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Wang L, Yang H, Cao L, Yang Y, Ding R. Integrative genomic pan-cancer analysis reveals the prognostic significance of DEFB1 in tumors. Discov Oncol 2025; 16:552. [PMID: 40244529 PMCID: PMC12006651 DOI: 10.1007/s12672-025-02340-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 04/08/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Defensin beta 1 (DEFB1) is a key immune response gene, but its role in cancer remains unclear. This study aims to explore DEFB1 expression, genetic alterations, immune infiltration, and prognostic significance across various cancer types. METHODS We analyzed DEFB1 expression and its association with cancer prognosis using data from public platforms, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA). Additionally, we examined DEFB1 genetic alterations, immune cell infiltration, and its molecular partners using various bioinformatics tools. RESULTS DEFB1 expression was highest in salivary glands, kidneys, and pancreas. In cancers, DEFB1 was upregulated in cholangiocarcinoma, kidney chromophobe, and melanoma, but downregulated in breast, colon, and rectal cancers. High DEFB1 expression was linked to poorer overall survival in lung adenocarcinoma and pancreatic adenocarcinoma, but better survival in head and neck squamous cell carcinoma. Genetic analysis revealed alterations in liver and gastric cancers. Immune infiltration analysis showed a correlation between DEFB1 and cancer-associated fibroblasts in liver cancer, while neutrophil infiltration was linked to bladder carcinoma, diffuse large B-cell lymphoma, and lung squamous cell carcinoma. Key genes associated with DEFB1 included KLK1, BSND, and CLCNKB. DISCUSSION This study highlights DEFB1's potential as a prognostic biomarker and its influence on the tumor immune microenvironment across different cancers. These findings suggest DEFB1 could be a target for future cancer therapies, although further studies are needed to validate these results.
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Affiliation(s)
- Li Wang
- Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
| | - Hongyu Yang
- Department of Rheumatology, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Lu Cao
- Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yang Yang
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300060, China
| | - Ran Ding
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Zhao H, Zhao S, Wang S, Liu Y. Human β-defensins: The multi-functional natural peptide. Biochem Pharmacol 2024; 227:116451. [PMID: 39059771 DOI: 10.1016/j.bcp.2024.116451] [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: 04/22/2024] [Revised: 07/21/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
The increasing threat of antibiotic resistance among pathogenic microorganisms and the urgent demand for new antibiotics require immediate attention. Antimicrobial peptides exhibit effectiveness against microorganisms, fungi, viruses, and protozoa. The discovery of human β-defensins represents a major milestone in biomedical research, opening new avenues for scientific investigation into the innate immune system and its resistance mechanisms against pathogenic microorganisms. Multiple defensins present a promising alternative in the context of antibiotic abuse. However, obstacles to the practical application of defensins as anti-infective therapies persist due to the unique properties of human β-defensins themselves and serious pharmacological and technical challenges. To overcome these challenges, diverse delivery vehicles have been developed and progressively improved for the conjugation or encapsulation of human β-defensins. This review briefly introduces the biology of human β-defensins, focusing on their multistage structure and diverse functions. It also discusses several heterologous systems for producing human β-defensins, various delivery systems created for these peptides, and patent applications related to their utilization, concluding with a summary of current challenges and potential solutions.
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Affiliation(s)
- Haile Zhao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock Jointly Constructed by Ministry and Province, School of Life Sciences, Inner Mongolia University, 24 Zhaojun Road, Hohhot, Inner Mongolia 010020, China
| | - Shuli Zhao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock Jointly Constructed by Ministry and Province, School of Life Sciences, Inner Mongolia University, 24 Zhaojun Road, Hohhot, Inner Mongolia 010020, China
| | - Simeng Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock Jointly Constructed by Ministry and Province, School of Life Sciences, Inner Mongolia University, 24 Zhaojun Road, Hohhot, Inner Mongolia 010020, China
| | - Ying Liu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock Jointly Constructed by Ministry and Province, School of Life Sciences, Inner Mongolia University, 24 Zhaojun Road, Hohhot, Inner Mongolia 010020, China.
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Duan J, Wang H, Liu M, Chen Y, Li N, Liu J, Wang L, Li L, Liu Y, Dong P, Wang X, Fan Z, Jiao S. Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+ T cell function in esophageal squamous cell carcinoma. Chin J Cancer Res 2024; 36:351-367. [PMID: 39246704 PMCID: PMC11377887 DOI: 10.21147/j.issn.1000-9604.2024.04.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 07/05/2024] [Indexed: 09/10/2024] Open
Abstract
Objective CD8+ T cells are the key effector cells in the anti-tumor immune response. The mechanism underlying the infiltration of CD8+ T cells in esophageal squamous cell carcinoma (ESCC) has not been clearly elucidated. Methods Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+ T cells. After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas (TCGA) ESCC data, a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+ T cells. Bioinformatics analyses, histological verification and in vitro experiments were then performed. Results DEFB1 was highly expressed in ESCC, and the high expression of DEFB1 was an independent risk factor for overall survival. Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation, migration and apoptosis of ESCC cells, we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics. Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response, and correlate to the infiltration of immature dendritic cell (imDC) in ESCC. Histological analyses further confirmed that there were less CD8+ T cells infiltrated, less CD83+ mature DC (mDC) infiltrated and more CD1a+ imDC infiltrated in those ESCC samples with high expression of DEFB1. After the treatment with recombinant DEFB1 protein, the maturation of DC was hindered significantly, followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro. Conclusions Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+ T cells, accounting for the immune tolerance in ESCC. The role of DEFB1 in ESCC deserves further exploration.
