET) in mesenteric mesothelial cells. Inflamm Res 2020; 69:1173-1179. [PMID: 32920669 PMCID: PMC7486969 DOI: 10.1007/s00011-020-01400-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
In this review we summarize the cellular and molecular events of inflammation induced epithelial-to-mesenchymal (EMT) and mesothelial-to-macrophage transition (MET) during regeneration. Since the receptor transmits the environmental stimulus, downregulating or upregulating the process on an epigenetic level, the intracellular localization of receptors (signaling organelles: early endosomes or lysosomal degradation: late endosomes) plays a crucial role in the signaling events regulating inflammation and regeneration. Therefore, we focused on the internalization of the receptors as well as the intracellular compartmentalization of signaling molecules during EMT and MET. The review draws the reader's attention to the plasticity of mesothelial cells and supports the idea that during inflammation an ambient macrophage population might derive from mesothelial cells.
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Shi L, Liu BY, Wang X, Zhu MJ, Chen L, Zhou MY, Gu YJ, Cheng L, Wang Y. RUNX3-dependent oxidative epithelial-to-mesenchymal transition in methamphetamine-induced chronic lung injury. Cell Stress Chaperones 2020; 25:793-802. [PMID: 32681471 PMCID: PMC7479662 DOI: 10.1007/s12192-020-01133-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/22/2020] [Accepted: 06/25/2020] [Indexed: 12/18/2022] Open
Abstract
Lung toxicity is the main cause of the death from methamphetamine (MA) abuse, but its mechanism has remained unclear. The purpose of our study was to investigate if MA can induce epithelial-to-mesenchymal transition (EMT) and if RUNX3 is involved in oxidative EMT in MA-induced chronic lung injury. The rats were divided into the control group and MA group. Extracted lungs were used for morphological measurements and Western blot. The alveolar epithelial cells were cultured or transfected and then treated with MA or/and N-acetyl cysteine (NAC) followed by flow cytometry, Western blot, and immunohistochemistry. Chronic exposure to MA resulted in the lower growth ratio of weight, increased right ventricular index, thickened alveolar walls, and reduced number of alveolar sacs. Long-term administration with MA caused oxidative stress and pulmonary EMT. NAC increased RUNX3 and alleviated EMT. However, after knockdown of RUNX3, reactive oxygen species (ROS) levels were significantly upregulated, indicating that RUNX3 was closely related to oxidative stress. Knockdown of RUNX3 aggravated MA-induced EMT by activating RUNX3-dependent TGF-β signaling. Therefore, RUNX3 may be the key to oxidative EMT in methamphetamine-induced chronic lung injury.
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Affiliation(s)
- Lin Shi
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Bing-Yang Liu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, People's Republic of China
| | - Xin Wang
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Mei-Jia Zhu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Lei Chen
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Ming-Yuan Zhou
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Ying-Jian Gu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Lin Cheng
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China
| | - Yun Wang
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China.
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Wang W, Kansakar U, Markovic V, Sossey-Alaoui K. Role of Kindlin-2 in cancer progression and metastasis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:901. [PMID: 32793745 DOI: 10.21037/atm.2020.03.64] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cancer metastasis is a complex and multistep process whereby cancer cells escape the confines of the primary site to establish a new residency at distant sites. This multistep process is also known as the invasion-metastasis cascade. The biological and molecular mechanisms that control the invasion-metastasis cascade, which ultimately leads to the spread of cancer cells into distant sites, remain poorly understood. Kindlin-2 (K2) belongs to the 4.1-ezrin-ridixin-moesin (FERM) domain family of proteins, which interact with the cytoplasmic tails of β-integrin subunits, leading to the activation of extensive biological functions. These biological functions include cell migration, differentiation, cancer initiation, development, and invasion. In this review, we will discuss the various molecular signaling pathways that are regulated by K2 during the invasion-metastasis cascade of cancer tumors. These signaling pathways include TGFβ, Wnt/β-Catenin, Hedgehog, p53 and senescence, and cancer stem cell (CSC) maintenance. We will also discuss the molecular signaling pathways that regulate K2 function both at the transcriptional and the posttranslational levels. Finally, we will consider molecular mechanisms to specifically target K2 as novel therapeutic options for cancer treatment.
