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Suwittayarak R, Klincumhom N, Phrueksotsai C, Limjeerajarus N, Limjeerajarus CN, Egusa H, Osathanon T. Shear stress preconditioning enhances periodontal ligament stem cell survival. Arch Oral Biol 2025; 173:106232. [PMID: 40086040 DOI: 10.1016/j.archoralbio.2025.106232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
OBJECTIVE The study investigated in vitro the influences of shear stress preconditioning on human periodontal ligament stem cells (hPDLSCs) under serum deprivation. DESIGN hPDLSCs were subjected to shear stress at 0.5 and 5 dyn/cm², both with and without serum starvation. Cell viability and apoptosis were assessed using the Resazurin assay and flow cytometry analysis, respectively. Gene and protein expressions were analysed by real-time polymerase chain reaction, immunofluorescent staining, and Western blotting. RESULTS Our results revealed that shear stress potentially mitigated serum derivation-induced cell death by inducing cell viability, enhancing colony formation, and inhibiting cell apoptosis. The addition of an ERK inhibitor inhibited the shear stress-induced cell apoptosis resistance. Shear stress treatment upregulated cell viability-related gene expression, including SOX2, SOD1 and BIRC5. In particular, shear stress promoted the nuclear translocation of SOX2. Meanwhile, the expression of BIRC5 was not inhibited by cycloheximide. Shear stress-induced SOX2 and BIRC5 expression was attenuated by PI3K and ERK inhibitors, respectively. CONCLUSIONS Shear stress contributes to promoting SOX2 and BIRC5 expression by hPDLSCs, implicating the promotion of stemness and cell survival under serum starvation.
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Affiliation(s)
- Ravipha Suwittayarak
- Center of Excellence for Dental Stem Cell Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nuttha Klincumhom
- Center of Excellence for Regenerative Dentistry and Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chaloemrit Phrueksotsai
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nuttapol Limjeerajarus
- Office of Academic Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chalida Nakalekha Limjeerajarus
- Center of Excellence for Dental Stem Cell Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand; Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Thanaphum Osathanon
- Center of Excellence for Dental Stem Cell Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
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Dong S, Zhang Y, Xie Y, Ouyang H, Zhou S, Shi J, Lu B, Mei X, Ji L. Uncovering the potential mechanism and bioactive compounds of Salviae Miltiorrhizae Radix et Rhizoma in attenuating diabetic retinopathy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156461. [PMID: 39986223 DOI: 10.1016/j.phymed.2025.156461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/12/2025] [Accepted: 02/01/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND Diabetic retinopathy (DR) is a serious microangiopathy resulting from diabetes. Salviae Miltiorrhizae Radix et Rhizoma (Danshen) is commonly used to treat cardiovascular diseases in clinics in China. However, whether it can also be used for DR treatment, along with its primary active compounds and underlying mechanisms of action, remains unclear. PURPOSE To evaluate the alleviation of water extract of Salvia miltiorrhiza Radix et Rhizoma (SWE) on DR, elucidate the underlying mechanisms, and identify the primary active compounds. METHODS Mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. Blood-retina barrier (BRB) breakdown was detected. The potential underlying mechanisms were predicted by network pharmacology and further validated by Western blot, leukostasis assay and real-time polymerase chain reaction (PCR). The primary active compounds in SWE were identified by integrating in vitro activity analysis and molecular docking. RESULTS SWE attenuated BRB breakdown in STZ-induced DR mice. Results of network pharmacology and further experimental validation implied that inhibiting retinal inflammation and angiogenesis, and reversing endothelial barrier dysfunction were involved in the SWE-provided alleviation of DR, and the key involved signaling pathways were PI3K-AKT, VEGF, TNF, and NFκB pathways. Further results in vitro demonstrated that salvianolic acid A (SalA), salvianolic acid B (SalB), salvianolic acid C (SalC), and Tanshinone IIA (TanIIA) not only reduced the expression of pro-inflammatory cytokines but also inhibited the adhesion of inflammatory cells. However, danshensu (DSS), cryptotanshinone (CTS), and tanshinone I (TanI) only downregulated the expression of pro-inflammatory cytokines. SalA, SalB, and CTS reversed endothelial barrier dysfunction in vitro. SalA, SalB, SalC, CTS, DSS, and TanIIA decreased VEGF mRNA expression, and TanIIA also inhibited VEGF-induced angiogenesis in vitro. Molecular docking predicted potential interactions between these active compounds and several key molecules involved in regulating inflammation, angiogenesis, and cell-cell junctions. These compounds abrogated hyperglycemia-induced phosphorylation of AKT1 and PI3 K in vitro. Furthermore, the interactions of SalA, SalB, SalC, and TanIIA with TNFR1 were further validated using cellular thermal shift assay (CETSA). CONCLUSION SWE alleviated DR via reversing BRB breakdown and suppressing retinal inflammation and angiogenesis. SalA, SalB, SalC, TanIIA, and CTS might be primary active compounds in SWE, and they contributed greatly to the improvement of SWE against DR via reversing endothelial barrier injury, inhibiting inflammation and angiogenesis.
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Affiliation(s)
- Shiyuan Dong
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Yue Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Yumin Xie
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Hao Ouyang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Siyan Zhou
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Jionghua Shi
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Xiyu Mei
- Key Laboratory of Pharmacodynamic Material Basis Research in Chinese Medicine of Zhejiang Province, Institute of Basic Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, PR China.
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
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Chen J, Meng A. Maternal control of embryonic dorsal organizer in vertebrates. Cells Dev 2025:204020. [PMID: 40058595 DOI: 10.1016/j.cdev.2025.204020] [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: 01/19/2025] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
The establishment of the body axis and developmental blueprint in embryos has remained to be a central question in developmental biology, captivating scientists for centuries. A milestone in this field was achieved in 1924 when Hans Spemann and Hilde Mangold discovered the dorsal organizer for embryonic body axis formation in amphibians. Since then, extensive studies have demonstrated that the dorsal organizer is evolutionarily conserved in vertebrates. This organizer functions as a signaling center, directing adjacent cells toward specific fates and orchestrating pattern formation to establish the embryonic axis. After 70 years since the discovery of the organizer, studies in different model animal species had revealed that locally activated β-catenin signaling during blastulation plays an indispensable role in organizer induction. Then, efforts have been made to identify initiators of β-catenin activation in blastulas. Now, it appears that maternal Huluwa, a transmembrane protein, is a bona fide organizer inducer at least in teleost fish and frog, which can activate downstream signaling pathways, including but probably not limited to β-catenin pathway. More studies are needed to decode the complete molecular network controlling organizer induction.
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Affiliation(s)
- Jing Chen
- Department of Pediatric Surgery and Laboratory of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Anming Meng
- Laboratory of Molecular Developmental Biology, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
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Gupta A, Diwaker P, Arora VK, Sharma S. Immunohistochemical Expression of Survivin and Vascular Endothelial Growth Factor in Cervical Squamous Cell Carcinoma. Indian J Surg Oncol 2025; 16:134-142. [PMID: 40114882 PMCID: PMC11920565 DOI: 10.1007/s13193-024-02056-z] [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: 08/24/2023] [Accepted: 07/30/2024] [Indexed: 03/22/2025] Open
Abstract
Uterine cervical cancer is the fourth leading cause of cancer death in women worldwide as per GLOBOCON (2020). In view of the higher incidence in the developing world and poor prognosis in cases presenting at advanced stage, there is an unmet need to explore new therapeutic targets for this neoplasm. Herein we sought to analyze and compare the immunoexpression of survivin (antiapoptotic factor) and vascular endothelial growth factor (VEGF). The study was conducted in the Department of Pathology at a tertiary care teaching institute from November 2018 to April 2020. Immunohistochemical (IHC) expression of survivin and VEGF was evaluated in 75 cervical squamous cell carcinomas (CSCC). The immunostaining was evaluated semi-quantitatively for its intensity (mild = 1; moderate = 2; intense = 3) and proportion of positivity (< 5% = 0; 5 to 25% = 1; 26 to 50% = 2; > 50% = 3). IHC score was calculated by multiplying the two scores as low positive (1-3), medium positive (4-6) and strong positive (7-9). Immunoexpression of survivin and VEGF was correlated using the Fisher's exact test and Kendall rank correlation coefficient. The median age of the CSCC patients was 55 years. Survivin expression was found in 98.6% while VEGF expression was observed in 68% of cases. A significant positive correlation (p - 0.001, τ - 0.404) was found between immunoexpression of survivin and VEGF. Our study results highlight the proposed role of survivin in angiogenesis by promoting VEGF expression. Hence, in view of survivin being an antiapoptotic protein and having a role in angiogenesis, targeted therapy against survivin might be of use for treatment and better prognostic outcomes in cervical squamous cell carcinomas.
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Affiliation(s)
- Anurag Gupta
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, 110095 India
| | - Preeti Diwaker
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, 110095 India
| | - Vinod Kumar Arora
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, 110095 India
| | - Sonal Sharma
- Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, 110095 India
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Zhu M, Li N, Fan L, Wu R, Cao L, Ren Y, Lu C, Zhang L, Cai Y, Shi Y, Lin Z, Lu X, Leng J, Zhong S, Hu X, Huang B, Huang R, Zhou W, Yao D, Wu L, Wu W, Liu Q, Xia P, Chen R, Shi W, Zhang R, Lv S, Wang C, Yu L, Li J, Wang Q, Li K, Jin H. Single-cell transcriptomic and spatial analysis reveal the immunosuppressive microenvironment in relapsed/refractory angioimmunoblastic T-cell lymphoma. Blood Cancer J 2024; 14:218. [PMID: 39695118 DOI: 10.1038/s41408-024-01199-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 11/26/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a kind of aggressive T-cell lymphoma with significant enrichment of non-malignant tumor microenvironment (TME) cells. However, the complexity of TME in AITL progression is poorly understood. We performed single-cell RNA-Seq (scRNA-seq) and imaging mass cytometry (IMC) analysis to compare the cellular composition and spatial architecture between relapsed/refractory AITL (RR-AITL) and newly diagnosed AITL (ND-AITL). Our results showed that the malignant T follicular helper (Tfh) cells showed significantly increased proliferation driven by transcriptional activation of YY1 in RR-AITL, which is markedly associated with the poor prognosis of AITL patients. The CD8+ T cell proportion and cytotoxicity decreased in RR-AITL TME, resulting from elevated expression of the inhibitory checkpoints such as PD-1, TIGIT, and CTLA4. Notably, the transcriptional pattern of B cells in RR-AITL showed an intermediate state of malignant transformation to B-cell-lymphoma, and contributed to immune evasion by highly expressing CD47 and PD-L1. Besides, compared to ND-AITL samples, myeloid-cells-centered spatial communities were more prevalent but showed reduced phagocytic activity and impaired antigen processing and presentation in RR-AITL TME. Furthermore, specific inhibitory ligand-receptor interactions, such as CLEC2D-KLRB1, CTLA4-CD86, and MIF-CD74, were exclusively identified in the RR-AITL TME. Our study provides a high-resolution characterization of the immunosuppression ecosystem and reveals the potential therapeutic targets for RR-AITL patients.
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Affiliation(s)
- Mengyan Zhu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ning Li
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Department of Hematology of the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huai'an, Jiangsu, China
| | - Lei Fan
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China
| | - Rongrong Wu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Cao
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China
| | - Yimin Ren
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China
| | - Chuanyang Lu
- Department of Hematology of the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huai'an, Jiangsu, China
| | - Lishen Zhang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yun Cai
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuzhu Shi
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zihan Lin
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xueying Lu
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China
| | - Jiayan Leng
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shiyang Zhong
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xingfei Hu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bin Huang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Runheng Huang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wanting Zhou
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Diru Yao
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lingxiang Wu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Wu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Quanzhong Liu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peng Xia
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ruize Chen
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China
| | - Wenyu Shi
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Ruohan Zhang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sali Lv
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chunling Wang
- Department of Hematology of the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huai'an, Jiangsu, China
| | - Liang Yu
- Department of Hematology of the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huai'an, Jiangsu, China
| | - Jianyong Li
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China.
| | - Qianghu Wang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China.
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
- Biomedical Big Data Center, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Kening Li
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China.
- Department of Hematology of the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huai'an, Jiangsu, China.
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.
- Biomedical Big Data Center, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Hui Jin
- Lymphoma Center, Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, Jiangsu, China.
- Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China.
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Fang XL, Cao XP, Xiao J, Hu Y, Chen M, Raza HK, Wang HY, He X, Gu JF, Zhang KJ. Overview of role of survivin in cancer: expression, regulation, functions, and its potential as a therapeutic target. J Drug Target 2024; 32:223-240. [PMID: 38252514 DOI: 10.1080/1061186x.2024.2309563] [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: 07/11/2023] [Accepted: 11/11/2023] [Indexed: 01/24/2024]
Abstract
Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin.
