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Braun T, Bisht A, Zhu C, Idrees M, Alabeedi F, Kujan O. Diagnostic, prognostic, and metastatic value of chemokines as biomarkers for oral squamous cell carcinoma and their precursor lesions - A systematic review. Crit Rev Oncol Hematol 2025; 211:104738. [PMID: 40268074 DOI: 10.1016/j.critrevonc.2025.104738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 02/26/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025] Open
Abstract
Oral cancer remains a significant public health concern, with many patients diagnosed at advanced stages and facing poor prognoses. Despite advances in cancer research, diagnosis has seen only limited improvements, with biopsies still being the primary reliable method. This systematic review investigates the role of chemokines as potential biomarkers for early detection, prognosis, and metastasis in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). Through an extensive literature search of MEDLINE, EMBASE, PubMed, and Scopus, 3350 articles were initially identified. After eliminating duplicates and screening for eligibility, 50 high-quality studies were included, offering a comprehensive overview of chemokine research in OSCC and OPMDs. Key findings indicate that CCR7 shows significant promise as a diagnostic, prognostic, and metastatic marker, although its function in precancerous conditions remains inadequately understood. CXCL10 and CCL22 were also highlighted for their strong prognostic and metastatic relevance, while CXCR4 and CXCL12 were identified as critical indicators of OSCC metastasis. Other chemokines, such as CXCR2, CCR4, XCR1, CXCL13, and CCL2 can aid OSCC differentiation and staging. However, the review emphasises the limitations of small patient cohorts and the lack of longitudinal research, stressing the need for further studies. Additionally, there is a pressing gap in research addressing chemokines as biomarkers for OPMDs. Rigorous validation is crucial to establish these biomarkers' reliability and clinical utility across various stages of oral cancer development.
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Affiliation(s)
- Timothy Braun
- UWA Dental School, The University of Western Australia, Nedlands, WA, Australia
| | - Abhimanyu Bisht
- UWA Dental School, The University of Western Australia, Nedlands, WA, Australia
| | - Christopher Zhu
- UWA Dental School, The University of Western Australia, Nedlands, WA, Australia
| | - Majdy Idrees
- UWA Dental School, The University of Western Australia, Nedlands, WA, Australia
| | - Faris Alabeedi
- UWA Dental School, The University of Western Australia, Nedlands, WA, Australia
| | - Omar Kujan
- UWA Dental School, The University of Western Australia, Nedlands, WA, Australia.
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Ma L, Liu X, Roopashree R, Kazmi SW, Jasim SA, Phaninder Vinay K, Fateh A, Yang F, Rajabivahid M, Dehghani-Ghorbi M, Akhavan R. Long non-coding RNAs (lncRNAs) in cancer development: new insight from STAT3 signaling pathway to immune evasion. Clin Exp Med 2025; 25:53. [PMID: 39932585 PMCID: PMC11813976 DOI: 10.1007/s10238-024-01532-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/26/2024] [Indexed: 02/14/2025]
Abstract
Overcoming cancer and enhancing patient survival are becoming increasingly challenging due to the uncontrolled growth and metastasis of colorectal cancer cells. In order to provide effective cancer treatment and minimize the malignancy of cancer cells, it is necessary to understand how complex signaling networks contribute to their invasion and proliferation. The signal transducer and activator of transcription 3 (STAT3) is a promising target due to its involvement in various cellular functions, including apoptosis, immunosuppression, cell invasion, migration, and proliferation. Dysregulation of STAT3 signaling is associated with diseases, particularly colorectal cancer. Long non-coding RNAs (lncRNAs), a subset of non-coding RNAs, are essential for the progression, apoptosis, and metastasis of CRC as they regulate key signaling pathways such as STAT3 signaling and contribute to gene regulation at the epigenetic, transcriptional, and post-transcriptional levels. Moreover, lncRNAs have a key function in regulating immune cells function through STAT3. In this study, we comprehensively reviewed the regulatory roles of different lncRNAs on STAT3 and the mutual effects of this pathway in various aspects of carcinogenesis, including proliferation, apoptosis, metastasis, drug resistance, and angiogenesis. Moreover, we investigate the effects of lncRNA/STAT3 axis on the function of different immune cells that play critical role in the tumor microenvironment.
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Affiliation(s)
- Lie Ma
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of PLA General Hospital, Beijing, 110000, China
| | - XuQing Liu
- Special Service Department, 923rd Hospital of The Joint Logistic Support Force of the Chinese Peoples Liberation Army (Geriatric Disease Area 2), Nanning, 530020, Guangxi, China
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Syeda Wajida Kazmi
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Punjab, 140307, India
| | | | - K Phaninder Vinay
- Department of ECE, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Ata Fateh
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
| | - Fang Yang
- Department of Emergency, The Eighth Medical Center of PLA General Hospital, Beijing, 10091, China
| | - Mansour Rajabivahid
- Hematology Oncology Subspecialist, Department of Internal Medicine, Valiasr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Mahmoud Dehghani-Ghorbi
- Hematology-Oncology Department, Imam Hossein Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan
- Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Warsaw, Poland
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Yang C, Wang R, Hardy P. The Multifaceted Roles of MicroRNA-181 in Stem Cell Differentiation and Cancer Stem Cell Plasticity. Cells 2025; 14:132. [PMID: 39851559 PMCID: PMC11763446 DOI: 10.3390/cells14020132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/26/2025] Open
Abstract
Stem cells are undifferentiated or partially differentiated cells with an extraordinary ability to self-renew and differentiate into various cell types during growth and development. The epithelial-mesenchymal transition (EMT), a critical developmental process, enhances stem cell-like properties in cells, and is associated with both normal stem cell function and the formation of cancer stem cells. Cell stemness and the EMT often coexist and are interconnected in various contexts. Cancer stem cells are a critical tumor cell population that drives tumorigenesis, cancer progression, drug resistance, and metastasis. Stem cell differentiation and the generation of cancer stem cells are regulated by numerous molecules, including microRNAs (miRNAs). These miRNAs, particularly through the modulation of EMT-associated factors, play major roles in controlling the stemness of cancer stem cells. This review presents an up-to-date summary of the regulatory roles of miR-181 in human stem cell differentiation and cancer cell stemness. We outline studies from the current literature and summarize the miR-181-controlled signaling pathways responsible for driving human stem cell differentiation or the emergence of cancer stem cells. Given its critical role in regulating cell stemness, miR-181 is a promising target for influencing human cell fate. Modulation of miR-181 expression has been found to be altered in cancer stem cells' biological behaviors and to significantly improve cancer treatment outcomes. Additionally, we discuss challenges in miRNA-based therapies and targeted delivery with nanotechnology-based systems.
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Affiliation(s)
- Chun Yang
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Rui Wang
- Departments of Pharmacology and Physiology, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Pierre Hardy
- CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC H3T 1C5, Canada;
- Departments of Pharmacology and Physiology, Université de Montréal, Montreal, QC H3T 1C5, Canada;
- Departments of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada
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Liu M, Wang T, Li M. Identification of Immune Infiltration-Associated CC Motif Chemokine Ligands as Biomarkers and Targets for Colorectal Cancer Prevention and Immunotherapy. Int J Mol Sci 2025; 26:625. [PMID: 39859340 PMCID: PMC11765793 DOI: 10.3390/ijms26020625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/27/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted the critical role of tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis and progression. Notably, CC chemokines (CCLs) have been shown to either promote or inhibit angiogenesis, metastasis, and immune responses in tumors, thereby influencing cancer development and patient outcomes. However, the diagnostic and prognostic significance of CCLs in CRC remains unclear. In this study, multiple online tools for bioinformatics analyses were utilized. The findings revealed that the mRNA expression levels of CCL3, CCL4, and CCL26 were significantly elevated in CRC tissues compared to normal tissues, whereas CCL2, CCL5, CCL11, CCL21, and CCL28 mRNA levels were markedly downregulated. Additionally, dysregulation of CCL4, CCL5, and CCL21 was strongly associated with clinical staging, and elevated levels of CCL4, CCL11, and CCL28 were linked to significantly prolonged survival in CRC patients. Functional enrichment analysis indicated that the cellular roles of CCLs were predominantly associated with the chemokine, Wnt, and Toll-like receptor signaling pathways, as well as protein kinase activity. Furthermore, transcriptional regulation of most CCLs involved RELA and NFKB1. Key downstream targets included members of the SRC family of tyrosine kinases (HCK, LYN, and LCK), serine/threonine kinases (ATR and ATM), and others such as CSNK1G2, NEK2, and CDK2. Moreover, CCLs (CCL2, CCL3, CCL4, CCL5, CCL11, CCL21, and CCL28) exhibited strong correlations with major infiltration-related immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. In conclusion, our study provides novel insights into the potential utility of CCLs as biomarkers and therapeutic targets for CRC prevention and immunotherapy.
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Wang J, Tao Q, Huang K, Wang Y, Hu L, Ren A, Wang H, Wan Y, Li J, Yi L, Ruan Y, Wanyan Z, Wu F, Zhai Z, Liu C. Chemotherapy-induced cellular senescence promotes stemness of aggressive B-cell non-Hodgkin's lymphoma via CCR7/ARHGAP18/IKBα signaling activation. J Immunother Cancer 2025; 13:e009356. [PMID: 39773566 PMCID: PMC11749403 DOI: 10.1136/jitc-2024-009356] [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: 03/30/2024] [Accepted: 11/23/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Resistance to existing therapies is a major cause of treatment failure in patients with refractory and relapsed B-cell non-Hodgkin's lymphoma (r/r B-NHL). Therapy-induced senescence (TIS) is one of the most important mechanisms of drug resistance. METHODS This study used single-cell RNA sequencing to analyze doxorubicin-induced senescent B-NHL cells. C-C chemokine receptor 7 (CCR7) expression in patients with aggressive B-NHL was assessed using immunohistochemistry and flow cytometry. Lentiviral transfection was used to target CCR7 expression in Raji and SU-DHL-2 cells. Protein localization was visualized through immunofluorescence, while western blotting and co-immunoprecipitation were used to analyze protein expression and interactions. Cell proliferation was measured with the Cell Counting Kit-8 assay, and senescent cells were detected using senescence-associated β-galactosidase staining. The stemness of cells was evaluated through colony and sphere formation assays. Transwell assays assessed cell migration and invasion. Finally, inhibitors GS143 and Y27632 were used to examine the effect of IKBα and ARHGAP/RhoA inhibition on B-NHL-TIS. RESULTS Here we identified a distinct group of TIS, composed of memory B-cell population characterized by strong positive expression of CCR7, which was significantly elevated in TIS population compared with normal proliferating and autonomously senescent lymphoma cell populations. Additionally, CCR7 expression was significantly upregulated in patients with r/r B-NHL, and was an independent prognostic factor in B-NHL, with high CCR7 expression being strongly associated with poor prognosis. In vitro results indicated that CCL21 induced migration and invasion of B-NHL cells via CCR7, while blocking CCR7 reduced doxorubicin-induced migration and invasion of these cells. Furthermore, B-NHL-TIS regulated by CCR7 and exhibited enhanced phenotypic and functional stemness features, including the upregulation of stemness markers, increased colony-forming, invasive and migratory capabilities. Mechanistically, blocking CCR7 reversed the stemness characteristics of senescent B-NHL cells by inhibiting the activation of ARHGAP18/IKBα signaling. CONCLUSIONS Together, TIS promotes the stemness of B-NHL cells via CCR7/ARHGAP18/IKBα signaling activation and targeting CCR7/ARHGAP18 might overcome the chemoresistance of senescent B-NHL cells by inhibiting stemness acquisition and maintenance.
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Affiliation(s)
- Jiyu Wang
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qianshan Tao
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Keke Huang
- Department of Internal Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yangyang Wang
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Linhui Hu
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Anwen Ren
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huiping Wang
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yang Wan
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jinlan Li
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Liuying Yi
- Department of Hematology, The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Yanjie Ruan
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhixiang Wanyan
- Department of Emergency, The Third People's Hospital of Hefei, Hefei, Anhui, China
| | - Fan Wu
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhimin Zhai
- Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chaohong Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Xiao D, Zhu H, Xiao X. Knockdown of HM13 Inhibits Metastasis, Proliferation, and M2 Macrophage Polarization of Non-small Cell Lung Cancer Cells by Suppressing the JAK2/STAT3 Signaling Pathway. Appl Biochem Biotechnol 2025; 197:570-586. [PMID: 39207680 DOI: 10.1007/s12010-024-05054-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
An upregulated histocompatibility minor 13 (HM13) has been studied in various tumors, yet the exact mechanism of HM13 in non-small cell lung cancer (NSCLC) is unclear. In view of same, the present study investigates crucial role and action mechanism of HM13 in human NSCLC. HM13 expression was higher in NSCLC tissue and cells through the Western blotting technique along with qRT-PCR. As per data from The Cancer Genome Atlas (TCGA), NSCLC patients having high HM13 expression show lower overall survival. 5-ethynyl-2-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and transwell tests were assessed for NSCLC cell growth, and invasion, and we found that silencing of HM13 inhibited the NSCLC cell proliferation, invasion. Additionally, to investigate the effects of HM13 on THP-1 macrophage polarization, a co-culture model of NSCLC and THP-1 macrophages were used. The CD206 + macrophages were examined using flow cytometry. As the markers of M2 macrophage, the mRNA levels of IL-10 and TGF-β of THP-1 cells were also detected by qRT-PCR. Knockdown of HM13 could inhibit the M2 polarization. Further experiments demonstrated that downregulated HM13 could inhibit the JAK2/STAT3 signaling pathway. RO8191 (activator of JAK/STAT3 pathway) influenced the invasion, proliferation, and expression of JAK2/STAT3 signaling pathway and Epithelial-mesenchymal transition (EMT) markers induced by HM13 silencing. HM13 knockdown also inhibited the tumor growth in vivo by xenograft nude mouse model. By inhibiting JAK2/STAT3 signaling pathway, HM13 knockdown inhibited the NSCLC cell proliferation, metastasis tumor growth, and tumor-associated macrophage M2 polarization. In NSCLC, HM13 could be a therapeutic target to treat the NSCLC.