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Affiliation(s)
- Jingjing Duan
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Haotian Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Minglu Liu
- Department of Oncology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yin Chen
- Beijing DCTY Biotech CO., LTD., Beijing 102200, China
| | - Ning Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Jieqiong Liu
- Department of Oncology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Lingxiong Wang
- Department of Oncology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Lin Li
- Beijing DCTY Biotech CO., LTD., Beijing 102200, China
| | - Yaru Liu
- Beijing DCTY Biotech CO., LTD., Beijing 102200, China
| | - Pengfei Dong
- Beijing DCTY Biotech CO., LTD., Beijing 102200, China
| | - Xiuxuan Wang
- Beijing DCTY Biotech CO., LTD., Beijing 102200, China
| | - Zhongyi Fan
- Department of Biotherapy Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen 518112, China
| | - Shunchang Jiao
- Department of Oncology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Sabit H, Pawlik TM, Abdel-Ghany S, Arneth B. Defensins: Exploring Their Opposing Roles in Colorectal Cancer Progression. Cancers (Basel) 2024; 16:2622. [PMID: 39123348 PMCID: PMC11311076 DOI: 10.3390/cancers16152622] [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: 07/03/2024] [Revised: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global healthcare burden, with a particularly concerning rising incidence among younger adults. This trend may highlight potential links between diet, gut microbiome, and CRC risk. Novel therapeutic options have been increasingly based on the understanding of molecular mechanisms and pathways. The PI3K/AKT/mTOR pathway, a crucial cell growth regulator, offers a promising target for CRC therapy. mTOR, a key component within this pathway, controls cell growth, survival, and metabolism. Understanding the specific roles of defensins, particularly human β-Defensin 1 (HBD-1), in CRC is crucial. HBD-1 exhibits potent antimicrobial activity and may influence CRC development. Deciphering defensin expression patterns in CRC holds the promise of improved understanding of tumorigenesis, which may pave the way for improved diagnostics and therapies. This article reviews recent advances in understanding regarding how HBD-1 influences CRC initiation and progression, highlighting the molecular mechanisms by which it impacts CRC. Further, we describe the interaction between defensins and mTOR pathway in CRC.
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Affiliation(s)
- Hussein Sabit
- Department of Medical Biotechnology, College of Biotechnology, Misr University for Science and Technology, Giza P.O. Box 77, Egypt;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, 250 Cunz Hall, 1841 Neil Ave. Columbus, OH 43210, USA;
| | - Shaimaa Abdel-Ghany
- Department of Environmental Biotechnology, College of Biotechnology, Misr University for Science and Technology, Giza P.O. Box 77, Egypt;
| | - Borros Arneth
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities of Giessen and Marburg (UKGM), Justus Liebig University Giessen, Feulgenstr. 12, 35392 Giessen, Germany
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities of Giessen and Marburg (UKGM), Philipps University Marburg, Baldinger Str., 35043 Marburg, Germany
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Li S, Mu R, Guo X. Defensins regulate cell cycle: Insights of defensins on cellular proliferation and division. Life Sci 2024; 349:122740. [PMID: 38777302 DOI: 10.1016/j.lfs.2024.122740] [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: 02/20/2024] [Revised: 05/12/2024] [Accepted: 05/18/2024] [Indexed: 05/25/2024]
Abstract
Defensins are a class of small antimicrobial peptides that play a crucial role against pathogens. However, recent research has highlighted defensins exhibit the ability to influence cell cycle checkpoints, promoting or inhibiting specific phases such as G1 arrest or S/M transition. By regulating the cell cycle, defensins impact the proliferation of normal and cancerous cells, with implications for cancer development and progression. Dysregulation of defensin expression can disrupt the delicate balance of cell cycle regulation, leading to uncontrolled cell growth and an increased risk of tumor formation. Defensins contribute to the resolution of inflammation, stimulate angiogenesis, and enhance the migration and proliferation of cells involved in tissue repair. Furthermore, The ability of defensins to respond to microenvironmental changes further demonstrates the significance of these peptides in host defense mechanisms and immune function. By adjusting their expression, defensins continue to combat pathogens effectively and maintain homeostasis within the body. This review highlights the multifaceted role of defensins in regulating the cell cycle and their broader implications in cancer progression, tissue repair, and microenvironmental response.
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Affiliation(s)
- Shuang Li
- Institute of Wound Prevention and Treatment, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China.
| | - Rongrong Mu
- Affiliated Hospital of Sichuan Nursing Vocational College, The Third People's Hospital of Sichuan Province, China
| | - Xueqin Guo
- Department of Pathology, Gaomi City People's Hospital, Gaomi 261500, China
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Zhao YX, Cui Y, Li XH, Yang WH, An SX, Cui JX, Zhang MY, Lu JK, Zhang X, Wang XM, Bao LL, Zhao PW. Human β-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long non-coding RNA TCONS_00014506. World J Gastrointest Oncol 2024; 16:1465-1478. [PMID: 38660658 PMCID: PMC11037056 DOI: 10.4251/wjgo.v16.i4.1465] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/15/2024] [Accepted: 02/18/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Colorectal cancer has a low 5-year survival rate and high mortality. Human β-defensin-1 (hBD-1) may play an integral function in the innate immune system, contributing to the recognition and destruction of cancer cells. Long non-coding RNAs (lncRNAs) are involved in the process of cell differentiation and growth. AIM To investigate the effect of hBD-1 on the mammalian target of rapamycin (mTOR) pathway and autophagy in human colon cancer SW620 cells. METHODS CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration. Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation. Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway. Additionally, p-mTOR (Ser2448), Beclin1, and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis. RESULTS hBD-1 inhibited the proliferative ability of SW620 cells, as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1. hBD-1 decreased the expression of p-mTOR (Ser2448) protein and increased the expression of Beclin1 and LC3II/I protein. Furthermore, bioinformatics analysis identified seven lncRNAs (2 upregulated and 5 downregulated) related to the mTOR pathway. The lncRNA TCONS_00014506 was ultimately selected. Following the inhibition of the lncRNA TCONS_00014506, exposure to hBD-1 inhibited p-mTOR (Ser2448) and promoted Beclin1 and LC3II/I protein expression. CONCLUSION hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.