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Affiliation(s)
- Xian-Long Fang
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
| | - Xue-Ping Cao
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
| | - Jun Xiao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Yun Hu
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
| | - Mian Chen
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
| | - Hafiz Khuram Raza
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
| | - Huai-Yuan Wang
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xu He
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jin-Fa Gu
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
| | - Kang-Jian Zhang
- Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou, China
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Godizzi F, Armando F, Boracchi P, Avallone G, Stefanello D, Ferrari R, Chiti LE, Cappelleri A, Zamboni C, Dell'Aere S, Corradi A, Roccabianca P. Survivin, β-catenin, and ki-67 immunohistochemical expression in canine perivascular wall tumors: Preliminary assessment of prognostic significance. Vet Pathol 2024; 61:912-927. [PMID: 38727195 DOI: 10.1177/03009858241246981] [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: 11/05/2024]
Abstract
High survivin expression has been correlated with poor outcomes in several canine tumors but not in soft tissue tumors (STTs). Survivin is a target gene of the Wnt/β-catenin pathway, which is involved in human STT oncogenesis. Immunohistochemistry for survivin, β-catenin, and Ki-67 was performed on 41 canine perivascular wall tumors (cPWTs), and statistical associations of protein expression and histopathologic and clinical variables with clinical outcomes were investigated. Immunohistochemically, there was nuclear positivity (0.9%-12.2% of tumor cells) for survivin in 41/41 (100%), cytoplasmic positivity (0 to > 75% of tumor cells) for survivin in 31/41 (76%), nuclear positivity (2.9%-67.2% of tumor cells) for β-catenin in 24/41 (59%), and cytoplasmic positivity (0% to > 75% of tumor cells) for β-catenin in 23/41 (56%) of cPWTs. All tumors expressed nuclear Ki-67 (2.2%-23.5%). In univariate analysis and multivariate analysis (UA and MA, respectively), every 1% increase of nuclear survivin was associated with an increase of the instantaneous death risk by a factor of 1.15 [hazard ratio (HR) = 1.15; P = .007]. Higher nuclear survivin was associated with grade II/III neoplasms (P = .043). Expression of cytoplasmic survivin, nuclear and cytoplasmic β-catenin, and nuclear Ki-67 were not significantly associated with prognosis in UA nor MA. Tumor size was a significant prognostic factor for local recurrence in UA [subdistribution HR (SDHR) = 1.19; P = .02] and for reduced overall survival time in MA. According to UA and MA, a unitary increase of mitotic count was associated with an increase of the instantaneous death risk by a factor of 1.05 (HR = 1.05; P = .014). Nuclear survivin, mitotic count, and tumor size seem to be potential prognostic factors for cPWTs. In addition, survivin and β-catenin may represent promising therapeutic targets for cPWTs.
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Affiliation(s)
- Francesco Godizzi
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine, Foundation, Hannover, Germany
| | - Patrizia Boracchi
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
| | - Giancarlo Avallone
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Italy
| | - Damiano Stefanello
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Roberta Ferrari
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Lavinia E Chiti
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Andrea Cappelleri
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
- Mouse and Animal Pathology Laboratory (MAPLab), Fondazione UniMi, Milan, Italy
| | - Clarissa Zamboni
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Silvia Dell'Aere
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Attilio Corradi
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Paola Roccabianca
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
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Fonódi M, Nagy L, Boratkó A. Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity. Int J Mol Sci 2024; 25:6868. [PMID: 38999976 PMCID: PMC11241275 DOI: 10.3390/ijms25136868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Tumor angiogenesis, the formation of new blood vessels to support tumor growth and metastasis, is a complex process regulated by a multitude of signaling pathways. Dysregulation of signaling pathways involving protein kinases has been extensively studied, but the role of protein phosphatases in angiogenesis within the tumor microenvironment remains less explored. However, among angiogenic pathways, protein phosphatases play critical roles in modulating signaling cascades. This review provides a comprehensive overview of the involvement of protein phosphatases in tumor angiogenesis, highlighting their diverse functions and mechanisms of action. Protein phosphatases are key regulators of cellular signaling pathways by catalyzing the dephosphorylation of proteins, thereby modulating their activity and function. This review aims to assess the activity of the protein tyrosine phosphatases and serine/threonine phosphatases. These phosphatases exert their effects on angiogenic signaling pathways through various mechanisms, including direct dephosphorylation of angiogenic receptors and downstream signaling molecules. Moreover, protein phosphatases also crosstalk with other signaling pathways involved in angiogenesis, further emphasizing their significance in regulating tumor vascularization, including endothelial cell survival, sprouting, and vessel maturation. In conclusion, this review underscores the pivotal role of protein phosphatases in tumor angiogenesis and accentuate their potential as therapeutic targets for anti-angiogenic therapy in cancer.
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Affiliation(s)
| | | | - Anita Boratkó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (M.F.); (L.N.)
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9
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Li Q, Liu H, Wang H, Xiong W, Dai L, Zhang X, Wang P, Ye H, Shi J, Fang Z, Wang K. Anti-BIRC5 autoantibody serves as a valuable biomarker for diagnosing AFP-negative hepatocellular carcinoma. PeerJ 2024; 12:e17494. [PMID: 38832035 PMCID: PMC11146321 DOI: 10.7717/peerj.17494] [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: 02/08/2024] [Accepted: 05/09/2024] [Indexed: 06/05/2024] Open
Abstract
Background Autoantibodies targeting tumor-associated antigens (TAAbs) have emerged as promising biomarkers for early cancer detection. This research aimed to assess the diagnostic capacity of anti-BIRC5 autoantibody in detecting AFP-negative hepatocellular carcinoma (ANHCC). Methods This research was carried out in three stages (discovery phase, validation phase, and evaluation phase) and included a total of 744 participants. Firstly, the anti-BIRC5 autoantibody was discovered using protein microarray, exhibiting a higher positive rate in ANHCC samples (ANHCCs) compared to normal control samples (NCs). Secondly, the anti-BIRC5 autoantibody was validated through enzyme-linked immunosorbent assay (ELISA) in 85 ANHCCs and 85 NCs from two clinical centers (Zhengzhou and Nanchang). Lastly, the diagnostic usefulness of the anti-BIRC5 autoantibody for hepatocellular carcinoma (HCC) was evaluated by ELISA in a cohort consisting of an additional 149 AFP-positive hepatocellular carcinoma samples (APHCCs), 95 ANHCCs and 244 NCs. The association of elevated autoantibody to high expression of BIRC5 in HCC was further explored by the database from prognosis, immune infiltration, DNA methylation, and gene mutation level. Results In the validation phase, the area under the ROC curve (AUC) of anti-BIRC5 autoantibody to distinguish ANHCCs from NCs in Zhengzhou and Nanchang centers was 0.733 and 0.745, respectively. In the evaluation phase, the AUCs of anti-BIRC5 autoantibody for identifying ANHCCs and HCCs from NCs were 0.738 and 0.726, respectively. Furthermore, when combined with AFP, the AUC for identifying HCCs from NCs increased to 0.914 with a sensitivity of 77.5% and specificity of 91.8%. High expression of BIRC5 gene is not only correlated with poor prognosis of HCCs, but also significantly associated with infiltration of immune cells, DNA methylation, and gene mutation. Conclusion The findings suggest that the anti-BIRC5 autoantibody could serve as a potential biomarker for ANHCC, in addition to its supplementary role alongside AFP in the diagnosis of HCC. Next, we can carry out specific verification and explore the function of anti-BIRC5 autoantibody in the occurrence and development of HCC.
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Affiliation(s)
- Qing Li
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Haiyan Liu
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Han Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Wenzhuo Xiong
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Liping Dai
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Xiuzhi Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
- Department of Pathology, Henan Medical College, Zhengzhou, Henan, China
| | - Peng Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Ye
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jianxiang Shi
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Zhihao Fang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Keyan Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
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Shao L, Wu Y, Cao J, Zhong F, Yang X, Xing C. Activation of M2 macrophage autophagy by rapamycin increases the radiosensitivity of colorectal cancer xenografts. J Cancer Res Ther 2024; 20:695-705. [PMID: 38687942 DOI: 10.4103/jcrt.jcrt_215_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 11/20/2023] [Indexed: 05/02/2024]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are intimately involved in cancer radiochemotherapy resistance. However, the mechanism by which macrophages affect radiosensitivity through autophagy remains unclear. The purpose of our study was to investigate how activating autophagy in type-II macrophages (M2) by using rapamycin (RAP) would affect the radiosensitivity of colorectal cancer (CRC) xenografts. MATERIALS AND METHODS A nude mouse CRC model was established by injecting LoVo CRC cells. After tumor formation, supernatant from M2 cells (autophagy-unactivated), autophagy-activated M2 cells, or autophagy-downregulated M2 cells was injected peritumorally. All tumor-bearing mice were irradiated with 8-Gy X-rays twice, and the radiosensitivity of CRC xenografts was analyzed in each group. RESULTS The mass, volume, and microvessel density (MVD) of tumors in the autophagy-unactivated M2 group significantly increased; however, supernatant from M2 cells that were autophagy-activated by rapamycin significantly decreased tumor weight, volume, and MVD compared with negative control. Combining bafilomycin A1 (BAF-A1) with RAP treatment restored the ability of the M2 supernatant to increase tumor mass, volume, and MVD. Immunohistochemical and Western blot results showed that compared with the negative control group, supernatant from M2 cells that were not activated by autophagy downregulated the expression of Livin and Survivin in tumor tissues; activation of M2 autophagy further downregulated the protein levels. CONCLUSIONS Therefore, autophagy-activated M2 supernatant can downregulate the expression of the antiapoptotic genes Livin and Survivin in CRC xenografts, improving the radiosensitivity of CRC by inducing apoptosis in combination with radiotherapy and inhibiting the growth of transplanted tumors.
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Affiliation(s)
- Lening Shao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yongyou Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianping Cao
- School of Radiation Medicine and Protection, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Fengyun Zhong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaodong Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chungen Xing
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Xie X, Cui Q, Jiang T, Zhao Z, Liu Z, Liu J, Yao Q, Wang Y, Dang E, Wang G, Xiao L, Wang N. A critical role of the endothelial S-phase kinase-associated protein 2/phosphatase and tensin homologue axis in angiogenesis and psoriasis. Br J Dermatol 2024; 190:244-257. [PMID: 37850885 DOI: 10.1093/bjd/ljad399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/24/2023] [Accepted: 10/14/2023] [Indexed: 10/19/2023]
Abstract
BACKGROUND Psoriasis is a common chronic skin disorder. Pathologically, it features abnormal epidermal proliferation, infiltrating inflammatory cells and increased angiogenesis in the dermis. Aberrant expression of E3 ubiquitin ligase and a dysregulated protein ubiquitination system are implicated in the pathogenesis of psoriasis. OBJECTIVES To examine the potential role of S-phase kinase-associated protein 2 (Skp2), an E3 ligase and oncogene, in psoriasis. METHODS Gene expression and protein levels were evaluated with quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence staining of skin samples from patients with psoriasis vulgaris and an imiquimod (IMQ)-induced mouse model, as well as from cultured endothelial cells (ECs). Protein interaction, substrate ubiquitination and degradation were examined using co-immunoprecipitation, Western blotting and a cycloheximide chase assay in human umbilical vein ECs. Angiogenesis was measured in vitro using human dermal microvascular ECs (HDMECs) for BrdU incorporation, migration and tube formation. In vivo angiogenesis assays included chick embryonic chorioallantoic membrane, the Matrigel plug assay and quantification of vasculature in the mouse lesions. Skp2 gene global knockout (KO) mice and endothelial-specific conditional KO mice were used. RESULTS Skp2 was increased in skin samples from patients with psoriasis and IMQ-induced mouse lesions. Immunofluorescent double staining indicated a close association of Skp2 expression with excessive vascularity in the lesional dermal papillae. In HDMECs, Skp2 overexpression was enhanced, whereas Skp2 knockdown inhibited EC proliferation, migration and tube-like structure formation. Mechanistically, phosphatase and tensin homologue (PTEN), which suppresses the phosphoinositide 3-kinase/Akt pathway, was identified to be a novel substrate for Skp2-mediated ubiquitination. A selective inhibitor of Skp2 (C1) or Skp2 small interfering RNA significantly reduced vascular endothelial growth factor-triggered PTEN ubiquitination and degradation. In addition, Skp2-mediated ubiquitination depended on the phosphorylation of PTEN by glycogen synthase kinase 3β. In the mouse model, Skp2 gene deficiency alleviated IMQ-induced psoriasis. Importantly, tamoxifen-induced endothelial-specific Skp2 KO mice developed significantly ameliorated psoriasis with diminished angiogenesis of papillae. Furthermore, topical use of the Skp2 inhibitor C1 effectively prevented the experimental psoriasis. CONCLUSIONS The Skp2/PTEN axis may play an important role in psoriasis-associated angiogenesis. Thus, targeting Skp2-driven angiogenesis may be a potential approach to treating psoriasis.
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Affiliation(s)
- Xinya Xie
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an , China
| | - Qi Cui
- The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian , China
| | - Tingting Jiang
- The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian , China
| | - Ziwei Zhao
- The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian , China
| | - Zheyi Liu
- The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian , China
| | - Jia Liu
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an , China
| | - Qinyu Yao
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an , China
| | - Yuxin Wang
- East China Normal University Health Science Center, Shanghai , China
| | - Erle Dang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an , China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an , China
| | - Lei Xiao
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an , China
| | - Nanping Wang
- East China Normal University Health Science Center, Shanghai , China
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Kondapuram SK, Ramachandran HK, Arya H, Coumar MS. Targeting survivin for cancer therapy: Strategies, small molecule inhibitors and vaccine based therapeutics in development. Life Sci 2023; 335:122260. [PMID: 37963509 DOI: 10.1016/j.lfs.2023.122260] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/16/2023]
Abstract
Survivin is a member of the family of inhibitors of apoptosis proteins (IAPs). It is involved in the normal mitotic process and acts as an anti-apoptotic molecule. While terminally differentiated normal tissues lack survivin, several human malignancies have significant protein levels. Resistance to chemotherapy and radiation in tumor cells is associated with survivin expression. Decreased tumor development, apoptosis, and increased sensitivity to chemotherapy and radiation are all effects of downregulating survivin expression or activity. As a prospective cancer treatment, small molecules targeting the transcription and translation of survivin and molecules that can directly bind with the survivin are being explored both in pre-clinical and clinics. Pre-clinical investigations have found and demonstrated the effectiveness of several small-molecule survivin inhibitors. Unfortunately, these inhibitors have also been shown to have off-target effects, which could limit their clinical utility. In addition to small molecules, several survivin peptide vaccines are currently under development. These vaccines are designed to elicit a cytotoxic T-cell response against survivin, which could lead to the destruction of tumor cells expressing survivin. Some survivin-based vaccines are advancing through Phase II clinical studies. Overall, survivin is a promising cancer drug target. However, challenges still need to be addressed before the survivin targeted therapies can be widely used in the clinics.