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Affiliation(s)
- Dashu Xiao
- Department of Pathology, Chaohu Hospital of Anhui Medical University, Chaohu, 238000, Anhui, China
| | - Hongbin Zhu
- Department of Respiratory Medicine, Chaohu Hospital of Anhui Medical University, Chaohu, 238000, Anhui, China
| | - Xin Xiao
- Department of Oncology, Chaohu Hospital of Anhui Medical University, No. 64 Chaohu North Road, Juchao District, Chaohu, 238000, Anhui, China.
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Li Q, Zhang H, He Y, Zhang H, Han C. Inhibition of Colorectal Cancer Metastasis by Total Flavones of Abelmoschus manihot via LncRNA AL137782-mediated STAT3/EMT Pathway Regulation. Curr Pharm Des 2025; 31:219-232. [PMID: 39289944 DOI: 10.2174/0113816128298998240828060306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) ranks among the most lethal malignancies globally, particularly following metastasis which results in poor prognosis. In recent years, CRC incidence in China has persistently increased. Total flavonoids (TFA) from Abelmoschus manihot, a natural compound, are recognized for their anti-inflammatory, analgesic, and antioxidant properties. However, despite extensive research into the therapeutic potential of TFA, coverage of its role in cancer treatment is notably lacking. To address this research void, our study aims to unveil the role and potential mechanisms of TFA in treating CRC. METHODS We conducted a series of experiments to assess the impact of TFA on CRC cells. Two specific CRC cell lines, DLD-1 and HCT116, were employed in cell proliferation, colony formation, flow cytometry, and cell migration assays. Additionally, to test the in vivo effects of TFA, we developed a nude mouse xenograft tumor model to assess TFA's impact on tumor growth and liver metastasis. Furthermore, we meticulously analyzed the gene expression differences between CRC cells pretreated with TGF-β and those treated with TFA using RNA-seq technology. We also examined the molecular mechanisms of TFA and assessed the expression of proteins related to the STAT3/EMT signaling pathway through Western blotting and siRNA technology. RESULTS Our research findings reveal for the first time the effect of TFA on CRC cells. Result shows that TFA could suppress cell proliferation, migration, and induce apoptosis. In vivo results showed that TFA inhibited tumor growth and liver metastasis. Molecular mechanism studies have shown that TFA exerts these effects by upregulating the expression of non-coding RNA AL137782, inhibiting the EMT/STAT3 signaling pathway. These results suggest that TFA is a potential candidate for mitigating CRC metastasis. CONCLUSION However, further research is needed to comprehensively evaluate the efficacy and safety of TFA in animal models and clinical settings. These findings bring great hope for the development of innovative CRC treatment methods.
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Affiliation(s)
- Qian Li
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, PR China
- Department of Proctology, Xinyi Hospital of Traditional Chinese Medicine, Xinyi, Jiangsu 221400, PR China
| | - Hui Zhang
- Department of Ultrasound, Xu Zhou Hospital of Traditional Chinese Medicine, Zhongshan South Road 169, Yunlong District, Xu Zhou, Jiangsu 221000, PR China
| | - Yongshan He
- Department of Colorectal Surgery, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Kongjiang Road 1665, Yangpu District, Shanghai 200092, PR China
| | - Hao Zhang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Daxue Road 4655, Changqing District, Jinan, Shandong, PR China
| | - Conghui Han
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, 221000, PR China
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Tang L, Chen B, Wang B, Xu J, Yan H, Shan Y, Zhao X. Mediation of FOXA2/IL-6/IL-6R/STAT3 signaling pathway mediates benzo[a]pyrene-induced airway epithelial mesenchymal transformation in asthma. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 357:124384. [PMID: 38901818 DOI: 10.1016/j.envpol.2024.124384] [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: 04/05/2024] [Revised: 05/30/2024] [Accepted: 06/16/2024] [Indexed: 06/22/2024]
Abstract
Benzo [a]pyrene (BaP), a toxic pollutant, increases the incidence and severity of asthma. However, the molecular mechanisms underlying the effects of BaP in asthma remain unclear. In terms of research methods, we used BaP to intervene in the animal model of asthma and the human bronchial epithelial (16HBE) cells, and the involved mechanisms were found from the injury, inflammation, and airway epithelial to mesenchymal transition (EMT) in asthma. We also constructed small interfering RNAs and overexpression plasmids to knockdown/overexpress IL-6R and FOXA2 in 16HBE cells and a serotype 9 adeno-associated viral vector for lung tissue overexpression of FOXA2 in mice to determine the mechanism of action of BaP-exacerbated asthma airway EMT. We observed that BaP aggravated inflammatory cell infiltration into the lungs, reduced the Penh value, increased collagen fibres in the lung tissue, and increased serum IgE levels in asthmatic mice. After BaP intervention, the expression of FOXA2 in the lung tissue of asthmatic mice decreased, the production and secretion of IL-6 were stimulated, and STAT3 phosphorylation and nuclear translocation increased, leading to changes in EMT markers. However, EMT decreased after increasing FOXA2 expression and decreasing that of IL-6R and was further enhanced after low FOXA2 expression. Our results revealed that BaP exacerbated airway epithelial cell injury and interfered with FOXA2, activating the IL-6/IL-6R/STAT3 signaling pathway to promote airway EMT in asthma. These findings provide toxicological evidence for the mechanism underlying the contribution of BaP to the increased incidence of asthma and its exacerbations.
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Affiliation(s)
- Lingling Tang
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Bailei Chen
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Bohan Wang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China
| | - Jing Xu
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Hua Yan
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Yiwen Shan
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Xia Zhao
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China; Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
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Zhang X, An Y, Mai D, Huang W, Zeng W. Modulation of esophageal squamous cell carcinoma progression: the impact of CCR7 on JAK2/STAT3 signaling pathway. Discov Oncol 2024; 15:421. [PMID: 39254762 PMCID: PMC11387284 DOI: 10.1007/s12672-024-01289-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/29/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Existing studies have already revealed the involvement of C-C chemokine receptor type 7 (CCR7) in diverse human cancers, including esophageal cell squamous carcinoma (ESCA). Our current study, aims to explore the relevant mechanisms implicated. METHODS ESCA cell lines were collected for CCR7 expression quantification using western blot. Following the transfection, the viability, migration and invasion of ESCA cells were evaluated via cell counting kit-8 and Transwell assays. The specific molecular mechanisms underlying the effects of CCR7 in ESCA cells were explored via calculating the expressions of proteins related to metastasis and Janus kinase 2/signal transduction and transcription activation 3 (JAK2/STAT3) signaling pathway via western blot. The correlation between CCR7 and metastasis-related proteins was explored via Pearson's correlation test. RESULTS CCR7 was high-expressed in ESCA cells and CCR7 knockdown repressed the viability, migration and invasion of ESCA cells, concurrent with the increased expression of E-cadherin (E-cad, which was also known as CDH1 and lowly expressed in ESCA cells) and the decreased expressions of vimentin (Vim, which was highly expressed in ESCA cells) and matrix metalloproteinase-9 (MMP-9, which was also highly expressed in ESCA cells). Meanwhile, CCR7 was positively correlated with Vim and MMP-9 yet negatively correlated with E-cad in ESCA cells, which indicated that CCR7 has a role in promoting tumor progression in ESCA cells. Besides, the phosphorylation of STAT3 and JAK2 in ESCA cells was elevated, which was diminished following CCR7 knockdown. CONCLUSION This study proves the modulation of CCR7 on ESCA in vitro, which was achieved via JAK2/STAT3 signaling pathway. Our discovery will provide new therapeutic basis and insights for ESCA.
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Affiliation(s)
- Xuewen Zhang
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Yuji An
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- Five Wards of Oncology Department, The Third Affiliated Hospital of Shandong First Medical University, Jinan, 250031, China
| | - Dongmei Mai
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Wan Huang
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Weian Zeng
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
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Hariri A, Mirian M, Khosravi A, Zarepour A, Iravani S, Zarrabi A. Intersecting pathways: The role of hybrid E/M cells and circulating tumor cells in cancer metastasis and drug resistance. Drug Resist Updat 2024; 76:101119. [PMID: 39111134 DOI: 10.1016/j.drup.2024.101119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 06/30/2024] [Accepted: 07/09/2024] [Indexed: 08/17/2024]
Abstract
Cancer metastasis and therapy resistance are intricately linked with the dynamics of Epithelial-Mesenchymal Transition (EMT) and Circulating Tumor Cells (CTCs). EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites. Concurrently, CTCs, which are detached from primary tumors and travel through the bloodstream, are crucial as potential biomarkers for cancer prognosis and therapeutic response. There is a significant interplay between EMT hybrid cells and CTCs, revealing a complex, bidirectional relationship that significantly influences metastatic progression and has a critical role in cancer drug resistance. This resistance is further influenced by the tumor microenvironment, with factors such as tumor-associated macrophages, cancer-associated fibroblasts, and hypoxic conditions driving EMT and contributing to therapeutic resistance. It is important to understand the molecular mechanisms of EMT, characteristics of EMT hybrid cells and CTCs, and their roles in both metastasis and drug resistance. This comprehensive understanding sheds light on the complexities of cancer metastasis and opens avenues for novel diagnostic approaches and targeted therapies and has significant advancements in combating cancer metastasis and overcoming drug resistance.
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Affiliation(s)
- Amirali Hariri
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran.
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Turkiye
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Siavash Iravani
- Independent Researcher, W Nazar ST, Boostan Ave, Isfahan, Iran.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkiye; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan.
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11
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Hu J, Xu H, Ma X, Bai M, Zhou Y, Miao R, Wang F, Li X, Cheng B. Modulating PCGF4/BMI1 Stability Is an Efficient Metastasis-Regulatory Strategy Used by Distinct Subtypes of Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1388-1404. [PMID: 38670529 DOI: 10.1016/j.ajpath.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/17/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm prone to metastasis. Whether cancer-associated fibroblasts (CAFs) affect the metastasis of ICC is unclear. Herein, ICC patient-derived CAF lines and related cancerous cell lines were established and the effects of CAFs on the tumor progressive properties of the ICC cancerous cells were analyzed. CAFs could be classified into cancer-restraining or cancer-promoting categories based on distinct tumorigenic effects. The RNA-sequencing analyses of ICC cancerous cell lines identified polycomb group ring finger 4 (PCGF4; alias BMI1) as a potential metastasis regulator. The changes of PCGF4 levels in ICC cells mirrored the restraining or promoting effects of CAFs on ICC migration. Immunohistochemical analyses on the ICC tissue microarrays indicated that PCGF4 was negatively correlated with overall survival of ICC. The promoting effects of PCGF4 on cell migration, drug resistance activity, and stemness properties were confirmed. Mechanistically, cancer-restraining CAFs triggered the proteasome-dependent degradation of PCGF4, whereas cancer-promoting CAFs enhanced the stability of PCGF4 via activating the IL-6/phosphorylated STAT3 pathway. In summary, the current data identified the role of CAFs in ICC metastasis and revealed a new mechanism of the CAFs on ICC progression in which PCGF4 acted as the key effector by both categories of CAFs. These findings shed light on developing comprehensive therapeutic strategies for ICC.
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Affiliation(s)
- Jinjing Hu
- School of Life Sciences, Lanzhou University, Lanzhou, China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Hao Xu
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xiaojun Ma
- School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Mingzhen Bai
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Yongqiang Zhou
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Ruidong Miao
- School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Fanghong Wang
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China.
| | - Bo Cheng
- School of Life Sciences, Lanzhou University, Lanzhou, China; Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou, China.