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Affiliation(s)
- Wei Wang
- Case Western Reserve University, Cleveland, OH, USA.,Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| | - Urna Kansakar
- Case Western Reserve University, Cleveland, OH, USA.,Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| | - Vesna Markovic
- Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
| | - Khalid Sossey-Alaoui
- Case Western Reserve University, Cleveland, OH, USA.,Division of Cancer Biology, MetroHealth System, Cleveland, OH, USA
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Saito Y, Takasawa A, Takasawa K, Aoyama T, Akimoto T, Ota M, Magara K, Murata M, Hirohashi Y, Hasegawa T, Sawada N, Saito T, Osanai M. Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma. Cancer Sci 2020; 111:3071-3081. [PMID: 32530543 PMCID: PMC7419050 DOI: 10.1111/cas.14524] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 05/30/2020] [Accepted: 06/08/2020] [Indexed: 12/29/2022] Open
Abstract
Recent studies have revealed that metabolic reprogramming is closely associated with epithelial-mesenchymal transition (EMT) during cancer progression. Aldolase A (ALDOA) is a key glycolytic enzyme that is highly expressed in several types of cancer. In this study, we found that ALDOA is highly expressed in uterine cervical adenocarcinoma and that high ALDOA expression promotes EMT to increase malignant potentials, such as metastasis and invasiveness, in cervical adenocarcinoma cells. In human surgical specimens, ALDOA was highly expressed in cervical adenocarcinoma and high ALDOA expression was correlated with lymph node metastasis, lymphovascular infiltration, and short overall survival. Suppression of ALDOA expression significantly reduced cell growth, migration, and invasiveness of cervical cancer cells. Aldolase A expression was partially regulated by hypoxia-inducible factor-1α (HIF-1α). Shotgun proteome analysis revealed that cell-cell adhesion-related proteins were significantly increased in ALDOA-overexpressing cells. Interestingly, overexpression of ALDOA caused severe morphological changes, including a cuboidal-to-spindle shape shift and reduced microvilli formation, coincident with modulation of the expression of typical EMT-related proteins. Overexpression of ALDOA increased migration and invasion in vitro. Furthermore, overexpression of ALDOA induced HIF-1α, suggesting a positive feedback loop between ALDOA and HIF-1α. In conclusion, ALDOA is overexpressed in cervical adenocarcinoma and contributes to malignant potentials of tumor cells through modulation of HIF-1α signaling. The feedback loop between ALDOA and HIF-1α could become a therapeutic target to improve the prognosis of this malignancy.
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Affiliation(s)
- Yuki Saito
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Taishi Akimoto
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Misaki Ota
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yoshihiko Hirohashi
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsuyoshi Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Umar S, Soni R, Durgapal SD, Soman S, Balakrishnan S. A synthetic coumarin derivative (4-flourophenylacetamide-acetyl coumarin) impedes cell cycle at G0/G1 stage, induces apoptosis, and inhibits metastasis via ROS-mediated p53 and AKT signaling pathways in A549 cells. J Biochem Mol Toxicol 2020; 34:e22553. [PMID: 32578917 DOI: 10.1002/jbt.22553] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 03/29/2020] [Accepted: 05/15/2020] [Indexed: 01/16/2023]
Abstract
New chemotherapeutic agents with minimum side effects are indispensable to treat non-small-cell lung cancer (NSCLC) since the mortality rate of patients suffering from NSCLC remains high despite receiving conventional medication. In our previous study, many coumarin derivatives were screened for their anticancer properties in A549, an in vitro NSCLC model. One of these, 4-flourophenylacetamide-acetyl coumarin (4-FPAC), induced cytotoxicity at a concentration as low as 0.16 nM. Herein, initially, the cytotoxic potential of 4-FPAC was tested on a noncancerous cell line NIH3T3 and was found safe at the selected dose of 0.16 nM. Further, we investigated the mechanism by which 4-FPAC induced cytotoxicity and arrested the progression of cell cycle as well as metastasis in A549. Results of ethidium bromide/acridine orange (EtBr/AO), 4,6-diamidino-2-phenylindole, comet, and lactate dehydrogenase assays revealed that 4-FPAC caused cytotoxicity via reactive oxygen species-induced p53-mediated mechanism, which involves both extrinsic and intrinsic pathways of apoptosis. Dichlorodihydrofluorescein diacetate, rhodamine 123, and AO staining confirmed the involvement of both mitochondria and lysosome in inducing apoptosis. However, flow cytometric analysis revealed that it causes cell cycle arrest at the G0/G1 phase by modulating p21, CDK2, and CDK4 expression. Aggregation, soft-agar, clonogenic, and scratch assays as well as gene expression analysis collectively confirmed that 4-FPAC minimizes the metastatic property of A549 by downregulating Snail, matrix metalloproteinase 9, and interleukin-8. Additional studies reaffirmed the above findings and substantiated the role of PI3K/AKT in achieving them. The cell-type-specific selective cytostatic and antimetastatic properties shown by 4-FPAC indicate its potential to emerge as a drug of choice against NSCLC in the future.
