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1
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Barcellos-Hoff MH, Yom SS. Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response. Nat Rev Cancer 2025:10.1038/s41568-025-00819-6. [PMID: 40389543 DOI: 10.1038/s41568-025-00819-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/01/2025] [Indexed: 05/21/2025]
Abstract
The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapuetic blockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.
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Affiliation(s)
| | - Sue S Yom
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
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2
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Ranjan G, Ranjan S, Sunita P, Pattanayak SP. Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4705-4725. [PMID: 39621087 DOI: 10.1007/s00210-024-03661-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/20/2024] [Indexed: 04/11/2025]
Abstract
Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.
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Affiliation(s)
- Gaurav Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Shashi Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Priyashree Sunita
- Department of Surgery, Case Comprehensive Cancer Centre, Case Western Reserve University, Wolstein Research Building 2103 Cornell Rd, Cleveland, OH, 44106, USA
| | - Shakti Prasad Pattanayak
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India.
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Woods Building, W437, 2109 Adelbert Road, Cleaveland, OH, 44106, USA.
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3
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Laouris P, Muñoz-Espín D. Current Methodologies to Assess Cellular Senescence in Cancer. Methods Mol Biol 2025; 2906:21-44. [PMID: 40082348 DOI: 10.1007/978-1-0716-4426-3_2] [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] [Indexed: 03/16/2025]
Abstract
Cellular senescence plays a critical role in cancer, acting as both a tumor-suppressive and tumor-promoting mechanism. Senescent cells undergo stable cell-cycle arrest in response to various stressors, including DNA damage and oncogenic signaling, and exhibit a complex secretory phenotype known as the senescence-associated secretory phenotype (SASP), which can impact the tumor microenvironment. The hallmarks of senescence include cell-cycle arrest, secretion of pro-inflammatory factors, structural changes, and metabolic alterations. These features, while initially suppressing tumorigenesis, can later contribute to cancer progression under certain conditions. Methods for studying senescence in preclinical models include in vitro assays, ex vivo tissue analysis, and in vivo detection techniques. Emerging therapeutic strategies focus on exploiting senescence for cancer treatment, particularly through the use of senolytic agents that selectively eliminate senescent cells and senomorphic compounds that modulate SASP activity. However, the identification of reliable and universal biomarkers for senescence remains a challenge, necessitating a multimarker approach to accurately detect and characterize senescent cells in various contexts.
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Affiliation(s)
- Panayiotis Laouris
- Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Daniel Muñoz-Espín
- Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
- CRUK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK.
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4
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Lee MJ, Yeon JH, Lee J, Kang YH, Park BS, Park J, Yun SH, Wirth D, Yoo SM, Park C, Gao SJ, Lee MS. Senescence of endothelial cells increases susceptibility to Kaposi's sarcoma-associated herpesvirus infection via CD109-mediated viral entry. J Clin Invest 2024; 135:e183561. [PMID: 39666389 PMCID: PMC11827841 DOI: 10.1172/jci183561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 12/10/2024] [Indexed: 12/13/2024] Open
Abstract
The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of increased Kaposi's sarcoma prevalence among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovered a link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR/Cas9-mediated KO of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting inhibitory activity of KSHV infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide insights into the complex interplay between aging and viral pathogenesis.
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Affiliation(s)
| | | | - Jisu Lee
- Department of Microbiology and Immunology, and
| | - Yun Hee Kang
- Department of Microbiology and Immunology, and
- Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, South Korea
| | - Beom Seok Park
- Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam, South Korea
| | - Joohee Park
- Department of Microbiology and Immunology, and
| | - Sung-Ho Yun
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju, South Korea
| | - Dagmar Wirth
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | | | - Shou-Jinag Gao
- Tumor Virology Program, UPMC Hillman Cancer Center, and Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Myung-Shin Lee
- Department of Microbiology and Immunology, and
- Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, South Korea
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5
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Karamikheirabad M, Zhang J, Ahn AR, Park HS, Park SH, Moon YJ, Kim KM, Jang KY. IL-13Rα2 Is Involved in Resistance to Doxorubicin and Survival of Osteosarcoma Patients. Pharmaceuticals (Basel) 2024; 17:1526. [PMID: 39598436 PMCID: PMC11597473 DOI: 10.3390/ph17111526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND/OBJECTIVES Interleukin 13 receptor alpha 2 (IL-13Rα2) is a receptor with a high affinity for IL-13 and is involved in the progression of human cancers. However, studies on the role of IL-13Rα2 in osteosarcoma are limited. Therefore, this study aimed to investigate the expression and roles of IL-13Rα2 in the progression of osteosarcoma. METHODS This study evaluated the roles of IL-13Rα2 in osteosarcomas by evaluating tumor tissues from 37 human osteosarcomas and osteosarcoma cells. RESULTS Immunohistochemical positivity of IL-13Rα2 was an independent indicator of shorter overall survival and relapse-free survival of 37 osteosarcoma patients and 26 subpopulations of patients who received adjuvant chemotherapy with multivariate analysis. In U2OS and KHOS/NP osteosarcoma cells, overexpression of IL-13Rα2 significantly increased proliferation, migration, and invasion of cells, all of which decreased with knockdown of IL-13Rα2. Overexpression of IL-13Rα2 increased expression of TGF-β, snail, cyclin D1, and BCL2 but decreased BAX, and knockdown of IL-13Rα2 caused a decrease in expression of these molecules. In addition, both in vitro and in vivo, proliferation of osteosarcoma cells increased, and apoptosis decreased with overexpression of IL-13Rα2 under treatment with doxorubicin. Knockdown of IL-13Rα2 sensitized osteosarcoma cells to the cytotoxic effect of doxorubicin. CONCLUSIONS The results of this study suggest that the expression of IL13Rα2 might be used as a potential prognostic indicator in osteosarcoma patients. Furthermore, it is observed that IL13Rα2 influences the resistance to the chemotherapeutic agent doxorubicin. Therefore, a therapeutic trial targeting IL13Rα2 might be a new therapeutic strategy for osteosarcoma, especially those highly expressing IL13Rα2.
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Affiliation(s)
- Maryam Karamikheirabad
- Department of Pathology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea; (M.K.); (J.Z.); (A.-R.A.); (H.S.P.)
| | - Junyue Zhang
- Department of Pathology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea; (M.K.); (J.Z.); (A.-R.A.); (H.S.P.)
| | - Ae-Ri Ahn
- Department of Pathology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea; (M.K.); (J.Z.); (A.-R.A.); (H.S.P.)
| | - Ho Sung Park
- Department of Pathology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea; (M.K.); (J.Z.); (A.-R.A.); (H.S.P.)
| | - See-Hyoung Park
- Department of Bio and Chemical Engineering, Hongik University, Sejong 30016, Republic of Korea;
| | - Young Jae Moon
- Department of Biochemistry and Molecular Biology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea;
- Department of Orthopedic Surgery, Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
| | - Kyoung Min Kim
- Department of Pathology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea; (M.K.); (J.Z.); (A.-R.A.); (H.S.P.)
- Research Institute of Clinical Medicine, Jeonbuk National University, Jeonju 54896, Republic of Korea
- Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Medical School, Jeonbuk National University, Jeonju 54896, Republic of Korea; (M.K.); (J.Z.); (A.-R.A.); (H.S.P.)
- Research Institute of Clinical Medicine, Jeonbuk National University, Jeonju 54896, Republic of Korea
- Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
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6
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Jang JJ, Kang D, Lee YS, Lee YS. The Versatile Roles of nc886, a Fascinating and Peculiar Regulatory Non-Coding RNA, in Cancer. Int J Mol Sci 2024; 25:10825. [PMID: 39409154 PMCID: PMC11476670 DOI: 10.3390/ijms251910825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
This review concerns nc886, a 101-nucleotide non-coding RNA (ncRNA). Because nc886 is transcribed by RNA polymerase III (Pol III) and contains a CpG island in its promoter region, its expression is regulated by several transcription factors and the DNA methylation status. These features drive nc886 expression in two opposing directions during tumorigenesis. The known function of nc886 is to bind to and modulate the activity of target proteins such as PKR, Dicer, and OAS1. By being differentially expressed during tumorigenesis and interacting with these proteins, nc886 plays a role in tumor surveillance, promotes or suppresses tumorigenesis, and influences the efficacy of cancer therapy. The multiple roles of nc886 have been well-documented in the literature. In this review, we have summarized this literature and critically discussed the roles and mechanisms of action of nc886 in various cancers.
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Affiliation(s)
- Jiyoung Joan Jang
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea;
- Fluorescence Core Imaging Center, Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea;
| | - Dongmin Kang
- Fluorescence Core Imaging Center, Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea;
| | - Yeon-Su Lee
- Division of Rare Cancer, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea;
| | - Yong Sun Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea;
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7
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Wang S, Shao D, Gao X, Zhao P, Kong F, Deng J, Yang L, Shang W, Sun Y, Fu Z. TEAD transcription factor family emerges as a promising therapeutic target for oral squamous cell carcinoma. Front Immunol 2024; 15:1480701. [PMID: 39430767 PMCID: PMC11486717 DOI: 10.3389/fimmu.2024.1480701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
The treatment of oral squamous cell carcinoma (OSCC) remains a significant difficulty, as there has been no improvement in survival rates over the past fifty years. Hence, exploration and confirmation of new dependable treatment targets and biomarkers is imperative for OSCC therapy. TEAD transcription factors are crucial for integrating and coordinating multiple signaling pathways that are essential for embryonic development, organ formation, and tissue homeostasis. In addition, by attaching to coactivators, TEAD modifies the expression of genes such as Cyr61, Myc, and connective tissue growth factor, hence facilitating tumor progression. Therefore, TEAD is regarded as an effective predictive biomarker due to its significant connection with clinical parameters in several malignant tumors, including OSCC. The efficacy of existing drugs that specifically target TEAD has demonstrated encouraging outcomes, indicating its potential as an optimal target for OSCC treatment. This review provides an overview of current targeted therapy strategies for OSCC by highlighting the transcription mechanism and involvement of TEAD in oncogenic signaling pathways. Finally, the feasibility of utilizing TEAD as an innovative approach to address OSCC and its potential clinical applications were analyzed and discussed.
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Affiliation(s)
- Shuang Wang
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
- Department of Stomatology, Medical College of Qingdao Huanghai University, Qingdao, China
| | - Dan Shao
- Department of Oral and Maxillofacial Surgery, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, China
| | - Xiaoyan Gao
- Department of Quality Inspection, Traditional Chinese Medical Hospital of Huangdao District, Qingdao, China
| | - Peng Zhao
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Fanzhi Kong
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Jiawei Deng
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Lianzhu Yang
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Wei Shang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yaping Sun
- Department of Stomatology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, People's Liberation Army of China (PLA), Beijing, China
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8
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Kochumon S, Al-Sayyar A, Jacob T, Bahman F, Akhter N, Wilson A, Sindhu S, Hannun YA, Ahmad R, Al-Mulla F. TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis. Front Immunol 2024; 15:1430187. [PMID: 39351229 PMCID: PMC11439675 DOI: 10.3389/fimmu.2024.1430187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/26/2024] [Indexed: 10/04/2024] Open
Abstract
Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-β and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a well-established MDA-MB-231 breast cancer model, we found that the synergy between TGF-β and TNF-α led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-β and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-β/TNF-α cooperativity was attenuated by selective inhibition of the TGF-βRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-β-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-β/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-β could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.