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12
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Nevarez-Mejia J, Pickering H, Sosa RA, Valenzuela NM, Fishbein GA, Baldwin WM, Fairchild RL, Reed EF. Spatial multiomics of arterial regions from cardiac allograft vasculopathy rejected grafts reveal novel insights into the pathogenesis of chronic antibody-mediated rejection. Am J Transplant 2024; 24:1146-1160. [PMID: 38219867 PMCID: PMC11239797 DOI: 10.1016/j.ajt.2024.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 12/22/2023] [Accepted: 01/04/2024] [Indexed: 01/16/2024]
Abstract
Cardiac allograft vasculopathy (CAV) causes late graft failure and mortality after heart transplantation. Donor-specific antibodies (DSAs) lead to chronic endothelial cell injury, inflammation, and arterial intimal thickening. In this study, GeoMx digital spatial profiling was used to analyze arterial areas of interest (AOIs) from CAV+DSA+ rejected cardiac allografts (N = 3; 22 AOIs total). AOIs were categorized based on CAV neointimal thickening and underwent whole transcriptome and protein profiling. By comparing our transcriptomic data with that of healthy control vessels of rapid autopsy myocardial tissue, we pinpointed specific pathways and transcripts indicative of heightened inflammatory profiles in CAV lesions. Moreover, we identified protein and transcriptomic signatures distinguishing CAV lesions exhibiting low and high neointimal lesions. AOIs with low neointima showed increased markers for activated inflammatory infiltrates, endothelial cell activation transcripts, and gene modules involved in metalloproteinase activation and TP53 regulation of caspases. Inflammatory and apoptotic proteins correlated with inflammatory modules in low neointima AOIs. High neointima AOIs exhibited elevated TGFβ-regulated transcripts and modules enriched for platelet activation/aggregation. Proteins associated with growth factors/survival correlated with modules enriched for proliferation/repair in high neointima AOIs. Our findings reveal novel insight into immunological mechanisms mediating CAV pathogenesis.
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Affiliation(s)
- Jessica Nevarez-Mejia
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA
| | - Rebecca A Sosa
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA
| | - Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA
| | - Gregory A Fishbein
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA
| | - William M Baldwin
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Robert L Fairchild
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA.
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13
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Sun Y, Chen Y, Zhao H, Wang J, Liu Y, Bai J, Hu C, Shang Z. Lactate-driven type I collagen deposition facilitates cancer stem cell-like phenotype of head and neck squamous cell carcinoma. iScience 2024; 27:109340. [PMID: 38500829 PMCID: PMC10945209 DOI: 10.1016/j.isci.2024.109340] [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: 11/05/2023] [Revised: 01/05/2024] [Accepted: 02/22/2024] [Indexed: 03/20/2024] Open
Abstract
Lactate is known to play a crucial role in the progression of malignancies. However, its mechanism in regulating the malignant phenotype of head and neck squamous cell carcinoma (HNSCC) remains unclear. This study found that lactate increases cancer stem cell (CSC) characteristics of HNSCC by influencing the deposition of type I collagen (Col I). Lactate promotes Col I deposition through two distinct pathways. One is to convert lactate to pyruvate, a substrate for Col I hydroxylation. The other is the activation of HIF1-α and P4HA1, the latter being a rate-limiting enzyme for Col I synthesis. Inhibition of these two pathways effectively counteracts lactate-induced enhanced cell stemness. Further studies revealed that Col I affects CSC properties by regulating cell cycle dynamics. In conclusion, our research proposes that lactate-driven Col I deposition is essential for the acquisition of CSC properties, and lactate-centric Col I deposition may be an effective target for CSCs.
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Affiliation(s)
- Yunqing Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hui Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jingjing Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yuantong Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Junqiang Bai
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Chuanyu Hu
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Zhengjun Shang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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14
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Guo Z, Zhao Y, Xu M, Zhao L, Wang X. Natural killer cell-based signature: Prognostic analysis in head and neck squamous cell carcinoma. J Gene Med 2024; 26:e3671. [PMID: 38384136 DOI: 10.1002/jgm.3671] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 12/12/2023] [Accepted: 01/18/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSC) is a challenging cancer with significant clinical implications. Natural killer (NK) cells have emerged as important players in tumor immunosurveillance, yet their role and potential as prognostic biomarkers in HNSC remain unclear. METHODS Quantitative analysis using multiple algorithms identified FCRL1, KIR3DL2 and ZNF541 as molecules significantly associated with local NK cell infiltration and patient survival. A prognostic model based on these molecules demonstrated robust predictive performance. RESULTS Analysis of high- and low-risk patient groups revealed distinct differences in the tumor microenvironment, indicating an inhibitory immune microenvironment in high-risk patients. Notably, low-risk patients exhibited potential sensitivity to immunotherapy and showed favorable responses to specific drugs such as axitinib, methotrexate, rapamycin and vorinostat. NK cells, important effectors of the innate immune response, were found to play a crucial role in HNSC immunity. The present study provides valuable insights into the correlation between FCRL1, KIR3DL2, ZNF541 and NK cell infiltration, paving the way for future investigations into their roles in HNSC. Activation of NOTCH signaling, MYC targets, DNA repair, E2F targets, epithelial-mesenchymal transition, G2M checkpoint and mitotic spindle pathways in high-risk patients suggests their involvement in disease progression and poor prognosis. CONCLUSIONS The present study reveals the significance of NK cells in HNSC and their potential as prognostic biomarkers. The CFKZ score offers a promising approach for predicting patient outcomes and guiding personalized treatment decisions in HNSC. These findings contribute to our understanding of HNSC immunobiology and hold implications for precision medicine in HNSC management.
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Affiliation(s)
- Zizhao Guo
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuxia Zhao
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meng Xu
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Long Zhao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaolei Wang
- Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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15
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Mukerjee N, Nag S, Bhattacharya B, Alexiou A, Mirgh D, Mukherjee D, Adhikari MD, Anand K, Muthusamy R, Gorai S, Thorat N. Clinical impact of epithelial–mesenchymal transition for cancer therapy. CLINICAL AND TRANSLATIONAL DISCOVERY 2024; 4. [DOI: 10.1002/ctd2.260] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2025]
Abstract
AbstractThe epithelial–mesenchymal transition (EMT) represents a pivotal frontier in oncology, playing a central role in the metastatic cascade of cancer—a leading global health challenge. This comprehensive review delves into the complexities of EMT, a process where cancer cells gain exceptional mobility, facilitating their invasion into distant organs and the establishment of secondary malignancies. We thoroughly examine the myriad of factors influencing EMT, encompassing transcription factors, signalling pathways, metabolic alterations, microRNAs, long non‐coding RNAs, epigenetic changes, exosomal interactions and the intricate dynamics of the tumour microenvironment. Particularly, the review emphasises the advanced stages of EMT, crucial for the development of highly aggressive cancer phenotypes. During this phase, cancer cells penetrate the vascular barrier and exploit the bloodstream to propagate life‐threatening metastases through the mesenchymal–epithelial transition. We also explore EMT's significant role in fostering tumour dormancy, senescence, the emergence of cancer stem cells and the formidable challenge of therapeutic resistance. Our review transcends a mere inventory of EMT‐inducing elements; it critically assesses the current state of EMT‐focused clinical trials, revealing both the hurdles and significant breakthroughs. Highlighting the potential of EMT research, we project its transformative impact on the future of cancer therapy. This exploration is aimed at paving the way towards an era of effectively managing this relentless disease, positioning EMT at the forefront of innovative cancer research strategies.
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Affiliation(s)
- Nobendu Mukerjee
- Department of Microbiology West Bengal State University, Barasat Kolkata India
| | - Sagnik Nag
- Department of Bio‐Sciences School of Biosciences & Technology Vellore Institute of Technology Vellore Tamil Nadu India
| | - Bikramjit Bhattacharya
- Department of Applied Microbiology School of Biosciences and Technology Vellore Institute of Technology Vellore Tamil Nadu India
| | - Athanasios Alexiou
- Department of Science and Engineering Novel Global Community Educational Foundation Hebersham New South Wales Australia
| | - Divya Mirgh
- Vaccine and Immunotherapy Canter Massachusetts General Hospital Boston Massachusetts USA
| | | | - Manab Deb Adhikari
- Department of Biotechnology University of North Bengal Darjeeling West Bengal India
| | - Krishnan Anand
- Department of Chemical Pathology School of Pathology Faculty of Health Sciences University of the Free State Bloemfontein South Africa
| | - Raman Muthusamy
- Center for Global Health Research Saveetha Medical College & Hospitals, Saveetha Institute of Medical and Technical Sciences Chennai Tamil Nadu India
| | | | - Nanasaheb Thorat
- Limerick Digital Cancer Research Centre and Department of Physics Bernal Institute University of Limerick, Castletroy Limerick Ireland
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16
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Gairola S, Sinha A, Kaundal RK. Linking NLRP3 inflammasome and pulmonary fibrosis: mechanistic insights and promising therapeutic avenues. Inflammopharmacology 2024; 32:287-305. [PMID: 37991660 DOI: 10.1007/s10787-023-01389-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 10/25/2023] [Indexed: 11/23/2023]
Abstract
Pulmonary fibrosis is a devastating disorder distinguished by redundant inflammation and matrix accumulation in the lung interstitium. The early inflammatory cascade coupled with recurring tissue injury orchestrates a set of events marked by perturbed matrix hemostasis, deposition of matrix proteins, and remodeling in lung tissue. Numerous investigations have corroborated a direct correlation between the NLR family pyrin domain-containing 3 (NLRP3) activation and the development of pulmonary fibrosis. Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Nevertheless, the precise mechanisms through which the NLRP3 inflammasome elicits pro-fibrogenic responses remain inadequately defined. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1β (IL-1β). IL-1β instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-β). This signaling cascade, in turn, exerts influence over various transcription factors, including SNAIL, TWIST, and zinc finger E-box-binding homeobox 1 (ZEB 1/2), which collectively foster myofibroblast activation and consequent lung fibrosis. Here, we have connected the dots to illustrate how the NLRP3 inflammasome orchestrates a multitude of signaling events, including the activation of transcription factors that facilitate myofibroblast activation and subsequent lung remodeling. In addition, we have highlighted the prominent role played by various cells in the formation of myofibroblasts, the primary culprit in lung fibrosis. We also provided a concise overview of various compounds that hold the potential to impede NLRP3 inflammasome signaling, thus offering a promising avenue for the treatment of pulmonary fibrosis.
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Affiliation(s)
- Shobhit Gairola
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India
| | - Antarip Sinha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India
| | - Ravinder K Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India.
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17
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Sun Y, Chen Y, Liu Z, Wang J, Bai J, Du R, Long M, Shang Z. Mitophagy-Mediated Tumor Dormancy Protects Cancer Cells from Chemotherapy. Biomedicines 2024; 12:305. [PMID: 38397907 PMCID: PMC10886527 DOI: 10.3390/biomedicines12020305] [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: 12/11/2023] [Revised: 01/18/2024] [Accepted: 01/22/2024] [Indexed: 02/25/2024] Open
Abstract
Despite obvious tumor shrinkage, relapse after chemotherapy remains a main cause of cancer-related mortality, indicating that a subpopulation of cancer cells acquires chemoresistance and lingers after treatment. However, the mechanism involved in the emergence of chemoresistant cells remains largely unknown. Here, we demonstrate that the degradation of mitochondria via autophagy leads to a dormant state in a subpopulation of cancer cells and confers on them resistance to lethal cisplatin (DDP) exposure. The surviving DDP-resistant cells (hereafter, DRCs) have a lower metabolic rate but a stronger potential malignant potential. In the absence of DDP, these DRCs exhibit an ever-increasing self-renewal ability and heightened tumorigenicity. The combination of chloroquine and DDP exerts potent tumor-suppressive effects. In summary, our findings illuminate the mechanism between mitophagy and tumor dormancy and prove that targeting mitophagy might be a promising approach for overcoming chemoresistance in head and neck squamous cell carcinoma (HNSCC).
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Affiliation(s)
- Yunqing Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
| | - Yang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zhenan Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
| | - Jingjing Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
| | - Junqiang Bai
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
| | - Ruixue Du
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
| | - Mingshu Long
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
| | - Zhengjun Shang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; (Y.S.); (Y.C.); (Z.L.); (J.W.); (J.B.); (R.D.); (M.L.)
- Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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18
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Mishra R. Oral tumor heterogeneity, its implications for patient monitoring and designing anti-cancer strategies. Pathol Res Pract 2024; 253:154953. [PMID: 38039738 DOI: 10.1016/j.prp.2023.154953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/11/2023] [Accepted: 11/15/2023] [Indexed: 12/03/2023]
Abstract
Oral cancer tumors occur in the mouth and are mainly derived from oral mucosa linings. It is one of the most common and fatal malignant diseases worldwide. The intratumor heterogeneity (ITH) of oral cancerous tumor is vast, so it is challenging to study and interpret. Due to environmental selection pressures, ITH arises through diverse genetic, epigenetic, and metabolic alterations. The ITH also talks about peri-tumoral vascular/ lymphatic growth, perineural permeation, tumor necrosis, invasion, and clonal expansion/ the coexistence of multiple subclones in a single tumor. The heterogeneity offers tumors the adaptability to survive, induce growth/ metastasis, and, most importantly, escape antitumor therapy. Unfortunately, the ITH is prioritized less in determining disease pathology than the traditional TNM classifications or tumor grade. Understanding ITH is challenging, but with the advancement of technology, this ITH can be decoded. Tumor genomics, proteomics, metabolomics, and other modern analyses can provide vast information. This information in clinics can assist in understanding a tumor's severity and be used for diagnostic, prognostic, and therapeutic decision-making. Lastly, the oral tumor ITH can lead to individualized, targeted therapy strategies fighting against OC.