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Affiliation(s)
- Yu-Xin Zhao
- Department of Anesthesiology, Inner Mongolia Chest Hospital, The Fourth Hospital, Hohhot 010035, Inner Mongolia Autonomous Region, China
| | - Yan Cui
- College of Humanities and Education, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Xin-Hong Li
- Department of Radiotherapy, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Wen-Hong Yang
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Shi-Xiang An
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Jia-Xian Cui
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Min-Yu Zhang
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Jing-Kun Lu
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Xuan Zhang
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Xiu-Mei Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Li-Li Bao
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
| | - Peng-Wei Zhao
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
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Abot A, Pomié N, Astre G, Cani PD, Aussant J, Barrat E, Knauf C. Effect of the dietary supplement PERMEAPROTECT+ TOLERANCE© on gut permeability in a human co-culture epithelial and immune cells model. Heliyon 2024; 10:e28320. [PMID: 38586362 PMCID: PMC10998107 DOI: 10.1016/j.heliyon.2024.e28320] [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: 11/13/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 04/09/2024] Open
Abstract
Background and objective The leaky gut syndrome is characterized by an intestinal hyperpermeability observed in multiple chronic disorders. Alterations of the gut barrier are associated with translocation of bacterial components increasing inflammation, oxidative stress and eventually dysfunctions of cellular interactions at the origin pathologies. Therapeutic and/or preventive approaches have to focus on the identification of novel targets to improve gut homeostasis. In this context, this study aims to identify the role of PERMEAPROTECT + TOLERANE©, known as PERMEA, a food complement composed of a combination of factors (including l-Glutamine) known to improve gut physiology. Methods We tested the effects of PERMEA or l-Glutamine alone (as reference) on gut permeability (FITC dextran method, expression of tight junctions) and its inflammatory/oxidative consequences (cytokines and redox assays, RT-qPCR) in a co-culture of human cells (peripheral blood mononuclear cells and intestinal epithelial cells) challenged with TNFα. Results PERMEA prevented intestinal hyperpermeability induced by inflammation. This was linked with its antioxidant and immunomodulatory properties showing a better efficacity than l-Glutamine alone on several parameters including permeability, global antioxidant charge and production of cytokines. Conclusion PERMEA is more efficient to restore intestinal physiology, reinforcing the concept that combination of food constituents could be used to prevent the development of numerous diseases.
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Affiliation(s)
| | | | | | - Patrice D. Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute LDRI, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, avenue Pasteur, 6, 1300, Wavre, Belgium
- NeuroMicrobiota, International Research Program (IRP) INSERM/UCLouvain, France Belgium
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research IREC, 1200, Brussels, Belgium
| | - Justine Aussant
- Laboratoire Lescuyer, Research Department, 15 rue Le Corbusier, 17440, Aytré, France
| | - Emmanuel Barrat
- Laboratoire Lescuyer, Research Department, 15 rue Le Corbusier, 17440, Aytré, France
| | - Claude Knauf
- NeuroMicrobiota, International Research Program (IRP) INSERM/UCLouvain, France Belgium
- INSERM U1220, Institut de Recherche en Santé Digestive IRSD, Université Paul Sabatier, Toulouse III, CHU Purpan, Place Du Docteur Baylac, CS 60039, CEDEX 3, 31024 Toulouse, France
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8
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Chen Y, Han Z, Zhang S, Liu H, Wang K, Liu J, Liu F, Yu S, Sai N, Mai H, Zhou X, Zhou C, Wen Q, Ma L. ERK1/2-CEBPB Axis-Regulated hBD1 Enhances Anti-Tuberculosis Capacity in Alveolar Type II Epithelial Cells. Int J Mol Sci 2024; 25:2408. [PMID: 38397085 PMCID: PMC10889425 DOI: 10.3390/ijms25042408] [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: 11/30/2023] [Revised: 02/05/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis with substantial morbidity and mortality rates. Type II alveolar epithelial cells (AEC-II) play a critical role in the pulmonary immune response against Mtb infection by secreting effector molecules such as antimicrobial peptides (AMPs). Here, human β-defensin 1 (hBD1), an important AMP produced by AEC-II, has been demonstrated to exert potent anti-tuberculosis activity. HBD1 overexpression effectively inhibited Mtb proliferation in AEC-II, while mice lacking hBD1 exhibited susceptibility to Mtb and increased lung tissue inflammation. Mechanistically, in A549 cells infected with Mtb, STAT1 negatively regulated hBD1 transcription, while CEBPB was the primary transcription factor upregulating hBD1 expression. Furthermore, we revealed that the ERK1/2 signaling pathway activated by Mtb infection led to CEBPB phosphorylation and nuclear translocation, which subsequently promoted hBD1 expression. Our findings suggest that the ERK1/2-CEBPB-hBD1 regulatory axis can be a potential therapeutic target for anti-tuberculosis therapy aimed at enhancing the immune response of AEC-II cells.
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Affiliation(s)
- Yaoxin Chen
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Zhenyu Han
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Sian Zhang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Honglin Liu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Ke Wang
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Jieyu Liu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Feichang Liu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Shiyun Yu
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Na Sai
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Haiyan Mai
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Xinying Zhou
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Chaoying Zhou
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Qian Wen
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
| | - Li Ma
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China; (Y.C.); (Z.H.); (S.Z.); (H.L.); (K.W.); (J.L.); (F.L.); (S.Y.); (N.S.); (H.M.); (X.Z.); (C.Z.)
- Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou 510515, China
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Zheng T, Wang Y, Zhou Z, Chen S, Jiang J, Chen S. PM2.5 Causes Increased Bacterial Invasion by Affecting HBD1 Expression in the Lung. J Immunol Res 2024; 2024:6622950. [PMID: 38314088 PMCID: PMC10838202 DOI: 10.1155/2024/6622950] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 12/12/2023] [Accepted: 12/19/2023] [Indexed: 02/06/2024] Open
Abstract
Our research addresses the critical environmental issue of a fine particulate matter (PM2.5), focusing on its association with the increased infection risks. We explored the influence of PM2.5 on human beta-defensin 1 (HBD1), an essential peptide in mucosal immunity found in the airway epithelium. Using C57BL/6J mice and human bronchial epithelial cells (HBE), we examined the effects of PM2.5 exposure followed by Pseudomonas aeruginosa (P. aeruginosa) infection on HBD1 expression at both mRNA and protein levels. The study revealed that PM2.5's toxicity to epithelial cells and animals varies with time and concentration. Notably, HBE cells exposed to PM2.5 and P. aeruginosa showed increased bacterial invasion and decreased HBD1 expression compared to the cells exposed to P. aeruginosa alone. Similarly, mice studies indicated that combined exposure to PM2.5 and P. aeruginosa significantly reduced survival rates and increased bacterial invasion. These harmful effects, however, were alleviated by administering exogenous HBD1. Furthermore, our findings highlight the activation of MAPK and NF-κB pathways following PM2.5 exposure. Inhibiting these pathways effectively increased HBD1 expression and diminished bacterial invasion. In summary, our study establishes that PM2.5 exposure intensifies P. aeruginosa invasion in both HBE cells and mouse models, primarily by suppressing HBD1 expression. This effect can be counteracted with exogenous HBD1, with the downregulation mechanism involving the MAPK and NF-κB pathways. Our study endeavors to elucidate the pathogenesis of lung infections associated with PM2.5 exposure, providing a novel theoretical basis for the development of prevention and treatment strategies, with substantial clinical significance.