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Affiliation(s)
- Sree Karani Kondapuram
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India
| | - Hema Kasthuri Ramachandran
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India
| | - Hemant Arya
- Institute for Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany
| | - Mohane Selvaraj Coumar
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.
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He Q, He Y, Li C, Wang J, Xia T, Xiong X, Xu J, Liu L. Downregulated BIRC5 inhibits proliferation and metastasis of melanoma through the β-catenin/HIF-1α/VEGF/MMPs pathway. J Cancer Res Clin Oncol 2023; 149:16797-16809. [PMID: 37728702 DOI: 10.1007/s00432-023-05425-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 09/12/2023] [Indexed: 09/21/2023]
Abstract
PURPOSE Melanoma is a malignant skin tumor caused by melanocytes and associated with high mortality rates. This study aims to investigate the specific mechanism of ZWZ-3 in melanoma proliferation and metastasis. METHODS RNA sequencing was performed to identify the effect of ZWZ-3 on gene expression. siRNA was used to inhibit BIRC5 gene expression in the B16F10 cell line. A zebrafish tumor model was used to assess the therapeutic effect of ZWZ-3 in vivo. Mechanistic insights into the inhibition of tumor metastasis by ZWZ-3 were obtained through analysis of tumor tissue sections in mice. RESULTS Our findings demonstrated that ZWZ-3 suppressed melanoma cell proliferation and migration. We performed RNA sequencing in melanoma cells after the treatment with ZWZ-3 and found that Birc5, which is closely associated with tumor metastasis, was significantly down-regulated. Bioinformatics analysis and the immuno-histochemical results of tissue chips for melanoma further confirmed the high expression of BIRC5 in melanoma and its effect on disease progression. Moreover, Birc5 knock-down significantly inhibited melanoma cell proliferation and metastasis, which was correlated with the β-catenin/HIF-1α/VEGF/MMPs pathway. Additionally, ZWZ-3 significantly inhibited tumor growth in the zebrafish tumor model without any evident side effects. Histological and immuno-histochemical analyses revealed that ZWZ-3 inhibited tumor cell metastasis by down-regulating HIF-1α, VEGF, and MMP9. CONCLUSION Our findings revealed that ZWZ-3 could downregulate BIRC5 and inhibit melanoma proliferation and metastasis through the β-catenin/HIF-1α/VEGF/MMPs pathway. Therefore, BIRC5 represents a promising therapeutic target for the treatment of melanoma.
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Affiliation(s)
- Qingqing He
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yijing He
- Department of Science and Technology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Changqiang Li
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jianv Wang
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Tong Xia
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xia Xiong
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jixiang Xu
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Li Liu
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
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Lobos-González L, Oróstica L, Díaz-Valdivia N, Rojas-Celis V, Campos A, Duran-Jara E, Farfán N, Leyton L, Quest AFG. Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models. Int J Mol Sci 2023; 24:16947. [PMID: 38069269 PMCID: PMC10707163 DOI: 10.3390/ijms242316947] [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: 09/07/2023] [Revised: 10/20/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023] Open
Abstract
Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag-/- immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.
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Affiliation(s)
- Lorena Lobos-González
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Avenida Lo Plaza 680, Las Condes 7610658, Chile; (L.L.-G.); (E.D.-J.)
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
| | - Lorena Oróstica
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad Diego Portales, Santiago 8370007, Chile
| | - Natalia Díaz-Valdivia
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Victoria Rojas-Celis
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - America Campos
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- CRUK Scotland Institute, Glasgow G61 1BD, UK
| | - Eduardo Duran-Jara
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Avenida Lo Plaza 680, Las Condes 7610658, Chile; (L.L.-G.); (E.D.-J.)
- Subdepartamento Genética Molecular, Instituto de Salud Pública de Chile, Santiago 7780050, Chile
| | - Nicole Farfán
- Cancer and ncRNAs Laboratory, Universidad Andres Bello, Santiago 7550611, Chile;
| | - Lisette Leyton
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Andrew F. G. Quest
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile; (N.D.-V.); (V.R.-C.); (A.C.)
- Laboratory of Cellular Communication, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
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Bui I, Baritaki S, Libra M, Zaravinos A, Bonavida B. Cancer Resistance Is Mediated by the Upregulation of Several Anti-Apoptotic Gene Products via the Inducible Nitric Oxide Synthase/Nitric Oxide Pathway: Therapeutic Implications. Antioxid Redox Signal 2023; 39:853-889. [PMID: 37466477 DOI: 10.1089/ars.2023.0250] [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] [Indexed: 02/25/2023]
Abstract
Significance: Several therapeutic strategies for cancer treatments have been developed with time, and significant milestones have been achieved recently. However, with these novel therapies, not all cancer types respond and in the responding cancer types only a subset is affected. The failure to respond is principally the result that these cancers develop several mechanisms of resistance. Thus, a focus of current research investigations is to unravel the various mechanisms that regulate resistance and identify suitable targets for new therapeutics. Recent Advances: Hence, many human cancer types have been reported to overexpress the inducible nitric oxide synthase (iNOS) and it has been suggested that iNOS/nitric oxide (NO) plays a pivotal role in the regulation of resistance. We have postulated that iNOS overexpression or NO regulates the overexpression of pivotal anti-apoptotic gene products such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma extra large (Bcl-xL), myeloid cell leukemia-1 (Mcl-1), and survivin. In this report, we describe the various mechanisms, transcriptional, post-transcriptional, and post-translational, by which iNOS/NO regulates the expression of the above anti-apoptotic gene products. Critical Issues: The iNOS/NO-mediated regulation of the four gene products is not the same with both specific and overlapping pathways. Our findings are, in large part, validated by bioinformatic analyses demonstrating, in several cancers, several direct correlations between the expression of iNOS and each of the four examined anti-apoptotic gene products. Future Directions: We have proposed that targeting iNOS may be highly efficient since it will result in the underexpression of multiple anti-apoptotic proteins and shifting the balance toward the proapoptotic gene products and reversal of resistance. Antioxid. Redox Signal. 39, 853-889.
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Affiliation(s)
- Indy Bui
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
| | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Department of Surgery, School of Medicine, University of Crete, Heraklion, Greece
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Italian League Against Cancer, Catania, Italy
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
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Liu J, Li X, Bai H, Yang X, Mu J, Yan R, Wang S. Traditional uses, phytochemistry, pharmacology, and pharmacokinetics of the root bark of Paeonia x suffruticosa andrews: A comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116279. [PMID: 36822345 DOI: 10.1016/j.jep.2023.116279] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/11/2023] [Accepted: 02/12/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Moutan Cortex (MC), commonly known as "Mu dan pi", refers to the dried root bark of Paeonia x suffruticosa Andrews and is broadly used as a traditional herbal medication in China, Japan, and Korea. For thousands of years, it has been utilized to treat female genital, extravasated blood, cardiovascular, and stagnant blood disorders. AIM OF THE REVIEW The purpose of this review article was to summarize information on the traditional uses, phytochemistry, pharmacology and pharmacokinetics of MC, as well as to outline the further research directions for the development of new drugs and the associations between traditional uses and pharmacological effects. MATERIALS AND METHODS The information involved in the study was gathered from a variety of electronic resources, including PubMed, Web of Science, ScienceDirect, SciFinder, China Knowledge Resource Integrated Database, and Google Scholar. The date was from 1992 to 2022. RESULTS Approximately 163 chemical compounds have been extracted and identified from MC, including monoterpenes, monoterpene glycosides, triterpenes, phenolics, flavonoids, volatile oils, alkaloids, and others. In these categories, the monoterpene glycosides and phenols being the most common. A wide variety of pharmacological effects have been described for MC crude extracts and active molecules, such as antioxidant, anti-inflammatory, antibacterial and antiviral, antitumor, antidiabetic, organ protection, and neuroprotective activities, as well as treating cardiovascular diseases. Pharmacokinetics has been also used in the study of MC, including its crude extracts or chemical constituents, in order to explore the therapeutic mechanism, direct clinically appropriate application and provide new ideas for the exploitation of innovative medicines. CONCLUSION Modern pharmacological research has demonstrated that MC, as a significant therapeutic resource, has the ability to heal a wide range of diseases, particularly female genital and cardiovascular problems. These researches propose therapeutic ideas for the development of novel MC medicines. Furthermore, preclinical and clinical study have verified several observed pharmacological properties related with the traditional usages of MC.
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Affiliation(s)
- Jincai Liu
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China
| | - Xiang Li
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China
| | - Huixin Bai
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China
| | - Xu Yang
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China
| | - Jun Mu
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China
| | - Ruonan Yan
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China
| | - Siwang Wang
- Northwest University Faculty of Life and Health Science, Northwest University, 229 Taibai Road, Xi'an, Shaanxi, 710069, China.
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Yesupatham ST, Dayanand CD, Azeem Mohiyuddin SM, Harendra Kumar ML. An Insight into Survivin in Relevance to Hematological, Biochemical and Genetic Characteristics in Tobacco Chewers with Oral Squamous Cell Carcinoma. Cells 2023; 12:1444. [PMID: 37408277 PMCID: PMC10217417 DOI: 10.3390/cells12101444] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Survivin is an inhibitor of apoptosis protein (IAP), encoded by the Baculoviral IAP Repeat Containing 5 (BIRC5) gene located on q arm (25.3) on chromosome 17. It is expressed in various human cancers and involved in tumor resistance to radiation and chemotherapy. The genetic analysis of the BIRC5 gene and its protein survivin levels in buccal tissue related to oral squamous cell carcinoma (OSCC) in South Indian tobacco chewers has not been studied. Hence, the study was designed to quantify survivin in buccal tissue and its association with pretreatment hematological parameters and to analyze the BIRC5 gene sequence. METHOD In a single centric case control study, buccal tissue survivin levels were measured by ELISA. A total of 189 study subjects were categorized into Group 1 (n = 63) habitual tobacco chewers with OSCC, Group 2 (n = 63) habitual tobacco chewers without OSCC, and Group 3 (n = 63) healthy subjects as control. Retrospective hematological data were collected from Group 1 subjects and statistically analyzed. The BIRC5 gene was sequenced and data were analyzed using a bioinformatics tool. RESULTS Survivin protein mean ± SD in Group 1 was (1670.9 ± 796.21 pg/mL), in Group 2 it was (1096.02 ± 346.17 pg/mL), and in Group 3 it was (397.5 ± 96.1 pg/mL) with significance (p < 0.001). Survivin levels showed significance with cut-off levels of absolute monocyte count (AMC), neutrophil/lymphocyte ratio (NLR), and lymphocyte/monocyte ratio (LMR) at (p = 0.001). The unique variants found only in OSCC patients were T → G in the promoter region, G → C in exon 3, C → A, A → G, G → T, T → G, A → C, G → A in exon 4, C → A, G → T, G → C in the exon 5 region. CONCLUSIONS The tissue survivin level increased in OSCC patients compared to controls; pretreatment AMC, LMR, and NLR may serve as add-on markers along with survivin to measure the progression of OSCC. Unique mutations in the promoter and exons 3-5 were observed in sequence analysis and were associated with survivin concentrations.
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Affiliation(s)
- Susanna Theophilus Yesupatham
- Department of Biochemistry, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India;
| | - C. D. Dayanand
- Allied Health and Basic Sciences, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India
| | - S. M. Azeem Mohiyuddin
- Department of Otorhinolaryngology and Head and Neck Surgery, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India
| | - M. L. Harendra Kumar
- Department of Pathology, Shridevi Institute of Medical Sciences and Research Hospital, Sira Road, Tumakuru 572106, Karnataka, India
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Bahamin N, Rafieian-Kopaei M, Ahmadian S, Karimi I, Doustimotlagh AH, Mobini G, Bijad E, Shafiezadeh M. Combined treatment with Alhagi maurorum and docetaxel inhibits breast cancer progression via targeting HIF-1α/VEGF mediated tumor angiogenesis in vivo. Heliyon 2023; 9:e16292. [PMID: 37234651 PMCID: PMC10205524 DOI: 10.1016/j.heliyon.2023.e16292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 05/06/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Breast cancer is a challenging disease and leading cause of cancer death in women. There is no effective agent for metastatic breast cancer after surgery and chemotherapy. Alhagi maurorum (A.m) has been reported to exhibit an anticancer effect on various types of cancer cells in vitro. This study aimed to examine the suppressive effect of A.m alone and combined with docetaxel (DTX) on the breast cancer growth in mice models and the possible underlying mechanisms. In the present study, the mice were inoculated subcutaneously with the injections of 4T1 cells. Then, A.m, DTX, and their combination were administered intraperitoneally. The expressions of β-catenin (β-cat), FZD7, MMP2, HIF1-α, and VEGF A (vascular endothelial growth factor A) were investigated using RT-PCR method. Also, plasma alkaline phosphatase (ALP), alanine aminotransferase (GPT or ALT), aspartate transaminase (GOT or AST), serum creatinine, and urea were examined, and histological analyses of the tissues were conducted. The results demonstrated that A.m (500 mg/kg) combined with DTX significantly decreased the expression of β-cat, MMP2, and FZD7 as compared with the negative control group and monotherapies. Also, the mRNA levels of HIF1-α and VEGF A were suppressed significantly by DTX + A.m (500 mg/kg). Tumor weights and sizes were significantly lower and tumor inhibition rate was significantly higher in the DTX + A.m group. The A.m 500 mg/kg + DTX also suppressed the serum GPT level in tumor-bearing mice and decreased the serum urea level. Taken together, our findings suggest that DTX combined with A.m at an optimal dose of 500 mg/kg as the optimal dose can inhibit β-cat, FZD7, MMP2, and breast cancer growth via interrupting HIF-1α/VEGF signaling and might be used as a promising antiangiogenic agent for breast cancer treatment.