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Affiliation(s)
- Shihab Kochumon
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Amnah Al-Sayyar
- Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, Marseille, France
| | - Texy Jacob
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fatemah Bahman
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Nadeem Akhter
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Ajit Wilson
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Sardar Sindhu
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Yusuf A. Hannun
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, United States
| | - Rasheed Ahmad
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Translational Research, Dasman Diabetes Institute, Dasman, Kuwait
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9
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Gan L, Wang W, Jiang J, Tian K, Liu W, Cao Z. Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges. Front Immunol 2024; 15:1429836. [PMID: 39286246 PMCID: PMC11402828 DOI: 10.3389/fimmu.2024.1429836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/12/2024] [Indexed: 09/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and ranks as the third leading cause of cancer-related mortality globally. The liver performs a wide range of tasks and is the primary organ responsible for metabolizing harmful substances and foreign compounds. Oxidative stress has a crucial role in growth and improvement of hepatocellular carcinoma (HCC). Nuclear factor erythroid 2 (1)-related factor 2 (Nrf2) is an element that regulates transcription located in the cytoplasm. It controls the balance of redox reactions by stimulating the expression of many genes that depend on antioxidant response elements. Nrf2 has contrasting functions in the normal, healthy liver and HCC. In the normal liver, Nrf2 provides advantageous benefits, while in HCC it promotes harmful effects that support the growth and survival of HCC. Continuous activation of Nrf2 has been detected in HCC and promotes its advancement and aggressiveness. In addition, Activation of Nrf2 may lead to immune evasion, weakening the immune cells' ability to attack tumors and thereby promoting tumor development. Furthermore, chemoresistance in HCC, which is considered a form of stress response to chemotherapy medications, significantly impedes the effectiveness of HCC treatment. Stress management is typically accomplished by activating specific signal pathways and chemical variables. One important element in the creation of chemoresistance in HCC is nuclear factor-E2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the activation and production of a group of genes that encode proteins responsible for protecting cells from damage. This occurs through the Nrf2/ARE pathway, which is a crucial mechanism for combating oxidative stress within cells.
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Affiliation(s)
- Lin Gan
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Wei Wang
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Jinxiu Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Wei Liu
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
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10
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Kolecka-Bednarczyk A, Frydrychowicz M, Budny B, Ruciński M, Dompe C, Gabryel P, Płachno BJ, Ruchała M, Ziemnicka K, Zieliński P, Budna-Tukan J. Specific Deletions of Chromosomes 3p, 5q, 13q, and 21q among Patients with G2 Grade of Non-Small Cell Lung Cancer. Int J Mol Sci 2024; 25:8642. [PMID: 39201328 PMCID: PMC11354976 DOI: 10.3390/ijms25168642] [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: 05/07/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 09/02/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) leads as a primary cause of cancer-related premature mortality in Western populations. This study leverages cutting-edge gene-expression-profiling technologies to perform an in-depth molecular characterization of NSCLC specimens, with the objective of uncovering tumor-specific genomic alterations. By employing DNA microarray analysis, our research aims to refine the classification of NSCLC for early detection, guide molecular-targeted treatment approaches, enhance prognostication, and broaden the scientific understanding of the disease's biology. We identified widespread genomic abnormalities in our samples, including the recurrent loss of chromosomal regions 3p, 5q, 13q, and 21q and the gain of 12p. Furthermore, utilizing Metascape for bioinformatic analysis revealed critical biological pathways disrupted in NSCLC, offering promising leads for novel therapeutic interventions.
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Affiliation(s)
- Agata Kolecka-Bednarczyk
- Department of Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (M.F.); (C.D.)
| | - Magdalena Frydrychowicz
- Department of Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (M.F.); (C.D.)
| | - Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (B.B.); (M.R.); (K.Z.)
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.R.); (J.B.-T.)
| | - Claudia Dompe
- Department of Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (M.F.); (C.D.)
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Piotr Gabryel
- Department of Thoracic Surgery, Poznan University of Medical Sciences, 60-569 Poznan, Poland; (P.G.); (P.Z.)
| | - Bartosz J. Płachno
- Department of Plant Cytology and Embryology, Institute of Botany, Faculty of Biology, Jagiellonian University in Kraków, 30-387 Cracow, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (B.B.); (M.R.); (K.Z.)
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (B.B.); (M.R.); (K.Z.)
| | - Paweł Zieliński
- Department of Thoracic Surgery, Poznan University of Medical Sciences, 60-569 Poznan, Poland; (P.G.); (P.Z.)
| | - Joanna Budna-Tukan
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.R.); (J.B.-T.)
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Gora, 65-046 Zielona Gora, Poland
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11
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Zhang B, Liu M, Mai F, Li X, Wang W, Huang Q, Du X, Ding W, Li Y, Barwick BG, Ni JJ, Osunkoya AO, Chen Y, Zhou W, Xia S, Dong JT. Interruption of KLF5 acetylation promotes PTEN-deficient prostate cancer progression by reprogramming cancer-associated fibroblasts. J Clin Invest 2024; 134:e175949. [PMID: 38781024 PMCID: PMC11245161 DOI: 10.1172/jci175949] [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: 09/19/2023] [Accepted: 05/21/2024] [Indexed: 05/25/2024] Open
Abstract
Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Krüppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-α, which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN-deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1.
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Affiliation(s)
- Baotong Zhang
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Mingcheng Liu
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
| | - Fengyi Mai
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
| | - Xiawei Li
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
- Inner Mongolia Institute of Quality and Standardization, Inner Mongolia Administration for Market Regulation, Hohhot, China
| | - Wenzhou Wang
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
| | - Qingqing Huang
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
| | - Xiancai Du
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
| | - Weijian Ding
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
| | - Yixiang Li
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Benjamin G. Barwick
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Jianping Jenny Ni
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Adeboye O. Osunkoya
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
- Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Yuanli Chen
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, China
| | - Wei Zhou
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Siyuan Xia
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Jin-Tang Dong
- Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen, Guangdong, China
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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12
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Wei Y, Wang D, Wu J, Zhang J. JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation. Int J Rheum Dis 2024; 27:e15164. [PMID: 38706209 DOI: 10.1111/1756-185x.15164] [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: 07/17/2023] [Revised: 01/01/2024] [Accepted: 04/14/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND JAK inhibitors are well known for the treatment of rheumatoid arthritis (RA), but whether they can be used to treat pulmonary fibrosis, a common extra-articular disease of RA, remains to be clarified. METHODS A jak2 inhibitor, CEP33779 (CEP), was administered to a rat model of RA-associated interstitial lung disease to observe the degree of improvement in both joint swelling and pulmonary fibrosis. HFL1 cells were stimulated with TGF-β1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGFβ-R1/2, and p-STAT3) or silencers (STAT3, JAK2) were administered to HFL1 cells, and the expression levels of related proteins were detected to explore the underlying mechanisms of action. RESULTS CEP not only reduced the degree of joint swelling and inflammation in rats but also improved lung function, inhibited the pro-inflammatory factors IL-1β and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGFβ-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-β1 induced HFL1 cells to highly express p-JAK2, with the most pronounced expression at 48 h. The levels of p-STAT3, p-SMAD3, and ECM-related proteins were significantly reduced after inhibition of either JAK2 or STAT3. CONCLUSION JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3.
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Affiliation(s)
- Yimei Wei
- Department of Geriatrics, Chongqing Medical University, Chongqing, China
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| | - Dandan Wang
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
- Department of Pulmonary Department of Respiratory and Critical Care Medicine, Southwest Medical University, Luzhou, China
| | - Juan Wu
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| | - Jie Zhang
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
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13
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Yang N, Hellevik T, Berzaghi R, Martinez‐Zubiaurre I. Radiation-induced effects on TGF-β and PDGF receptor signaling in cancer-associated fibroblasts. Cancer Rep (Hoboken) 2024; 7:e2018. [PMID: 38488488 PMCID: PMC10941573 DOI: 10.1002/cnr2.2018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 12/11/2023] [Accepted: 12/28/2023] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) consist of heterogeneous connective tissue cells and are often constituting the most abundant cell type in the tumor stroma. Radiation effects on tumor stromal components like CAFs in the context of radiation treatment is not well-described. AIM This study explores potential changes induced by ionizing radiation (IR) on platelet-derived growth factor (PDGF)/PDGFRs and transforming growth factor-beta (TGF-β)/TGFβRs signaling systems in CAFs. METHODS AND RESULTS Experiments were carried out by employing primary cultures of human CAFs isolated from freshly resected non-small cell lung carcinoma tumor tissues. CAF cultures from nine donors were treated with one high (1 × 18 Gy) or three fractionated (3 × 6 Gy) radiation doses. Alterations in expression levels of TGFβRII and PDGFRα/β induced by IR were analyzed by western blots and flow cytometry. In the presence or absence of cognate ligands, receptor activation was studied in nonirradiated and irradiated CAFs. Radiation exposure did not exert changes in expression of PDGF or TGF-β receptors in CAFs. Additionally, IR alone was unable to trigger activation of either receptor. The radiation regimens tested did not affect PDGFRβ signaling in the presence of PDGF-BB. In contrast, signaling via pSmad2/3 and pSmad1/5/8 appeared to be down-regulated in irradiated CAFs after stimulation with TGF-β, as compared with controls. CONCLUSION Our data demonstrate that IR by itself is insufficient to induce measurable changes in PDGF or TGF-β receptor expression levels or to induce receptor activation in CAFs. However, in the presence of their respective ligands, exposure to radiation at certain doses appear to interfere with TGF-β receptor signaling.
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Affiliation(s)
- Nannan Yang
- Department of Community Medicine, Faculty of Health SciencesUiT The Arctic University of NorwayTromsøNorway
| | - Turid Hellevik
- Department of Radiation OncologyUniversity Hospital of North NorwayTromsøNorway
| | - Rodrigo Berzaghi
- Department of Clinical Medicine, Faculty of Health SciencesUiT The Arctic University of NorwayTromsøNorway
| | - Inigo Martinez‐Zubiaurre
- Department of Clinical Medicine, Faculty of Health SciencesUiT The Arctic University of NorwayTromsøNorway
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14
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Ahuja S, Zaheer S. Multifaceted TGF-β signaling, a master regulator: From bench-to-bedside, intricacies, and complexities. Cell Biol Int 2024; 48:87-127. [PMID: 37859532 DOI: 10.1002/cbin.12097] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/08/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Physiological embryogenesis and adult tissue homeostasis are regulated by transforming growth factor-β (TGF-β), an evolutionarily conserved family of secreted polypeptide factors, acting in an autocrine and paracrine manner. The role of TGF-β in inflammation, fibrosis, and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, especially fibrosis and cancer, overexpressed TGF-β causes extracellular matrix deposition, epithelial-mesenchymal transition, cancer-associated fibroblast formation, and/or angiogenesis. In this review article, we have tried to dive deep into the mechanism of action of TGF-β in inflammation, fibrosis, and carcinogenesis. As TGF-β and its downstream signaling mechanism are implicated in fibrosis and carcinogenesis blocking this signaling mechanism appears to be a promising avenue. However, targeting TGF-β carries substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. There is a need for careful dosing of TGF-β drugs for therapeutic use and patient selection.
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Affiliation(s)
- Sana Ahuja
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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15
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Aleksandrova E, Mindov I, Petrov B, Dimitrova I, Petrov N, Ananiev J, Vlaykova T, Valkanov S. Role of Elevated Serum TGF-β1 and the Common Promoter TGFB1-509C/T Polymorphism in the Development and Progression of Primary Glial Tumors and Brain Metastases. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:146. [PMID: 38256406 PMCID: PMC10819302 DOI: 10.3390/medicina60010146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024]
Abstract
Background and Objectives: The role of transforming growth factor-beta1 (TGF-β1) has been widely studied in the context of carcinogenesis. It has been involved in the pathogenesis of primary brain tumors or brain metastases due to its pleiotropic effects on immune regulation and tissue homeostasis. In line with recent findings, the aim of the current study was to examine the role of circulating TGF-β1 and the -509C/T functional polymorphism (rs1800469) in the TGFB1 gene promoter in the susceptibility and progression of primary brain tumors and brain metastases among patients from the Bulgarian population. Materials and Methods: Cases with a confirmed diagnosis were genotyped by the polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Serum TGF-β1 levels were determined by ELISA. Immunohistochemical evaluation of the expression of TGF-β1 and the TGF-β1 receptor-type II was conducted. Results: We observed that TGF-β1 serum levels correlate with the genotype and are sex-related. TGF-β1 serum levels were significantly elevated in patients compared to controls. Additionally, the T/T-genotype determined higher circulating levels of the cytokine. The same genotype determined the shorter median survival after surgery for the patients. The immunohistochemical analysis revealed a statistical tendency: cases expressing TGF-β1 in the cytoplasm had elevated levels of the cytokine in the serum compared to the negative cases. Conclusions: Overall, our results indicate a negative effect of the T-allele on the predisposition and prognosis of brain malignancies, and the genetically determined higher TGF-β1 serum levels might contribute to the worse prognosis and metastatic capacity of brain malignancies.