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Affiliation(s)
- Tianqi Zheng
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yajun Wang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zheng Zhou
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shuyang Chen
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinjun Jiang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Respiratory Research Institute, Shanghai, China
| | - Shujing Chen
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
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10
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Fu J, Zong X, Jin M, Min J, Wang F, Wang Y. Mechanisms and regulation of defensins in host defense. Signal Transduct Target Ther 2023; 8:300. [PMID: 37574471 PMCID: PMC10423725 DOI: 10.1038/s41392-023-01553-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/11/2023] [Accepted: 06/26/2023] [Indexed: 08/15/2023] Open
Abstract
As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.
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Affiliation(s)
- Jie Fu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China
| | - Xin Zong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China
| | - Mingliang Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
- The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
| | - Yizhen Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China.
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China.
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11
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Role of Defensins in Tumor Biology. Int J Mol Sci 2023; 24:ijms24065268. [PMID: 36982340 PMCID: PMC10049535 DOI: 10.3390/ijms24065268] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/02/2023] [Accepted: 03/04/2023] [Indexed: 03/12/2023] Open
Abstract
Defensins have long been considered as merely antimicrobial peptides. Throughout the years, more immune-related functions have been discovered for both the α-defensin and β-defensin subfamily. This review provides insights into the role of defensins in tumor immunity. Since defensins are present and differentially expressed in certain cancer types, researchers started to unravel their role in the tumor microenvironment. The human neutrophil peptides have been demonstrated to be directly oncolytic by permealizing the cell membrane. Further, defensins can inflict DNA damage and induce apoptosis of tumor cells. In the tumor microenvironment, defensins can act as chemoattractants for subsets of immune cells, such as T cells, immature dendritic cells, monocytes and mast cells. Additionally, by activating the targeted leukocytes, defensins generate pro-inflammatory signals. Moreover, immuno-adjuvant effects have been reported in a variety of models. Therefore, the action of defensins reaches beyond their direct antimicrobial effect, i.e., the lysis of microbes invading the mucosal surfaces. By causing an increase in pro-inflammatory signaling events, cell lysis (generating antigens) and attraction and activation of antigen presenting cells, defensins could have a relevant role in activating the adaptive immune system and generating anti-tumor immunity, and could thus contribute to the success of immune therapy.
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12
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Bonamy C, Pesnel S, Ben Haddada M, Gorgette O, Schmitt C, Morel AL, Sauvonnet N. Impact of Green Gold Nanoparticle Coating on Internalization, Trafficking, and Efficiency for Photothermal Therapy of Skin Cancer. ACS OMEGA 2023; 8:4092-4105. [PMID: 36743010 PMCID: PMC9893490 DOI: 10.1021/acsomega.2c07054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/29/2022] [Indexed: 06/18/2023]
Abstract
Skin cancer is a global health issue and mainly composed of melanoma and nonmelanoma cancers. For the first clinical proof of concept on humans, we decided to study good prognosis skin cancers, i.e., carcinoma basal cell. In UE, the first-line treatment remains surgical resection, healing most of the tumors, but presents aesthetic disadvantages with a high reoccurrence rate on exposed areas. Moreover, the therapeutic indications could extend to melanoma and metastasis, which is a different medical strategy that could combine this treatment. Indeed, patients with late-stage melanoma are in a therapeutic impasse, despite recent targeted and immunological therapies. Photothermal therapy using gold nanoparticles is the subject of many investigations due to their strong potential to treat cancers by physical, thermal destruction. We developed gold nanoparticles synthesized by green chemistry (gGNPs), using endemic plant extract from Reunion Island, which have previously showed their efficiency at a preclinical stage. Here, we demonstrate that these gGNPs are less cytotoxic than gold nanoparticles synthesized by Turkevich's method. Furthermore, our work describes the optimization of gGNP coating and stabilization, also taking into consideration the gGNP path in cells (endocytosis, intracellular trafficking, and exocytosis), their specificity toward cancerous cells, their cytotoxicity, and their in vivo efficiency. Finally, based on the metabolic switch of cancerous cells overexpressing Glut transporters in skin cancers, we demonstrated that glucose-stabilized gGNP (gGNP@G) enables a quick internalization, fourfold higher in cancerous cells in contrast to healthy cells with no side cytotoxicity, which is particularly relevant to target and treat cancer.
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Affiliation(s)
- Clément Bonamy
- Torskal, 2 rue Maxime Rivière, 97490 Sainte-Clotilde, France
- Group
Intracellular Trafficking and Tissue Homeostasis, Institut Pasteur, Université Paris Cité, 75015 Paris, France
| | - Sabrina Pesnel
- Torskal, 2 rue Maxime Rivière, 97490 Sainte-Clotilde, France
| | | | - Olivier Gorgette
- Ultrastructural
BioImaging, Institut Pasteur, Université
Paris Cité, 75015 Paris, France
| | - Christine Schmitt
- Ultrastructural
BioImaging, Institut Pasteur, Université
Paris Cité, 75015 Paris, France
| | | | - Nathalie Sauvonnet
- Group
Intracellular Trafficking and Tissue Homeostasis, Institut Pasteur, Université Paris Cité, 75015 Paris, France
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13
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Huang S, Ma Y, Wang F, Li J, Yang Z, Jiang Y, Chen X, Hu S, Yi Q. ERK is involved in the regulation of CpG ODN 2395 on the expression levels of anti-lipopolysaccharide factors in Chinese mitten crab, Eriocheir sinensis. FISH & SHELLFISH IMMUNOLOGY 2022; 131:1206-1213. [PMID: 36403703 DOI: 10.1016/j.fsi.2022.11.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/10/2022] [Accepted: 11/12/2022] [Indexed: 06/16/2023]
Abstract
CpG oligodeoxynucleotides (ODN), as an effective adjuvant or immunopotentiator, activate the immune system and induce various immune responses. Recently, it has also been reported that high dose of CpG ODN can lead to immunosuppression. However, the underlying mechanism of CpG ODN-mediated immune response remains largely unknown in invertebrates. In the present study, the role of ERK in regulating expression levels of anti-lipopolysaccharide factors (ALFs) induced by different doses of CpG ODN 2395 was analyzed in Chinese mitten crab, Eriocheir sinensis. The mRNA expression levels of EsALFs (EsALF1, EsALF2 and EsALF3) and EsERK in haemocytes were observed to increase from 6 h to 48 h post low doses of CpG ODN 2395 (0.5 μg and 2.5 μg) stimulation, while they were suppressed after high dose of CpG ODN 2395 (12.5 μg) injection. Meanwhile, the phosphorylation levels of ERK in haemocytes were significantly promoted after low doses of CpG ODN 2395 injection, and a reduce level of ERK phosphorylation was observed after high dose of CpG ODN 2395 injection. Further investigation showed that the expression levels of EsALFs induced by CpG ODN 2395 were markedly down-regulated after knocking down the expression of EsERK. Similarly, the EsALFs mRNA expression were also inhibited post different doses of CpG ODN 2395 stimulation in PD98059 (ERK inhibitor) injection crabs. These results collectively suggest that ERK is involved in regulating the expression level of EsALFs induced by different dose of CpG ODN 2395 in Chinese mitten crab, which contribute to the understanding of the regulation of CpG ODN involving in immune response in crustaceans.