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Affiliation(s)
- Nayereh Bahamin
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Shahin Ahmadian
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Iraj Karimi
- Pathobiology Department, Veterinary Faculty, Shahrekord University, Shahrekord, Iran
| | - Amir Hossein Doustimotlagh
- Department of Clinical Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Gholamreza Mobini
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Bijad
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahshid Shafiezadeh
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
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19
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Yu F, Chang J, Li J, Li Z, Li Z, Zhang H, Liu Q. Protective effects of oridonin against osteoporosis by regulating immunity and activating the Wnt3a/β-catenin/VEGF pathway in ovariectomized mice. Int Immunopharmacol 2023; 118:110011. [PMID: 36924567 DOI: 10.1016/j.intimp.2023.110011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 03/17/2023]
Abstract
This study was performed with the aim of investigating the effect of oridonin (ORI) on estrogen deprivation-induced osteoporosis in mice and its mechanism. Animal experiments were used in this work to validate the anti-osteoporotic efficacy of ORI. Morphometric analysis was performed by micro-CT. A special protein meter was used to detect the content of immunoglobulin lgM, immunoglobulin lgG, complement C3 and C4 in the serum of mice. The expression of CD4+CD25+Foxp3+ Treg cell and CD4+/CD8+ lymphocyte subsets in mice was detected by flow cytometry. ELISA was used to detect the content of insulin-like growth factor (IGF-1), tumor necrosis factor (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). In addition, key signaling molecules in the Wnt3a/β-catenin signaling pathway were detected by Western blotting. The results showed that compared with the model group, the contents of calcium and phosphorus in the femurs of mice in the ORI groups were increased, and the spleen coefficient was decreased. The ALP activity in the serum of mice in the high and medium dose ORI groups was decreased, and the uterine coefficient was increased. ORI significantly increased the maximum bending load and the maximum bending stress of the femurs of mice, increased the number of trabeculae, and repaired the bone microstructure. At the same time, ORI could significantly increase the levels of immunoglobulin (lgG and lgM) and complement (C3 and C4), increase the activity of peritoneal macrophages in mice, increase the expression of CD4+CD25+Foxp3+ Tregs and CD4+/CD8+ in the spleen, increase the content of IGF-1, reduce the content of TNF-α, IL-1 and IL-6 and increase the expression levels of VEGF, Wnt3a, p-GSK3β/GSK3β and β-catenin/Lamin in the femoral tissue. These results indicated that ORI might regulate the expression of VEGF through the Wnt3a/β-catenin signaling pathway, improve the immunity of mice, maintain the balance of the immune system, and promote angiogenesis, thereby improving the bone mineral density and bone tissue morphology of mice and playing an anti-osteoporotic role.
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Affiliation(s)
- Fengxiu Yu
- Basic Medical College, Shandong First Medical University & Shangdong Academy of Medical Sciences, Tai'an City, Shandong Province 271000, China
| | - Jin Chang
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, No. 366, Taishan Street, Tai'an City, Shandong Province 271000, China
| | - Jinglei Li
- Department of Medical Imaging, Taian Disabled Soldiers' Hospital of Shandong Province, No. 123, Taishan Street, Tai'an City, Shandong Province 271000, China
| | - Zhen Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Shandong First Medical University, No. 366, Taishan Road, Tai'an City, Shandong Province 271000, China
| | - Zhen Li
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, No. 366, Taishan Road, Tai'an City, Shandong Province 271000, China
| | - Hong Zhang
- Department of Hematology, The Second Affiliated Hospital of Shandong First Medical University, No. 366, Taishan Road, Tai'an City, Shandong Province 271000, China
| | - Qinghua Liu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Shandong First Medical University, No. 366, Taishan Road, Tai'an City, Shandong Province 271000, China.
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20
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Barrionuevo E, Cornier PG, Delpiccolo CML, Mata EG, Roguin LP, Blank VC. Antiangiogenic activity of the penicillin derivative TAP7f in melanoma. J Mol Med (Berl) 2023; 101:249-263. [PMID: 36688961 DOI: 10.1007/s00109-023-02287-7] [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: 07/19/2022] [Revised: 12/19/2022] [Accepted: 01/16/2023] [Indexed: 01/24/2023]
Abstract
Previously , we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of β-catenin and integrin αVβ3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16-F10 melanoma cells pre-treated with TAP7f were injected intradermally in mice, we observed a decrease in the number and thickness of the capillaries surrounding the tumor. Additionally, TAP7f downregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor-B (PDGF-B) expression in B16-F10 cells and VEGF receptor expression in HMEC-1 endothelial cells. When the antitumor effect of TAP7f was studied in C57BL/6 J mice challenged with B16-F10 melanoma cells, a significant reduction of tumor growth was observed. Furthermore, a decreased expression of VEGF, PDGF-B, and the endothelial cell marker CD34 was observed in tumors from TAP7f-treated mice. Together, our results suggest that the antiangiogenic activity of TAP7f contributes to its antitumor and antimetastatic action and positions this penicillin derivative as an alternative or complementary agent for the treatment of melanoma. KEY MESSAGES: • TAP7f inhibits proliferation, migration, tube formation, and actin cytoskeleton organization of endothelial cells. • TAP7f downregulates VEGF receptor expression in endothelial cells. • TAP7f downregulates VEGF and PDGF expression in melanoma cells. • TAP7f inhibits angiogenesis in vivo.
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Affiliation(s)
- Elizabeth Barrionuevo
- Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Patricia G Cornier
- Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina
| | - Carina M L Delpiccolo
- Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina
| | - Ernesto G Mata
- Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina
| | - Leonor P Roguin
- Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Viviana C Blank
- Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina.
- , Buenos Aires, 956, C1113AAD, Argentina.
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21
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Chang WH, Liu Y, Hammes EA, Bryant KL, Cerione RA, Antonyak MA. Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein family member Survivin. J Biol Chem 2023; 299:102842. [PMID: 36581205 PMCID: PMC9860443 DOI: 10.1016/j.jbc.2022.102842] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 12/15/2022] [Accepted: 12/18/2022] [Indexed: 12/28/2022] Open
Abstract
The small GTPase KRAS is frequently mutated in pancreatic cancer and its cooperation with the transcription factor MYC is essential for malignant transformation. The key to oncogenic KRAS and MYC working together is the stabilization of MYC expression due to KRAS activating the extracellular signal-regulated kinase 1/2, which phosphorylates MYC at serine 62 (Ser 62). This prevents the proteasomal degradation of MYC while enhancing its transcriptional activity. Here, we identify how this essential signaling connection between oncogenic KRAS and MYC expression is mediated by the inhibitor of apoptosis protein family member Survivin. This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRASG12C inhibitor Sotorasib. We went on to show that oncogenic KRAS increases Survivin expression by activating extracellular signal-regulated kinase 1/2 in pancreatic cancer cells and that treating the cells either with siRNAs targeting Survivin or with YM155, a small molecule that potently blocks Survivin expression, downregulates MYC and strongly inhibited their growth. We further determined that Survivin protects MYC from degradation by blocking autophagy, which then prevents cellular inhibitor of protein phosphatase 2A from undergoing autophagic degradation. Cellular inhibitor of protein phosphatase 2A, by inhibiting protein phosphatase 2A, helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers.
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Affiliation(s)
- Wen-Hsuan Chang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yinzhe Liu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA
| | - Emma A Hammes
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA
| | - Kirsten L Bryant
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Richard A Cerione
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, USA; Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
| | - Marc A Antonyak
- Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
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22
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Zhuang Y, Liu K, He Q, Gu X, Jiang C, Wu J. Hypoxia signaling in cancer: Implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e203. [PMID: 36703877 PMCID: PMC9870816 DOI: 10.1002/mco2.203] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023] Open
Abstract
Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia-targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.
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Affiliation(s)
- Yan Zhuang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Kua Liu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Qinyu He
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Xiaosong Gu
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Chunping Jiang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Junhua Wu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
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23
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Sadowska A, Sawicka D, Godlewska K, Guzińska-Ustymowicz K, Zapora E, Sokołowska E, Car H. Beneficial Proapoptotic Effect of Heterobasidion Annosum Extract in Colorectal Cancer Xenograft Mouse Model. Molecules 2023; 28:molecules28031352. [PMID: 36771018 PMCID: PMC9919637 DOI: 10.3390/molecules28031352] [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: 12/28/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
Fungal extracts possess potential anticancer activity against many malignant neoplastic diseases. In this research, we focused on the evaluation of Heterobasidion annosum (HA) extract in colorectal cancer in an in vivo model. The mice with implanted DLD-1 human cancer cells were given HA extract, the referential drug-5-fluorouracil (5FU), or were treated with its combination. Thereafter, tumor volume was measured and apoptotic proteins such as caspase-8, caspase-3, p53, Bcl-2, and survivin were analyzed in mice serum with an ELISA assay. The Ki-67 protein was assessed in tumor cells by immunohistochemical examination. The biggest volumes of tumors were confirmed in the DLD-1 group, while the lowest were observed in the population treated with 5FU and/or HA extract. The assessment of apoptosis showed increased concentrations of caspase 8 and p53 protein after the combined administration of 5FU and HA extract. The levels of survivin and Bcl-2 were decreased in all tested groups compared to the DLD-1 group. Moreover, we observed a positive reaction for Ki-67 protein in all tested groups. Our findings confirm the apoptotic effect of extract given alone or with 5FU. The obtained results are innovative and provide a basis for further research concerning the antitumor activity of the HA extract, especially in the range of its interaction with an anticancer chemotherapeutic agent.
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Affiliation(s)
- Anna Sadowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
- Correspondence: ; Tel.: +48-85-748-5554
| | - Diana Sawicka
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
| | - Katarzyna Godlewska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
- Department of Haematology, Medical University of Bialystok, M. Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland
| | | | - Ewa Zapora
- Department of Silviculture and Forest Use, Institute of Forest Sciences, Bialystok University of Technology, Wiejska 45E, 15-351 Bialystok, Poland
| | - Emilia Sokołowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
| | - Halina Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland
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Yu S, Han R, Gan R. The Wnt/β-catenin signalling pathway in Haematological Neoplasms. Biomark Res 2022; 10:74. [PMID: 36224652 PMCID: PMC9558365 DOI: 10.1186/s40364-022-00418-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 11/10/2022] Open
Abstract
Leukaemia and lymphoma are common malignancies. The Wnt pathway is a complex network of proteins regulating cell proliferation and differentiation, as well as cancer development, and is divided into the Wnt/β-catenin signalling pathway (the canonical Wnt signalling pathway) and the noncanonical Wnt signalling pathway. The Wnt/β-catenin signalling pathway is highly conserved evolutionarily, and activation or inhibition of either of the pathways may lead to cancer development and progression. The aim of this review is to analyse the mechanisms of action of related molecules in the Wnt/β-catenin pathway in haematologic malignancies and their feasibility as therapeutic targets.
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Affiliation(s)
- Siwei Yu
- Cancer Research Institute, Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P. R. China
| | - Ruyue Han
- Cancer Research Institute, Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P. R. China
| | - Runliang Gan
- Cancer Research Institute, Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, P. R. China.
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25
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Thota R, Aggarwal S, Chirom AS, Thakar A, Gupta SD, Sharma SC, Das SN. Serum Survivin in Oral Submucosal Fibrosis and Squamous Cell Carcinoma. Indian J Otolaryngol Head Neck Surg 2022; 74:2027-2032. [PMID: 36452695 PMCID: PMC9702048 DOI: 10.1007/s12070-020-01980-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 07/16/2020] [Indexed: 11/26/2022] Open
Abstract
Survivin, an inhibitor of apoptosis protein is a biomarker of significance in prognostication of many malignancies. In the current study we investigated the serum survivin levels in patients with oral submucosal fibrosis (OSMF) and squamous cell carcinoma (OSCC). Serum was isolated from, peripheral blood collected of clinically and histopathologically confirmed OSMF and OSCC patients. Circulating level of survivin was measured in patients and control subjects by ELISA and analyzed further using Kruskal-Wallis test and two-sample Wilcoxon rank-sum (Mann-Whitney) test. Serum Survivin levels were significantly reduced in the OSCC group as compared to the control group. No significant correlation was noted between the serum survivin level and various clinicopathological characteristics of OSCC and OSMF patients. Our study suggests that free, wild form of circulating survivin probably has no role in predicting the prognosis of oral cancer or the malignant transformation potential of oral submucosal fibrosis.