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Affiliation(s)
- Rajakishore Mishra
- Department of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Kamre, Ranchi 835 222, Jharkhand, India.
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Tangsiri M, Hheidari A, Liaghat M, Razlansari M, Ebrahimi N, Akbari A, Varnosfaderani SMN, Maleki-Sheikhabadi F, Norouzi A, Bakhtiyari M, Zalpoor H, Nabi-Afjadi M, Rahdar A. Promising applications of nanotechnology in inhibiting chemo-resistance in solid tumors by targeting epithelial-mesenchymal transition (EMT). Biomed Pharmacother 2024; 170:115973. [PMID: 38064969 DOI: 10.1016/j.biopha.2023.115973] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/25/2023] [Accepted: 11/29/2023] [Indexed: 01/10/2024] Open
Abstract
The resistance of cancer cells to chemotherapy, also known as chemo-resistance, poses a significant obstacle to cancer treatment and can ultimately result in patient mortality. Epithelial-mesenchymal transition (EMT) is one of the many factors and processes responsible for chemo-resistance. Studies have shown that targeting EMT can help overcome chemo-resistance, and nanotechnology and nanomedicine have emerged as promising approaches to achieve this goal. This article discusses the potential of nanotechnology in inhibiting EMT and proposes a viable strategy to combat chemo-resistance in various solid tumors, including breast cancer, lung cancer, pancreatic cancer, glioblastoma, ovarian cancer, gastric cancer, and hepatocellular carcinoma. While nanotechnology has shown promising results in targeting EMT, further research is necessary to explore its full potential in overcoming chemo-resistance and discovering more effective methods in the future.
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Affiliation(s)
- Mona Tangsiri
- Department of Medical Entomology and Vector Control, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Hheidari
- Department of Mechanical Engineering, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mahsa Liaghat
- Department of Medical Laboratory sciences, Faculty of Medical Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran; Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mahtab Razlansari
- Faculty of Mathematics and Natural Sciences, Tübingen University, Tübingen 72076, Germany
| | - Narges Ebrahimi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Abdullatif Akbari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Fahimeh Maleki-Sheikhabadi
- Department of Hematology and Blood Banking, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Norouzi
- Dental Research Center, Faculty of Dentistry, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Bakhtiyari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol 98613-35856, Iran.
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Vastrad SJ, Ritesh G, V SS, Saraswathy GR, Augustine D, Alzahrani KJ, Alzahrani FM, Halawani IF, Ashi H, Alshahrani M, Hassan RN, Baeshen HA, Saravanan KS, Satish KS, Vutukuru P, Patil S. Panoramic view of key cross-talks underpinning the oral squamous cell carcinoma stemness - unearthing the future opportunities. Front Oncol 2023; 13:1247399. [PMID: 38170015 PMCID: PMC10759990 DOI: 10.3389/fonc.2023.1247399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/09/2023] [Indexed: 01/05/2024] Open
Abstract
The clinical management of oral cancer is often frequented with challenges that arise from relapse, recurrence, invasion and resistance towards the cornerstone chemo and radiation therapies. The recent conceptual advancement in oncology has substantiated the role of cancer stem cells (CSC) as a predominant player of these intricacies. CSC are a sub-group of tumor population with inherent adroitness to self-renew with high plasticity. During tumor evolution, the structural and functional reprogramming persuades the cancer cells to acquire stem-cell like properties, thus presenting them with higher survival abilities and treatment resistance. An appraisal on key features that govern the stemness is of prime importance to confront the current challenges encountered in oral cancer. The nurturing niche of CSC for maintaining its stemness characteristics is thought to be modulated by complex multi-layered components encompassing neoplastic cells, extracellular matrix, acellular components, circulatory vessels, various cascading signaling molecules and stromal cells. This review focuses on recapitulating both intrinsic and extrinsic mechanisms that impart the stemness. There are contemplating evidences that demonstrate the role of transcription factors (TF) in sustaining the neoplastic stem cell's pluripotency and plasticity alongside the miRNA in regulation of crucial genes involved in the transformation of normal oral mucosa to malignancy. This review illustrates the interplay between miRNA and various known TF of oral cancer such as c-Myc, SOX, STAT, NANOG and OCT in orchestrating the stemness and resistance features. Further, the cross-talks involved in tumor micro-environment inclusive of cytokines, macrophages, extra cellular matrix, angiogenesis leading pathways and influential factors of hypoxia on tumorigenesis and CSC survival have been elucidated. Finally, external factorial influence of oral microbiome gained due to the dysbiosis is also emphasized. There are growing confirmations of the possible roles of microbiomes in the progression of oral cancer. Given this, an attempt has been made to explore the potential links including EMT and signaling pathways towards resistance and stemness. This review provides a spectrum of understanding on stemness and progression of oral cancers at various regulatory levels along with their current therapeutic knowledge. These mechanisms could be exploited for future research to expand potential treatment strategies.
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Affiliation(s)
- Soujanya J. Vastrad
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Giri Ritesh
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Sowmya S. V
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, India
| | | | - Dominic Augustine
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, India
| | - Khalid J. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Fuad M. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ibrahim F. Halawani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
- Haematology and Immunology Department, Faculty of Medicine, Umm Al-Qura University, AI Abdeyah, Makkah, Saudi Arabia
| | - Heba Ashi
- Department of Dental Public Health, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Alshahrani
- Department of Endodontic, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Reem Nabil Hassan
- Department of Biological Sciences (Genome), Faculty of Sciences, King Abdul-Aziz University, Jeddah, Saudi Arabia
| | - Hosam Ali Baeshen
- Department of Orthodontics Faculty of Dentistry, King Abdulaziz University, Bengaluru, India
| | - Kamatchi Sundara Saravanan
- Department of Pharmacognosy, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Kshreeraja S. Satish
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Pravallika Vutukuru
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Shankargouda Patil
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT, United States
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Shao J, Wang W, Tao B, Cai Z, Li H, Chen J. Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma. Front Med 2023; 17:1186-1203. [PMID: 37707678 DOI: 10.1007/s11684-023-0999-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/01/2023] [Indexed: 09/15/2023]
Abstract
Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial-to-mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.
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Affiliation(s)
- Jie Shao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Wenjuan Wang
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Baorui Tao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Zihao Cai
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Haixia Li
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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Sun Y, Yang X, Guan S, Ma T, Jiang Z, Gao M, Xu Y, Cong B. The role of phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) in regulating the progression of oral squamous cell carcinoma. Arch Oral Biol 2023; 156:105810. [PMID: 37852106 DOI: 10.1016/j.archoralbio.2023.105810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/12/2023] [Accepted: 09/27/2023] [Indexed: 10/20/2023]
Abstract
OBJECTIVE The aim of this study was to explore the role of the tumor suppressor phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) on oral squamous cell carcinoma (OSCC) and its molecular mechanism. DESIGN Immunohistochemistry detected the expression of PAG1 in normal and tumor tissues. The PAG1 overexpressed OSCC cell lines were constructed by lentivirus transfection. Cell Counting Kit-8 assay (CCK-8), clone formation and flow cytometry evaluated the impact of PAG1 on the proliferation and apoptosis of OSCC cells. RNA sequencing (RNA-seq) detected the changes in intracellular genes, and transmission electron microscope (TEM) was used to compare the number of autophagosomes in OSCC cells between Negative and PAG1 group. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blot were used to determine the expression of signaling pathway-related mRNA and proteins respectively. RESULTS In contrast to the normal tissues, PAG1 expression was significantly downregulated in tumor tissues. Treatment with lentivirus transfection, the expression of PAG1 in the OSCC cell lines was increase. Notably, transfected with PAG1-overexpressing lentivirus cells inhibited the proliferation of OSCC cells and promoted OSCC cells apoptosis. RNA-seq revealed that PAG1 mainly modulated the mitophagy and autophagy pathway, and many autophagosomes were observed in the PAG1 group using TEM. Mechanistically, we found that PAG1 upregulated the expression of autophagy related factors through inhibiting PI3K/Akt/mTOR signal pathway activation. CONCLUSION Overexpression of PAG1 inhibited OSCC progression by activating autophagy, its mechanism might be related to inhibition of PI3K/Akt/mTOR signal pathway phosphorylation.
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Affiliation(s)
- Yu Sun
- Medical College, Qingdao University, Qingdao 266071, China
| | - Xinting Yang
- Institute of Stomatology, Binzhou Medical University, Yantai 264003, China
| | - Shulong Guan
- Department of Surgery, Qingdao Shinan District People's Hospital, Qingdao 266520, China
| | - Tengyu Ma
- Institute of Stomatology, Binzhou Medical University, Yantai 264003, China
| | - Zhou Jiang
- Department of Reproductive, Women and Children's Hospital Affiliated to Qingdao University, Qingdao 266034, China
| | - Meihua Gao
- Central laboratory, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao 266001, China.
| | - Yingjie Xu
- Central laboratory, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao 266001, China.
| | - Beibei Cong
- Central laboratory, Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao 266001, China.
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Wu Y, Chen L, Feng C, Wang T, He S, Zheng D, Lin L. Antitumor effect of toosendanin on oral squamous cell carcinoma via suppression of p-STAT3. BMC Oral Health 2023; 23:846. [PMID: 37946196 PMCID: PMC10634166 DOI: 10.1186/s12903-023-03602-x] [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: 04/27/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Toosendanin (TSN) exhibits potent antitumor activity against various tumor cell lines. However, its efficacy against oral squamous cell carcinoma (OSCC) remains unknown. Here, we investigated the effects of TSN on OSCC cells in vitro and verified them in vivo using a patient-derived xenograft (PDX) model. METHODS The effect of TSN on OSCC cells was investigated by cytotoxicity assays and flow cytometry. The expression of proteins was detected by western blotting. An OSCC PDX model was constructed to further investigate the role of TSN in regulating the function of OSCC. RESULTS The cell viability of CAL27 and HN6 cells decreased as the concentration of TSN increased within the experimental range. Compared with controls, TSN at lower doses inhibited cell proliferation and induced apoptosis through S-phase cell cycle arrest. TSN inhibited OSCC cell proliferation by downregulating the STAT3 pathway through the inhibition of STAT3 phosphorylation. After successful construction of the OSCC PDX model with high pathological homology to the primary tumor and treatment with an intraperitoneal injection of TSN, we showed that TSN significantly reduced the tumor size of the PDX model mice without obvious toxicity. CONCLUSIONS Both in vitro and in vivo, TSN significantly inhibits the proliferation and promoted apoptosis of OSCC cells. Furthermore, TSN demonstrates potent inhibition of STAT3 phosphorylation, indicating its potential as a promising therapeutic agent for OSCC. Therefore, TSN holds great promise as a viable drug candidate for the treatment of OSCC.
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Affiliation(s)
- Ye Wu
- Fujian Key Laboratory of Oral Diseases & Stomatological Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Lingling Chen
- Fujian Key Laboratory of Oral Diseases & Stomatological Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Cheng Feng
- Fujian Key Laboratory of Oral Diseases & Stomatological Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Tao Wang
- Fujian Key Laboratory of Oral Diseases & Stomatological Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Shaohai He
- Fujian Key Laboratory of Oral Diseases & Stomatological Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Dali Zheng
- Fujian Key Laboratory of Oral Diseases & Stomatological Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, China.
| | - Lisong Lin
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.
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Bu X, Zhang J, Sun H, Wang W, Ma X, Sun L. SEC61 translocon subunit gamma enhances low-dose cisplatin-induced cancer-stem cell properties of head and neck squamous cell carcinoma via enhancing Ca 2+-mediated autophagy. J Dent Sci 2023; 18:1685-1692. [PMID: 37799908 PMCID: PMC10547946 DOI: 10.1016/j.jds.2023.01.024] [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: 01/13/2023] [Revised: 01/23/2023] [Indexed: 02/07/2023] Open
Abstract
Background/purpose High SEC61 translocon subunit gamma (SEC61G) expression is associated with an unfavorable prognosis in patients with head and neck squamous cell carcinoma (HNSCC), but the underlying mechanisms remain poorly understood. Materials and methods HNSCC representative cell lines SCC15 and CAL27 were used to explore the regulation of SEC61G on Ca2+ leak from the endoplasmic reticulum (ER). Ca2+-activated autophagy was monitored by fluorescent labeling of autophagosomes and western blotting assays. CSC marker expression, sphere formation, colony formation, and transwell of invasion were detected to investigate the role of SEC61G in regulating cancer-stem cell (CSC) properties. Results Among the SEC61 complex genes, only SEC61G upregulation is consistently associated with unfavorable progression-free interval and disease-specific survival in patients with HNSCC. Low-dose cisplatin (CDDP) treatment induced SEC61G upregulation in SCC15 and CAL27 cells. SEC61G knockdown significantly impaired CDDP-induced Ca2+ from the ER and the phosphorylation of ERK1/2 and AMPK. CDDP-induced autophagy in HNSCC cells were hampered by SEC61G shRNA, in terms of impaired autophagosome formation, lowered LC3-II/GAPDH ratio and restored p62 expression. CDDP-induced CSC properties, including CSC marker expression, sphere formation, colony formation, and invasive capabilities could be suppressed by shSEC61G and chloroquine, a specific autophagy inhibitor. Conclusion Findings of this study revealed the contribution of SEC61G in promoting cisplatin-induced CSC properties of HNSCC cells via promoting Ca2+-mediated autophagy.