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Affiliation(s)
- Shu Huang
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Yuhan Ma
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Fengchi Wang
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Jiaming Li
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Zhichao Yang
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Yusheng Jiang
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Xi Chen
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Shengyang Hu
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China
| | - Qilin Yi
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, 11026, China.
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14
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Qian L, Lai X, Gu B, Sun X. An Immune-Related Gene Signature for Predicting Neoadjuvant Chemoradiotherapy Efficacy in Rectal Carcinoma. Front Immunol 2022; 13:784479. [PMID: 35603163 PMCID: PMC9121132 DOI: 10.3389/fimmu.2022.784479] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 04/07/2022] [Indexed: 11/24/2022] Open
Abstract
Background Locally advanced rectal cancers (LARC) show a highly variable response to neoadjuvant chemoradiotherapy (nCRT), and the impact of the tumor immune response in this process is poorly understood. This study aimed to characterize the immune-related gene expression profiles (GEP), pathways, and cell types associated with response or resistance to neoadjuvant chemoradiotherapy. Methods The transcriptomic and clinical data of Rectal carcinoma from the Gene Expression Omnibus database and Immune-related genes (IRGs) from ImmPort were downloaded to identify the differentially expressed immune-related genes (DEIRGs) between responder and non-responder to neoadjuvant chemoradiotherapy. Gene set enrichment analyses were performed to uncover significantly enriched GO terms and KEGG pathways. Immune cell infiltration was estimated from RNA-sequencing data using ImmuCellAI. Afterward, we constructed an immune-related gene-based predictive model (IRGPM) by Support Vector Machine and validated it in an external cohort. Result A 15-gene signature (HLA-DPB1, HLA-DQA1, CXCL9, CXCL10, TAP2, INHBB, BMP2, CD74, IL33, CCL11, CXCL11, DEFB1, HLA-DPA1, CCN3, STAT1) was identified as DEIRGs and found to be significantly associated with nCRT outcomes. Gene set enrichment analyses indicated that the 15 genes play active roles in inflammation-related biological processes. In addition, ImmuCellAI revealed that CD4 naive T cells, Tex, Th1 were significantly up-regulated (p=0.035, p=0.02, p=0.0086, respectively), while Tfh were significantly down-regulated (p=0.015) in responder subgroup. Finally, a novel predictive model was developed by SVM based on DEIRGs with an AUC of 80% (internal validation) and 73.5% (external validation). Conclusion Our team conducted a genomic study of the relationship between gene expression profile and response to nCRT in LARC. Our data suggested that the DEIRGs signature could help predict the efficacy of nCRT. And a DEIRGs‐based SVM model was developed to monitor the outcomes of nCRT in LARC.
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15
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Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Bozkurt S, Pahor N, Fuss C, Schirbel A, Schülein-Völk C, Buchberger A, Calzado Canale MA, Rosenfeldt M, Dikic I, Münch C, Diefenbacher ME. USP28 enables oncogenic transformation of respiratory cells and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K. Mol Oncol 2022; 16:3082-3106. [PMID: 35364627 PMCID: PMC9441007 DOI: 10.1002/1878-0261.13217] [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: 09/07/2021] [Revised: 03/04/2022] [Accepted: 03/29/2022] [Indexed: 11/23/2022] Open
Abstract
Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto‐oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl‐terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto‐oncogenes such as c‐JUN, c‐MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed‐forward loop, driven by increased amounts of oncogenic transcription factors such as c‐MYC and c‐JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small‐molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R‐, BRAFV600E‐ or PI3KH1047R‐driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early‐stage lung tumours, and the observed synergism with current standard‐of‐care inhibitors holds the potential for improved targeting of established tumours.