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Affiliation(s)
- Shweta Umar
- Department of Zoology, Faculty of Science, The M. S. University of Baroda, Vadodara, India
| | - Rina Soni
- Department of Chemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, India
| | - Sunil D Durgapal
- Department of Chemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, India
| | - Subhangi Soman
- Department of Chemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, India
| | - Suresh Balakrishnan
- Department of Zoology, Faculty of Science, The M. S. University of Baroda, Vadodara, India
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Latifi Z, Nejabati HR, Abroon S, Mihanfar A, Farzadi L, Hakimi P, Hajipour H, Nouri M, Fattahi A. Dual role of TGF-β in early pregnancy: clues from tumor progression. Biol Reprod 2020; 100:1417-1430. [PMID: 30772900 DOI: 10.1093/biolre/ioz024] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/25/2018] [Accepted: 02/14/2019] [Indexed: 01/10/2023] Open
Abstract
TGF-β signaling in the endometrium is active during the implantation period and has a pivotal role in regulating endometrial receptivity and embryo implantation. During embryo implantation, both apoptosis and proliferation of endometrial cells happen at the same time and it seems TGF-β is the factor that controls both of these processes. As shown in cancer cells, in special conditions this cytokine can have a dual effect and switch the action from apoptosis to proliferation. Owing to the similarity between embryo implantation and cancer development and also unusual pattern of proliferation and remodeling in the uterus, in this review we suggest the existence of such a switching in endometrium during the early pregnancy. Moreover, we address some potential mechanisms that could regulate the switching. A better understanding of the molecular mechanisms regulating TGF-β action and signaling during the implantation period could pave the way for introducing novel therapeutic strategies in order to solve implantation-associated issues such as repeated implantation failure.
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Affiliation(s)
- Zeinab Latifi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Reza Nejabati
- Department of Biochemistry and Clinical Laboratories, Faculty of Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Abroon
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aynaz Mihanfar
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Laya Farzadi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Hakimi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Hajipour
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Fattahi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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Cai Q, Chen Y, Zhang D, Pan J, Xie Z, Ma S, Liu C, Zuo J, Zhou X, Quan C, Xin Z, Niu Y. Loss of epithelial AR increase castration resistant stem-like prostate cancer cells and promotes cancer metastasis via TGF-β1/EMT pathway. Transl Androl Urol 2020; 9:1013-1027. [PMID: 32676386 PMCID: PMC7354287 DOI: 10.21037/tau.2020.03.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background Previous study has reported that loss of epithelial androgen receptor (AR) may promote tumor progression and cause TRAMP mouse model die earlier. The detail mechanisms, however, remain unclear. Methods Immunohistochemistry assay, Western blot and real-time PCR were used to detect the expression of epithelial and mesenchymal markers. RNA extraction, RT-PCR, quantitative RT-PCR, BrdU incorporation assays, flow cytometry and other experimental technics were also used in present work. Results Decreased expression of epithelial markers (Cytokeratin 8, NKX3.1 and E-cadherin) and increased expression of mesenchymal markers (α-SMA, Vimentin, and N-cadherin) in were found in AR knockout TRAMP tumors. Further investigation indicated that AR signal deprivation is associated with cell morphology transition, high cell mobility, high cell invasion rate and resistance to anoikis in TRAMP prostate tumor cells. Together, these findings implied knockout AR in TRAMP prostate tumor may lead to EMT, which may result in earlier metastasis, and then cause TRAMP mice die earlier. TGF-β1 is responsible for EMT in AR knockout TRAMP tumor cells. Conclusions In conclusion, ADT therapy induced hormone refractory prostate cancer may gain the ability of metastasis through cell’s EMT which is a phase of poor differentiation. Anti-EMT drugs should be developed to battle the tumor metastasis induced by ADT therapy.