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Affiliation(s)
- Ramya Thota
- Department of Otorhinolaryngology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Sadhna Aggarwal
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Amit Singh Chirom
- Department of Otorhinolaryngology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Alok Thakar
- Department of Otorhinolaryngology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Siddhartha Dutta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Suresh C. Sharma
- Department of Otorhinolaryngology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
| | - Satya N. Das
- Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029 India
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26
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Yuan X, Wu H, Li X, Chen L, Xiao Y, Chen Z, Liu G, Lu P. SDF‑1α/CXCR4 signaling promotes capillary tube formation of human retinal vascular endothelial cells by activating ERK1/2 and PI3K pathways in vitro. Mol Med Rep 2022; 26:305. [PMID: 35946444 PMCID: PMC9435019 DOI: 10.3892/mmr.2022.12821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 06/09/2022] [Indexed: 11/06/2022] Open
Abstract
The purpose of this study is to address the effect and mechanism of stromal cell‑derived factor‑1 (SDF‑1)α/chemokine (C‑X‑C motif) receptor 4 (CXCR4) signaling on capillary tube formation of human retinal vascular endothelial cells (HRECs). The expression of CXCR4 in HRECs was quantified by reverse transcription (RT‑PCR) and western blotting. The effects of SDF‑1α/CXCR4 signaling in capillary tube formation and migration of HRECs was examined using three‑dimensional Matrigel assay and wound scratching assay respectively in vitro. Cell proliferation of HRECs was examined using cell counting kit (CCK)‑8 assay in the presence of different concentrations of SDF‑1α protein. The effect of SDF‑1α/CXCR4 signaling in HREC expression of VEGF, basic fibroblast growth factor (bFGF), IL‑8 and intercellular cell adhesion molecule (ICAM)‑1 was examined using RT‑PCR and western blotting. RT‑PCR and western blot analysis revealed CXCR4 was expressed in HRECs. The number of intact capillary tubes formed by HRECs in the presence of SDF‑1α was markedly more compared with a PBS treated control group. However, it was reduced with treatment with an CXCR4 antagonist. Wound scratching assay showed a significant increase in the number of migrated HRECs under SDF‑1α stimulation and the number was reduced with treatment with an CXCR4 antagonist. RT‑PCR and western blotting showed that SDF‑1α significantly promoted VEGF, bFGF, IL‑8 and ICAM‑1 expression in HRECs. The proliferation of HRECs in the presence of SDF‑1α was promoted in a dosage‑dependent manner. SDF‑1α/CXCR4 signaling can increase HREC capillary tube formation through promoting HREC migration, proliferation and expression of VEGF, bFGF, IL‑8 and ICAM‑1.
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Affiliation(s)
- Xianbin Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Hongya Wu
- Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xin Li
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Lei Chen
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yanhui Xiao
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhigang Chen
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Gaoqin Liu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Peirong Lu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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27
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Martínez-Sifuentes MA, Bassol-Mayagoitia S, Nava-Hernández MP, Ruiz-Flores P, Ramos-Treviño J, Haro-Santa Cruz J, Hernández-Ibarra JA. Survivin in Breast Cancer: A Review. Genet Test Mol Biomarkers 2022; 26:411-421. [PMID: 36166738 DOI: 10.1089/gtmb.2021.0286] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer-related death in women. Gene technology has led to the recognition that breast cancer is a heterogeneous disease composed of different biological subtypes, and genetic profiling enables the response to chemotherapy to be predicted. This fact emphasizes the importance of selecting sensitive diagnostic and prognostic markers in the early disease stage and more efficient targeted treatments for this disease. One such prognostic marker appears to be survivin. Many studies have shown that survivin is strongly expressed in different types of cancers. Its overexpression has been demonstrated in breast cancer, and high activity of the survivin gene has been associated with a poor prognosis and worse survival rates.
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Affiliation(s)
- Manuel Antonio Martínez-Sifuentes
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Susana Bassol-Mayagoitia
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Martha P Nava-Hernández
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Pablo Ruiz-Flores
- Department of Genetics and Molecular Medicine, Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Juan Ramos-Treviño
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Jorge Haro-Santa Cruz
- Department of Genetics and Molecular Medicine, Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - José Anselmo Hernández-Ibarra
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
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Firnau MB, Brieger A. CK2 and the Hallmarks of Cancer. Biomedicines 2022; 10:1987. [PMID: 36009534 PMCID: PMC9405757 DOI: 10.3390/biomedicines10081987] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is a leading cause of death worldwide. Casein kinase 2 (CK2) is commonly dysregulated in cancer, impacting diverse molecular pathways. CK2 is a highly conserved serine/threonine kinase, constitutively active and ubiquitously expressed in eukaryotes. With over 500 known substrates and being estimated to be responsible for up to 10% of the human phosphoproteome, it is of significant importance. A broad spectrum of diverse types of cancer cells has been already shown to rely on disturbed CK2 levels for their survival. The hallmarks of cancer provide a rationale for understanding cancer's common traits. They constitute the maintenance of proliferative signaling, evasion of growth suppressors, resisting cell death, enabling of replicative immortality, induction of angiogenesis, the activation of invasion and metastasis, as well as avoidance of immune destruction and dysregulation of cellular energetics. In this work, we have compiled evidence from the literature suggesting that CK2 modulates all hallmarks of cancer, thereby promoting oncogenesis and operating as a cancer driver by creating a cellular environment favorable to neoplasia.
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Affiliation(s)
| | - Angela Brieger
- Department of Internal Medicine I, Biomedical Research Laboratory, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
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29
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Sun EC, Dong SS, Li ZJ, Li CX. Clinicopathological Significance of AKT1 and PLK1 Expression in Oral Squamous Cell Carcinoma. DISEASE MARKERS 2022; 2022:7300593. [PMID: 35756492 PMCID: PMC9232379 DOI: 10.1155/2022/7300593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022]
Abstract
Purpose Oral squamous cell carcinoma (OSCC) is the sixth leading cause of cancer-related death worldwide and is characterized by metastasis and recurrence. We aimed to evaluate the expression of AKT1 and PLK1 in OSCC and identify their correlation with the clinical and histological features and prognosis of patients with OSCC. Methods Tissue samples were collected from 70 patients with OSCC and 50 patients with normal oral mucosa. The expression levels of AKT1 and PLK1 in OSCC tissues and normal oral mucosa were detected by immunohistochemistry. The chi-square test was used to identify correlations between the expression levels of AKT1 and PLK1 with patients' clinicopathologic characteristics. Survival analysis was assessed by the Kaplan-Meier method. Spearman's rank correlation test was used to determine the relationships between AKT1 and PLK1 expressions. The bioinformatics database GEPIA was used to verify the experimental results. Results The chi-square test and Fisher's exact test showed that the positive expression rate of AKT1 and PLK1 in OSCC tissue was significantly higher than that in the normal oral mucosa (P < 0.05). PLK1 expression levels were significantly correlated with tumor stage and size (P < 0.05). Kaplan-Meier analysis showed that the survival time of AKT1 and PLK1 with high expression was significantly shorter than that of patients with low expression (P < 0.05). Spearman's rank correlation test showed a strong correlation between AKT1 and PLK1 expression in OSCC tissue (R = 0.53; P < 0.05). GEPIA bioinformatics database analysis results show that the expression and overall survival of AKT1 and PLK1 analysis and the correlation analysis of AKT1 and PLK1 were consistent with experimental results. Conclusion AKT1 and PLK1 expressions are associated with the occurrence and progression of OSCC and may be used as diagnostic and prognostic indicators of OSCC. There may be a correlation between AKT1 and PLK1 in OSCC tissue.
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Affiliation(s)
- Er-Can Sun
- Department of Stomatology, Shihezi University School of Medicine & the First Affiliated Hospital to Shihezi University School of Medicine, Shihezi, 832002 Xinjiang, China
| | - Shuang-Shuang Dong
- Department of Pathology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu 225000, China
| | - Zhi-Jun Li
- Department of Stomatology, Shihezi University School of Medicine & the First Affiliated Hospital to Shihezi University School of Medicine, Shihezi, 832002 Xinjiang, China
| | - Chang-Xue Li
- Department of Stomatology, Shihezi University School of Medicine & the First Affiliated Hospital to Shihezi University School of Medicine, Shihezi, 832002 Xinjiang, China
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30
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Morales F, Pérez P, Tapia JC, Lobos-González L, Herranz JM, Guevara F, de Santiago PR, Palacios E, Andaur R, Sagredo EA, Marcelain K, Armisén R. Increase in ADAR1p110 activates the canonical Wnt signaling pathway associated with aggressive phenotype in triple negative breast cancer cells. Gene 2022; 819:146246. [PMID: 35122924 DOI: 10.1016/j.gene.2022.146246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/13/2021] [Accepted: 01/18/2022] [Indexed: 12/21/2022]
Abstract
Triple-negative breast cancer (TNBC) represents a challenge in the search for new therapeutic targets. TNBCs are aggressive and generate resistance to chemotherapy. Tumors of TNBC patients with poor prognosis present a high level of adenosine deaminase acting on RNA1 (ADAR1). We explore the connection of ADAR1 with the canonical Wnt signaling pathway and the effect of modulation of its expression in TNBC. Expression data from cell line sequencing (DepMap) and TCGA samples were downloaded and analyzed. We lentivirally generated an MDA-MB-231 breast cancer cell line that overexpress (OE) ADAR1p110 or an ADAR knockdown. Abundance of different proteins related to Wnt/β-catenin pathway and activity of nuclear β-catenin were analyzed by Western blot and luciferase TOP/FOP reporter assay, respectively. Cell invasion was analyzed by matrigel assay. In mice, we study the behavior of tumors generated from ADAR1p110 (OE) cells and tumor vascularization immunostaining were analyzed. ADAR1 connects to the canonical Wnt pathway in TNBC. ADAR1p110 overexpression decreased GSK-3β, while increasing active β-catenin. It also increased the activity of nuclear β-catenin and increased its target levels. ADAR1 knockdown has the opposite effect. MDA-MB-231 ADAR1 (OE) cells showed increased capacity of invasion. Subsequently, we observed that tumors derived from ADAR1p110 (OE) cells showed increased invasion towards the epithelium, and increased levels of Survivin and CD-31 expressed in vascular endothelial cells. These results indicate that ADAR1 overexpression alters the expression of some key components of the canonical Wnt pathway, favoring invasion and neovascularization, possibly through activation of the β-catenin, which suggests an unknown role of ADAR1p110 in aggressiveness of TNBC tumors.
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Affiliation(s)
- Fernanda Morales
- Centro de Investigación y Tratamiento del Cáncer, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile; Center of Excellence in Precision Medicine, Pfizer Chile, Obispo Arturo Espinoza Campos 2526, Santiago, Chile
| | - Paola Pérez
- Center of Excellence in Precision Medicine, Pfizer Chile, Obispo Arturo Espinoza Campos 2526, Santiago, Chile; NIDCR, National Institute of Health, 9000 Rockville Pike, Bldg 10, Room 1A01, Bethesda, MD, USA
| | - Julio C Tapia
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile
| | - Lorena Lobos-González
- Centro De Medicina Regenerativa, Facultad de Medicina - Clínica Alemana, Universidad Del Desarrollo, Av. Las Condes 12496, Santiago, Chile; Fundación Ciencia & Vida - Andes Biotechnologies S.A., Av. Zanartu 1482, Santiago, Chile
| | - José Manuel Herranz
- Departamento de Anatomía Patológica, Hospital Clínico Universidad de Chile, Santos Dumont 999, Santiago, Chile
| | - Francisca Guevara
- Fundación Ciencia & Vida - Andes Biotechnologies S.A., Av. Zanartu 1482, Santiago, Chile
| | - Pamela Rojas de Santiago
- Center of Excellence in Precision Medicine, Pfizer Chile, Obispo Arturo Espinoza Campos 2526, Santiago, Chile; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Avda. Libertador Bernardo ÓHiggins 340, Santiago, Chile
| | - Esteban Palacios
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile
| | - Rodrigo Andaur
- Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile; Comisión Chilena de Energía Nuclear, Nueva Bilbao 12501, Las Condes, Santiago Chile
| | - Eduardo A Sagredo
- Centro de Investigación y Tratamiento del Cáncer, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile; Center of Excellence in Precision Medicine, Pfizer Chile, Obispo Arturo Espinoza Campos 2526, Santiago, Chile; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrhenius väg 20C, 106 91 Stockholm, Sweden
| | - Katherine Marcelain
- Centro de Investigación y Tratamiento del Cáncer, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile; Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile
| | - Ricardo Armisén
- Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12461, Edificio 3, oficina 205, CP 7590943, Santiago, Chile.