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Affiliation(s)
- Elina Aleksandrova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria; (N.P.)
| | - Ivan Mindov
- Department of Surgery, Neurosurgery, Urology and Anaesthesiology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria (B.P.); (I.D.); (S.V.)
| | - Bozhidar Petrov
- Department of Surgery, Neurosurgery, Urology and Anaesthesiology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria (B.P.); (I.D.); (S.V.)
| | - Ivelina Dimitrova
- Department of Surgery, Neurosurgery, Urology and Anaesthesiology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria (B.P.); (I.D.); (S.V.)
| | - Nikolay Petrov
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria; (N.P.)
| | - Julian Ananiev
- Department of General and Clinical Pathology, Forensic Medicine, Deontology and Dermatovenerology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria
| | - Tatyana Vlaykova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria; (N.P.)
| | - Stefan Valkanov
- Department of Surgery, Neurosurgery, Urology and Anaesthesiology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria (B.P.); (I.D.); (S.V.)
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16
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Schmidt KE, Höving AL, Kiani Zahrani S, Trevlopoulou K, Kaltschmidt B, Knabbe C, Kaltschmidt C. Serum-Induced Proliferation of Human Cardiac Stem Cells Is Modulated via TGFβRI/II and SMAD2/3. Int J Mol Sci 2024; 25:959. [PMID: 38256034 PMCID: PMC10815425 DOI: 10.3390/ijms25020959] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/22/2023] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
The ageing phenotype is strongly driven by the exhaustion of adult stem cells (ASCs) and the accumulation of senescent cells. Cardiovascular diseases (CVDs) and heart failure (HF) are strongly linked to the ageing phenotype and are the leading cause of death. As the human heart is considered as an organ with low regenerative capacity, treatments targeting the rejuvenation of human cardiac stem cells (hCSCs) are of great interest. In this study, the beneficial effects of human blood serum on proliferation and senescence of hCSCs have been investigated at the molecular level. We show the induction of a proliferation-related gene expression response by human blood serum at the mRNA level. The concurrent differential expression of the TGFβ target and inhibitor genes indicates the participation of TGFβ signalling in this context. Surprisingly, the application of TGFβ1 as well as the inhibition of TGFβ type I and type II receptor (TGFβRI/II) signalling strongly increased the proliferation of hCSCs. Likewise, both human blood serum and TGFβ1 reduced the senescence in hCSCs. The protective effect of serum on senescence in hCSCs was enhanced by simultaneous TGFβRI/II inhibition. These results strongly indicate a dual role of TGFβ signalling in terms of the serum-mediated effects on hCSCs. Further analysis via RNA sequencing (RNA-Seq) revealed the participation of Ras-inactivating genes wherefore a prevention of hyperproliferation upon serum-treatment in hCSCs via TGFβ signalling and Ras-induced senescence is suggested. These insights may improve treatments of heart failure in the future.
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Affiliation(s)
- Kazuko E. Schmidt
- Department of Cell Biology, Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany; (K.E.S.); (S.K.Z.); (K.T.); (B.K.); (C.K.)
- Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre NRW, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
- Medical Faculty OWL, University of Bielefeld, 33615 Bielefeld, Germany
| | - Anna L. Höving
- Department of Cell Biology, Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany; (K.E.S.); (S.K.Z.); (K.T.); (B.K.); (C.K.)
- Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre NRW, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
- Medical Faculty OWL, University of Bielefeld, 33615 Bielefeld, Germany
| | - Sina Kiani Zahrani
- Department of Cell Biology, Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany; (K.E.S.); (S.K.Z.); (K.T.); (B.K.); (C.K.)
| | - Katerina Trevlopoulou
- Department of Cell Biology, Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany; (K.E.S.); (S.K.Z.); (K.T.); (B.K.); (C.K.)
| | - Barbara Kaltschmidt
- Department of Cell Biology, Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany; (K.E.S.); (S.K.Z.); (K.T.); (B.K.); (C.K.)
- AG Molecular Neurobiology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Cornelius Knabbe
- Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre NRW, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
- Medical Faculty OWL, University of Bielefeld, 33615 Bielefeld, Germany
| | - Christian Kaltschmidt
- Department of Cell Biology, Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany; (K.E.S.); (S.K.Z.); (K.T.); (B.K.); (C.K.)
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17
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Boudreault J, Wang N, Ghozlan M, Lebrun JJ. Transforming Growth Factor-β/Smad Signaling Inhibits Melanoma Cancer Stem Cell Self-Renewal, Tumor Formation and Metastasis. Cancers (Basel) 2024; 16:224. [PMID: 38201651 PMCID: PMC10778361 DOI: 10.3390/cancers16010224] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/20/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
The secreted protein transforming growth factor-beta (TGFβ) plays essential roles, ranging from cell growth regulation and cell differentiation in both normal and cancer cells. In melanoma, TGFβ acts as a potent tumor suppressor in melanoma by blocking cell cycle progression and inducing apoptosis. In the present study, we found TGFβ to regulate cancer stemness in melanoma through the Smad signaling pathway. We discovered that TGFβ/Smad signaling inhibits melanosphere formation in multiple melanoma cell lines and reduces expression of the CD133+ cancer stem cell subpopulation in a Smad3-dependent manner. Using preclinical models of melanoma, we further showed that preventing Smad3/4 signaling, by means of CRISPR knockouts, promoted both tumorigenesis and lung metastasis in vivo. Collectively, our results define new functions for the TGFβ/Smad signaling axis in melanoma stem-cell maintenance and open avenues for new therapeutic approaches to this disease.
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Affiliation(s)
| | | | | | - Jean-Jacques Lebrun
- Cancer Research Program, Department of Medicine, Research Institute of McGill University Health Center, Montreal, QU H4A 3J1, Canada; (J.B.); (N.W.); (M.G.)
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18
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Ye S, Si W, Qin W, Yang L, Luo Z, Li Z, Xie Y, Pan H, Li X, Huang Z, Zhu M, Chen D. Atractylodes lancea volatile oils target ADAR2-miR-181a-5p signaling to mesenchymal stem cell chondrogenic differentiation. Anat Rec (Hoboken) 2023; 306:3006-3020. [PMID: 35446511 DOI: 10.1002/ar.24930] [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: 09/20/2021] [Revised: 02/17/2022] [Accepted: 03/20/2022] [Indexed: 11/07/2022]
Abstract
Atractylodeslancea Rhizoma (Rhizoma atractylodis [RA]) has long been recommended for the treatment of arthritis in traditional Chinese medicine, but its mechanism of action is still unclear. RA contains a large amount of Atractylodes lancea volatile oils (Atr). In this study, we investigated whether Atr can promote mesenchymal stem cells (MSCs) chondrogenic differentiation. The Atr were extracted from RA by steam distillation method, and the effect of Atr on MSCs was detected by the CCK8 assay. The optimal concentration of Atr for MSCs cultivation was 3 μg/ml. The differentially expressed miR-181a-5p was screened by miRNA microarray assay, and its mimics and inhibitors were transfected into MSCs. It was found that the inhibitor of miR-181a-5p could upregulate cartilage-specific genes such as SOX9, COL2A1, and ACAN. Meanwhile, we also found that the expression of gene editing enzyme ADAR2 was significantly increased in the chondrogenic differentiation of MSCs induced by Atr, and the bases of precursor sequence of miR-181a-5p were changed from A to G. After ADAR2 deletion, the expression of cartilage-specific genes was significantly down-regulated and the precursor sequence bases of miR-181a-5p were not changed. Bioinformatics analysis revealed that the predicted target gene of miR-181a-5p was yingyang1 (YY1), and the targeting relationship was verified by dual-luciferase reporter assay. After deleting YY1, the expression of cartilage-specific genes was significantly down-regulated. In conclusion, our study demonstrated that Atr can promote chondrogenic differentiation of MSC through regulation of the ADAR2-miR-181a-5p signaling pathway. This may provide a new insight into the possible mechanism of traditional Chinese medicine (Atr) in treating inflammatory joint diseases.
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Affiliation(s)
- Shanyu Ye
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenwen Si
- Shenzhen BaoAn Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wei Qin
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lin Yang
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziwei Luo
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhen Li
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yulu Xie
- School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hao Pan
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinrong Li
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zifeng Huang
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Meiling Zhu
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Dongfeng Chen
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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19
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Wu S, Luwor RB, Zhu HJ. Dynamics of transforming growth factor β signaling and therapeutic efficacy. Growth Factors 2023; 41:82-100. [PMID: 37229558 DOI: 10.1080/08977194.2023.2215335] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 03/14/2023] [Indexed: 05/27/2023]
Abstract
Transforming growth factor β (TGFβ) is a multifunctional cytokine, and its signalling responses are exerted via integrated intracellular pathways and complex regulatory mechanisms. Due to its high potency, TGFβ signalling is tightly controlled under normal circumstances, while its dysregulation in cancer favours metastasis. The recognised potential of TGFβ as a therapeutic target led to emerging development of anti-TGFβ reagents with preclinical success, yet these therapeutics failed to recapitulate their efficacy in experimental settings. In this review, possible reasons for this inconsistency are discussed, addressing the knowledge gap between theoretical and actual behaviours of TGFβ signalling. Previous studies on oncogenic cells have demonstrated the spatiotemporal heterogeneity of TGFβ signalling intensity. Under feedback mechanisms and exosomal ligand recycling, cancer cells may achieve cyclic TGFβ signalling to facilitate dissemination and colonisation. This challenges the current presumption of persistently high TGFβ signalling in cancer, pointing to a new direction of research on TGFβ-targeted therapeutics.
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Affiliation(s)
- Siqi Wu
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia
| | - Rodney Brian Luwor
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia
- Fiona Elsey Cancer Research Institute, Ballarat, Australia
- Health, Innovation and Transformation Centre, Federation University, Ballarat, Australia
| | - Hong-Jian Zhu
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia
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20
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Bazyari MJ, Saadat Z, Firouzjaei AA, Aghaee-Bakhtiari SH. Deciphering colorectal cancer progression features and prognostic signature by single-cell RNA sequencing pseudotime trajectory analysis. Biochem Biophys Rep 2023; 35:101491. [PMID: 37601456 PMCID: PMC10439350 DOI: 10.1016/j.bbrep.2023.101491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 08/22/2023] Open
Abstract
Colorectal cancer is the third most common cancer and second cancer with the highest mortality rate in the world. Progression, which leads to metastasis, is one of the biggest challenges in cancer treatment, and despite improvement in screening and treatment techniques, 5 years of survival of colorectal cancer patients drop from 91% in stage I to 12% in stage IV. Single-cell RNA sequencing is one of the most powerful tools to study complex diseases such as cancer, and despite its recent emergence, it's rapidly growing. In contrast to bulk RNA sequencing, which averages out expression of thousands of cells, single-cell RNA sequencing can capture intra-tumor heterogeneity. Moreover, cellular dynamic events like progression can be studied by pseudotime trajectory analysis of single-cell RNA sequencing data. Herein we used Samsung Medical Center (SMC) colorectal cancer single-cell RNA sequencing dataset to find important tumor epithelial cells subtypes. Subsequently, we've found important genes with a dynamic pattern along cancer progression by using pseudo-time trajectory analysis. Also, we found TGFB1 and IL1B as effective ligands and several transcription factors which may regulate the expression of pseudo-time related genes. In the end, we've constructed a LASSO cox regression using 20 psudotime genes, which can predict 3-year survival of colorectal cancer patients with AUC >0.7.