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Affiliation(s)
- Cristian Prieto-Garcia
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany.,Molecular Signaling Group, Institute of Biochemistry II, Goethe University, Frankfurt, Germany
| | - Oliver Hartmann
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany
| | - Michaela Reissland
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany
| | - Fabian Braun
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany
| | - Süleyman Bozkurt
- Protein quality control, Institute of Biochemistry II, Goethe University, Frankfurt, Germany
| | - Nikolett Pahor
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany
| | - Carmina Fuss
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany.,Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany
| | - Andreas Schirbel
- Department of Nuclear Medicine, University Hospital, University of Wuerzburg, Wuerzburg, Germany
| | | | | | - Marco A Calzado Canale
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.,Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain.,Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Mathias Rosenfeldt
- Mildred Scheel Early Career Center, Wuerzburg, Germany.,Institut für Pathologie, Universitaetsklinikum Wuerzburg
| | - Ivan Dikic
- Molecular Signaling Group, Institute of Biochemistry II, Goethe University, Frankfurt, Germany.,Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Germany
| | - Christian Münch
- Protein quality control, Institute of Biochemistry II, Goethe University, Frankfurt, Germany
| | - Markus E Diefenbacher
- Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany.,Mildred Scheel Early Career Center, Wuerzburg, Germany
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16
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Redweik GAJ, Kogut MH, Arsenault RJ, Lyte M, Mellata M. Reserpine improves Enterobacteriaceae resistance in chicken intestine via neuro-immunometabolic signaling and MEK1/2 activation. Commun Biol 2021; 4:1359. [PMID: 34862463 PMCID: PMC8642538 DOI: 10.1038/s42003-021-02888-3] [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: 05/11/2021] [Accepted: 11/10/2021] [Indexed: 02/07/2023] Open
Abstract
Salmonella enterica persist in the chicken gut by suppressing inflammatory responses via expansion of intestinal regulatory T cells (Tregs). In humans, T cell activation is controlled by neurochemical signaling in Tregs; however, whether similar neuroimmunological signaling occurs in chickens is currently unknown. In this study, we explore the role of the neuroimmunological axis in intestinal Salmonella resistance using the drug reserpine, which disrupts intracellular storage of catecholamines like norepinephrine. Following reserpine treatment, norepinephrine release was increased in both ceca explant media and Tregs. Similarly, Salmonella killing was greater in reserpine-treated explants, and oral reserpine treatment reduced the level of intestinal Salmonella Typhimurium and other Enterobacteriaceae in vivo. These antimicrobial responses were linked to an increase in antimicrobial peptide and IL-2 gene expression as well as a decrease in CTLA-4 gene expression. Globally, reserpine treatment led to phosphorylative changes in epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), and the mitogen-associated protein kinase 2(MEK2). Exogenous norepinephrine treatment alone increased Salmonella resistance, and reserpine-induced antimicrobial responses were blocked using beta-adrenergic receptor inhibitors, suggesting norepinephrine signaling is crucial in this mechanism. Furthermore, EGF treatment reversed reserpine-induced antimicrobial responses, whereas mTOR inhibition increased antimicrobial activities, confirming the roles of metabolic signaling in these responses. Finally, MEK1/2 inhibition suppressed reserpine, norepinephrine, and mTOR-induced antimicrobial responses. Overall, this study demonstrates a central role for MEK1/2 activity in reserpine induced neuro-immunometabolic signaling and subsequent antimicrobial responses in the chicken intestine, providing a means of reducing bacterial colonization in chickens to improve food safety.
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Affiliation(s)
- Graham A. J. Redweik
- grid.34421.300000 0004 1936 7312Department of Food Science and Human Nutrition, Iowa State University, Ames, IA USA ,grid.34421.300000 0004 1936 7312Interdepartmental Microbiology Graduate Program, Iowa State University, Ames, IA USA ,grid.266190.a0000000096214564Present Address: Molecular, Cellular & Developmental Biology, Colorado University-Boulder, Boulder, CO USA
| | - Michael H. Kogut
- grid.512846.c0000 0004 0616 2502Southern Plains Agricultural Research Center, USDA-ARS College Station, TX USA
| | - Ryan J. Arsenault
- grid.33489.350000 0001 0454 4791Department of Animal and Food Sciences, University of Delaware, Newark, DE USA
| | - Mark Lyte
- grid.34421.300000 0004 1936 7312Interdepartmental Microbiology Graduate Program, Iowa State University, Ames, IA USA ,grid.34421.300000 0004 1936 7312Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA USA
| | - Melha Mellata
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA. .,Interdepartmental Microbiology Graduate Program, Iowa State University, Ames, IA, USA.
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17
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Qiao Q, Bai R, Song W, Gao H, Zhang M, Lu J, Hong M, Zhang X, Sun P, Zhang Q, Zhao P. Human α-defensin 5 suppressed colon cancer growth by targeting PI3K pathway. Exp Cell Res 2021; 407:112809. [PMID: 34487729 DOI: 10.1016/j.yexcr.2021.112809] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 08/23/2021] [Accepted: 09/01/2021] [Indexed: 01/06/2023]
Abstract
Defensins are highly conserved antimicrobial peptides, which ubiquitously expressed in different species. In addition to the functions in host defense, their aberrant expression have also been documented in cancerous tissue including breast cancer, lung caner and renal carcinoma etc. Whereas, roles of Defensin Alpha 5 (DEFA5) in colon cancer has not been explored. Bioinformatic analysis was used to study the expression of DEFA5 and its correlation with clinical outcomes; Western blot, qPCR, Co-immunoprecipitation, xenograft models were used to the study the molecular mechanism. Decreased expression of DEFA5 at protein level was observed in colon tissues. Colon cancer cell lines proliferation and colony formation capacity were significantly suppressed by DEFA5 overexpression. Moreover, in vivo tumor growth in nude mice was also suppressed by DEFA5 overexpression, suggesting a tumor suppressor role of DEFA5 in colon cancer. Mechanistically, DEFA5 directly binds to the subunits of PI3K complex, thus attenuates the downstream signaling transduction, leads to delayed cell growth and metastasis. Collectively, we concluded that DEFA5 showed an inhibitory effect in colon cancer cell growth and may serve as a potential tumor suppressor in colon cancer.
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Affiliation(s)
- Qiao Qiao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Inner Mongolia Medical University, No.1, Tongdao North Street, Huimin District, Hohhot, 010050, PR China.
| | - Ruixia Bai
- Department of Clinical Laboratory, Inner Mongolia People's Hospital, Zhaowuda Road, Hohhot, 010018, PR China.
| | - Wanying Song
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Haining Gao
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Minyu Zhang
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Jingkun Lu
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Mei Hong
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Xuan Zhang
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Peng Sun
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
| | - Qian Zhang
- Pediatric Intensive Care Unit, Affiliated Hospital of Inner Mongolia Medical University, 1#, Xinhua Street, Hohhot, 010050, PR China.
| | - Pengwei Zhao
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Xinhua Street, Hohhot, 010059, PR China.
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18
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Zhang QY, Yan ZB, Meng YM, Hong XY, Shao G, Ma JJ, Cheng XR, Liu J, Kang J, Fu CY. Antimicrobial peptides: mechanism of action, activity and clinical potential. Mil Med Res 2021; 8:48. [PMID: 34496967 PMCID: PMC8425997 DOI: 10.1186/s40779-021-00343-2] [Citation(s) in RCA: 322] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/30/2021] [Indexed: 12/15/2022] Open
Abstract
The management of bacterial infections is becoming a major clinical challenge due to the rapid evolution of antibiotic resistant bacteria. As an excellent candidate to overcome antibiotic resistance, antimicrobial peptides (AMPs) that are produced from the synthetic and natural sources demonstrate a broad-spectrum antimicrobial activity with the high specificity and low toxicity. These peptides possess distinctive structures and functions by employing sophisticated mechanisms of action. This comprehensive review provides a broad overview of AMPs from the origin, structural characteristics, mechanisms of action, biological activities to clinical applications. We finally discuss the strategies to optimize and develop AMP-based treatment as the potential antimicrobial and anticancer therapeutics.