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Sato K, Osaka E, Fujiwara K, Fujii R, Takayama T, Tokuhashi Y, Nakanishi K. miRNA‑218 targets multiple oncogenes and is a therapeutic target for osteosarcoma. Oncol Rep 2022; 47:92. [PMID: 35293593 PMCID: PMC8968766 DOI: 10.3892/or.2022.8303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/18/2022] [Indexed: 11/25/2022] Open
Abstract
Survivin is overexpressed in various cancers and is correlated with treatment resistance and prognosis. MicroRNAs (miRNAs) directly regulate several target genes and are potential therapeutic agents for various cancers. The present study evaluated multiple gene targets of miR-218, including survivin, in osteosarcoma and compared the anti-tumor effects of miR-218 with those of YM155, an anti-survivin agent. It assessed the expression levels of miR-218 and survivin in osteosarcoma and osteoblast cell lines, as well as the proliferative, migratory and invasive capacities of cells following treatment with miR-218 or YM155. The form of cell death was assessed using fluorescence-activated cell sorting analysis to examine the expression of invasion ability-related genes. Osteosarcoma cell lines were subcutaneously injected into immunodeficient mice; the mice were then treated with miR-218 or YM155 to assess the anti-tumor effects of these agents. The results showed that miR-218 was downregulated, whereas survivin was overexpressed in the osteosarcoma cell line compared with normal osteoblast cells. The expression of survivin was suppressed upon overexpression of miR-218 (miR-218 group) or administration of YM155 (YM155 group), leading to apoptosis and inhibition of osteosarcoma cell proliferation. Invasion and migration abilities were inhibited in the miR-218 group, but not in the YM155 group. In the animal model, both the miR-218 and YM155 groups showed a reduced tumor volume and decreased survivin expression. In osteosarcoma, miR-218 showed a wider range of therapeutic efficacy compared with YM155, suggesting that miR-218 should be evaluated as a treatment target.
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Affiliation(s)
- Kentaro Sato
- Department of Orthopedic Surgery, Nihon University Hospital, Chiyoda‑ku, Tokyo 101‑8309, Japan
| | - Eiji Osaka
- Department of Orthopedic Surgery, Nihon University School of Medicine, Itabashi‑ku, Tokyo 173‑8610, Japan
| | - Kyoko Fujiwara
- Department of Internal Medicine, Nihon University School of Medicine, Itabashi‑ku, Tokyo 173‑8610, Japan
| | - Ryota Fujii
- Department of Orthopedic Surgery, Nihon University School of Medicine, Itabashi‑ku, Tokyo 173‑8610, Japan
| | - Tadateru Takayama
- Department of Internal Medicine, Nihon University School of Medicine, Itabashi‑ku, Tokyo 173‑8610, Japan
| | - Yasuaki Tokuhashi
- Department of Orthopedic Surgery, Tachikawa Kinen Hospital, Kasama City, Ibaraki 309‑1736, Japan
| | - Kazuyoshi Nakanishi
- Department of Orthopedic Surgery, Nihon University School of Medicine, Itabashi‑ku, Tokyo 173‑8610, Japan
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Pre-Administration of Berberine Exerts Chemopreventive Effects in AOM/DSS-Induced Colitis-Associated Carcinogenesis Mice via Modulating Inflammation and Intestinal Microbiota. Nutrients 2022; 14:nu14040726. [PMID: 35215376 PMCID: PMC8879943 DOI: 10.3390/nu14040726] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory activation and intestinal flora imbalance play an essential role in the development and progression of colorectal cancer (CRC). Berberine (BBR) has attracted great attention in recent years due to its heath-related benefits in inflammatory disorders and tumors, but the intricate mechanisms have not been fully elucidated. In this study, the effects and the mechanism of BBR on colon cancer were investigated in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis mice model. Our results showed that pre-administration of BBR showed a decrease in weight loss, disease activity index (DAI) score, and the number of colon tumors in mice, compared with the model group. The evidence from pathological examination indicated that the malignancy of intestinal tumors was ameliorated after pre-administration of BBR. Additionally, pre-administration with BBR suppressed the expression of pro-inflammatory factors (interleukin (IL)-6, IL-1β, cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)-α) and the cell-proliferation marker Ki67, while expression of the tight junction proteins (ZO-1 and occludin) were increased in colon tissue. Moreover, the levels of critical pathway proteins involved in the inflammatory process (p-STAT3 and p-JNK) and cell cycle regulation molecules (β-catenin, c-Myc and CylinD1) exhibited lower expression levels. Besides, 16S rRNA sequence analysis indicated that pre-administration of BBR increased the ratio of Firmicutes/Bacteroidetes (F:M) and the relative abundance of potentially beneficial bacteria, while the abundance of cancer-related bacteria was decreased. Gavage with Lactobacillus rhamnosus can improve the anti-tumor effect of BBR. Overall, pre-administration of BBR exerts preventive effects in colon carcinogenesis, and the mechanisms underlying these effects are correlated with the inhibition of inflammation and tumor proliferation and the maintenance of intestinal homeostasis.
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Ahluwalia A, Patel K, Hoa N, Brzozowska I, Jones MK, Tarnawski AS. Melatonin ameliorates aging-related impaired angiogenesis in gastric endothelial cells via local actions on mitochondria and VEGF-survivin signaling. Am J Physiol Gastrointest Liver Physiol 2021; 321:G682-G689. [PMID: 34668398 DOI: 10.1152/ajpgi.00101.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
Tissue injury healing is impaired in aging, and this impairment is caused in part by reduced angiogenesis. Melatonin, a neuroendocrine hormone that regulates sleep and circadian rhythm, is also produced in the gastrointestinal tract. The expression of melatonin receptors MT1 and MT2 in gastric endothelial cells and their roles in aging-related impairment of gastric angiogenesis have not been examined. We hypothesized that MT1 and MT2 expression is reduced in gastric endothelial cells of aging rats and that melatonin treatment can upregulate their expression and improve angiogenesis. We examined the expression of MT1 and MT2 in gastric endothelial cells (GECs) isolated from young and aging rats. We also examined the effects of melatonin treatment on angiogenesis, GEC mitochondrial function, expression of vascular endothelial growth factor (VEGF), its signaling receptor (VEGFR-2), and the inhibitor of apoptosis protein, survivin. Young and aging GECs expressed MT1 (in the cytoplasm and mitochondria) and MT2 (in nucleus and mitochondria). In aging GECs, MT1 and MT2 levels, in vitro angiogenesis, and mitochondrial membrane potential were significantly reduced (by 1.5-fold, 1.9-fold, 3.1-fold, and 1.63-fold, respectively) compared with young GECs. Melatonin treatment of aging GECs significantly increased MT1 and MT2 expression compared with the controls, induced nuclear translocation of MT1, and significantly ameliorated the aging-related impairment of angiogenesis and mitochondrial function. Aging GECs have significantly reduced MT1 and MT2 expression, angiogenesis, and mitochondrial membrane potential compared with young GECs. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function.NEW & NOTEWORTHY This study showed reduced expression of melatonin receptors MT1 and MT2, angiogenesis, and mitochondrial function in gastric endothelial cells (GECs) isolated from aging rats. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function. These studies provide new insight into the mechanisms of the aging-related impairment of angiogenesis and delayed tissue injury healing and provide a rationale for melatonin treatment to reverse these abnormalities.
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MESH Headings
- Age Factors
- Angiogenesis Inducing Agents/pharmacology
- Animals
- Cells, Cultured
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Gastric Mucosa/blood supply
- Melatonin/pharmacology
- Mitochondria/drug effects
- Mitochondria/metabolism
- Neovascularization, Physiologic/drug effects
- Rats, Inbred F344
- Receptor, Melatonin, MT1/agonists
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/agonists
- Receptor, Melatonin, MT2/metabolism
- Signal Transduction
- Survivin/metabolism
- Vascular Endothelial Growth Factor A/metabolism
- Rats
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Affiliation(s)
- Amrita Ahluwalia
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
| | - Khushin Patel
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
| | - Neil Hoa
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
| | - Iwona Brzozowska
- Department of Anatomy, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Michael K Jones
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Andrzej S Tarnawski
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
- Department of Medicine, University of California, Irvine, California
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Shen S, Wang R, Qiu H, Li C, Wang J, Xue J, Tang Q. Development of an Autophagy-Based and Stemness-Correlated Prognostic Model for Hepatocellular Carcinoma Using Bulk and Single-Cell RNA-Sequencing. Front Cell Dev Biol 2021; 9:743910. [PMID: 34820373 PMCID: PMC8606524 DOI: 10.3389/fcell.2021.743910] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/11/2021] [Indexed: 01/10/2023] Open
Abstract
Accumulating evidence has proved that autophagy serves as a tumor promoter in formed malignancies, and the autophagy-related prognostic signatures have been constructed as clinical tools to predict prognosis in many high-mortality cancers. Autophagy-related genes have participated in the development and metastasis of hepatocellular carcinoma (HCC), but the understanding of their prognostic value is limited. Thereafter, LIMMA and survival analysis were conducted in both ICGC and TCGA databases and a total of 10 hub autophagy-related genes, namely, NPC1, CDKN2A, RPTOR, SPHK1, HGS, BIRC5, SPNS1, BAK1, ATIC, and MAPK3, were collected. Then, GO, KEGG, correlation, consensus, and PCA analyses were utilized to reveal their potential targeted role in HCC treatment. Single-cell RNA-seq of cancer stem cells also indicated that there was a positive correlation between these genes and stemness. In parallel, we applied univariate, LASSO, and multivariate regression analyses to study the autophagy-related genes and finally proposed that ATIC and BIRC5 were the valuable prognostic indicators of HCC. The signature based on ATIC and BIRC5 exhibited moderate power for predicting the survival of HCC in the ICGC cohort, and its efficacy was further validated in the TCGA cohort. Taken together, we suggested that 10 aforementioned hub genes are promising therapeutic targets of HCC and the ATIC/BIRC5 prognostic signature is a practical prognostic indicator for HCC patients.
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Affiliation(s)
- Shengwei Shen
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Rui Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hua Qiu
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chong Li
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jinghan Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qinghe Tang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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Mebed R, Ali YB, Shehata N, El-Guendy N, Gamal N, Zekri AR, Sabet S. Combining Bevacizumab with knocked-down β-catenin reduces VEGF-A and Slug mRNA in HepG2 but not in Caco-2 cell lines. Curr Mol Med 2021; 22:374-383. [PMID: 34429048 DOI: 10.2174/1573405617666210824120618] [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: 01/07/2021] [Revised: 06/10/2021] [Accepted: 06/17/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Bevacizumab (Bev) resistance is hypothesized to be overcome by combination with inhibitors of other signalling pathways. OBJECTIVE We aimed to study the effect of combining Bev with knocked down β-catenin (Bev-β-cat-siRNA) on the expression of VEGF-A, Slug, NFКB and its two target genes c-Flip and FasR in HepG2. Expression of VEGF-A and Slug was also studied in Caco-2 cells. METHODS Cultured cells were divided into six groups 1) cells treated with Bev only 2) cells treated with β-catenin-siRNA 3) cells treated with Bev-β-cat-siRNA 4) cells treated with negative control 5) cells treated with Bev-negative control and untreated cells. Expressions were assessed using qPCR and western blotting. RESULTS Bev-β-cat-siRNA significantly reduced the mRNA level of VEGF-A, which was initially increased in response to Bev alone in HepG2 but not in Caco-2. Additionally, Bev-β-cat-siRNA significantly decreased Slug mRNA level compared to Bev only treated HepG2 cells. In contrast, VEGF-A and Slug mRNA levels in Bev only group were remarkably lower than Bev-β-cat-siRNA in Caco-2 cells. Distinct β-catenin and Slug protein expressions were noticed in HepG2 and Caco-2 cells. On the other hand, Bev-β-cat-siRNA remarkably reduced the level of NFКB, FasR and c-Flip compared to Bev only treated HepG2 cells although the difference was not statistically significant. CONCLUSION We conclude that, combining Bevacizumab with knocked down β-catenin reduce the expression of VEGF-A and Slug in HepG2 but not in Caco-2 cells.
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Affiliation(s)
- Reem Mebed
- Chemical control unit, National Organization for Research and Control of Biologicals, Cairo. Egypt
| | - Yasser Bm Ali
- Molecular Biology unit, Genetic Engineering and Biotechnology Research Institute, University of Sadat City. Egypt
| | - Nahla Shehata
- Lot release unit, National Organization for Research and Control of Biologicals, Cairo. Egypt
| | - Nadia El-Guendy
- Department of Cancer Biology, National Institute of Cancer, Cairo University. Egypt
| | - Nahla Gamal
- Department of Applied Research, Research & Development Sector, VACSERA, Cairo. Egypt
| | - Abdel-Rahman Zekri
- Department of Cancer Biology, National Institute of Cancer, Cairo University. Egypt
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University. Egypt
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El-Ashmawy NE, El-Zamarany EA, Khedr NF, Selim HM, Khedr EG. Inhibition of PKC/MEK pathway suppresses β1-integrin and mitigates breast cancer cells proliferation. Toxicol Rep 2021; 8:1530-1537. [PMID: 34408972 PMCID: PMC8361284 DOI: 10.1016/j.toxrep.2021.07.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
PGE2 enhanced β1- integrin expression via EP1 receptor, PKC, MEK and NfҡB. FOXC2, E2F1 and survivin play a role in PGE2 mediated effect in MCF7 cells. PGE2 enhances breast cancer cell cycle through E2F1, FOXC2, survivin and β integrin. Biochemical mediators of PKC/MEK pathway could be considered as targets for breast cancer treatment. Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.