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Affiliation(s)
- Xiangbin Bu
- Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Jun Zhang
- Department of Interventional Catheter Room, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Hengyan Sun
- Department of Stomatology, Yantai Penglai Traditional Chinese Medicine Hospital, Shandong, China
| | - Wenlong Wang
- Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xiangrui Ma
- Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Legang Sun
- Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
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Kang XF, Lu XL, Bi CF, Hu XD, Li Y, Li JK, Yang LS, Liu J, Ma L, Zhang JF. Xuebijing injection protects sepsis induced myocardial injury by mediating TLR4/NF-κB/IKKα and JAK2/STAT3 signaling pathways. Aging (Albany NY) 2023; 15:8501-8517. [PMID: 37650558 PMCID: PMC10496990 DOI: 10.18632/aging.204990] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/20/2023] [Indexed: 09/01/2023]
Abstract
OBJECTIVE Compelling evidence has demonstrated that Xuebijing (XBJ) exerted protective effects against SIMI. The aims of this study were to investigate whether TLR4/IKKα-mediated NF-κB and JAK2/STAT3 pathways were involved in XBJ's cardio-protection during sepsis and the mechanisms. METHODS In this study, rats were randomly assigned to three groups: Sham group; CLP group; XBJ group. Rats were treated with XBJ or sanitary saline after CLP. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1β, IL-6 and TNF-α in serum were measured using ELISA kits. Cardiomyocyte apoptosis were tested by TUNEL staining. The protein levels of Bax, Bcl-2, Bcl-xl, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3 in the myocardium were assayed by western blotting. And finally, immunofluorescence was used to assess the level of p-JAK2 and p-STAT3 in heart tissue. RESULTS The results of echocardiography, myocardial enzyme and HE test showed that XBJ could significantly improve SIMI. The IL-1β, IL-6 and TNF-α levels in the serum were markedly lower in the XBJ group than in the CLP group (p<0.05). TUNEL staining's results showed that XBJ ameliorated CLP-induced cardiomyocyte apoptosis. Meanwhile, XBJ downregulated the protein levels of Bax, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3, as well as upregulated the protein levels of Bcl-2, Bcl-xl (p <0.05). CONCLUSIONS In here, we observed that XBJ's cardioprotective advantages may be attributable to its ability to suppress inflammation and apoptosis via inhibiting the TLR4/ IKKα-mediated NF-κB and JAK2/STAT3 pathways during sepsis.
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Affiliation(s)
- Xiang-Fei Kang
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Xiao-Li Lu
- Laboratory Animal Centre, Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Cheng-Fei Bi
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
- School of Clinical Medicine, Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Xiao-Dong Hu
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Ying Li
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Jin-Kui Li
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Li-Shan Yang
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Jia Liu
- Medical Experimental Center, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Lei Ma
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
| | - Jun-Fei Zhang
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan 750000, Ningxia, China
- School of Clinical Medicine, Ningxia Medical University, Yinchuan 750000, Ningxia, China
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Huang J, Yang JG, Ren JG, Xia HF, Chen GH, Fu QY, Zhang LZ, Liu HM, Wang KM, Xie QH, Chen G. Overexpression of RAB27A in Oral Squamous Cell Carcinoma Promotes Tumor Migration and Invasion via Modulation of EGFR Membrane Stability. Int J Mol Sci 2023; 24:13103. [PMID: 37685910 PMCID: PMC10488256 DOI: 10.3390/ijms241713103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck tumors, highly prone to lymph node metastasis. This study aims to examine the expression pattern of Ras-related protein Rab-27A (RAB27A) and explore its potential implications in OSCC. The expression of RAB27A was assessed through immunohistochemical analysis utilizing tissue microarrays. In vitro experiments were conducted using RAB27A-knockdown cells to investigate its impact on OSCC tumor cells. Additionally, transcriptome sequencing was performed to elucidate potential underlying mechanisms. RAB27A was significantly overexpressed in OSCC, and particularly in metastatic lymph nodes. It was positively correlated with the clinical progression and poor survival prognosis. Silencing RAB27A notably decreased the proliferation, migration, and invasion abilities of OSCC cells in vitro. A Gene Ontology (GO) enrichment analysis indicated a strong association between RAB27A and the epidermal growth factor receptor (EGFR) signaling pathway. Further investigations revealed that RAB27A regulated the palmitoylation of EGFR via zinc finger DHHC-type containing 13 (ZDHHC13). These findings provide insights into OSCC progression and highlight RAB27A as a potential therapeutic target for combating this aggressive cancer.
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Affiliation(s)
- Jue Huang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Jie-Gang Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Jian-Gang Ren
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Hou-Fu Xia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Gao-Hong Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Qiu-Yun Fu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Lin-Zhou Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Hai-Ming Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Kui-Ming Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Qi-Hui Xie
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
| | - Gang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China (H.-M.L.)
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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Zhang X, Zhao P, Ma M, Wu H, Liu R, Liu Z, Cai Z, Liu M, Xie F, Ma X. Missing link between tissue specific expressing pattern of ERβ and the clinical manifestations in LGBLEL. Front Med (Lausanne) 2023; 10:1168977. [PMID: 37457559 PMCID: PMC10346852 DOI: 10.3389/fmed.2023.1168977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Purpose Lacrimal gland benign lymphoepithelial lesion (LGBLEL) is an IgG4-related disease of unknown etiology with a risk for malignant transformation. Estrogen is considered to be related to LGBLEL onset. Methods Seventy-eight LGBLEL and 13 control clinical samples were collected and studied to determine the relationship between estrogen and its receptors and LGBLEL development. Results The serological analysis revealed no significant differences in the levels of three estrogens be-tween the LGBLEL and control groups. However, immunohistochemical analyses indicated that the expression levels of ERβ and its downstream receptor RERG were relatively lower in LGBLEL samples than in control samples, with higher expression in the lacrimal gland and lower expression in the lymphocyte infiltration region. However, low expression of ERα was detected. The transcriptome sequence analysis revealed upregulated genes associated with LGBLEL enriched in lymphocyte proliferation and activation function; downregulated genes were enriched in epithelial and vascular proliferation functions. The key genes and gene networks were further analyzed. Interactions between B cells and epithelial cells were analyzed due to the identified involvement of leukocyte subsets and epithelial cells. B cell proliferation was found to potentially contribute to lacrimal gland apoptosis. Conclusion Therefore, the tissue-heterogeneous expression pattern of ERβ is potentially related to the clinical manifestations and progression of LGBLEL, although further investigations are required to confirm this finding.
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Affiliation(s)
- Xujuan Zhang
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Pengxiang Zhao
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Mingshen Ma
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hao Wu
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Rui Liu
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ziyi Liu
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Zisong Cai
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Mengyu Liu
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Fei Xie
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
| | - Xuemei Ma
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
- Beijing Molecular Hydrogen Research Center, Beijing, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, China
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Ribet F, Bendes A, Fredolini C, Dobielewski M, Böttcher M, Beck O, Schwenk JM, Stemme G, Roxhed N. Microneedle Patch for Painless Intradermal Collection of Interstitial Fluid Enabling Multianalyte Measurement of Small Molecules, SARS-CoV-2 Antibodies, and Protein Profiling. Adv Healthc Mater 2023; 12:e2202564. [PMID: 36748807 PMCID: PMC11468663 DOI: 10.1002/adhm.202202564] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/19/2023] [Indexed: 02/08/2023]
Abstract
Blood sampling is a common practice to monitor health, but it entails a series of drawbacks for patients including pain and discomfort. Thus, there is a demand for more convenient ways to obtain samples. Modern analytical techniques enable monitoring of multiple bioanalytes in smaller samples, opening possibilities for new matrices, and microsampling technologies to be adopted. Interstitial fluid (ISF) is an attractive alternative matrix that shows good correlation with plasma concentration dynamics for several analytes and can be sampled in a minimally invasive and painless manner from the skin at the point-of-care. However, there is currently a lack of sampling devices compatible with clinical translation. Here, to tackle state-of-the-art limitations, a cost-effective and compact single-microneedle-based device designed to painlessly collect precisely 1.1 µL of dermal ISF within minutes is presented. The fluid is volume-metered, dried, and stably stored into analytical-grade paper within the microfluidic device. The obtained sample can be mailed to a laboratory, quantitatively analyzed, and provide molecular insights comparable to blood testing. In a human study, the possibility to monitor various classes of molecular analytes is demonstrated in ISF microsamples, including caffeine, hundreds of proteins, and SARS-CoV-2 antibodies, some being detected in ISF for the first time.
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Affiliation(s)
- Federico Ribet
- Division of Micro and NanosystemsSchool of Electrical Engineering and Computer ScienceKTH Royal Institute of TechnologyStockholm10044Sweden
| | - Annika Bendes
- Division of Affinity ProteomicsSchool of Engineering Sciences in ChemistryBiotechnology and Health (CBH)SciLifeLabSolna17165Sweden
| | - Claudia Fredolini
- Division of Affinity ProteomicsSchool of Engineering Sciences in ChemistryBiotechnology and Health (CBH)SciLifeLabSolna17165Sweden
| | - Mikolaj Dobielewski
- Division of Micro and NanosystemsSchool of Electrical Engineering and Computer ScienceKTH Royal Institute of TechnologyStockholm10044Sweden
| | - Michael Böttcher
- MVZ Medizinische Labor Dessau Kassel GmbHD‐06847Dessau‐RosslauGermany
| | - Olof Beck
- Department of Clinical NeuroscienceKarolinska InstituteStockholm17177Sweden
| | - Jochen M. Schwenk
- Division of Affinity ProteomicsSchool of Engineering Sciences in ChemistryBiotechnology and Health (CBH)SciLifeLabSolna17165Sweden
| | - Göran Stemme
- Division of Micro and NanosystemsSchool of Electrical Engineering and Computer ScienceKTH Royal Institute of TechnologyStockholm10044Sweden
| | - Niclas Roxhed
- Division of Micro and NanosystemsSchool of Electrical Engineering and Computer ScienceKTH Royal Institute of TechnologyStockholm10044Sweden
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29
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Lei W, Jia L, Wang Z, Liang Z, Aizhen Z, Liu Y, Tian Y, Zhao L, Chen Y, Shi G, Yang Z, Yang Y, Xu X. CC chemokines family in fibrosis and aging: From mechanisms to therapy. Ageing Res Rev 2023; 87:101900. [PMID: 36871782 DOI: 10.1016/j.arr.2023.101900] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/21/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Fibrosis is a universal aging-related pathological process in the different organ, but is actually a self-repair excessive response. To date, it still remains a large unmet therapeutic need to restore injured tissue architecture without detrimental side effects, due to the limited clinical success in the treatment of fibrotic disease. Although specific organ fibrosis and the associated triggers have distinct pathophysiological and clinical manifestations, they often share involved cascades and common traits, including inflammatory stimuli, endothelial cell injury, and macrophage recruitment. These pathological processes can be widely controlled by a kind of cytokines, namely chemokines. Chemokines act as a potent chemoattractant to regulate cell trafficking, angiogenesis, and extracellular matrix (ECM). Based on the position and number of N-terminal cysteine residues, chemokines are divided into four groups: the CXC group, the CX3C group, the (X)C group, and the CC group. The CC chemokine classes (28 members) is the most numerous and diverse subfamily of the four chemokine groups. In this Review, we summarized the latest advances in the understanding of the importance of CC chemokine in the pathogenesis of fibrosis and aging and discussed potential clinical therapeutic strategies and perspectives aimed at resolving excessive scarring formation.
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Affiliation(s)
- Wangrui Lei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China
| | - Liyuan Jia
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China
| | - Zheng Wang
- Department of Cardiothoracic Surgery, Central Theater Command General Hospital of Chinese People's Liberation Army, Wuhan, 430064, China
| | - Zhenxing Liang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East, Zhengzhou 450052, China
| | - Zhao Aizhen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China
| | - Yanqing Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China
| | - Ye Tian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China
| | - Lin Zhao
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yawu Chen
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Guangyong Shi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Zhi Yang
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China.
| | - Xuezeng Xu
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
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Elmakaty I, Elsayed B, Elmarasi M, Kujan O, Malki MI. Clinicopathological and prognostic value of chemokine receptor CCR7 expression in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2023; 23:443-453. [PMID: 36744447 DOI: 10.1080/14737140.2023.2177156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES This study aimed to identify the clinicopathological characteristics and prognostic value of CC chemokine receptor 7 (CCR7) expression in patients with head and neck squamous cell carcinoma (HNSSC). METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in this meta-analysis. Up to the 2nd of July 2022 a search was conducted using five databases: PubMed, Embase, Scopus, ProQuest, and Web of Science. The methodological standards for the epidemiological research scale were used to assess the quality of the included articles, and Stata software was used to synthesise the meta-analysis. RESULTS We considered 13 of the 615 studies which included 1005 HNSCC patients. High expression of CCR7 increased the pooled odds ratio (OR) of advanced stage, tumour size, metastasis and recurrence by 2.82 [95% confidence interval (CI) 1.84 to 4.33], 2.48 (95% CI 1.68, to 3.67), 3.57, 95% CI 2.25 to 5.05) and 3.93 (95% CI 2.03 to 7.64), respectively. High CCR7 reduced overall patient survival [hazard ratio 2.62 (95% CI 1.59 to 4.32)]. CONCLUSION This study showed that high expression of CCR7 in HNSCC tumours was significantly associated with worse clinicopathological and survival outcomes, suggesting that CCR7 and its pathway could be potential therapeutic strategies for HNSCC.