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Affiliation(s)
- Qi-Yu Zhang
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China
| | - Zhi-Bin Yan
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China
| | - Yue-Ming Meng
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China
| | - Xiang-Yu Hong
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China
| | - Gang Shao
- Department of Oncology, The 903rd Hospital of PLA, Hangzhou, 310013, Zhejiang, China
| | - Jun-Jie Ma
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China
| | - Xu-Rui Cheng
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China
| | - Jun Liu
- Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd. South, San Francisco, CA, 94158, USA
| | - Jian Kang
- Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Cai-Yun Fu
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 928, Street 2, Xiasha Higher Education Zone, Hangzhou, 310018, Zhejiang, China.
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19
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Kato T, Matsuhashi N, Tomita H, Takahashi T, Iwata Y, Fukada M, Yasufuku I, Suetsugu T, Imai T, Mori R, Imai H, Tanaka Y, Okumura N, Hara A, Yoshida K. MYC Up-regulation Is a Useful Biomarker for Preoperative Neoadjuvant Chemotherapy Combined With Anti-EGFR in Liver Metastasis from Colorectal Cancer. In Vivo 2021; 35:203-213. [PMID: 33402467 DOI: 10.21873/invivo.12249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 10/02/2020] [Accepted: 10/15/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM At present, there are no biomarkers to predict the effects of molecular targeted drugs in patients with CRC with liver metastasis. Thus, we performed this study to explore potential biomarkers for these patients. MATERIALS AND METHODS We obtained cancer tissue specimens from liver metastasis-bearing CRC patients who received the following preoperative neoadjuvant chemotherapies with molecular targeted drugs: i) no therapy (n=3), ii) 5-FU+oxaliplatin+anti-EGFR (n=3), iii) and 5-FU+oxaliplatin+anti-VEGF (n=3). RESULTS We investigated the RNA expression of 84 genes related to cancer drug resistance using an RT-PCR array. The MYC gene was the only gene that was significantly up-regulated in CRC tissue specimens from anti-EGFR group in comparison to the anti-VEGF group. CONCLUSION MYC up-regulation in the primary CRC tissues may be a potentially useful biomarker for selecting anti-EGFR combination therapy in neoadjuvant chemotherapy for CRC with liver metastasis.
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Affiliation(s)
- Takazumi Kato
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan;
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshinori Iwata
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahiro Fukada
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Itaru Yasufuku
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomonari Suetsugu
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takeharu Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryutaro Mori
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisashi Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Naoki Okumura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
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20
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Genomic Study of Chinese Quadruple-negative GISTs Using Next-generation Sequencing Technology. Appl Immunohistochem Mol Morphol 2020; 29:34-41. [PMID: 33002893 DOI: 10.1097/pai.0000000000000842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE Approximately 10% of gastrointestinal stromal tumors (GISTs) are devoid of KIT, PDGFRA (platelet-derived growth factor-alpha), BRAF, and SDH alterations. The aim of this study was to characterize molecular drivers in Chinese patients with quadruple-negative GISTs. PATIENTS AND METHODS In 1022 Chinese patients with GIST, mutations of KIT and PDGFRA were analyzed by direct sequencing. Of these mutations, 142 KIT/PDGFRA wild-type (WT) GISTs were detected, and succinate dehydrogenase (SDH) deficiency was determined using immunohistochemistry analysis of succinate dehydrogenase B. In 78 KIT/PDGFRA/SDH cases, we performed targeted 425 cancer-related gene analysis using next-generation sequencing. The correlation between molecular findings and clinicopathologic features was also analyzed. RESULTS We defined 72 quadruple-negative GISTs from enrollments. They featured nongastric localization with histologic characteristics of spindle cells and male predilection. An overall 27.78% (20/72) of quadruple-negative tumors carried TP53, and 25.00% (18/72) carried RB1 mutations, which were frequently associated with high mitotic index and large size. TP53 analyses demonstrated coexistence with mutational activation of other oncogenes in 12 of 20 cases. A total of 18 RB1-mutated cases were independent of TP53. Further, no tumors carried NF1 and BRAF mutations. CONCLUSIONS We report the genomic analysis of Chinese quadruple-negative patients. These databases may help advance our understanding of quadruple-negative GISTs' progression. Next-generation sequencing from GISTs is feasible to provide relevant data for guiding individualized therapy.
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21
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Liao M, Zeng F, Li Y, Gao Q, Yin M, Deng G, Chen X. A novel predictive model incorporating immune-related gene signatures for overall survival in melanoma patients. Sci Rep 2020; 10:12462. [PMID: 32719391 PMCID: PMC7385638 DOI: 10.1038/s41598-020-69330-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/09/2020] [Indexed: 12/15/2022] Open
Abstract
Melanoma is the most invasive type of skin cancer, in which the immune system plays a vital role. In this study, we aimed to establish a prognostic prediction nomogram for melanoma patients that incorporates immune-related genes (IRGs). Ninety-seven differentially expressed IRGs between melanoma and normal skin were screened using gene expression omnibus database (GEO). Among these IRGs, a two-gene signature consisting of CCL8 and DEFB1 was found to be closely associated with patient prognosis using the cancer genome atlas (TCGA) database. Survival analysis verified that the IRGs score based on the signature gene expressions efficiently distinguished between high- and low-risk patients, and was identified to be an independent prognostic factor. A nomogram integrating the IRGs score, age and TNM stage was established to predict individual prognosis for melanoma. The prognostic performance was validated by the TCGA/GEO-based concordance indices and calibration plots. The area under the curve demonstrated that the nomogram was superior than the conventional staging system, which was confirmed by the decision curve analysis. Overall, we developed and validated a nomogram for prognosis prediction in melanoma based on IRGs signatures and clinical parameters, which could be valuable for decision making in the clinic.