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Affiliation(s)
- Mohammad Javad Bazyari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zakie Saadat
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Ahmadizad Firouzjaei
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hamid Aghaee-Bakhtiari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Bioinformatics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Gögenur M, Balsevicius L, Bulut M, Colak N, Justesen TF, Fiehn AMK, Jensen MB, Høst-Rasmussen K, Cappelen B, Gaggar S, Tajik A, Zahid JA, Bennedsen ALB, D'Ondes TDB, Raskov H, Sækmose SG, Hansen LB, Salanti A, Brix S, Gögenur I. Neoadjuvant intratumoral influenza vaccine treatment in patients with proficient mismatch repair colorectal cancer leads to increased tumor infiltration of CD8+ T cells and upregulation of PD-L1: a phase 1/2 clinical trial. J Immunother Cancer 2023; 11:jitc-2023-006774. [PMID: 37172969 DOI: 10.1136/jitc-2023-006774] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND In colorectal cancer, the effects of immune checkpoint inhibitors are mostly limited to patients with deficient mismatch repair tumors, characterized by a high grade infiltration of CD8+T cells. Interventions aimed at increasing intratumoral CD8+T-cell infiltration in proficient mismatch repair tumors are lacking. METHODS We conducted a proof of concept phase 1/2 clinical trial, where patients with non-metastasizing sigmoid or rectal cancer, scheduled for curative intended surgery, were treated with an endoscopic intratumorally administered neoadjuvant influenza vaccine. Blood and tumor samples were collected before the injection and at the time of surgery. The primary outcome was safety of the intervention. Evaluation of pathological tumor regression grade, immunohistochemistry, flow cytometry of blood, tissue bulk transcriptional analyses, and spatial protein profiling of tumor regions were all secondary outcomes. RESULTS A total of 10 patients were included in the trial. Median patient age was 70 years (range 54-78), with 30% women. All patients had proficient mismatch repair Union of International Cancer Control stage I-III tumors. No endoscopic safety events occurred, with all patients undergoing curative surgery as scheduled (median 9 days after intervention). Increased CD8+T-cell tumor infiltration was evident after vaccination (median 73 vs 315 cells/mm2, p<0.05), along with significant downregulation of messenger RNA gene expression related to neutrophils and upregulation of transcripts encoding cytotoxic functions. Spatial protein analysis showed significant local upregulation of programmed death-ligand 1 (PD-L1) (adjusted p value<0.05) and downregulation of FOXP3 (adjusted p value<0.05). CONCLUSIONS Neoadjuvant intratumoral influenza vaccine treatment in this cohort was demonstrated to be safe and feasible, and to induce CD8+T-cell infiltration and upregulation of PD-L1 proficient mismatch repair sigmoid and rectal tumors. Definitive conclusions regarding safety and efficacy can only be made in larger cohorts. TRIAL REGISTRATION NUMBER NCT04591379.
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Affiliation(s)
- Mikail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Lukas Balsevicius
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Mustafa Bulut
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
- Department of Clinical Medicine, University of Copenhagen, Kobenhavn, Denmark
| | - Nesibe Colak
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Tobias Freyberg Justesen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Anne-Marie Kanstrup Fiehn
- Department of Clinical Medicine, University of Copenhagen, Kobenhavn, Denmark
- Department of Pathology, Zealand University Hospital Roskilde, Roskilde, Denmark
| | | | - Kathrine Høst-Rasmussen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Britt Cappelen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Shruti Gaggar
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Asma Tajik
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | - Jawad Ahmad Zahid
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | | | - Tommaso Del Buono D'Ondes
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Hans Raskov
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
| | | | | | - Ali Salanti
- Department of Infectious Diseases, Copenhagen University Hospital, Kobenhavn, Denmark
| | - Susanne Brix
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital Koge, Koge, Denmark
- Department of Clinical Medicine, University of Copenhagen, Kobenhavn, Denmark
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22
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Dehner CA, Moon T, Lyu Y, Zhang X, Zhou Z, Yang K, Chrisinger JSA, Griffin A, Wunder J, Dickson BC, Hirbe AC. Mutations involving TGFB and MAPK may be associated with malignancy in granular cell tumors. Genes Chromosomes Cancer 2023; 62:301-307. [PMID: 36680529 DOI: 10.1002/gcc.23123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 01/11/2023] [Accepted: 01/15/2023] [Indexed: 01/22/2023] Open
Abstract
Granular cell tumors (GrCTs) are mesenchymal neoplasms of presumed schwannian differentiation that may present as solitary or multifocal lesions with excision usually being curative. A minority of cases, however, show histological features associated with an increased risk for metastasis and are highly aggressive leading to death in about a third of cases. While benign and malignant cases have been shown to harbor mutations in the H + ATPase genes, there is only limited data examining molecular aberrations associated with malignancy. The departmental archives were searched for cases of atypical/malignant GrCTs. Clinical and histopathological features were noted. Whole-exome sequencing was performed. Three cases of malignant GrCTs and one case of atypical GrCTs were included. All three malignant tumors metastasized to distant sites with a median disease-free survival of 16 months and an overall follow-up time of 35 months. Whole-exome sequencing showed mutations involving TGFβ and MAPK pathways in all four tumors. Although the cohort size is small, our preliminary findings suggest that mutations involving the TGFβ and MAPK pathways may be associated with tumor progression or malignant transformation in GrCT pathogenesis.
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Affiliation(s)
- Carina A Dehner
- Department of Pathology and Immunology, Division of Anatomic Pathology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Tyler Moon
- Department of Orthopedic Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Yang Lyu
- Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Xiaochun Zhang
- Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Zhaohe Zhou
- Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Kuangying Yang
- Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - John S A Chrisinger
- Department of Pathology and Immunology, Division of Anatomic Pathology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Anthony Griffin
- University Musculoskeletal Oncology Unit, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Jay Wunder
- University Musculoskeletal Oncology Unit, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Brendan C Dickson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Angela C Hirbe
- Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
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Zhang X, Zhang X, Jiang D, Zheng W, Wang H, Tian Y, Cheng B. INHA acts as a novel and potential biomarker in lung adenocarcinoma and shapes the immune-suppressive tumor microenvironment. Transl Oncol 2023; 33:101679. [PMID: 37105130 PMCID: PMC10182329 DOI: 10.1016/j.tranon.2023.101679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 04/05/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND INHA expression has been correlated with the development, growth, and progression of multiple cancer types. However, the biological role of INHA has not been investigated in patients with lung adenocarcinoma (LUAD). Here, we performed a comprehensive bioinformatics analysis of the LUAD dataset to determine the mechanisms underlying the regulation of tumorigenesis by INHA. MATERIALS AND METHODS INHA expression and clinical information of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) database. Protein levels in LUAD cell lines and human lung epithelial cells were examined by western blotting. Next, the prognostic value of INHA in LUAD was assessed using Cox regression analysis, while the potential biological functions and the impact on the immune microenvironment of INHA were investigated using gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA). Finally, the effect of INHA on LUAD cell proliferation and invasion was determined in vitro and in vivo. RESULTS We found significantly high mRNA and protein expression levels of INHA in LUAD tissues and cell lines. Additionally, a higher expression of INHA was linked to a shorter overall survival (OS) and a worse pathological stage, while INHA expression was associated with immune cell infiltration and immune-related markers in the LUAD tumor microenvironment. LUAD with high INHA expression tends to be a cold tumor. Furthermore, GO and KEGG enrichment analysis indicated that INHA-related genes were enriched in the cell adhesion and immune signaling pathways of LUAD. INHA promoted LUAD cell proliferation and invasion, in vitro and in vivo, by inducing the EGFR pathway. CONCLUSION Our findings revealed that INHA is overexpressed in LUAD and is linked to a poor prognosis. Our study demonstrates the potential of INHA as an immunotherapeutic and predictive biomarker in LUAD.
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Affiliation(s)
- Xun Zhang
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China
| | - Xinyu Zhang
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China
| | - Dizhi Jiang
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China
| | - Wendi Zheng
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China
| | - Huimin Wang
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China
| | - Yu Tian
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China.
| | - Bo Cheng
- Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China.
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24
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Pal R, Dutta S. Association Study of Transforming Growth Factor Beta 1 + 29 T/C exon 1 Polymorphism in Breast Cancer Patients from North Indian Population. Appl Biochem Biotechnol 2023; 195:3671-3680. [PMID: 36951937 DOI: 10.1007/s12010-023-04438-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2023] [Indexed: 03/24/2023]
Abstract
BACKGROUND TGFB1 cytokine is involved in normal mammary epithelial development as well as in breast tumorigenesis. It has role in both breast tumor suppression and progression. TGFB1 gene has several single nucleotide polymorphisms (SNPs) many of which modulate the activity of TGFB1. Our aim in this study was to analyze TGFB1 + 29 polymorphism in breast cancer individuals from North Indian population. METHODS TGFB1 + 29 T/C polymorphism was analyzed using Sanger sequencing in 285 breast cancer patients and age matched 363 healthy controls from North Indian population. Next, transcript expression of 13 apoptotic genes, TRAIL, DR4, DR5, DcR1, DcR2, Bcl2, cytochrome c, Casp8L, Casp8, FlipS, FlipL, Casp3s and Casp3 were carried out in 77 breast tumor tissues obtained from 77 individuals. RESULTS TGFB1 + 29 CC genotype provided protection against the development of breast cancer (P = 0.012). This was mainly attributable to higher age group (> 45 years) women (P = 0.016). Individuals having CC protector genotype showed significantly higher expression of TGFB1 transcript compared to the TT and TC risk genotypes (P = 0.044). Furthermore, we observed that TGFB1 + 29 CC genotype showed increased TRAIL mediated apoptosis via the extrinsic pathway in breast tumor patients with age greater than 45 years (P = 0.027). CONCLUSION TGFB1 + 29 homozygous mutant CC genotype is related to protection against breast cancer in North Indian women population greater than 45 years of age.
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Affiliation(s)
- Ranjana Pal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India.
- Department of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
| | - Siddhartha Dutta
- Department of Life Sciences, Jawaharlal Nehru University, New Delhi, India
- Department of Biotechnology, University of Engineering and Management, Kolkata, West Bengal, India
- Department of Microbiology and Biotechnology, Sister Nivedita University, Kolkata, West Bengal, India
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25
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Sun Y, Zhang C, Fang Q, Zhang W, Liu W. Abnormal signal pathways and tumor heterogeneity in osteosarcoma. J Transl Med 2023; 21:99. [PMID: 36759884 PMCID: PMC9912612 DOI: 10.1186/s12967-023-03961-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/01/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Osteosarcoma (OS) is the most frequent and aggressive primary malignant sarcoma among adolescents and chemotherapy has not substantially progressed for decades. New insights into OS development and therapeutic strategies are urgently needed. METHODS We analyzed integrated single-cell transcriptomes, bulk RNA-seq, and microarray data from Gene Expression Omnibus (GEO) datasets. We also used Weighted Gene Co-expression Network Analysis (WGCNA), Gene set enrichment analysis (GSEA), and Gene set variation analysis (GSVA), along with Simple ClinVar and Enrichr web servers. RESULTS The findings of integrated single-cell analysis showed that OS arises from imperfect osteogenesis during development. Novel abnormalities comprised deficient TGFβ and P53 signal pathways, and cell cycle pathway activation, and a potentially new driver mutation in the interferon induced transmembrane protein 5 (IFITM5) that might function as a pathogenic factor in OS. Osteosarcoma is characterized by oncocyte heterogeneity, especially in immunogenic and adipocyte-like subtypes that respectively promote and hamper OS treatment. Etoposide is a promising chemotherapeutic that provides palliation by affecting the subtype of OS and correcting the abnormal pathways. CONCLUSION Various abnormal signal pathways play indispensable roles in OS development. We explored the heterogeneity and underlying mechanisms of OS and generated findings that will assist with OS assessment and selecting optimal therapies.