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Affiliation(s)
| | - Basel Elsayed
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | | | - Omar Kujan
- Oral Diagnostic and Surgical Sciences Division, UWA Dental School, the University of Western Australia, Perth, Australia
| | - Mohammed Imad Malki
- Pathology Unit, Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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31
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Liu Z, He J, Jin P, Ran Y, Yin N, Qi H. CCL21/CCR7 Axis Contributes to Trophoblastic Cell Migration and Invasion in Preeclampsia by Affecting the Epithelial Mesenchymal Transition via the ERK1/2 Signaling Pathway. BIOLOGY 2023; 12:biology12020150. [PMID: 36829431 PMCID: PMC9952405 DOI: 10.3390/biology12020150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/27/2022] [Accepted: 12/29/2022] [Indexed: 01/20/2023]
Abstract
Preeclampsia (PE) is a pregnancy-related disorder that is a leading cause of maternal death. The failure of spiral artery remodeling due to insufficient trophoblast migration and invasion is critical in the pathogenesis of PE. Recently, the CC motif chemokine ligand 21 (CCL21) has been widely linked to cancer cell invasion and migration. However, their potential mechanisms are still unknown. In this study, we found that CCL21 expression was significantly lower in the PE group than that in the control group. In vitro experiments revealed that recombinant CCL21 could promote trophoblast cell epithelial-to-mesenchymal transitions (EMTs) and improve migration and invasion. Furthermore, an inhibitor of the ERK1/2 signaling pathway inhibited the CCL21-induced EMT process. Finally, a PE mouse model was established using the NOS inhibitor L-NAME, and we obtained similar results, with downregulated CCL21 and EMT biomarkers and upregulated CCR7. Taken together, these findings suggest that the CCL21/CCR7 axis influences EMT by activating the ERK1/2 signaling pathway, thereby affecting trophoblast cell migration and invasion, which may play a crucial role in the pathogenesis of PE.
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Affiliation(s)
- Zheng Liu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Jie He
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Pingsong Jin
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yuxin Ran
- Department of Obstetrics, Women and Children’s Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Nanlin Yin
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Correspondence: (N.Y.); (H.Q.)
| | - Hongbo Qi
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Obstetrics, Women and Children’s Hospital of Chongqing Medical University, Chongqing 401147, China
- Correspondence: (N.Y.); (H.Q.)
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CD44 and CD133 aptamer directed nanocarriers for cancer stem cells targeting. Eur Polym J 2023. [DOI: 10.1016/j.eurpolymj.2022.111770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Lv X, Wang X, Liu J, Wang F, Sun M, Fan X, Ye Z, Liu P, Wen J. Potential biomarkers and immune cell infiltration involved in aortic valve calcification identified through integrated bioinformatics analysis. Front Physiol 2022; 13:944551. [PMID: 36589450 PMCID: PMC9797982 DOI: 10.3389/fphys.2022.944551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Background: Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the aging population, resulting in a significant health and economic burden worldwide, but its underlying diagnostic biomarkers and pathophysiological mechanisms are not fully understood. Methods: Three publicly available gene expression profiles (GSE12644, GSE51472, and GSE77287) from human Calcific aortic valve disease (CAVD) and normal aortic valve samples were downloaded from the Gene Expression Omnibus database for combined analysis. R software was used to identify differentially expressed genes (DEGs) and conduct functional investigations. Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), were applied to identify key feature genes as potential biomarkers for Calcific aortic valve disease (CAVD). Receiver operating characteristic (ROC) curves were used to evaluate the discriminatory ability of key genes. The CIBERSORT deconvolution algorithm was used to determine differential immune cell infiltration and the relationship between key genes and immune cell types. Finally, the Expression level and diagnostic ability of the identified biomarkers were further validated in an external dataset (GSE83453), a single-cell sequencing dataset (SRP222100), and immunohistochemical staining of human clinical tissue samples, respectively. Results: In total, 34 identified DEGs included 21 upregulated and 13 downregulated genes. DEGs were mainly involved in immune-related pathways such as leukocyte migration, granulocyte chemotaxis, cytokine activity, and IL-17 signaling. The machine learning algorithm identified SCG2 and CCL19 as key feature genes [area under the ROC curve (AUC) = 0.940 and 0.913, respectively; validation AUC = 0.917 and 0.903, respectively]. CIBERSORT analysis indicated that the proportion of immune cells in Calcific aortic valve disease (CAVD) was different from that in normal aortic valve tissues, specifically M2 and M0 macrophages. Key genes SCG2 and CCL19 were significantly positively correlated with M0 macrophages. Single-cell sequencing analysis and immunohistochemical staining of human aortic valve tissue samples showed that SCG2 and CCL19 were increased in Calcific aortic valve disease (CAVD) valves. Conclusion: SCG2 and CCL19 are potential novel biomarkers of Calcific aortic valve disease (CAVD) and may play important roles in the biological process of Calcific aortic valve disease (CAVD). Our findings advance understanding of the underlying mechanisms of Calcific aortic valve disease (CAVD) pathogenesis and provide valuable information for future research into novel diagnostic and immunotherapeutic targets for Calcific aortic valve disease (CAVD).
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Affiliation(s)
- Xiaoshuo Lv
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China,Graduate School of Peking Union Medical College, Beijing, China
| | - Xiaohui Wang
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China,Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Jingwen Liu
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China,Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Feng Wang
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China,Graduate School of Peking Union Medical College, Beijing, China
| | - Mingsheng Sun
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China,Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Xueqiang Fan
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Zhidong Ye
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Peng Liu
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Jianyan Wen
- Department of Cardiovascular Surgery, China-Japan Friendship Hospital, Beijing, China,*Correspondence: Jianyan Wen,
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Guo ZC, Jing SL, Jumatai S, Gong ZC. Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by activating the neutrophil chemotaxis in the tumour microenvironment. Cancer Immunol Immunother 2022; 72:1523-1539. [PMID: 36513851 DOI: 10.1007/s00262-022-03348-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND We aimed to determine the significance of Porphyromonas gingivalis (P. gingivalis) in promoting tumour progression in the tumour microenvironment (TME) of oral squamous cell carcinoma (OSCC). METHODS The Gene Expression Omnibus (GEO) was used to screen out the differentially expressed genes from the two datasets of GEO138206 and GSE87539. Immunohistochemistry and immunofluorescence analysis of samples, cell biological behaviour experiments, and tumour-bearing animal experiments were used to verify the results in vivo and in vitro. The mechanism was revealed at the molecular level, and rescue experiments were carried out by using inhibitors and lentiviruses. RESULTS CXCL2 was selected by bioinformatics analysis and was found to be related to a poor prognosis in OSCC patients. Samples with P. gingivalis infection in the TME of OSCC had the strongest cell invasion and proliferation and the largest tumour volume in tumour-bearing animal experiments and exhibited JAK1/STAT3 signalling pathway activation and epithelial-mesenchymal transition (EMT). The expression of P. gingivalis, CXCL2 and TANs were independent risk factors for poor prognosis in OSCC patients. A CXCL2/CXCR2 signalling axis inhibitor significantly decreased the invasion and proliferation ability of cells and the tumour volume in mice. When lentivirus was used to block the CXCL2/CXCR2 signalling axis, the activity of the JAK1/STAT3 signalling pathway was decreased, and the phenotype of EMT was reversed. CONCLUSION Porphyromonas gingivalis promotes OSCC progression by recruiting TANs via activation of the CXCL2/CXCR2 axis in the TME of OSCC.
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Affiliation(s)
- Zhi-Chen Guo
- Oncological Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Institute of Stomatology, No.137, Li Yu Shan South Road, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Si-Li Jing
- Department of Ophthalmology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Sakendeke Jumatai
- Oncological Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Institute of Stomatology, No.137, Li Yu Shan South Road, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Zhong-Cheng Gong
- Oncological Department of Oral and Maxillofacial Surgery, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region Institute of Stomatology, No.137, Li Yu Shan South Road, Urumqi, 830054, Xinjiang, People's Republic of China.
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35
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Zhou W, Zhang X, Feng Y, Zhang Y, Liu Z. The CC ligand chemokine family members CCL17/CCL22 predict the survival and response to immune checkpoint blockade therapy of patients with head and neck squamous cell carcinoma. Curr Probl Cancer 2022; 46:100896. [PMID: 36167005 DOI: 10.1016/j.currproblcancer.2022.100896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 08/07/2022] [Accepted: 08/24/2022] [Indexed: 01/30/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is considered an immunosuppressive malignancy. Cross-talk between cancer cells and immune cells is modulated in part by CC ligand (CCL) chemokines, having a major effect on tumor progression. However, the predictive value and function of CCL family members in HNSCC have not been elucidated. Here, the predictive value of CCL members in cancer prognosis and Immune checkpoint blockade therapy response was investigated. CCL17 and CCL22 were screened as the key CCL chemokines in HNSCC through co-expression analysis. Further, the correlation between CCL17/CCL22 expression and cancer immune infiltration were evaluated based on TIMER and were validated by a set of scRNA-seq data. Moreover, the expression level of CCL17/CCL22 we evaluated to predict the response to Immune checkpoint blockade therapy in a panel of cancer types by using the TIDE database. Results indicated that CCL17/CCL22 had a high co-expression correlation and had a marginally statistical significance with the overall survival in HNSCC patients (P value = 0.057 and 0.055, respectively). Our findings showed high expression of CCL17/CCL22 was positively correlated with CD4+ T cell infiltration levels in HNSCCs and activate mTORC1 signaling pathway in CD4+ T cells. Further analysis from TIDE showed the high expression of CCL17/CCL22 might predict favorable responses to immune checkpoint blockade therapy in HNSCC patients. These findings provide an insight into the predictive roles of CCL17/CCL22 in HNSCC.
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Affiliation(s)
- Wenkai Zhou
- Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Xu Zhang
- Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Yisheng Feng
- Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Yu Zhang
- Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
| | - Zheqi Liu
- Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
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Zhang R, Meng Z, Wu X, Zhang M, Piao Z, Jin T. PD‐L1
/
p‐STAT3
promotes the progression of
NSCLC
cells by regulating
TAM
polarization. J Cell Mol Med 2022; 26:5872-5886. [DOI: 10.1111/jcmm.17610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 10/12/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Rui Zhang
- Department of Pathology and Cancer Research Center Yanbian University Medical College Yanji China
- Key Laboratory of the Science and Technology Department of Jilin Province Yanji China
| | - Ziqi Meng
- Department of Pathology and Cancer Research Center Yanbian University Medical College Yanji China
- Key Laboratory of the Science and Technology Department of Jilin Province Yanji China
| | - Xuwei Wu
- Department of Pathology and Cancer Research Center Yanbian University Medical College Yanji China
- Key Laboratory of the Science and Technology Department of Jilin Province Yanji China
| | - Meihua Zhang
- Department of Health Examination Centre Yanbian University Hospital Yanji China
| | - Zhengri Piao
- Department of radiology Yanbian University Hospital Yanji China
| | - Tiefeng Jin
- Department of Pathology and Cancer Research Center Yanbian University Medical College Yanji China
- Key Laboratory of the Science and Technology Department of Jilin Province Yanji China
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Mughees M, Kaushal JB, Sharma G, Wajid S, Batra SK, Siddiqui JA. Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis. Semin Cancer Biol 2022; 86:497-512. [PMID: 35181473 PMCID: PMC9793433 DOI: 10.1016/j.semcancer.2022.02.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 01/27/2023]
Abstract
Chemokines are recognized as the major contributor to various tumorigenesis, tumor heterogeneity, and failures of current cancer therapies. The tumor microenvironment (TME) is enriched with chemokines and cytokines and plays a pivotal role in cancer progression. Chronic inflammation is also considered an instructive process of cancer progression, where chemokines are spatiotemporally secreted by malignant cells and leukocyte subtypes that initiate cell trafficking into the TME. In various cancers, prostate cancer (PCa) is reported as one of the leading cancers in the worldwide male population. The chemokines-mediated signaling pathways are intensively involved in PCa progression and metastasis. Emerging evidence suggests that chemokines and cytokines are responsible for the pleiotropic actions in cancer, including the growth, angiogenesis, endothelial mesenchymal transition, leukocyte infiltration, and hormone escape for advanced PCa and therapy resistance. Chemokine's system and immune cells represent a promising target to suppress tumorigenic environments and serve as potential therapy/immunotherapy for the PCa. In this review, an attempt has been made to shed light on the alteration of chemokine and cytokine profiles during PCa progression and metastasis. We also discussed the recent findings of the diverse molecular signaling of these circulating chemokines and their corresponding receptors that could become future targets for therapeutic management of PCa.