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Affiliation(s)
- Mengting Liao
- Health Management Center, Xiangya Hospital, Central South University, Changsha, 410008, China.,Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China
| | - Furong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China
| | - Yao Li
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China
| | - Qian Gao
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China
| | - Mingzhu Yin
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China.,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China. .,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China. .,Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, China. .,Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, China.
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22
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Lee YJ, Lee EY, Choi BH, Jang H, Myung JK, You HJ. The Role of Nuclear Receptor Subfamily 1 Group H Member 4 (NR1H4) in Colon Cancer Cell Survival through the Regulation of c-Myc Stability. Mol Cells 2020; 43:459-468. [PMID: 32299194 PMCID: PMC7264475 DOI: 10.14348/molcells.2020.0041] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 02/06/2023] Open
Abstract
Nuclear receptor subfamily group H member 4 (NR1H4), also known as farnesoid X receptor, has been implicated in several cellular processes in the liver and intestine. Preclinical and clinical studies have suggested a role of NR1H4 in colon cancer development; however, how NR1H4 regulates colon cancer cell growth and survival remains unclear. We generated NR1H4 knockout (KO) colon cancer cells using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (CAS9) technology and explored the effects of NR1H4 KO in colon cancer cell proliferation, survival, and apoptosis. Interestingly, NR1H4 KO cells showed impaired cell proliferation, reduced colony formation, and increased apoptotic cell death compared to control colon cancer cells. We identified MYC as an important mediator of the signaling pathway alterations induced by NR1H4 KO. NR1H4 silencing in colon cancer cells resulted in reduced MYC protein levels, while NR1H4 activation using an NR1H4 ligand, chenodeoxycholic acid, resulted in time- and dose-dependent MYC induction. Moreover, NR1H4 KO enhanced the anti-cancer effects of doxorubicin and cisplatin, supporting the role of MYC in the enhanced apoptosis observed in NR1H4 KO cells. Taken together, our findings suggest that modulating NR1H4 activity in colon cancer cells might be a promising alternative approach to treat cancer using MYC-targeting agents.
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Affiliation(s)
- Yun Jeong Lee
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 0408, Korea
- These authors contributed equally to this work
| | - Eun-Young Lee
- Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 8541, Korea
- These authors contributed equally to this work
| | - Bo Hee Choi
- Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408, Korea
| | - Hyonchol Jang
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 0408, Korea
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 1008, Korea
| | - Jae-Kyung Myung
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 0408, Korea
| | - Hye Jin You
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 0408, Korea
- Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408, Korea
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23
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Abstract
Defensins are a major family of host defense peptides expressed predominantly in neutrophils and epithelial cells. Their broad antimicrobial activities and multifaceted immunomodulatory functions have been extensively studied, cementing their role in innate immunity as a core host-protective component against bacterial, viral and fungal infections. More recent studies, however, paint defensins in a bad light such that they are "alleged" to promote viral and bacterial infections in certain biological settings. This mini review summarizes the latest findings on the potential pathogenic properties of defensins against the backdrop of their protective roles in antiviral and antibacterial immunity. Further, a succinct description of both tumor-proliferative and -suppressive activities of defensins is also given to highlight their functional and mechanistic complexity in antitumor immunity. We posit that given an enabling environment defensins, widely heralded as the "Swiss army knife," can function as a "double-edged sword" in host immunity.
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Affiliation(s)
- Dan Xu
- Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Sciences and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Wuyuan Lu
- Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States
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24
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Prasad SV, Fiedoruk K, Daniluk T, Piktel E, Bucki R. Expression and Function of Host Defense Peptides at Inflammation Sites. Int J Mol Sci 2019; 21:ijms21010104. [PMID: 31877866 PMCID: PMC6982121 DOI: 10.3390/ijms21010104] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/09/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023] Open
Abstract
There is a growing interest in the complex role of host defense peptides (HDPs) in the pathophysiology of several immune-mediated inflammatory diseases. The physicochemical properties and selective interaction of HDPs with various receptors define their immunomodulatory effects. However, it is quite challenging to understand their function because some HDPs play opposing pro-inflammatory and anti-inflammatory roles, depending on their expression level within the site of inflammation. While it is known that HDPs maintain constitutive host protection against invading microorganisms, the inducible nature of HDPs in various cells and tissues is an important aspect of the molecular events of inflammation. This review outlines the biological functions and emerging roles of HDPs in different inflammatory conditions. We further discuss the current data on the clinical relevance of impaired HDPs expression in inflammation and selected diseases.
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25
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Ghosh SK, McCormick TS, Weinberg A. Human Beta Defensins and Cancer: Contradictions and Common Ground. Front Oncol 2019; 9:341. [PMID: 31131258 PMCID: PMC6509205 DOI: 10.3389/fonc.2019.00341] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 04/12/2019] [Indexed: 12/31/2022] Open
Abstract
Human beta-defensins (hBDs, −1, 2, 3) are a family of epithelial cell derived antimicrobial peptides (AMPs) that protect mucosal membranes from microbial challenges. In addition to their antimicrobial activities, they possess other functions; e.g., cell activation, proliferation, regulation of cytokine/chemokine production, migration, differentiation, angiogenesis, and wound healing processes. It has also become apparent that defensin levels change with the development of neoplasia. However, inconsistent observations published by various laboratories make it difficult to reach a consensus as to the direction of the dysregulation and role the hBDs may play in various cancers. This is particularly evident in studies focusing on oral squamous cell carcinoma (OSCC). By segregating each hBD by cancer type, interrogating methodologies, and scrutinizing the subject cohorts used in the studies, we have endeavored to identify the “take home message” for each one of the three hBDs. We discovered that (1) consensus-driven findings indicate that hBD-1 and−2 are down- while hBD-3 is up-regulated in OSCC; (2) hBD dysregulation is cancer-type specific; (3) the inhibition/activation effect an hBD has on cancer cell lines is related to the direction of the hBD dysregulation (up or down) in the cancer from which the cell lines derive. Therefore, studies addressing hBD dysregulation in various cancers are not generalizable and comparisons should be avoided. Systematic delineation of the fate and role of the hBDs in a specific cancer type may lead to innovative ways to use defensins as prospective biomarkers for diagnostic/prognostic purposes and/or in novel therapeutic modalities.
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Affiliation(s)
- Santosh K Ghosh
- Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Thomas S McCormick
- Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States.,Dermatology, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Aaron Weinberg
- Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, United States
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