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Affiliation(s)
| | - Enas A El-Zamarany
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt
| | - Naglaa F Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Hend M Selim
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Eman G Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
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A Novel Recombinant Fcγ Receptor-Targeted Survivin Combines with Chemotherapy for Efficient Cancer Treatment. Biomedicines 2021; 9:biomedicines9070806. [PMID: 34356870 PMCID: PMC8301409 DOI: 10.3390/biomedicines9070806] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/03/2021] [Accepted: 07/09/2021] [Indexed: 01/03/2023] Open
Abstract
Formyl peptide receptor-like 1 inhibitor (FLIPr), an Fcγ receptor (FcγR) antagonist, can be used as a carrier to guide antigen-FLIPr fusion protein to FcγR then enhances antigen-specific immune responses. Survivin, a tumor-associated antigen, is over-expressed in various types of human cancer. In this study, we demonstrate that recombinant survivin-FLIPr fusion protein (rSur-FLIPr) binds to FcγRs, and efficient uptake by dendritic cells in vivo. In addition, rSur-FLIPr alone stimulates survivin-specific immune responses, which effectively suppresses the tumor growth. The antitumor immunities are through TAP-mediated and CD8-dependent pathways. Furthermore, preexisting anti-FLIPr antibody does not abolish antitumor responses induced by rSur-FLIPr immunization. These results suggest that FLIPr is an effective antigen delivery vector and can be repeatedly used. Combination of chemotherapy with rSur-FLIPr treatment reveals a great benefit to tumor-bearing mice. Altogether, these findings suggest that rSur-FLIPr is a potential candidate for efficient cancer therapy.
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González A, Alonso-González C, González-González A, Menéndez-Menéndez J, Cos S, Martínez-Campa C. Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments. Cancers (Basel) 2021; 13:3263. [PMID: 34209857 PMCID: PMC8268559 DOI: 10.3390/cancers13133263] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 02/07/2023] Open
Abstract
Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.
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Affiliation(s)
| | | | | | | | - Samuel Cos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain; (A.G.); (A.G.-G.); (J.M.-M.); (C.M.-C.)
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Xie W, Yan O, Liu F, Han Y, Wang H. Prognostic Value of Survivin in Nasopharyngeal Carcinoma: A Systematic Review and Meta-analysis. J Cancer 2021; 12:4399-4407. [PMID: 34093840 PMCID: PMC8176404 DOI: 10.7150/jca.46282] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/26/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Previous studies have shown that survivin has potential prognostic value in nasopharyngeal carcinoma. However, the results remained controversial until now. Thus, to investigate the influence of survivin expression on prognosis and clinical characteristics in nasopharyngeal carcinoma, we performed this meta-analysis. Methods: We searched PubMed, PMC, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure electronic databases from their establishment to 1 March 2021. The pooled hazard ratio (HR) and the pooled odds ratio (OR) were used to evaluate the prognostic and clinicopathological values of survivin in nasopharyngeal carcinoma. We used the I2 statistic and the Q test to evaluate heterogeneity. Meta-regression, publication bias, and sensitivity analyses were also conducted. Results: A total of 26 eligible studies with 2278 patients were included in our meta-analysis. We found that the expression of survivin is connected with poor overall survival (HR=1.94; 95% confidence interval (CI)=1.52-2.48; P<0.001), lymph node metastasis (OR=3.01; 95% CI=2.31- 3.91; P<0.001), local recurrence (OR=2.40; 95% CI=1.60-3.61, P<0.001), distant metastasis (OR=2.58; 95% CI=1.74-3.84, P<0.001), and a higher clinical stage (OR=4.58; 95% CI=2.81-7.47, P<0.001). However, no significant correlations were found between survivin expression and radio-sensitivity (OR=1.33; 95% CI=0.25-7.17, P=0.737) or gender (OR=1.02; 95% CI=0.75-1.39, P=0.887). Conclusions: This meta-analysis indicates that survivin could be used as a biomarker for predicting prognosis in nasopharyngeal carcinoma.
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Affiliation(s)
- Wenji Xie
- Department of Radiotherapy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha 410013, Hunan, China
| | - Ouying Yan
- Department of Radiotherapy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha 410013, Hunan, China
| | - Feng Liu
- Department of Radiotherapy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha 410013, Hunan, China
| | - Yaqian Han
- Department of Radiotherapy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha 410013, Hunan, China
| | - Hui Wang
- Department of Radiotherapy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha 410013, Hunan, China
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40
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Luo Y, Liu F, Han S, Qi Y, Hu X, Zhou C, Liang H, Zhang Z. Autophagy-Related Gene Pairs Signature for the Prognosis of Hepatocellular Carcinoma. Front Mol Biosci 2021; 8:670241. [PMID: 34095224 PMCID: PMC8173133 DOI: 10.3389/fmolb.2021.670241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/05/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has been recognized as the third leading cause of cancer-related deaths worldwide. There is increasing evidence that the abnormal expression of autophagy-related genes plays an important role in the occurrence and development of HCC. Therefore, the study of autophagy-related genes can further elucidate the genetic drivers of cancer and provide valuable therapeutic targets for clinical treatment. In this study, we used 232 autophagy-related genes extracted from the Human Autophagy Database (HADb) and Molecular Signatures Database (MSigDB) to construct 1884 autophagy-related gene pairs. On this basis, we developed a prognostic model based on autophagy-related gene pairs using least absolute shrinkage and selection operator (LASSO) Cox regression to evaluate the prognosis of patients after liver cancer resection. We then used 845 liver cancer samples from three different databases to test the reliability of the risk signature through survival analysis, receiver operating characteristic (ROC) curve analysis, univariate and multivariate analysis. To further explore the underlying biological mechanisms, we conducted an enrichment analysis of autophagy-related genes. Finally, we combined the signature with independent prognostic factors to construct a nomogram. Based on the autophagy-related gene pair (ARGP) signature, we can divide patients into high- or low-risk groups. Survival analysis and ROC curve analysis verified the validity of the signature (AUC: 0.786—0.828). Multivariate Cox regression showed that the risk score can be used as an independent predictor of the clinical outcomes of liver cancer patients. Notably, this model has a more accurate predictive effect than most prognostic models for hepatocellular carcinoma. Moreover, our model is a powerful supplement to the HCC staging indicator, and a nomogram comprising both indicators can provide a better prognostic effect. Based on pairs of multiple autophagy-related genes, we proposed a prognostic model for predicting the overall survival rate of HCC patients after surgery, which is a promising prognostic indicator. This study confirms the importance of autophagy in the occurrence and development of HCC, and also provides potential biomarkers for targeted treatments.
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Affiliation(s)
- Yiming Luo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Shenqi Han
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Yongqiang Qi
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Xinsheng Hu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Chenyang Zhou
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Zhiwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Tay BQ, Wright Q, Ladwa R, Perry C, Leggatt G, Simpson F, Wells JW, Panizza BJ, Frazer IH, Cruz JLG. Evolution of Cancer Vaccines-Challenges, Achievements, and Future Directions. Vaccines (Basel) 2021; 9:vaccines9050535. [PMID: 34065557 PMCID: PMC8160852 DOI: 10.3390/vaccines9050535] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.
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Affiliation(s)
- Ban Qi Tay
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Quentin Wright
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Rahul Ladwa
- Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia;
- Faculty of Medicine, University of Queensland, Woolloongabba, QLD 4102, Australia; (C.P.); (B.J.P.)
| | - Christopher Perry
- Faculty of Medicine, University of Queensland, Woolloongabba, QLD 4102, Australia; (C.P.); (B.J.P.)
- Department of Otolaryngology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
| | - Graham Leggatt
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Fiona Simpson
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - James W. Wells
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Benedict J. Panizza
- Faculty of Medicine, University of Queensland, Woolloongabba, QLD 4102, Australia; (C.P.); (B.J.P.)
- Department of Otolaryngology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
| | - Ian H. Frazer
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Jazmina L. G. Cruz
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
- Correspondence: ; Tel.: +61-0478912737
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Yan Q, Zheng W, Wang B, Ye B, Luo H, Yang X, Zhang P, Wang X. A prognostic model based on seven immune-related genes predicts the overall survival of patients with hepatocellular carcinoma. BioData Min 2021; 14:29. [PMID: 33962640 PMCID: PMC8106157 DOI: 10.1186/s13040-021-00261-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 04/20/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a disease with a high incidence and a poor prognosis. Growing amounts of evidence have shown that the immune system plays a critical role in the biological processes of HCC such as progression, recurrence, and metastasis, and some have discussed using it as a weapon against a variety of cancers. However, the impact of immune-related genes (IRGs) on the prognosis of HCC remains unclear. METHODS Based on The Cancer Gene Atlas (TCGA) and Immunology Database and Analysis Portal (ImmPort) datasets, we integrated the ribonucleic acid (RNA) sequencing profiles of 424 HCC patients with IRGs to calculate immune-related differentially expressed genes (DEGs). Survival analysis was used to establish a prognostic model of survival- and immune-related DEGs. Based on genomic and clinicopathological data, we constructed a nomogram to predict the prognosis of HCC patients. Gene set enrichment analysis further clarified the signalling pathways of the high-risk and low-risk groups constructed based on the IRGs in HCC. Next, we evaluated the correlation between the risk score and the infiltration of immune cells, and finally, we validated the prognostic performance of this model in the GSE14520 dataset. RESULTS A total of 100 immune-related DEGs were significantly associated with the clinical outcomes of patients with HCC. We performed univariate and multivariate least absolute shrinkage and selection operator (Lasso) regression analyses on these genes to construct a prognostic model of seven IRGs (Fatty Acid Binding Protein 6 (FABP6), Microtubule-Associated Protein Tau (MAPT), Baculoviral IAP Repeat Containing 5 (BIRC5), Plexin-A1 (PLXNA1), Secreted Phosphoprotein 1 (SPP1), Stanniocalcin 2 (STC2) and Chondroitin Sulfate Proteoglycan 5 (CSPG5)), which showed better prognostic performance than the tumour/node/metastasis (TNM) staging system. Moreover, we constructed a regulatory network related to transcription factors (TFs) that further unravelled the regulatory mechanisms of these genes. According to the median value of the risk score, the entire TCGA cohort was divided into high-risk and low-risk groups, and the low-risk group had a better overall survival (OS) rate. To predict the OS rate of HCC, we established a gene- and clinical factor-related nomogram. The receiver operating characteristic (ROC) curve, concordance index (C-index) and calibration curve showed that this model had moderate accuracy. The correlation analysis between the risk score and the infiltration of six common types of immune cells showed that the model could reflect the state of the immune microenvironment in HCC tumours. CONCLUSION Our IRG prognostic model was shown to have value in the monitoring, treatment, and prognostic assessment of HCC patients and could be used as a survival prediction tool in the near future.
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Affiliation(s)
- Qian Yan
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenjiang Zheng
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Boqing Wang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Baoqian Ye
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huiyan Luo
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinqian Yang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ping Zhang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiongwen Wang
- Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Zhan Q, Yi K, Li X, Cui X, Yang E, Chen N, Yuan X, Zhao J, Hou X, Kang C. Phosphatidylcholine-Engineered Exosomes for Enhanced Tumor Cell Uptake and Intracellular Antitumor Drug Delivery. Macromol Biosci 2021; 21:e2100042. [PMID: 33949800 DOI: 10.1002/mabi.202100042] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/31/2021] [Indexed: 12/19/2022]
Abstract
Exosomes derived from non-tumor cells hold great potential as drug delivery vehicles because of their good biosafety and natural transference of bioactive cargo between cells. However, compared to tumor-derived exosomes, efficient delivery is limited by their weak interactions with tumor cells. It is essential to engineer exosomes that improve tumor cellular internalization efficiency. A simple and effective strategy to enhance tumor cell uptake by engineering the exosome membrane lipids can be established by drawing on the role of lipids in tumor exosomes interacting with tumor cells. Amphiphilic phosphatidylcholine (PC) molecules are inserted into the membrane lipid layer of reticulocyte-derived exosomes (Exos) by simple incubation to construct PC-engineered exosomes (PC-Exos). It is demonstrated that PC-Exos showed significantly enhanced tumor cell internalization and uptake rate compared to native Exos, up to a twofold increase. After therapeutic agent loading, PC-Exos remarkably promotes intracellular drug or RNA accumulation in cancer cells, thus showing enhanced in vitro anti-tumor activity. This work demonstrates the crucial role of engineering exosomal lipids in modulating cancer cellular uptake, which may shed light on the design of high-efficiency exosome-based drug delivery carriers.
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Affiliation(s)
- Qi Zhan
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin, 300072, China
| | - Kaikai Yi
- Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China
| | - Xueping Li
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin, 300072, China
| | - Xiaoteng Cui
- Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China
| | - Eryan Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China
| | - Ning Chen
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin, 300072, China
| | - Xubo Yuan
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin, 300072, China
| | - Jin Zhao
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin, 300072, China
| | - Xin Hou
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin, 300072, China
| | - Chunsheng Kang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China
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Gao J, Hou D, Hu P, Mao G. Curcumol increases the sensitivity of colon cancer to 5-FU by regulating Wnt/β-catenin signaling. Transl Cancer Res 2021; 10:2437-2450. [PMID: 35116559 PMCID: PMC8798486 DOI: 10.21037/tcr-21-689] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/06/2021] [Indexed: 12/16/2022]
Abstract
Background 5-fluorouracil (5-FU) resistance is the leading cause of treatment failure in colon cancer. Combination therapy is an effective strategy to inhibit cancer cells and prevent drug resistance. Therefore, we studied the antitumor effect of curcumol alone or combined with 5-FU on human colon cancer drug-resistant cells. Methods The 5-FU resistant HCT116 cell line (HCT116/5-FU) was established by repeated exposure to gradually increasing concentrations of 5-FU; Cell viability was measured by cell counting kit-8 (CCK-8); apoptosis rate of HCT116 cells was detected using Annexin V-fluorescein isothiocyanate (FITC) assay kit; cell proliferation and invasion were detected using colony formation assays, wound healing assay and transwell invasion assays; activity of transplanted tumor in vivo in specific pathogen free (SPF) BALB/c nude mice (6 weeks old, male) was monitored by bioluminescence imaging, immunohistochemistry and western blot analysis. Results Our study showed the potent antitumor effect of curcumol by induction of apoptosis, inhibition of proliferation, invasion, migration, and improvement of the therapeutic efficacy of 5-FU toward human colon cancer HCT116 cells. From our results, curcumol could chemosensitize 5-FU-resistant HCT116 cells. The combination of curcumol and 5-FU exerted a synergistic inhibitory effect on the induction of apoptosis. Also, this combination inhibited the proliferation, invasion, and migration of both chemo-resistant and sensitive cells. Curcumol treatment decreased multidrug resistance-associated protein 2 (MRP-2), P-glycoprotein (P-gp), survivin, and β-catenin expression, which correlated with multidrug resistance (MDR) and the target genes of Wnt/β-catenin. It significantly increased the p-β-catenin level and Bad/Bcl-2 ratio in HCT116/5-FU cells compared with 5-FU treatment. In vivo, curcumol significantly inhibited the growth of transplanted tumors and the expression of Ki-67, proliferating cell nuclear antigen (PCNA), and vascular endothelial growth factor (VEGF) in colon cancer cells. Conclusions Curcumol as a potential chemotherapeutic agent combined with 5-FU can overcome colon cancer resistance.