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Affiliation(s)
- Mohd Mughees
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA(1)
| | - Jyoti Bala Kaushal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Gunjan Sharma
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Saima Wajid
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Fortis SP, Goulielmaki M, Aubert N, Batsaki P, Ouzounis S, Cavouras D, Marodon G, Stokidis S, Gritzapis AD, Baxevanis CN. Radiotherapy-Related Gene Signature in Prostate Cancer. Cancers (Basel) 2022; 14:cancers14205032. [PMID: 36291815 PMCID: PMC9599894 DOI: 10.3390/cancers14205032] [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: 09/15/2022] [Revised: 10/06/2022] [Accepted: 10/11/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Radiation therapy (RT) is an established therapeutic regimen for prostate cancer patients which aims for the direct elimination of tumor cells in the prostate gland and occasionally at distant anatomic sites. In this study, we performed next-generation sequencing-based gene expression analysis in peripheral blood from prostate cancer patients obtained pre- and post-radiotherapy and found six independently down-regulated genes including CCR7, FCGR2B, BTLA, CD6, CD3D, and CD3E. The analysis of the expression of the 6-genes as a signature also revealed significantly lower levels post- vs. pre-radiotherapy. Data extracted from the PRAD (PRostate ADenocarcinomas) dataset linked low levels of the 6-gene signature to better survival. More importantly, this 6-gene signature strongly correlated with a favorable prognosis regardless of poor standard clinicopathological parameters (i.e., Gleason score ≥ 8 and T3), thus highlighting its potential predictive value. Abstract Radiotherapy for localized prostate cancer has increased the cure and survival rates of patients. Besides its local tumoricidal effects, ionizing radiation has been linked to mechanisms leading to systemic immune activation, a phenomenon called the abscopal effect. In this study, we performed gene expression analysis on peripheral blood from prostate cancer patients obtained post- radiotherapy and showed that 6 genes, including CCR7, FCGR2B, BTLA, CD6, CD3D, and CD3E, were down-regulated by a range of 1.5–2.5-fold as compared to pre-radiotherapy samples. The expression of the signature consisting of these six genes was also significantly lower post- vs. pre-radiotherapy. These genes are involved in various tumor-promoting immune pathways and their down-regulation post-radiotherapy could be considered beneficial for patients. This is supported by the fact that low mRNA expression levels for the 6-gene signature in the prostate tumor tissue was linked to better survival. Importantly, we report that this 6-gene signature strongly correlated with a favorable prognosis regardless of poor standard clinicopathological parameters (i.e., Gleason score ≥ 8 and T3 (including T3a and T3b). Our pioneering data open the possibility that the 6-gene signature identified herein may have a predictive value, but this requires further long-term studies.
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Affiliation(s)
- Sotirios P. Fortis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
| | - Maria Goulielmaki
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
| | - Nicolas Aubert
- Centre d’Immunologie et Maladies Infectieuses-Paris, CIMI-PARIS, Sorbonne Université, INSERM, CNRS, 75013 Paris, France
| | - Panagiota Batsaki
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
| | - Sotirios Ouzounis
- Department of Biomedical Engineering, University of West Attica, 12243 Athens, Greece
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Dionisis Cavouras
- Department of Biomedical Engineering, University of West Attica, 12243 Athens, Greece
| | - Gilles Marodon
- Centre d’Immunologie et Maladies Infectieuses-Paris, CIMI-PARIS, Sorbonne Université, INSERM, CNRS, 75013 Paris, France
| | - Savvas Stokidis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
| | - Angelos D. Gritzapis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
| | - Constantin N. Baxevanis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522 Athens, Greece
- Correspondence: ; Tel.: +30-21-0640-9380
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Chemokine/GPCR Signaling-Mediated EMT in Cancer Metastasis. JOURNAL OF ONCOLOGY 2022; 2022:2208176. [PMID: 36268282 PMCID: PMC9578795 DOI: 10.1155/2022/2208176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/08/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022]
Abstract
Metastasis, the chief cause of cancer-related deaths, is associated with epithelial-mesenchymal transition (EMT). In the tumor microenvironment, EMT can be triggered by chemokine/G-protein-coupled receptor (GPCR) signaling, which is closely associated with tumor progression. However, the functional links between chemokine/GPCR signaling-mediated EMT and metastasis remain unclear. Herein, we summarized the mechanisms of chemokine/GPCR signaling-mediated EMT with an insight into facilitating metastasis and clarified the role of chemokine in the local invasion, intravasation, circulation, extravasation, and colonization, respectively. Moreover, several potential pathways that might contribute to EMT based on the latest studies on GPCR signaling were proposed, including signaling mediated by G protein, β-arrestin, intracellular, dimerization activation, and transactivation. However, there is still limited evidence to support the EMT programme functional contribution to metastasis, which keeps a key question still open whether we should target EMT programme of cancer cells. Answers to that question might help develop an anticancer strategy or guide new directions for anticancer metastasis therapy.
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Huang C, Li H, Zhou L, Li D. Circ_0005050 promotes the proliferation of oral squamous cell carcinoma and inhibits the apoptosis by activating JAK/STAT3 signaling pathway. Pathol Res Pract 2022; 238:154058. [PMID: 36155326 DOI: 10.1016/j.prp.2022.154058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/22/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is the most predominant type of oral cancer, featured with poor prognosis and high mortality. Circular RNA (circRNA) exerts its function in a variety of human cancers, including OSCC. Circ_0005050, as a novel circRNA, has not been well explored in OSCC so far. This study centered on investigating the impact of circ_0005050 on OSCC cell growth and its molecular mechanism. RNA or protein expression was detected by RT-qPCR or western blot analysis. Functional assays were employed to uncover the changes of OSCC cell biological behaviors. Mechanistic assays were done to verify the underlying mechanism of circ_0005050 in OSCC cells. According to the collected data, circ_0005050 was significantly up-regulated in OSCC cells compared to normal cells. Circ_0005050 depletion hampered proliferative ability of OSCC cells while promoting cell apoptotic ability. As for mechanism analyses, circ_0005050 knockdown led to the reduction of STAT3 expression and JAK/STAT3 signaling pathway activity. Moreover, circ_0005050 competitively bound to miR-23a-3p and miR-625-5p to up-regulate STAT3, thus prompting malignant behaviors of OSCC cells. In conclusion, circ_0005050 regulates miR-23a-3p/miR-625-5p/STAT3 axis to activate JAK/STAT3 signaling pathway, consequently facilitating OSCC cell proliferation and inhibiting cell apoptosis.
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Affiliation(s)
- Chunming Huang
- Department of Oral and Maxillofacial Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Haosen Li
- Department of Oral and Maxillofacial Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Leilei Zhou
- Department of Oral and Maxillofacial Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Dianqi Li
- Department of Oral and Maxillofacial Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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DiNatale A, Castelli MS, Nash B, Meucci O, Fatatis A. Regulation of Tumor and Metastasis Initiation by Chemokine Receptors. J Cancer 2022; 13:3160-3176. [PMID: 36118530 PMCID: PMC9475358 DOI: 10.7150/jca.72331] [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: 02/23/2022] [Accepted: 08/10/2022] [Indexed: 12/13/2022] Open
Abstract
Tumor-initiating cells (TICs) are a rare sub-population of cells within the bulk of a tumor that are major contributors to tumor initiation, metastasis, and chemoresistance. TICs have a stem-cell-like phenotype that is dictated by the expression of master regulator transcription factors, including OCT4, NANOG, and SOX2. These transcription factors are expressed via activation of multiple signaling pathways that drive cancer initiation and progression. Importantly, these same signaling pathways can be activated by select chemokine receptors. Chemokine receptors are increasingly being revealed as major drivers of the TIC phenotype, as their signaling can lead to activation of stemness-controlling transcription factors. Additionally, the cell surface expression of chemokine receptors provides a unique therapeutic target to disrupt signaling pathways that control the expression of master regulator transcription factors and the TIC phenotype. This review summarizes the master regulator transcription factors known to dictate the TIC phenotype, along with the complex signaling pathways that can mediate their expression and the chemokine receptors that are most upstream of this phenotype.
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Affiliation(s)
- Anthony DiNatale
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Present Address: Janssen Oncology, Spring House, PA, USA
| | - Maria Sofia Castelli
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Bradley Nash
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - Olimpia Meucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Program in Immune Cell Regulation & Targeting, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Alessandro Fatatis
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Program in Translational and Cellular Oncology, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA 19107, USA
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Meng XW, Zhang M, Hu JK, Chen XY, Long YQ, Liu H, Feng XM, Ji FH, Peng K. Activation of CCL21-GPR174/CCR7 on cardiac fibroblasts underlies myocardial ischemia/reperfusion injury. Front Genet 2022; 13:946524. [PMID: 36159993 PMCID: PMC9505909 DOI: 10.3389/fgene.2022.946524] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/15/2022] [Indexed: 11/22/2022] Open
Abstract
Background: The mechanisms underlying myocardial ischemia/reperfusion (I/R) injury are not fully understood. This study aims to explore key candidate genes and potential therapeutic targets for treatment of myocardial I/R injury. Methods: The transcriptional profiles of ventricular myocardium during cardiac arrest, ischemia, and reperfusion were obtained from the Gene Expression Omnibus database. Based on the transcriptional data of GSE6381, functional pathway and process enrichment analyses, protein–protein interaction network, and gene set enrichment analyses were conducted. In the animal experiments, we established the myocardial I/R injury model in mice. We validated the mRNA and protein expression of the key genes using the qPCR and western blots. We further assessed the expression and localization of CCL21 and its receptors using immunofluorescence staining experiments. Results: The microarray analyses identified five key genes (CCL21, XCR1, CXCL13, EDN1, and CASR). Myocardial I/R process in mice resulted in significant myocardial infraction, histological damage, and myocardial apoptosis. The results of qPCR and western blots showed that the expression of CCL21 and CXCL13 were increased following myocardial I/R injury in mice. Furthermore, the immunofluorescence staining results revealed that the expression of GPR174/CCR7 (CCL21 receptors), but not CXCR5 (CXCL13 receptor), was elevated following myocardial I/R injury. Moreover, the activated CCL21-GPR174/CCR7 signaling was located on the cardiac fibroblasts of the myocardium with I/R injury. Conclusion: This study revealed several key factors underlying myocardial I/R injury. Of these, the activation of CCL21-GPR174/CCR7 signaling on cardiac fibroblasts was highlighted, which provides potential therapeutic targets for cardioprotection.
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Affiliation(s)
- Xiao-Wen Meng
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Mian Zhang
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Jun-Kai Hu
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Xin-Yu Chen
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Yu-Qin Long
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Hong Liu
- Department of Anesthesiology and Pain Medicine, Davis Health System, University of California, Davis, Sacramento, CA, United States
| | - Xiao-Mei Feng
- Department of Anesthesiology, University of Utah, Salt Lake City, UT, United States
| | - Fu-Hai Ji
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
- *Correspondence: Fu-Hai Ji, ; Ke Peng,
| | - Ke Peng
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Anesthesiology, Soochow University, Suzhou, China
- *Correspondence: Fu-Hai Ji, ; Ke Peng,
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Li H, Wang J, He L, Zhang F, Meng Q, Huang J, Li Y, Liu R, Yang X, Wei J. Construction of a combined hypoxia and EMT index for head and neck squamous cell carcinoma. Front Cell Dev Biol 2022; 10:961858. [PMID: 36046345 PMCID: PMC9420946 DOI: 10.3389/fcell.2022.961858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
Objectives: In head and neck squamous cell carcinoma (HNSCC), the interaction between epithelial-mesenchymal transformation (EMT) and hypoxia has been confirmed, and corresponding treatment methods have been investigated. Few studies have examined its combined effects and its potential clinical use, however. As a result, we developed a new scoring system based on EMT and hypoxia.Methods: We combined 200 hypoxia-related genes with 1184 EMT-related genes and finally constructed a score risk model containing 14 characteristic factors named the comprehensive index of EMT and hypoxia (CIEH) by the Lasso-Cox regression and univariate Cox regression method, which is used to predict prognosis and to guide treatment planning in HNSCC patients. Furthermore, we examined HNSCC expression of CIEH-related genes using the human protein atlas database.Results: Based on survival analysis results, CIEH value had a high prognostic value in HNSCC patients, a high CIEH value carries a poor prognostic significance in HNSCC. It is noteworthy that the CIEH value was correlated with tumor immune infiltration. Moreover, the CIEH had significant differences in age, stage, N, laterality, and peripheral nerve invasion, and that the CIEH could be an independent prognostic factor.Conclusions: This study constructed a CIEH model containing 14 characteristic factors, including hypoxia-related genes and EMT genes, that may be able to serve as potential biomarkers for HNSCC. According to the 14 characteristic factors in the CIEH model, a diagnostic kit can be packaged in the future to evaluate the survival of patients before tumor surgery and guide the subsequent treatment plan.