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Affiliation(s)
- Yifeng Sun
- grid.452422.70000 0004 0604 7301Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014 Shandong People’s Republic of China ,grid.410712.10000 0004 0473 882XDepartment of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Chunming Zhang
- grid.452422.70000 0004 0604 7301Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014 Shandong People’s Republic of China
| | - Qiongxuan Fang
- grid.11135.370000 0001 2256 9319MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871 China
| | - Wenqiang Zhang
- grid.452422.70000 0004 0604 7301Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014 Shandong People’s Republic of China
| | - Wei Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014, Shandong, People's Republic of China.
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26
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Kimura Y, Fujimori M, Rajagopalan NR, Poudel K, Kim K, Nagar K, Vroomen LGPH, Reis H, Al-Ahmadie H, Coleman JA, Srimathveeravalli G. Macrophage activity at the site of tumor ablation can promote murine urothelial cancer via transforming growth factor-β1. Front Immunol 2023; 14:1070196. [PMID: 36761730 PMCID: PMC9902765 DOI: 10.3389/fimmu.2023.1070196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/02/2023] [Indexed: 01/26/2023] Open
Abstract
Cell death and injury at the site of tumor ablation attracts macrophages. We sought to understand the status and activity of these cells while focusing on transforming growth factor-β1 (TGF-β1), a potent immunosuppressive and tumorigenic cytokine. Patients with urothelial cancer who underwent ablation using electrocautery or laser demonstrated increased infiltration and numbers of CD8+ T cells, along with FoxP3+ regulatory T cells, CD68+ macrophages and elevated levels of TGF-β1 in recurrent tumors. Similar findings were reproduced in a mouse model of urothelial cancer (MB49) by partial tumor ablation with irreversible electroporation (IRE). Stimulation of bone marrow derived macrophages with MB49 cell debris produced using IRE elicited strong M2 polarization, with exuberant secretion of TGF-β1. The motility, phenotypic markers and cytokine secretion by macrophages could be muted by treatment with Pirfenidone (PFD), a clinically approved drug targeting TGF-β1 signaling. MB49 cancer cells exposed to TGF-β1 exhibited increased migration, invasiveness and upregulation of epithelial-mesenchymal transition markers α-Smooth Muscle Actin and Vimentin. Such changes in MB49 cells were reduced by treatment with PFD even during stimulation with TGF-β1. IRE alone yielded better local tumor control when compared with control or PFD alone, while also reducing the overall number of lung metastases. Adjuvant PFD treatment did not provide additional benefit under in vivo conditions.
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Affiliation(s)
- Yasushi Kimura
- Department of Diagnosis and Interventional Radiology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Dept. of Mechanical and Industrial Engineering, University of Massachusetts Amherst,
Amherst, MA, United States
| | | | | | - Krish Poudel
- Dept. of Mechanical and Industrial Engineering, University of Massachusetts Amherst,
Amherst, MA, United States
| | - Kwanghee Kim
- Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, United States
| | - Karan Nagar
- Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, United States
| | - Laurien GPH. Vroomen
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center (UMC), Amsterdam, Netherlands
| | - Henning Reis
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Hikmat Al-Ahmadie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jonathan A. Coleman
- Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, United States
| | - Govindarajan Srimathveeravalli
- Dept. of Mechanical and Industrial Engineering, University of Massachusetts Amherst,
Amherst, MA, United States
- Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, United States
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27
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Hanna DN, Smith PM, Novitskiy SV, Washington MK, Zi J, Weaver CJ, Hamaamen JA, Lewis KB, Zhu J, Yang J, Liu Q, Beauchamp RD, Means AL. SMAD4 Suppresses Colitis-associated Carcinoma Through Inhibition of CCL20/CCR6-mediated Inflammation. Gastroenterology 2022; 163:1334-1350.e14. [PMID: 35863523 PMCID: PMC9613509 DOI: 10.1053/j.gastro.2022.07.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 06/16/2022] [Accepted: 07/07/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS We previously reported that colon epithelial cell silencing of Smad4 increased epithelial expression of inflammatory genes, including the chemokine c-c motif chemokine ligand 20 (CCL20), and increased susceptibility to colitis-associated cancer. Here, we examine the role of the chemokine/receptor pair CCL20/c-c motif chemokine receptor 6 (CCR6) in mediating colitis-associated colon carcinogenesis induced by SMAD4 loss. METHODS In silico analysis of SMAD4, CCL20, and CCR6 messenger RNA expression was performed on published transcriptomic data from human ulcerative colitis (UC), and colon and rectal cancer samples. Immunohistochemistry for CCL20 and CCR6 was performed on human tissue microarrays comprising human UC-associated cancer specimens, Mice with conditional, epithelial-specific Smad4 loss with and without germline deletion of the Ccr6 gene were subjected to colitis and followed for up to 3 months. Tumors were quantified histologically, and immune cell populations were analyzed by flow cytometry and immunostaining. RESULTS In human UC-associated cancers, loss of epithelial SMAD4 was associated with increased CCL20 expression and CCR6+ cells. SMAD4 loss in mouse colon epithelium led to enlarged gut-associated lymphoid tissues and recruitment of immune cells to the mouse colon epithelium and stroma, particularly T regulatory, Th17, and dendritic cells. Loss of CCR6 abrogated these immune responses and significantly reduced the incidence of colitis-associated tumors observed with loss of SMAD4 alone. CONCLUSIONS Regulation of mucosal inflammation is central to SMAD4 tumor suppressor function in the colon. A key downstream node in this regulation is suppression of epithelial CCL20 signaling to CCR6 in immune cells. Loss of SMAD4 in the colon epithelium increases CCL20 expression and chemoattraction of CCR6+ immune cells, contributing to greater susceptibility to colon cancer.
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Affiliation(s)
- David N Hanna
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Paula Marincola Smith
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Sergey V Novitskiy
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - M Kay Washington
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jinghuan Zi
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Connie J Weaver
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jalal A Hamaamen
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keeli B Lewis
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jing Zhu
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jing Yang
- Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Qi Liu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - R Daniel Beauchamp
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
| | - Anna L Means
- Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
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28
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Takasugi M, Yoshida Y, Ohtani N. Cellular senescence and the tumour microenvironment. Mol Oncol 2022; 16:3333-3351. [PMID: 35674109 PMCID: PMC9490140 DOI: 10.1002/1878-0261.13268] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/16/2022] [Accepted: 06/07/2022] [Indexed: 12/04/2022] Open
Abstract
The senescence-associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP-mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour-suppressive and tumour-promoting effects, as observed in senescence surveillance effects (tumour-suppressive) and suppression of anti-tumour immunity in most senescent cancer-associated fibroblasts and senescent T cells (tumour-promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context-dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.
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Affiliation(s)
- Masaki Takasugi
- Department of Pathophysiology, Graduate School of MedicineOsaka Metropolitan University (formerly, Osaka City University)OsakaJapan
| | - Yuya Yoshida
- Department of Pathophysiology, Graduate School of MedicineOsaka Metropolitan University (formerly, Osaka City University)OsakaJapan
| | - Naoko Ohtani
- Department of Pathophysiology, Graduate School of MedicineOsaka Metropolitan University (formerly, Osaka City University)OsakaJapan
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29
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Dai Y, Wang H, Sun R, Diao J, Ma Y, Shao M, Xu Y, Zhang Q, Gao Z, Zeng Z, Zhang L, Sun X. Modified Shenlingbaizhu Decoction represses the pluripotency of colorectal cancer stem cells by inhibiting TGF-β mediated EMT program. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 103:154234. [PMID: 35689903 DOI: 10.1016/j.phymed.2022.154234] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 05/25/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND The Modified Shenlingbaizhu Decoction (MSD) utilizes various phytomedicines has been applied to treat colorectal cancer (CRC). Colorectal cancer stem cells (CSCs) have proven to be tightly associated with CRC progression and metastasis. The mechanism of MSD's inhibitory effect on CSCs has not been determined. PURPOSE To figure out how MSD inhibits the pluripotency of CSCs and impedes the EMT program. METHODS The ingredients of MSD extracts were characterized by high-performance liquid chromatography (HPLC). BALB/c-nu mice were transplanted into EGFP labeled SW480 CRC cells and the tumor weight and volume were recorded before and after various doses of MSD treatment. The concentration of TGF-β1 was quantified with an Enzyme-linked immunosorbent assay. To delineate the logical relationship between EMT and CSCs regulated by MSD, TGF-β/Smad inhibitor and activator were adopted in tumor-bearing mice and diverse CRC cell lines. Cancer stem cell markers were analyzed by flow cytometry. In vitro analysis of cell motility and viability were done using CCK-8, wound healing, and invasion assay. Immunohistochemistry (IHC) and western blotting (WB) were used for detecting protein expression. The collected results were statistically analyzed with GraphPad Prism 8.0. RESULTS MSD treatment significantly reduced the size of colorectal cancer tumors and lowered the serum content of TGF-β1 in mice. Importantly, MSD markedly reduced the expression of pluripotent factors and depressed CD133+ stem cells in the tumor tissues. The TGF-β/Smad inhibitor neutralized the EMT signaling and lowered the pluripotency by dephosphorylation of SMAD2/3. Similarly, MSD attenuated the pluripotency by limiting TGF-β/Smad signaling-induced EMT in vivo. MSD inhibited colorectal cancer cell proliferation, migration, and invasion. CONCLUSIONS MSD inhibits the growth of colorectal cancer. It dampens the pluripotency of CSCs by repressing the TGF-β-induced EMT program.
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Affiliation(s)
- Yu Dai
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Hao Wang
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Ruibo Sun
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jianxin Diao
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Ye Ma
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Meng Shao
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yihua Xu
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Qingyuan Zhang
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Zhuowei Gao
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China; Shunde Hospital, Guangzhou University of Chinese Medicine, Foshan, 528333, Guangdong, China
| | - Zhiyun Zeng
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Lihua Zhang
- Traditional Chinese Medicine Integrated Hospital, Southern Medical University, Guangzhou, 510315, Guangdong, China
| | - Xuegang Sun
- The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China; Department of traditional Chinese medicine, Zhujiang Hospital of Southern Medical University, Guangzhou, 510260, Guangdong, China.
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Jung YY, Mohan CD, Eng H, Narula AS, Namjoshi OA, Blough BE, Rangappa KS, Sethi G, Kumar AP, Ahn KS. 2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells. Biomolecules 2022; 12:891. [PMID: 35883447 PMCID: PMC9312507 DOI: 10.3390/biom12070891] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 02/01/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial process in which the polarized epithelial cells acquire the properties of mesenchymal cells and gain invasive properties. We have previously demonstrated that manganese superoxide dismutase (MnSOD) can regulate the EMT phenotype by modulating the intracellular reactive oxygen species. In this report, we have demonstrated the EMT-suppressive effects of 2,3,5,6-Tetramethylpyrazine (TMP, an alkaloid isolated from Chuanxiong) in colon cancer cells. TMP suppressed the expression of MnSOD, fibronectin, vimentin, MMP-9, and N-cadherin with a parallel elevation of occludin and E-cadherin in unstimulated and TGFβ-stimulated cells. Functionally, TMP treatment reduced the proliferation, migration, and invasion of colon cancer cells. TMP treatment also modulated constitutive activated as well as TGFβ-stimulated PI3K/Akt/mTOR, Wnt/GSK3/β-catenin, and MAPK signaling pathways. TMP also inhibited the EMT program in the colon cancer cells-transfected with pcDNA3-MnSOD through modulation of MnSOD, EMT-related proteins, and oncogenic pathways. Overall, these data indicated that TMP may inhibit the EMT program through MnSOD-mediated abrogation of multiple signaling events in colon cancer cells.