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Affiliation(s)
- Jinfeng Gao
- Department of Oncology, Affiliated Nanjing Jiangbei Hospital to Nantong University, Nanjing, China
| | - Daorong Hou
- Animal Core Facility, Nanjing Medical University, Nanjing, China
| | - Ping Hu
- Department of Oncology, Affiliated Nanjing Jiangbei Hospital to Nantong University, Nanjing, China
| | - Guoxin Mao
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, China
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Puskas R, Bikov A, Horvath P, Lazar Z, Kunos L, Nagy R, Pinter G, Galffy G. Circulating Survivin Protein Levels in Lung Cancer Patients Treated With Platinum-Based Chemotherapy. Pathol Oncol Res 2021; 27:631969. [PMID: 34257598 PMCID: PMC8262151 DOI: 10.3389/pore.2021.631969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 04/01/2021] [Indexed: 12/27/2022]
Abstract
The survivin protein contributes to the development and progression of tumors. Protein expression and mRNA levels correlate with clinicopathological parameters and survival of cancer patients. Our purpose was to evaluate whether circulating survivin levels have any diagnostic or predictive value in lung cancer. 118 patients with advanced stage lung cancer participated in our study. 53 suffered from adenocarcinoma (ADC), 33 from squamous cell carcinoma (SqCC), and 32 from small cell lung cancer (SCLC). We also enrolled 21 control subjects. Blood samples were collected before and after two cycles of chemotherapy. We measured survivin concentrations with ELISA. Non-parametric tests were used for analysis. We did not find significant difference in survivin levels between patients and control subjects (17.19/0–829.74/vs. 49.13/0–165.92/pg/ml; p = 0.07). We found lower survivin concentrations in patients with SqCC (0/0–171.24/pg/ml) than in those with ADC (24.94/0–626.46 pg/ml) and SCLC (45.51/0–829.74/pg/ml) (ADC vs. SqCC p < 0.0001, ADC vs. SCLC p = 0.0405, SqCC vs. SCLC p < 0.0001). Survivin levels were higher in stage IV patients than in patients without distant metastases (p = 0.0061), and concentrations were progressively higher with increasing number of metastatic organ sites (p = 0.04). We observed a decrease in survivin levels in ADC patients after platinum plus pemetrexed chemotherapy (26.22/0–626.46/pg/ml before vs. 0/0–114.36/pg/ml after; p = 0.01). Neither progression-free nor overall survival correlated with survivin levels at baseline. Our data imply that survivin may be involved in the development of metastases and it might be used as a biomarker of disease progression. However, circulating survivin concentrations do not predict survival of patients with lung cancer.
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Affiliation(s)
- Rita Puskas
- Department of Pulmonology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.,Törökbálint Pulmonology Hospital, Törökbálint, Hungary
| | - Andras Bikov
- Department of Pulmonology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.,Manchester University NHS Foundation Trust (MFT), Manchester, United Kingdom
| | - Peter Horvath
- Department of Pulmonology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Zsofia Lazar
- Department of Pulmonology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Laszlo Kunos
- Department of Pulmonology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.,Törökbálint Pulmonology Hospital, Törökbálint, Hungary
| | - Reka Nagy
- Semmelweis University, Budapest, Hungary
| | | | - Gabriella Galffy
- Department of Pulmonology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.,Törökbálint Pulmonology Hospital, Törökbálint, Hungary.,Department of Thoracic Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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Yin L, Yang Y, Zhu W, Xian Y, Han Z, Huang H, Peng L, Zhang K, Zhao Y. Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling. Front Oncol 2021; 11:620907. [PMID: 33738259 PMCID: PMC7960917 DOI: 10.3389/fonc.2021.620907] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/09/2021] [Indexed: 12/29/2022] Open
Abstract
Ovarian cancer is the most lethal gynaecologic tumor, with which multi-drug resistance as the major therapeutic hindrance. Heat shock protein 90 (Hsp90) has been involved in cancer malignant behaviors. However, its role and mechanism in multi-drug resistance of ovarian cancer remains poorly understood. Our results demonstrated that Hsp90 was overexpressed in multi-drug resistant ovarian cancer cells. Hsp90 downregulation by shHsp90 or inhibitor BIIB021 increased the sensitivity of multi-drug resistant ovarian cancer cells to paclitaxel and cisplatin, and augmented the drugs-induced apoptosis. Hsp90 positively regulated the expressions of multi-drug resistance protein 1 (P-gp/MDR1), breast cancer resistance protein (BCRP), Survivin and Bcl-2 expressions closely associated with multi-drug resistance. Moreover, overexpression of Hsp90 promoted β-catenin accumulation, while Hsp90 downregulation decreased the accumulation, nuclear translocation and transcriptional activity of β-catenin. We also identified that β-catenin was responsible for Hsp90-mediated expressions of P-gp, BCRP, Survivin, and Bcl-2. Furthermore, Hsp90 enhanced the AKT/GSK3β signaling, and AKT signaling played a critical role in Hsp90-induced accumulation and transcriptional activity of β-catenin, as well as multi-drug resistance to paclitaxel and cisplatin. In conclusion, Hsp90 enhanced the AKT/GSK3β/β-catenin signaling to induce multi-drug resistance of ovarian cancer. Suppressing Hsp90 chemosensitized multi-drug resistant ovarian cancer cells via impairing the AKT/GSK3β/β-catenin signaling, providing a promising therapeutic strategy for a successful treatment of ovarian cancer.
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Affiliation(s)
- Lan Yin
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Yuhan Yang
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Wanglong Zhu
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Yu Xian
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Zhengyu Han
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Houyi Huang
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Liaotian Peng
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Kun Zhang
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Ye Zhao
- School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
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Liu X, Chen L, Zhang Y, Xin X, Qi L, Jin M, Guan Y, Gao Z, Huang W. Enhancing anti-melanoma outcomes in mice using novel chitooligosaccharide nanoparticles loaded with therapeutic survivin-targeted siRNA. Eur J Pharm Sci 2021; 158:105641. [DOI: 10.1016/j.ejps.2020.105641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 10/17/2020] [Accepted: 11/08/2020] [Indexed: 12/17/2022]
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Fei Y, Zhao B, Zhu J, Fang W, Li Y. XQ-1H promotes cerebral angiogenesis via activating PI3K/Akt/GSK3β/β-catenin/VEGF signal in mice exposed to cerebral ischemic injury. Life Sci 2021; 272:119234. [PMID: 33607158 DOI: 10.1016/j.lfs.2021.119234] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/25/2021] [Accepted: 02/10/2021] [Indexed: 12/11/2022]
Abstract
Stroke still ranks as a most lethal disease worldwide. Angiogenesis during the chronic phase of ischemic stroke can alleviate ischemic injury and attenuate neurological deficit. XQ-1H is a new compound derived from the structure modification of ginkgolide B, which exerts anti-inflammation and neuroprotection against cerebral ischemic injury during the acute or subacute phase. However, whether XQ-1H facilitates angiogenesis and neural functional recovery during the chronic phase remains unclear. This research was designed to explore whether XQ-1H promotes angiogenesis after ischemic stroke and to preliminarily elucidate the mechanism. In vitro, XQ-1H was found to facilitate proliferation, migration and tube formation in bEnd.3 cells. In vivo, XQ-1H raised the CD31 positive microvessel number and increased focal cerebral blood flow in mice exposed to cerebral ischemic injury, and improved the neurological function. Mechanism studies revealed that XQ-1H exerted angiogenesis promoting effect via the PI3K/Akt/GSK3β/β-catenin/VEGF signal pathway, which was reversed by LY294002 (the specific inhibitor of PI3K/Akt). In conclusion, XQ-1H exerts angiogenetic effect both in vivo and in vitro, which is a potential agent against ischemic stroke during chronic phase.
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Affiliation(s)
- Yuxiang Fei
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Bo Zhao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jianping Zhu
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Weirong Fang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Yunman Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
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Fan H, Hu Z, Wang S, Wu W, Liu X, Geng H. 5-aminolevulinic-acid-mediated sonodynamic therapy improves the prognosis of melanoma by inhibiting survivin expression. Cancer Biomark 2021; 28:301-308. [PMID: 32390599 DOI: 10.3233/cbm-190681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND This study aimed to evaluate the relationship between survivin expression and melanoma after 5-aminolevulinic acid (5-ALA)-mediated sonodynamic therapy. METHODS Immunohistochemistry was used to detect survivin protein expression in human melanoma clinical samples. Subsequently, the effects of 5-ALA-mediated sonodynamic therapy were determined by measuring the volume of melanoma xenografts and the bodyweights of melanoma-bearing nude mice. The MTT assay was used to detect the viability of melanoma B16-F10 cells under the action of 5-ALA-mediated sonodynamic therapy, and Western blotting and PCR were used to detect survivin expression in melanoma cells and in the melanoma-xenograft model. RESULTS Survivin expression was significantly upregulated in human melanoma tissues compared with that of non-melanoma tissues. In the in vivo case, 5-ALA-mediated sonodynamic therapy significantly delayed tumor growth, prolonged the survival of mice, and inhibited the expression of survivin. In the in vitro case, 5-ALA-mediated sonodynamic therapy inhibited B16-F10 cell proliferation and decreased survivin expression at both protein and mRNA levels. CONCLUSION Our results suggest that 5-ALA-mediated sonodynamic therapy inhibited B16-F10 cell proliferation and melanoma-xenograft growth and prolonged survival of melanoma-bearing nude mice, which might be through downregulation of survivin expression.
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Affiliation(s)
- Haixia Fan
- Department of Oral Medicine, Jining Medical College, Shandong, China.,Department of Oral Medicine, Jining Medical College, Shandong, China
| | - Zheng Hu
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, Heilongjiang, China.,Department of Oral Medicine, Jining Medical College, Shandong, China
| | - Shan Wang
- Department of Oral Pathology, Hospital of Stomatology, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China
| | - Wen Wu
- Department of Oral Medicine, Jining Medical College, Shandong, China
| | - Xue Liu
- Department of Oral Medicine, Jining Medical College, Shandong, China
| | - Haixia Geng
- Department of Oral Medicine, Jining Medical College, Shandong, China
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Yangxue Jiedu Fang Ameliorates Psoriasis by Regulating Vascular Regression via Survivin/PI3K/Akt Pathway. J Immunol Res 2021; 2021:4678087. [PMID: 33532507 PMCID: PMC7834796 DOI: 10.1155/2021/4678087] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 12/18/2020] [Indexed: 12/22/2022] Open
Abstract
Background Psoriasis (PA) is a chronic autoimmune disease of the skin that adversely affects patients' quality of life. Yangxue Jiedu Fang (YXJD) has been used for decades to treat psoriasis in China. However, its antipsoriatic mechanisms are still poorly understood. In this study, we explored the effects of YXJD on angiogenesis and apoptosis of microvessels in PA, the underlying mechanisms in HUVEC cells transfected by Survivin overexpression plasmid and in a mouse model of imiquimod-induced psoriasis and the relationship between VEGF (vascular endothelial growth factor) and Survivin. Methods A BALB/c mouse model of imiquimod- (IMQ-) induced PA was established, and the mice were treated with YXJD. Cell viability was assessed by CCK8 assay. Apoptosis was detected by annexin V–FITC/PI double-staining and caspase-3 assays. The PI3K/Akt/β-catenin pathway was analyzed by western blotting, ELISA, and immunochemical analysis. Results YXJD ameliorated symptoms and psoriasis area and severity index (PASI) scores and also reduced the number of microvessels, as determined by the microvessel density (MVD). The expression of apoptotic protein Survivin in endothelial cells, autophagy-related proteins p62, and angiogenic proteins VEGF was inhibited by YXJD, and the repressed expression of LC3II/I increased by YXJD. The proteins related to the PI3K/Akt pathway and β-catenin expression and the nuclear entry of β-catenin were reduced in IMQ-induced PA mice treated with YXJD. In HUVEC cells transfected by Survivin overexpression plasmid, we observed YXJD regulated the expression of Survivin, LC3II/I, and p62, VEGF, and PI3K/Akt pathway-relative proteins and the nuclear entry of β-catenin. Conclusions YXJD inhibited the expression of Survivin via PI3K/Akt pathway to adjust apoptosis, autophagy, and angiogenesis of microvessels and thus improve the vascular sustainability in psoriasis. YXJD may represent a new direction of drug research and development for immunomodulatory therapy for psoriasis.
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