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Affiliation(s)
- Huan Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Jun Wang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an, China
| | - Fengrui Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Qingzhe Meng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Junhong Huang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Yahui Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Rong Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
| | - Xinjie Yang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
- *Correspondence: Jianhua Wei, ; Xinjie Yang,
| | - Jianhua Wei
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, China
- *Correspondence: Jianhua Wei, ; Xinjie Yang,
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Correlation of Serum Chemokine (C-C Motif) Ligand 21 and Heat Shock Protein 90 with Preeclampsia. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2156424. [PMID: 35966726 PMCID: PMC9365573 DOI: 10.1155/2022/2156424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 11/17/2022]
Abstract
Objective The study aimed to explore the correlation of serum chemokine (C-C motif) ligand 21 (CCL21) and heat shock protein 90 (Hsp90) with preeclampsia (PE). Methods Between June 2021 and June 2022, 50 pregnant women with PE were included in the PE group, and 50 healthy pregnant women were included in the control group. The serum levels of CCL21 and Hsp90 were compared between the two groups. Results PE patients showed significantly higher levels of CCL21 and Hsp90 than healthy pregnant women (P < 0.05). Correlation analysis showed a positive correlation between CCL21 and Hsp90 levels (r > 0, (P < 0.05)). Binary logistic regression analysis suggested that high expression of CCL21 and Hsp90 were influencing factors for PE (OR >1, (P < 0.05)). The area under the receiver operating characteristic (AUC) curves of Hsp90 and CCL21 levels for predicting PE were 0.895 and 0.864, respectively, suggesting a good predictive value. Conclusion Serum CCL21 and Hsp90 show great potential as disease markers for PE prediction. Further trials are, however, required prior to clinical promotion.
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A Study of Heat Shock Protein 90 and Serum CCL21 Expression in Pregnant Women with Preeclampsia. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1601431. [PMID: 35958932 PMCID: PMC9363183 DOI: 10.1155/2022/1601431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/26/2022] [Accepted: 06/29/2022] [Indexed: 11/24/2022]
Abstract
Objective The purpose of the study was to determine the significance of heat shock protein 90 (HSP 90) and serum chemokine ligand 21 (CCL-21) in pregnant women with preeclampsia (PE). Methods From June 2021 to June 2022, the study enrolled 100 women undergoing obstetric examinations and delivering in our hospital; 50 PE patients undergoing routine obstetric examinations and delivering during the same period were enrolled in the research group; according to the severity, they were divided into mild PE and severe PE groups, while 50 healthy pregnant women undergoing obstetric examinations and delivering in our hospital during the same period were enrolled in the control group. In a subsequent analysis, serum levels of CCL-21 and HSP90 were compared between the two groups, and the correlation among CCL-21, HSP 90, and PE severity was analyzed. Results An overall total of 50 patients with PE were enrolled in the study, which included 32 patients with mild PE and 18 patients with severe PE. Patients with severe PE had lower mean arterial pressure (MAP), HSP 90, and CCL21 index levels than those with mild PE; MAP, HSP 90, and CCL21 in the severe PE group were higher than those in the mild PE group, but the difference was not statistically significant; In the research group, MAP was weakly correlated with HSP90 concentration and CCL21 concentration, with correlation coefficients of 0.33 and 0.30, respectively, and the correlation analysis was significant. Conclusion Patients with PE showed significantly increased serum concentrations of HSP90 and CCL-21, but a significant difference did not exist between mild and severe PE. In addition, there was a weak relationship between HSP90 and CCL-21 concentrations in PE patients and MAP, suggesting that HSP90 and CCL-21 play an instrumental role in the pathogenesis of PE, although more studies are needed to clarify the exact mechanisms.
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Khatoon E, Hegde M, Kumar A, Daimary UD, Sethi G, Bishayee A, Kunnumakkara AB. The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer. Arch Pharm Res 2022; 45:507-534. [PMID: 35987863 DOI: 10.1007/s12272-022-01398-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 07/20/2022] [Indexed: 12/20/2022]
Abstract
Oral cancer is one of the leading causes of cancer-related deaths, and it has become a matter of serious concern due to the alarming rise in its incidence rate worldwide. Despite recent advancements in oral cancer treatment strategies, there are no significant improvements in patient's survival rate. Among the numerous cell signaling pathways involved in oral cancer development and progression, STAT3 is known to play a multifaceted oncogenic role in shaping the tumor pathophysiology. STAT3 hyperactivation in oral cancer contributes to survival, proliferation, invasion, epithelial to mesenchymal transition, metastasis, immunosuppression, chemoresistance, and poor prognosis. A plethora of pre-clinical and clinical studies have documented the role of STAT3 in the initiation and development of oral cancer and showed that STAT3 inhibition holds significant potential in the prevention and treatment of this cancer. However, to date, targeting STAT3 activation mainly involves inhibiting the upstream signaling molecules such as JAK and IL-6 receptors. The major challenge in targeting STAT3 lies in the complexity of its phosphorylation- and dimerization-independent functions, which are not affected by disrupting the upstream regulators. The present review delineates the significance of the STAT3 pathway in regulating various hallmarks of oral cancer. In addition, it highlights the STAT3 inhibitors identified to date through various preclinical and clinical studies that can be employed for the therapeutic intervention in oral cancer treatment.
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Affiliation(s)
- Elina Khatoon
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India. .,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.
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Zhou WH, Wang Y, Yan C, Du WD, Al-Aroomi MA, Zheng L, Lin SF, Gao JX, Jiang S, Wang ZX, Sun CF, Liu FY. CC chemokine receptor 7 promotes macrophage recruitment and induces M2-polarization through CC chemokine ligand 19&21 in oral squamous cell carcinoma. Discov Oncol 2022; 13:67. [PMID: 35904690 PMCID: PMC9338204 DOI: 10.1007/s12672-022-00533-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/13/2022] [Indexed: 12/14/2022] Open
Abstract
PURPOSE This study aimed to investigate the impact of CC chemokine receptor 7 (CCR7) on the recruitment and polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC). METHODS We analyzed CCR7 expression pattern, clinicopathological significance, and its association with M2 macrophage infiltration in OSCC by bioinformatic methods. Small interfering RNA (siRNA) was utilized to silence CCR7 in OSCC cells. Conditioned media (CM) was harvested from transfected OSCC cells to establish a co-culture model of THP-1 derived macrophages and OSCC cells. Transwell assay and cell adhesion assay were performed to examine the effect of CCR7 on macrophages recruitment and adhesion. Cytoskeleton was labelled by phalloidin to observe macrophage morphological changes. Moreover, phenotypic alteration of macrophages was measured using quantitative real-time PCR (qRT-PCR), flow cytometry, and immunofluorescence (IF) staining. Ultimately, recombinant human CCL19 and CCL21 were added into the medium of THP-1 derived macrophages to explore their effects on polarization in vitro. RESULTS In OSCC patients, the overexpression of CCR7 positively correlated with lymph node metastasis and M2 macrophage infiltration. Macrophage not only exhibited enhanced migration, invasion and adhesion abilities, but also appeared more spindle and branched in vitro when treated with CM from OSCC cells. However, these phenomena were abrogated with knockdown of CCR7. We also discovered that inhibition of CCR7 in OSCC cells suppressed TAMs polarization to an M2 phenotype. In addition, recombinant human CCL19 and CCL21 promoted macrophage M2-polarization in vitro. CONCLUSION CCR7 in OSCC cells promoted recruitment and M2-polarization of THP-1 derived macrophages in vitro by regulating production of CCL19 and CCL21.
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Affiliation(s)
- Wan-Hang Zhou
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Yao Wang
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Cong Yan
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Wei-Dong Du
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Maged Ali Al-Aroomi
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Li Zheng
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Shan-Feng Lin
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Jia-Xing Gao
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Sheng Jiang
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Zeng-Xu Wang
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Chang-Fu Sun
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China
| | - Fa-Yu Liu
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Oral Diseases Laboratory of Liaoning, 117 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China.
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Zhang S, Zhang W, Zhang J. 8-Gene signature related to CD8+ T cell infiltration by integrating single-cell and bulk RNA-sequencing in head and neck squamous cell carcinoma. Front Genet 2022; 13:938611. [PMID: 35938006 PMCID: PMC9355512 DOI: 10.3389/fgene.2022.938611] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background: CD8+ T cells, a critical component of the tumor immune microenvironment, have become a key target of cancer immunotherapy. Considering the deficiency of robust biomarkers for head and neck squamous cell carcinoma (HNSCC), this study aimed at establishing a molecular signature associated with CD8+T cells infiltration. Methods: Single-cell RNA sequencing data retrieved from the Gene Expression Omnibus (GEO) database was analyzed to obtain the different cell types. Next, the cell proportions were investigated through deconvolution of RNA sequencing in the Cancer Genome Atlas (TCGA) database, and then the immune-related genes (IRGs) were identified by weighted gene co-expression network analysis (WGCNA). LASSO-Cox analysis was employed to establish a gene signature, followed by validation using a GEO dataset. Finally, the molecular and immunological properties, and drug responses between two subgroups were explored by applying “CIBERSORT”, “ESTIMATE”, and single sample gene set enrichment analysis (ssGSEA) methods. Results: A total of 215 differentially expressed IRGs were identified, of which 45 were associated with the overall survival of HNSCC. A risk model was then established based on eight genes, including DEFB1, AICDA, TYK2, CCR7, SCARB1, ULBP2, STC2, and LGR5. The low-risk group presented higher infiltration of memory activated CD4+ T cells, CD8+ T cells, and plasma cells, as well as a higher immune score, suggesting that they could benefit more from immunotherapy. On the other hand, the high-risk group showed higher abundance of activated mast cells and M2 macrophages, as well as a lower immune score. Conclusion: It was evident that the 8-gene signature could accurately predict HNSCC prognosis and thus it may serve as an index for clinical treatment.
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Affiliation(s)
- Shoujing Zhang
- Department of Oral and Maxillofacial Surgery, Tianjin Medical University School and Hospital of Stomatology, Tianjin, China
| | - Wenyi Zhang
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, China
| | - Jian Zhang
- Department of Oral and Maxillofacial Surgery, Tianjin Medical University School and Hospital of Stomatology, Tianjin, China
- *Correspondence: Jian Zhang,
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Lv Y, Lv Y, Wang Z, Yuan K, Zeng Y. Noncoding RNAs as sensors of tumor microenvironmental stress. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:224. [PMID: 35842651 PMCID: PMC9288030 DOI: 10.1186/s13046-022-02433-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 07/06/2022] [Indexed: 12/19/2022]
Abstract
The tumor microenvironment (TME) has been demonstrated to modulate the biological behavior of tumors intensively. Multiple stress conditions are widely observed in the TME of many cancer types, such as hypoxia, inflammation, and nutrient deprivation. Recently, accumulating evidence demonstrates that the expression levels of noncoding RNAs (ncRNAs) are dramatically altered by TME stress, and the dysregulated ncRNAs can in turn regulate tumor cell proliferation, metastasis, and drug resistance. In this review, we elaborate on the signal transduction pathways or epigenetic pathways by which hypoxia-inducible factors (HIFs), inflammatory factors, and nutrient deprivation in TME regulate ncRNAs, and highlight the pivotal roles of TME stress-related ncRNAs in tumors. This helps to clarify the molecular regulatory networks between TME and ncRNAs, which may provide potential targets for cancer therapy.
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Affiliation(s)
- Yue Lv
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yinghao Lv
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Zhen Wang
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Kefei Yuan
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. .,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yong Zeng
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. .,Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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50
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Shen T, Yang T, Yao M, Zheng Z, He M, Shao M, Li J, Fang C. BTC as a Novel Biomarker Contributing to EMT via the PI3K-AKT Pathway in OSCC. Front Genet 2022; 13:875617. [PMID: 35846125 PMCID: PMC9283838 DOI: 10.3389/fgene.2022.875617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck, while metastasis is the main cause of OSCC-related death. There is an urgent need to explore novel prognostic biomarkers and identify biological targets related to metastasis in OSCC treatment.Methods: Analysis of differential expression was performed using datasets in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry (IHC) was conducted to assess the expression of betacellulin (BTC) in OSCC. SCC4 and CAL27 cells were used for in vitro experiments, in which CCK-8, transwell assays, and wounding healing assays were performed to verify the biological functions of BTC. The role of BTC in EMT was analyzed by EMT score and Western blot.Results: Through the analysis of the mRNA expression profile data from TCGA database in OSCC, we found that only low expression of BTC was significantly correlated with a poor prognosis in OSCC patients. The results of IHC assays and TCGA databases showed that the expression level of BTC was related to the tumor stage, histological grade, and metastasis status. In vitro analysis showed that overexpression of BTC significantly suppressed the proliferation and migration of OSCC cells. Furthermore, we confirmed that BTC could affect EMT through the PI3K-AKT signaling pathway.Conclusion: The overexpression of BTC suppresses the proliferation, migration, and EMT of OSCC cells via the PI3K-AKT pathways, leading to a better prognosis in OSCC. BTC may be used as a novel molecular marker to assess the prognosis of OSCC patients.
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Affiliation(s)
- Ting Shen
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Tianru Yang
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Mianfeng Yao
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Ziran Zheng
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Mi He
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Mengying Shao
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
| | - Jiang Li
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
- *Correspondence: Jiang Li, ; Changyun Fang,
| | - Changyun Fang
- Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, China
- *Correspondence: Jiang Li, ; Changyun Fang,
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