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Affiliation(s)
- Qiliang Cai
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Yegang Chen
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Dingnrong Zhang
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Jiancheng Pan
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Zunke Xie
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Shenze Ma
- Department of Urology, ZiBo Central Hospital, ZiBo 255000, China
| | - Chuanfeng Liu
- Department of Urology, Women & Children's Health Care Hospital of Linyi, Linyi 276000, China
| | - Jiquan Zuo
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xiaodong Zhou
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Changyi Quan
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
| | - Zhongcheng Xin
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.,Andrology Center, Peking University First Hospital, Peking University, Beijing 100034, China
| | - Yuanjie Niu
- Department of Urology, the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China
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Differential functions of ERK1 and ERK2 in lung metastasis processes in triple-negative breast cancer. Sci Rep 2020; 10:8537. [PMID: 32444778 PMCID: PMC7244517 DOI: 10.1038/s41598-020-65250-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 04/27/2020] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.
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44
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Li X, Geng J, Ren Z, Xiong C, Li Y, Liu H. WAVE3 upregulation in esophageal squamous cell carcinoma and its effect on the migration of human esophageal cancer cell lines in vitro. Mol Med Rep 2020; 22:465-473. [PMID: 32377706 PMCID: PMC7248532 DOI: 10.3892/mmr.2020.11126] [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] [Received: 07/11/2019] [Accepted: 03/31/2020] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to investigate the role of Wiskott-Aldrich syndrome verprolin-homologous protein 3 (WAVE3) in the progression of esophageal squamous cell carcinoma (ESCC), and to explore its effect on the migration of esophageal cancer cell lines in vitro. The expression level of WAVE3 in ESCC tissues was determined via immunohistochemistry, and the relative levels of WAVE3 mRNA and micro (mi)RNA200b were assessed in the serum of patients with ESCC using reverse transcription-quantitative PCR (RT-qPCR). Following cell transfection, the levels of miRNA200b and WAVE3 protein were determined via RT-qPCR and western blot analysis, and cell migration was examined using a Transwell assay. Subsequently, the clinical parameters were used to analyze whether the expression of WAVE3 in tissues and serum was associated with the occurrence and development of ESCC. The results demonstrated that the expression of WAVE3 was increased in ESCC tissues compared with normal tissues. The results also revealed increased expression levels of WAVE3 and decreased expression levels of miRNA200b in the serum of patients with ESCC, compared with healthy volunteers. High expression of WAVE3 was significantly associated with tumor TNM stage, invasion depth and lymphatic invasion of ESCC. In cells transfected with miRNA200b mimic, the miRNA200b was overexpressed, WAVE3 protein was downregulated and cell migration ability was decreased. The results of the present study suggest that WAVE3 may serve as an oncogene in ESCC, and its inhibition via miRNA200b decreased tumor cell migration. Therefore, WAVE3 may serve as a novel biological marker and therapeutic target for ESCC.