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Affiliation(s)
- Young Yun Jung
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
| | | | - Huiyan Eng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | | | - Ojas A. Namjoshi
- Engine Biosciences, 733 Industrial Rd., San Carlos, CA 94070, USA;
| | - Bruce E. Blough
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27616, USA;
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea;
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31
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Aljohani AA, Alqarni YS, Alrashidi MN, Aljuhani MH, Shehata SA, El-Kherbetawy MK, Prabahar K, Alshaman R, Alattar A, Helaly AMN, Ateyya H, Ismail EA, Zaitone SA. The Anti-Rheumatic Drug, Leflunomide, Induces Nephrotoxicity in Mice via Upregulation of TGFβ-Mediated p53/Smad2/3 Signaling. TOXICS 2022; 10:274. [PMID: 35622687 PMCID: PMC9144816 DOI: 10.3390/toxics10050274] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/15/2022] [Accepted: 05/19/2022] [Indexed: 02/01/2023]
Abstract
Recent studies indicated renal toxicity and interstitial nephritis in patients receiving leflunomide (LEFN), but the exact mechanism is still unknown. The transforming growth factor β (TGFβ)/p53/Smad2/3 pathway crucially mediates renal fibrosis. We aimed to assess the nephrotoxic effect of LEFN in mice and the possible role of TGFβ-stimulated p53/SMAD2/3 signaling. The study design involved distributing sixty male albino mice into four groups: (i) vehicle-treated mice, (ii) LEFN (2.5 mg/kg), (iii) LEFN (5 mg/kg), and (iv) LEFN (10 mg/kg). The drug was given orally every 48 h and continued for 8 weeks. Blood samples were then taken from mice for the determination of kidney function parameters. Right kidneys were used for histopathologic staining and immunohistochemistry, whereas left kidneys were frozen and used for Western blot analysis of the target proteins, p-p53 and Smad2/3. Results indicated that chronic administration of LEFN in mice resulted in a four- and nine-fold increase in serum urea and creatinine levels, respectively. Kidney specimens stained with hematoxylin and eosin or periodic acid-Schiff showed significant histopathological manifestations, such as cellular irregularity, interstitial congestion, and moderate lymphocytic inflammatory infiltrate in mice treated with LEFN. Western blotting indicated upregulation of the p-p53/Smad2/3 proteins. LEFN, especially in the highest dose (10 mg/kg), produced prominent nephrotoxicity in mice. This toxicity is mediated through stimulating fibrotic changes through TGFβ-stimulated p53/Smad2/3 signaling and induction of glomerular and tubular apoptosis. An improved understanding of LEFN-induced nephrotoxicity would have great implications in the prediction, prevention, and management of leflunomide-treated rheumatic patients, and may warrant further clinical studies for following up these toxidromes.
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Affiliation(s)
- Alhanouf A. Aljohani
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Yasmeen S. Alqarni
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Maram N. Alrashidi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Maha H. Aljuhani
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Shaimaa A. Shehata
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | | | - Kousalya Prabahar
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Reem Alshaman
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.); (A.A.)
| | - Abdullah Alattar
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.); (A.A.)
| | - Ahmed M. N. Helaly
- Department of Forensic Medicine and Toxicology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
- Clinical Science, Faculty of Medicine, Yarmouk University, Irbid 566, Jordan
| | - Hayam Ateyya
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Giza 11559, Egypt; or
- Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt
| | - Ezzat A. Ismail
- Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Sawsan A. Zaitone
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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Parthenolide reverses the epithelial to mesenchymal transition process in breast cancer by targeting TGFbeta1: In vitro and in silico studies. Life Sci 2022; 301:120610. [PMID: 35525305 DOI: 10.1016/j.lfs.2022.120610] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/23/2022] [Accepted: 04/30/2022] [Indexed: 12/12/2022]
Abstract
AIMS Breast cancer metastasis is the leading cause of mortality among breast cancer patients. Epithelial to mesenchymal transition (EMT) is a biological process that plays a fundamental role in facilitating breast cancer metastasis. The present study assessed the efficacy of parthenolide (PTL Tanacetum parthenium) on EMT and its underlying mechanisms in both lowly metastatic, estrogen-receptor positive, MCF-7 cells and highly metastatic, triple-negative MDA-MB-231 cells. MAIN METHODS MCF-7 and MDA-MB-231 cells were treated with PTL (2 μM and 5 μM). Cell viability was determined by MTT (3-(4,5-dimethy lthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Apoptosis was analyzed by the FITC (fluorescein isothiocyanate) annexin V apoptosis detection kit. The monolayer wound scratch assay was employed to evaluate cancer cell migration. Proteins were separated and identified by Western blotting. Gene expression was analyzed by quantitative real-time PCR. KEY FINDINGS PTL treatment significantly reduced cell viability and migration while inducing apoptosis in both cell lines. Also, PTL treatment reverses the EMT process by decreasing the mesenchymal marker vimentin and increasing the epithelial marker E-cadherin compared to the control treatment. Importantly, PTL downregulates TWIST1 (a transcription factor and regulator of EMT) gene expression, concomitant with the reduction of transforming growth factor beta1 (TGFβ1) protein and gene expression in both cell lines. Additionally, molecular docking studies suggest that PTL may induce anticancer properties by targeting TGFβ1 in both breast cancer cell lines. SIGNIFICANCE Our findings provide insights into the therapeutic potential of PTL to mitigate EMT and breast cancer metastasis. These promising results demand in vivo studies.
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Shukla P, Yeleswarapu S, Heinrich M, Prakash J, Pati F. Mimicking Tumor Microenvironment by 3D Bioprinting: 3D Cancer Modeling. Biofabrication 2022; 14. [PMID: 35512666 DOI: 10.1088/1758-5090/ac6d11] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/05/2022] [Indexed: 11/12/2022]
Abstract
The tumor microenvironment typically comprises cancer cells, tumor vasculature, stromal components like fibroblasts, and host immune cells that assemble to support tumorigenesis. However, preexisting classic cancer models like 2D cell culture methods, 3D cancer spheroids, and tumor organoids seem to lack essential tumor microenvironment components. 3D bioprinting offers enormous advantages for developing in vitro tumor models by allowing user-controlled deposition of multiple biomaterials, cells, and biomolecules in a predefined architecture. This review highlights the recent developments in 3D cancer modeling using different bioprinting techniques to recreate the TME. 3D bioprinters enable fabrication of high-resolution microstructures to reproduce TME intricacies. Furthermore, 3D bioprinted models can be applied as a preclinical model for versatile research applications in the tumor biology and pharmaceutical industries. These models provide an opportunity to develop high-throughput drug screening platforms and can further be developed to suit individual patient requirements hence giving a boost to the field of personalized anti-cancer therapeutics. We underlined the various ways the existing studies have tried to mimic the TME, mimic the hallmark events of cancer growth and metastasis within the 3D bioprinted models and showcase the 3D drug-tumor interaction and further utilization of such models to develop personalized medicine.
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Affiliation(s)
- Priyanshu Shukla
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Hyderabad, Telangana, 502285, INDIA
| | - Sriya Yeleswarapu
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Hyderabad, Telangana, 502285, INDIA
| | - Marcel Heinrich
- Department of Biomaterials, Science and Technology, University of Twente Faculty of Science and Technology, Department of Biomaterials, Science and Technology, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7500AE, Enschede, The Netherlands, Enschede, Overijssel, 7500 AE, NETHERLANDS
| | - Jai Prakash
- Department of Biomaterials, Science and Technology, University of Twente Faculty of Science and Technology, Department of Biomaterials, Science and Technology, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7500AE, Enschede, The Netherlands, Enschede, Overijssel, 7500 AE, NETHERLANDS
| | - Falguni Pati
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Hyderabad, Telangana, 502285, INDIA
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Nagao M, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Taketo MM, Ferrer J, Tsuruyama T, Nakanuma Y, Taura K, Uemoto S, Seno H. Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice. Cancer Res 2022; 82:1803-1817. [PMID: 35247892 DOI: 10.1158/0008-5472.can-21-2176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 12/31/2021] [Accepted: 02/25/2022] [Indexed: 11/16/2022]
Abstract
Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFβ pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFβ signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFβ pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. SIGNIFICANCE This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.
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Affiliation(s)
- Munemasa Nagao
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Mayuki Omatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Mio Namikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Makoto Sono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuichi Fukunaga
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.,Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Tomonori Masuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Osamu Araki
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takaaki Yoshikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Satoshi Ogawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Kenji Masuo
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Norihiro Goto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Makoto Mark Taketo
- Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka, Japan.,iACT, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan
| | - Jorge Ferrer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Spain.,Genetics and Genomics Section, Department of Metabolism, Digestion and Reproduction, National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Imperial College London, London, United Kingdom
| | - Tatsuaki Tsuruyama
- Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yasuni Nakanuma
- Department of Diagnostic Pathology, Fukui Prefecture Saiseikai Hospital, Fukui, Japan
| | - Kojiro Taura
- Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
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De Luca F, Di Chio C, Zappalà M, Ettari R. Dihydrochalcones as antitumor agents. Curr Med Chem 2022; 29:5042-5061. [PMID: 35430969 DOI: 10.2174/0929867329666220415113219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/16/2022] [Accepted: 01/25/2022] [Indexed: 11/22/2022]
Abstract
Dihydrochalcones are a class of secondary metabolites, possessing several biological properties such as antitumor, antioxidant, antibacterial, antidiabetic, estrogenic, anti-inflammatory, antithrombotic, antiviral, neuroprotective and immunomodulator properties; therefore, they are currently considered promising candidates in the drug discovery process. This review intend to debate their pharmacological actions with a particular attention to their antitumor activity against a panel of cancer cell-lines and to the description of the inhibition mechanisms of cell proliferation such as the regulation of angiogenesis, apoptosis, etc etc.
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Affiliation(s)
- Fabiola De Luca
- Department of Chemical, Biological, Pharmaceutical and Environmental Chemistry, University of Messina, Italy
| | - Carla Di Chio
- Department of Chemical, Biological, Pharmaceutical and Environmental Chemistry, University of Messina, Italy
| | - Maria Zappalà
- Department of Chemical, Biological, Pharmaceutical and Environmental Chemistry, University of Messina, Italy
| | - Roberta Ettari
- Department of Chemical, Biological, Pharmaceutical and Environmental Chemistry, University of Messina, Italy
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AMTB, a TRPM8 antagonist, suppresses growth and metastasis of osteosarcoma through repressing the TGFβ signaling pathway. Cell Death Dis 2022; 13:288. [PMID: 35361751 PMCID: PMC8971393 DOI: 10.1038/s41419-022-04744-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 02/23/2022] [Accepted: 03/18/2022] [Indexed: 12/15/2022]
Abstract
Since its first identification in prostate cancers and prostate tissues, transient receptor potential melastatin-subfamily member 8 (TRPM8) is subsequently found to be overexpressed in a wide range of cancers and is shown to be implicated in tumorigenesis and tumor progression. Here, we used N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy] -N-(2-thienylmethyl) benzamide hydrochloride (AMTB), a specific TRPM8 antagonist, to explore its antitumoral effect on osteosarcoma. We find that AMTB suppresses osteosarcoma cell proliferation, metastasis and induces cellular apoptosis. Xenograft model in nude mice experiments also define that AMTB can increase the sensitivity of tumor cells to cisplatin, the cytotoxic chemotherapeutic regimens in treating osteosarcoma. Molecularly, AMTB specifically antagonizes TRPM8 which is upregulated in osteosarcoma and its expression level in osteosarcoma tissues is negatively related to patients’ prognosis. Finally, RNA sequencing analysis was performed to explore the mechanism underlying the antitumoral effect of AMTB on osteosarcoma cells and the results prove that AMTB suppresses the Transforming Growth Factor β (TGFβ) signaling pathway. Our study provides evidence that TRPM8 could be a potential therapeutic target and AMTB can suppress growth and metastasis of osteosarcoma cells through repressing the TGFβ signaling pathway and increase the sensitivity of tumor cells to cisplatin.