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Affiliation(s)
- Xuebing Li
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jie Geng
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhenzhen Ren
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Chao Xiong
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yuqing Li
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongchun Liu
- Department of Medical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Kiepas A, Voorand E, Senecal J, Ahn R, Annis MG, Jacquet K, Tali G, Bisson N, Ursini-Siegel J, Siegel PM, Brown CM. The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation. J Biol Chem 2020; 295:10535-10559. [PMID: 32299913 DOI: 10.1074/jbc.ra119.011903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/14/2020] [Indexed: 12/12/2022] Open
Abstract
SHC adaptor protein (SHCA) and lipoma-preferred partner (LPP) mediate transforming growth factor β (TGFβ)-induced breast cancer cell migration and invasion. Reduced expression of either protein diminishes breast cancer lung metastasis, but the reason for this effect is unclear. Here, using total internal reflection fluorescence (TIRF) microscopy, we found that TGFβ enhanced the assembly and disassembly rates of paxillin-containing adhesions in an SHCA-dependent manner through the phosphorylation of the specific SHCA tyrosine residues Tyr-239, Tyr-240, and Tyr-313. Using a BioID proximity labeling approach, we show that SHCA exists in a complex with a variety of actin cytoskeletal proteins, including paxillin and LPP. Consistent with a functional interaction between SHCA and LPP, TGFβ-induced LPP localization to cellular adhesions depended on SHCA. Once localized to the adhesions, LPP was required for TGFβ-induced increases in cell migration and adhesion dynamics. Mutations that impaired LPP localization to adhesions (mLIM1) or impeded interactions with the actin cytoskeleton via α-actinin (ΔABD) abrogated migratory responses to TGFβ. Live-cell TIRF microscopy revealed that SHCA clustering at the cell membrane preceded LPP recruitment. We therefore hypothesize that, in the presence of TGFβ, SHCA promotes the formation of small, dynamic adhesions by acting as a nucleator of focal complex formation. Finally, we defined a previously unknown function for SHCA in the formation of invadopodia, a process that also required LPP. Our results reveal that SHCA controls the formation and function of adhesions and invadopodia, two key cellular structures required for breast cancer metastasis.
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Affiliation(s)
- Alex Kiepas
- Department of Physiology, McGill University, Montréal H3G 1Y6, Québec, Canada.,Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada
| | - Elena Voorand
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada.,Department of Biochemistry, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Julien Senecal
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada.,Division of Experimental Medicine, McGill University, Montréal H4A 3J1, Québec, Canada
| | - Ryuhjin Ahn
- Division of Experimental Medicine, McGill University, Montréal H4A 3J1, Québec, Canada.,Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada
| | - Matthew G Annis
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada.,Department of Medicine, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Kévin Jacquet
- Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, Québec G1R 2J6, Canada
| | - George Tali
- Department of Physiology, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Nicolas Bisson
- Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, Québec G1R 2J6, Canada.,PROTEO Network and Cancer Research Centre, Université Laval, Québec, Québec G1V 0A6, Canada
| | - Josie Ursini-Siegel
- Department of Biochemistry, McGill University, Montréal H3G 1Y6, Québec, Canada.,Lady Davis Institute for Medical Research, Montréal, Québec H3T 1E2, Canada.,Department of Oncology, McGill University, Montréal H4A 3T2, Québec, Canada
| | - Peter M Siegel
- Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Québec, Canada .,Department of Biochemistry, McGill University, Montréal H3G 1Y6, Québec, Canada.,Department of Medicine, McGill University, Montréal H3G 1Y6, Québec, Canada
| | - Claire M Brown
- Department of Physiology, McGill University, Montréal H3G 1Y6, Québec, Canada .,Advanced BioImaging Facility (ABIF), McGill University, Montréal H3G 0B1, Québec, Canada
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46
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Margetts PJ, Bonniaud P. Basic Mechanisms and Clinical Implications of Peritoneal Fibrosis. Perit Dial Int 2020. [DOI: 10.1177/089686080302300604] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Peter J. Margetts
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Philippe Bonniaud
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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Epithelial-Mesenchymal Plasticity in Circulating Tumor Cells, the Precursors of Metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1220:11-34. [PMID: 32304077 DOI: 10.1007/978-3-030-35805-1_2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Circulating tumor cells offer an unprecedented window into the metastatic cascade, and to some extent can be considered as intermediates in the process of metastasis. They exhibit dynamic oscillations in epithelial to mesenchymal plasticity and provide important opportunities for prognosis, therapy response monitoring, and targeting of metastatic disease. In this manuscript, we review the involvement of epithelial-mesenchymal plasticity in the early steps of metastasis and what we have learned about its contribution to genomic instability and genetic diversity, tumor progression and therapeutic responses using cell culture, mouse models and circulating tumor cells enriched from patients.
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York JR, McCauley DW. The origin and evolution of vertebrate neural crest cells. Open Biol 2020; 10:190285. [PMID: 31992146 PMCID: PMC7014683 DOI: 10.1098/rsob.190285] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/06/2020] [Indexed: 12/13/2022] Open
Abstract
The neural crest is a vertebrate-specific migratory stem cell population that generates a remarkably diverse set of cell types and structures. Because many of the morphological, physiological and behavioural novelties of vertebrates are derived from neural crest cells, it is thought that the origin of this cell population was an important milestone in early vertebrate history. An outstanding question in the field of vertebrate evolutionary-developmental biology (evo-devo) is how this cell type evolved in ancestral vertebrates. In this review, we briefly summarize neural crest developmental genetics in vertebrates, focusing in particular on the gene regulatory interactions instructing their early formation within and migration from the dorsal neural tube. We then discuss how studies searching for homologues of neural crest cells in invertebrate chordates led to the discovery of neural crest-like cells in tunicates and the potential implications this has for tracing the pre-vertebrate origins of the neural crest population. Finally, we synthesize this information to propose a model to explain the origin of neural crest cells. We suggest that at least some of the regulatory components of early stages of neural crest development long pre-date vertebrate origins, perhaps dating back to the last common bilaterian ancestor. These components, originally directing neuroectodermal patterning and cell migration, served as a gene regulatory 'scaffold' upon which neural crest-like cells with limited migration and potency evolved in the last common ancestor of tunicates and vertebrates. Finally, the acquisition of regulatory programmes controlling multipotency and long-range, directed migration led to the transition from neural crest-like cells in invertebrate chordates to multipotent migratory neural crest in the first vertebrates.
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Affiliation(s)
| | - David W. McCauley
- Department of Biology, University of Oklahoma, 730 Van Vleet Oval, Norman, OK 73019, USA
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Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 2019; 20:69-84. [PMID: 30459476 DOI: 10.1038/s41580-018-0080-4] [Citation(s) in RCA: 2434] [Impact Index Per Article: 405.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell-cell and cell-extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas.
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Affiliation(s)
- Anushka Dongre
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Robert A Weinberg
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA. .,MIT Ludwig Center for Molecular Oncology, Cambridge, MA, USA. .,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
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50
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Rocha M, Singh N, Ahsan K, Beiriger A, Prince VE. Neural crest development: insights from the zebrafish. Dev Dyn 2019; 249:88-111. [PMID: 31591788 DOI: 10.1002/dvdy.122] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/21/2019] [Accepted: 09/22/2019] [Indexed: 12/12/2022] Open
Abstract
Our understanding of the neural crest, a key vertebrate innovation, is built upon studies of multiple model organisms. Early research on neural crest cells (NCCs) was dominated by analyses of accessible amphibian and avian embryos, with mouse genetics providing complementary insights in more recent years. The zebrafish model is a relative newcomer to the field, yet it offers unparalleled advantages for the study of NCCs. Specifically, zebrafish provide powerful genetic and transgenic tools, coupled with rapidly developing transparent embryos that are ideal for high-resolution real-time imaging of the dynamic process of neural crest development. While the broad principles of neural crest development are largely conserved across vertebrate species, there are critical differences in anatomy, morphogenesis, and genetics that must be considered before information from one model is extrapolated to another. Here, our goal is to provide the reader with a helpful primer specific to neural crest development in the zebrafish model. We focus largely on the earliest events-specification, delamination, and migration-discussing what is known about zebrafish NCC development and how it differs from NCC development in non-teleost species, as well as highlighting current gaps in knowledge.
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Affiliation(s)
- Manuel Rocha
- Committee on Development, Regeneration and Stem Cell Biology, The University of Chicago, Chicago, Illinois
| | - Noor Singh
- Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois
| | - Kamil Ahsan
- Committee on Development, Regeneration and Stem Cell Biology, The University of Chicago, Chicago, Illinois
| | - Anastasia Beiriger
- Committee on Development, Regeneration and Stem Cell Biology, The University of Chicago, Chicago, Illinois
| | - Victoria E Prince
- Committee on Development, Regeneration and Stem Cell Biology, The University of Chicago, Chicago, Illinois.,Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois
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