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37
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Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 144] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
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Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
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He Y, Zhang H, Zhang Y, Wang P, Zhu K, Ba Y. Comprehensive Characterization of Transforming Growth Factor Beta Receptor 1 in Stomach Adenocarcinoma Identifies a Prognostic Signature for Predicting Clinical Outcomes and Immune Infiltrates. Int J Gen Med 2022; 15:3375-3391. [PMID: 35368798 PMCID: PMC8965104 DOI: 10.2147/ijgm.s353879] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/08/2022] [Indexed: 11/30/2022] Open
Abstract
Background Stomach adenocarcinoma (STAD) ranks as the third leading cause of cancer death worldwide. TGF‑β receptor 1 (TGFBR1), serving important roles in the TGF‑β family, the mechanisms whereby TGFBR1 governs tumor progression, immune cell infiltration in STAD remains unintelligible. Methods We used the TCGA, GEPIA, and HPA databases to explore TGFBR1 expression in STAD, the correlation between TGFBR1 expression and the clinical features. A receiver operating characteristic (ROC) curve and nomogram were constructed, and LASSO (the Least Absolute Shrinkage and Selection Operator)-selected features were used to build the TGFBR1 prognostic signature. GSEA is used to find the potential mechanism of TGFBR1 to promote the malignant process of STAD. We explored the influence of the TGFBR1 on the immune microenvironment of STAD through the TIMER2.0 and GEPIA database. Results In our study, TGFBR1 expression was significantly elevated in STAD and positively co-expression with pathologic stage, lymph node metastases (LNM) stage and histopathological grade. Nine factors with non-zero coefficients were identified by LASSO-selected features. Survival analysis revealed that patients with high TGFBR1 had shorter OS, FP, and PPS. Multivariate Cox analysis revealed that TGFBR1 was an independent prognostic factor for OS in STAD. The ROC analysis suggested that high diagnostic value with the AUC of TGFBR1 was 0.739. GSEA revealed that high TGFBR1 expression was correlated with pathway in cancer, MAPK signaling pathway, NOTCH signaling pathway, and VEGF-C production. ssGSEA showed that TGFBR1 is correlated with NK cells, Tem and Th17 cells. Furthermore, elevated TGFBR1 expression was found to be significantly correlated with several immune checkpoint and immune markers associated with immune cell subsets. Conclusion In summary, TGFBR1 could be a prognostic biomarker and an important regulator of immune cell infiltration in STAD. The present study revealed the probable underlying molecular mechanisms of TGFBR1 in STAD and provided a potential target for improving the prognosis.
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Affiliation(s)
- Yi He
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
| | - Haiyang Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
| | - Yan Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
- Department of Gastroenterology, Tianjin Haihe Hospital, Tianjin, 300350, People’s Republic of China
| | - Peiyun Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
| | - Kegan Zhu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
| | - Yi Ba
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
- Correspondence: Yi Ba, Email
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Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, Hameed Zargar M, Afroze D. Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front Pharmacol 2022; 13:791272. [PMID: 35295334 PMCID: PMC8918694 DOI: 10.3389/fphar.2022.791272] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 02/09/2022] [Indexed: 12/11/2022] Open
Abstract
A ubiquitously expressed cytokine, transforming growth factor-beta (TGF-β) plays a significant role in various ongoing cellular mechanisms. The gain or loss-of-function of TGF-β and its downstream mediators could lead to a plethora of diseases includes tumorigenesis. Specifically, at the early onset of malignancy TGF-β act as tumour suppressor and plays a key role in clearing malignant cells by reducing the cellular proliferation and differentiation thus triggers the process of apoptosis. Subsequently, TGF-β at an advanced stage of malignancy promotes tumorigenesis by augmenting cellular transformation, epithelial-mesenchymal-transition invasion, and metastasis. Besides playing the dual roles, depending upon the stage of malignancy, TGF-β also regulates cell fate through immune and stroma components. This oscillatory role of TGF-β to fight against cancer or act as a traitor to collaborate and crosstalk with other tumorigenic signaling pathways and its betrayal within the cell depends upon the cellular context. Therefore, the current review highlights and understands the dual role of TGF-β under different cellular conditions and its crosstalk with other signaling pathways in modulating cell fate.
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Huang X, Yang Z, Zhang J, Wang R, Fan J, Zhang H, Xu R, Li X, Yu S, Long L, Huang H. A Bibliometric Analysis Based on Web of Science: Current Perspectives and Potential Trends of SMAD7 in Oncology. Front Cell Dev Biol 2022; 9:712732. [PMID: 35252215 PMCID: PMC8894759 DOI: 10.3389/fcell.2021.712732] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 12/31/2021] [Indexed: 12/11/2022] Open
Abstract
Background: The number of publications on SMAD7 in the field of oncology is increasing rapidly with an upward tendency. In most cases, the mechanisms of carcinogenesis usually relate to disorders of signaling activity. Considering the crucial role of SMAD7 in the crosstalk of multiple signaling pathways, it is necessary to clarify and define the dominant research topics, core authors, and their cumulative research contributions, as well as the cooperative relationships among documents or researchers. Methods: Altogether, 3477 documents were retrieved from the Web of Science Core Collection with the following criteria: TS= (SMAD7 OR SMAD7-protein OR Small-Mothers-Against-Decapentaplegic-7) refined by WEB OF SCIENCE CATEGORY (ONCOLOGY) AND [excluding] PUBLICATION YEARS (2021) AND DOCUMENT TYPES (ARTICLE OR REVIEW) AND LANGUAGES (ENGLISH) AND WEB OF SCIENCE INDEX (Web of Science Core Collection, SCI), and the timespan of 2011–2020. Bibliometric visualization analysis was conducted with CiteSpace and VOSviewer. Results: The number of documents grew each year. A total of 2703 articles and 774 reviews were identified from 86 countries/regions, 3524 organizations, 928 journals, and 19,745 authors. China was the most prolific country, with 1881 documents. Contributions from China, the United States, and Germany were the most substantial. The most influential author was Lan Huiyao at The Chinese University of Hong Kong, with 24 publications and 2348 total citations. The bibliometric analysis showed that multilateral cooperation among diverse institutions or investigators was beneficial to high-quality outputs. The keyword “PPAR-gamma” exhibited the strongest burst in recent years, suggesting a potent research focus in the future. Conclusion: Research on SMAD7 in oncology is continuously developing. Bibliometrics is an interesting tool to present the characteristics of publication years, main authors, and productive organizations in a visualized way. It is worth mentioning that a prospective focus might be the specific mechanism of the interaction of PPAR-gamma with SMAD7 in oncology. In all, bibliometric analysis provides an overview and identifies potential research trends for further studies in this academic field.
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Affiliation(s)
- Xueying Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhiying Yang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
- Changsha Health Vocational College, Changsha, China
| | - Jinning Zhang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruojiao Wang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Jiahui Fan
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Heng Zhang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Rong Xu
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Xia Li
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
- Department of Histology and Embryology, School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
| | - Siying Yu
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Linna Long
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
- *Correspondence: He Huang,
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Yang MH, Jung SH, Um JY, Kumar AP, Sethi G, Ahn KS. Daidzin targets epithelial-to-mesenchymal transition process by attenuating manganese superoxide dismutase expression and PI3K/Akt/mTOR activation in tumor cells. Life Sci 2022; 295:120395. [PMID: 35181309 DOI: 10.1016/j.lfs.2022.120395] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/26/2021] [Accepted: 02/08/2022] [Indexed: 12/14/2022]
Abstract
AIMS Epithelial-mesenchymal transition (EMT) is a process during which epithelial cells lose their polarity and gain invasive properties to transform into mesenchymal cells. A few recent studies have reported that manganese superoxide dismutase (MnSOD) can effectively modulate EMT phenotype by influencing cellular redox environment via altering the intracellular ratio between O2- and H2O2. Daidzin (DDZ), a naturally occurring isoflavone isolated from Pueraria lobate (Fabaceae), has numerous pharmacologic effects including anti-cholesterol, anti-angiocardiopathy, anti-cancer. However, the potential inhibitory impact of DDZ on cancer metastasis and specifically on the EMT process has not been evaluated. We aimed to evaluate the possible relationship between MnSOD and EMT as well as influence of DDZ on these two processes in colon and prostate carcinoma cells. MAIN METHODS Cell viability was measured by MTT and real time cell analysis (RTCA) assay. Protein expression level of EMT markers and Akt/mTOR/PI3K signaling pathway were evaluated by Western blot analysis. Expression of EMT markers in cells was observed by immunocytochemistry. Cell invasion and migrations were evaluated by wound healing assay and Boyden chamber assay. KEY FINDINGS DDZ can block EMT accompanied with down-regulation of MnSOD, fibronectin, vimentin, MMP-9, MMP-2, N-cadherin, twist, and Snail, and up-regulation of occludin and E-cadherin in both unstimulated and TGFβ-induced cells. In addition, DDZ exposure also attenuated cell proliferation, invasion, and metastasis by reversing the EMT process in SNU-C2A, DU145, and PC-3 cells. DDZ treatment also modulated activation of PI3K/Akt/mTOR signaling cascades in DU145 cells. Moreover, an overexpression of MnSOD or silencing of MnSOD expression modulated EMT-related proteins, PI3K/Akt/mTOR activation and invasive activity. SIGNIFICANCE This is first finding on the DDZ in regulating MnSOD and EMT process by targeting PI3K/Akt/mTOR pathway in both colorectal and prostate cancer cell lines. Our data indicated that DDZ might act as a potent suppressor of EMT by affecting MnSOD expression in tumor cells.
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Affiliation(s)
- Min Hee Yang
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sang Hoon Jung
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Young Um
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.
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Feng D, Shi X, Xiong Q, Zhang F, Li D, Yang L. A Gene Prognostic Index Associated With Epithelial-Mesenchymal Transition Predicting Biochemical Recurrence and Tumor Chemoresistance for Prostate Cancer. Front Oncol 2022; 11:805571. [PMID: 35096608 PMCID: PMC8790245 DOI: 10.3389/fonc.2021.805571] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/14/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We aimed to establish a novel epithelial-mesenchymal transition (EMT)-related gene prognostic index (EMTGPI) associated with biochemical recurrence (BCR) and drug resistance for prostate cancer (PCa). METHODS We used Lasso and Cox regression analysis to establish the EMTGPI. All analyses were conducted with R version 3.6.3 and its suitable packages. RESULTS We established the EMTGPI based on SFRP4 and SPP1. Patients in high-risk group had 2.23 times of BCR risk than those in low-risk group (p = 0.003), as well as 2.36 times of metastasis risk (p = 0.053). In external validation, we detected similar diagnostic efficacy and prognostic value in terms of BCR free survival. For drug resistance, we observe moderately diagnostic accuracy of EMTGPI score (AUC: 0.804). We found that PDCD1LG2 (p = 0.04) and CD96 (p = 0.01) expressed higher in BCR patients compared with their counterpart. For TME analysis, we detected that CD8+ T cells and M1 macrophages expressed higher in BCR group. Moreover, stromal score (p = 0.003), immune score (p = 0.01), and estimate score (p = 0.003) were higher in BCR patients. We found that EMTGPI was significantly related to HAVCR2 (r: 0.34), CD96 (r: 0.26), CD47 (r: 0.22), KIR3DL1 (r: -0.21), KLRD1 (r: -0.21), and CD2 (r: 0.21). In addition, we observed that EMTGPI was significantly associated with M1 macrophages (r: 0.6), M2 macrophages (r: -0.33), monocytes (r: -0.18), neutrophils (r: -0.43), CD8+ T cells (r: 0.13), and dendritic cells (r: 0.37). PHA-793887 was the common drug sensitive to SPP1 and SFRP4, and PC3 and DU145 were the common PCa-related cell lines of SPP1, SFRP4, and PHA-793887. CONCLUSIONS We concluded that the EMTGPI score based on SFRP4 and SPP1 could be used to predict BCR for PCa patients. We confirmed the impact of immune evasion on the BCR process of PCa.
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Affiliation(s)
| | | | | | | | | | - Lu Yang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
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Zhang M, Zhang YY, Chen Y, Wang J, Wang Q, Lu H. TGF-β Signaling and Resistance to Cancer Therapy. Front Cell Dev Biol 2021; 9:786728. [PMID: 34917620 PMCID: PMC8669610 DOI: 10.3389/fcell.2021.786728] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
The transforming growth factor β (TGF-β) pathway, which is well studied for its ability to inhibit cell proliferation in early stages of tumorigenesis while promoting epithelial-mesenchymal transition and invasion in advanced cancer, is considered to act as a double-edged sword in cancer. Multiple inhibitors have been developed to target TGF-β signaling, but results from clinical trials were inconsistent, suggesting that the functions of TGF-β in human cancers are not yet fully explored. Multiple drug resistance is a major challenge in cancer therapy; emerging evidence indicates that TGF-β signaling may be a key factor in cancer resistance to chemotherapy, targeted therapy and immunotherapy. Finally, combining anti-TGF-β therapy with other cancer therapy is an attractive venue to be explored for the treatment of therapy-resistant cancer.
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Affiliation(s)
- Maoduo Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ying Yi Zhang
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Yongze Chen
- College of Biological Sciences, China Agricultural University, Beijing, China
| | - Jia Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Hezhe Lu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
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Roger I, Milara J, Belhadj N, Cortijo J. Senescence Alterations in Pulmonary Hypertension. Cells 2021; 10:3456. [PMID: 34943963 PMCID: PMC8700581 DOI: 10.3390/cells10123456] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is the arrest of normal cell division and is commonly associated with aging. The interest in the role of cellular senescence in lung diseases derives from the observation of markers of senescence in chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (IPF), and pulmonary hypertension (PH). Accumulation of senescent cells and the senescence-associated secretory phenotype in the lung of aged patients may lead to mild persistent inflammation, which results in tissue damage. Oxidative stress due to environmental exposures such as cigarette smoke also promotes cellular senescence, together with additional forms of cellular stress such as mitochondrial dysfunction and endoplasmic reticulum stress. Growing recent evidence indicate that senescent cell phenotypes are observed in pulmonary artery smooth muscle cells and endothelial cells of patients with PH, contributing to pulmonary artery remodeling and PH development. In this review, we analyze the role of different senescence cell phenotypes contributing to the pulmonary artery remodeling process in different PH clinical entities. Different molecular pathway activation and cellular functions derived from senescence activation will be analyzed and discussed as promising targets to develop future senotherapies as promising treatments to attenuate pulmonary artery remodeling in PH.
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Affiliation(s)
- Inés Roger
- Centro de Investigación en Red Enfermedades Respiratorias CIBERES, Health Institute Carlos III, 28029 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Javier Milara
- Centro de Investigación en Red Enfermedades Respiratorias CIBERES, Health Institute Carlos III, 28029 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
- Pharmacy Unit, University General Hospital Consortium of Valencia, 46014 Valencia, Spain
| | - Nada Belhadj
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Julio Cortijo
- Centro de Investigación en Red Enfermedades Respiratorias CIBERES, Health Institute Carlos III, 28029 Valencia, Spain;
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain;
- Research and Teaching Unit, University General Hospital Consortium, 46014 Valencia, Spain
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Chung J, Huda MN, Shin Y, Han S, Akter S, Kang I, Ha J, Choe W, Choi TG, Kim SS. Correlation between Oxidative Stress and Transforming Growth Factor-Beta in Cancers. Int J Mol Sci 2021; 22:ijms222413181. [PMID: 34947978 PMCID: PMC8707703 DOI: 10.3390/ijms222413181] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/30/2021] [Accepted: 12/04/2021] [Indexed: 12/14/2022] Open
Abstract
The downregulation of reactive oxygen species (ROS) facilitates precancerous tumor development, even though increasing the level of ROS can promote metastasis. The transforming growth factor-beta (TGF-β) signaling pathway plays an anti-tumorigenic role in the initial stages of cancer development but a pro-tumorigenic role in later stages that fosters cancer metastasis. TGF-β can regulate the production of ROS unambiguously or downregulate antioxidant systems. ROS can influence TGF-β signaling by enhancing its expression and activation. Thus, TGF-β signaling and ROS might significantly coordinate cellular processes that cancer cells employ to expedite their malignancy. In cancer cells, interplay between oxidative stress and TGF-β is critical for tumorigenesis and cancer progression. Thus, both TGF-β and ROS can develop a robust relationship in cancer cells to augment their malignancy. This review focuses on the appropriate interpretation of this crosstalk between TGF-β and oxidative stress in cancer, exposing new potential approaches in cancer biology.
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Affiliation(s)
- Jinwook Chung
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
| | - Md Nazmul Huda
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biochemistry and Molecular Biology, UAMS Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences UAMS, Little Rock, AR 72205, USA
| | - Yoonhwa Shin
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Sunhee Han
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Salima Akter
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
| | - Insug Kang
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Joohun Ha
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Wonchae Choe
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Tae Gyu Choi
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Correspondence: (T.G.C.); (S.S.K.); Tel.: +82-2-961-0287 (T.G.C.); +82-2-961-0524 (S.S.K.)
| | - Sung Soo Kim
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (T.G.C.); (S.S.K.); Tel.: +82-2-961-0287 (T.G.C.); +82-2-961-0524 (S.S.K.)
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Luo F, Huang Y, Li Y, Zhao X, Xie Y, Zhang Q, Mei J, Liu X. A narrative review of the relationship between TGF-β signaling and gynecological malignant tumor. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1601. [PMID: 34790807 PMCID: PMC8576662 DOI: 10.21037/atm-21-4879] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/14/2021] [Indexed: 12/24/2022]
Abstract
Objective This paper reviews the association between transforming growth factor-β (TGF-β) and its receptor and tumor, focusing on gynecological malignant tumors. we hope to provide more methods to help increase the potential of TGF-β signaling targeted treatment of specific cancers. Background The occurrence of a malignant tumor is a complex process of multi-step, multi-gene regulation, and its progression is affected by various components of the tumor cells and/or tumor microenvironment. The occurrence of gynecological diseases not only affect women's health, but also bring some troubles to their normal life. Especially when gynecological malignant tumors occur, the situation is more serious, which will endanger the lives of patients. Due to differences in environmental and economic conditions, not all women have access to assistance and treatment specifically meeting their needs. TGF-β is a multi-potent growth factor that maintains homeostasis in mammals by inhibiting cell growth and promoting apoptosis in vivo. TGF-β signaling is fundamental to inflammatory disease and favors the emergence of tumors, and it also plays an important role in immunosuppression in the tumor microenvironment. In the early stages of the tumor, TGF-β acts as a tumor inhibitor, whereas in advanced tumors, mutations or deletion of the TGF-β signaling core component initiate neogenesis. Methods Literatures about TGF-β and gynecological malignant tumor were extensively reviewed to analyze and discuss. Conclusions We discussed the role of TGF-β signaling in different types of gynecological tumor cells, thus demonstrating that targeted TGF-β signaling may be an effective tumor treatment strategy.
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Affiliation(s)
- Fangyuan Luo
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China.,Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Yu Huang
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Yilin Li
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiaolan Zhao
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Yao Xie
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Qianwen Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Jie Mei
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xinghui Liu
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
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Long noncoding RNA SGO1-AS1 inactivates TGFβ signaling by facilitating TGFB1/2 mRNA decay and inhibits gastric carcinoma metastasis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:342. [PMID: 34706749 PMCID: PMC8555099 DOI: 10.1186/s13046-021-02140-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022]
Abstract
Background Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a few lncRNAs have been characterized functionally. In this study, we aimed to identify novel lncRNAs involved in the progression of gastric carcinoma (GC) and explore their regulatory mechanisms and clinical significance in GC. Methods A lncRNA expression microarray was used to identify differential lncRNA expression profiles between paired GCs and adjacent normal mucosal tissues. Using the above method, the lncRNA SGO1-AS1 was selected for further study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) were performed to detect SGO1-AS1 expression in GC tissues. Gain-of-function and loss-of-function analyses were performed to investigate the functions of SGO1-AS1 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Results SGO1-AS1 was downregulated in gastric carcinoma tissues compared to adjacent normal tissues, and its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. The functional experiments revealed that SGO1-AS1 inhibited GC cell invasion and metastasis in vitro and in vivo. Mechanistically, SGO1-AS1 facilitated TGFB1/2 mRNA decay by competitively binding the PTBP1 protein, resulting in reduced TGFβ production and, thus, preventing the epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, in turn, TGFβ inhibited SGO1-AS1 transcription by inducing ZEB1. Thus, SGO1-AS1 and TGFβ form a double-negative feedback loop via ZEB1 to regulate the EMT and metastasis. Conclusions SGO1-AS1 functions as an endogenous inhibitor of the TGFβ pathway and suppresses gastric carcinoma metastasis, indicating a novel potential target for GC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02140-0.
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Stuelten CH, Zhang YE. Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment. Front Cell Dev Biol 2021; 9:764727. [PMID: 34712672 PMCID: PMC8545984 DOI: 10.3389/fcell.2021.764727] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
Transforming Growth Factor-β (TGF-β) is a key regulator of embryonic development, adult tissue homeostasis, and lesion repair. In tumors, TGF-β is a potent inhibitor of early stage tumorigenesis and promotes late stage tumor progression and metastasis. Here, we review the roles of TGF-β as well as components of its signaling pathways in tumorigenesis. We will discuss how a core property of TGF-β, namely its ability to change cell differentiation, leads to the transition of epithelial cells, endothelial cells and fibroblasts to a myofibroblastoid phenotype, changes differentiation and polarization of immune cells, and induces metabolic reprogramming of cells, all of which contribute to the progression of epithelial tumors.
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Affiliation(s)
- Christina H. Stuelten
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
| | - Ying E. Zhang
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
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The Role of Latent Transforming Growth Factor β Binding Protein 2 (LTBP2) in the Diagnosis and Stage Discrimination of Gastric Cancer. Indian J Surg 2021. [DOI: 10.1007/s12262-021-03133-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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50
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Chen P, Lin C, Yang S, Chang Y. Oral submucous fibrosis stimulates invasion and epithelial-mesenchymal transition in oral squamous cell carcinoma by activating MMP-2 and IGF-IR. J Cell Mol Med 2021; 25:9814-9825. [PMID: 34528373 PMCID: PMC8505822 DOI: 10.1111/jcmm.16929] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/15/2021] [Accepted: 09/01/2021] [Indexed: 12/11/2022] Open
Abstract
Oral submucous fibrosis (OSF) involves a high risk of malignant transformation and has been implicated in oral cancer. Limited studies have been conducted on the role of OSF in relation to the invasive capabilities and epithelial-mesenchymal transition (EMT) in oral cancer. Herein, we investigated the effects of OSF on the microenvironment of human oral cancer cells. The results showed that the conditioned medium (CM) of fibrotic buccal mucosal fibroblasts (fBMFs) strongly induced the invasion of oral cancer cells and increased the activities of matrix metalloproteinase-2. OSF significantly induced the EMT in oral cancer cells and downregulated epithelial markers, such as E-cadherin, but significantly elevated vimentin, fibronectin, N-cadherin, RhoA, Rac-1 and FAK. Insulin-like growth factor-1 (IGF-1) was elevated in OSF. The protein levels of the IGF-1R were upregulated specifically in fBMF CM treatment for oral cancer cells, and the IGFR gene was confirmed by The Cancer Genome Atlas patient transcriptome data. The Kaplan-Meier curve analysis revealed that patients with oral squamous cell carcinoma and high IGFR expression levels had poorer 5-year survival than those with low IGFR expression (p = 0.004). The fBMF-stimulated EMT cell model may recapture some of the molecular changes during EMT progression in clinical patients with oral cancer.
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Affiliation(s)
- Pei‐Ni Chen
- Clinical LaboratoryChung Shan Medical University HospitalTaichungTaiwan
- Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
| | - Chiao‐Wen Lin
- Institute of Oral SciencesChung Shan Medical UniversityTaichungTaiwan
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
| | - Shun‐Fa Yang
- Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
| | - Yu‐Chao Chang
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
- School of DentistryChung Shan Medical UniversityTaichungTaiwan
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