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Abedi Dorcheh F, Balmeh N, Hejazi SH, Allahyari Fard N. Investigation of the mutated antimicrobial peptides to inhibit ACE2, TMPRSS2 and GRP78 receptors of SARS-CoV-2 and angiotensin II type 1 receptor (AT1R) as well as controlling COVID-19 disease. J Biomol Struct Dyn 2025; 43:1641-1664. [PMID: 38109185 DOI: 10.1080/07391102.2023.2292307] [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: 12/08/2022] [Accepted: 11/23/2023] [Indexed: 12/19/2023]
Abstract
SARS-CoV-2 is a global problem nowadays. Based on studies, some human receptors are involved in binding to SARS-CoV-2. Thus, the inhibition of these receptors can be effective in the treatment of Covid-19. Because of the proven benefits of antimicrobial peptides (AMPs) and the side effects of chemical drugs, they can be known as an alternative to recent medicines. RCSB PDB to obtain PDB id, StraPep and PhytAMP to acquire Bio-AMPs information and 3-D structure, and AlgPred, Toxinpred, TargetAntiAngio, IL-4pred, IL-6pred, ACPred and Hemopred databases were used to find the best score peptide features. HADDOCK 2.2 was used for molecular docking analysis, and UCSF Chimera software version 1.15, SWISS-MODEL and BIOVIA Discovery Studio Visualizer4.5 were used for mutation and structure modeling. Furthermore, MD simulation results were achieved from GROMACS 4.6.5. Based on the obtained results, the Moricin peptide was found to have the best affinity for ACE2. Moreover, Bacteriocin leucocin-A had the highest affinity for GRP78, Cathelicidin-6 had the best affinity for AT1R, and Bacteriocin PlnK had the best binding affinity for TMPRSS2. Additionally, Bacteriocin glycocin F, Bacteriocin lactococcin-G subunit beta and Cathelicidin-6 peptides were the most common compounds among the four receptors. However, these peptides also have some side effects. Consequently, the mutation eliminated the side effects, and MD simulation results indicated that the mutation proved the result of the docking analysis. The effect of AMPs on ACE2, GRP78, TMPRSS2 and AT1R receptors can be a novel treatment for Covid-19.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Fatemeh Abedi Dorcheh
- Department of Biotechnology, School of Bioscience and Biotechnology, Shahid Ashrafi Esfahani University of Isfahan, Sepahan Shahr, Iran
| | - Negar Balmeh
- Skin Diseases and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Hossein Hejazi
- Skin Diseases and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najaf Allahyari Fard
- Department of Systems Biotechnology, National Institute of Genetic Engineering & Biotechnology (NIGEB), Tehran, Iran
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Mancarella C, Morrione A, Scotlandi K. Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches. Int J Mol Sci 2024; 25:5915. [PMID: 38892104 PMCID: PMC11172729 DOI: 10.3390/ijms25115915] [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: 05/09/2024] [Revised: 05/24/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.
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Affiliation(s)
- Caterina Mancarella
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Andrea Morrione
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
| | - Katia Scotlandi
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
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Luo L, Zeng Z, Li T, Liu X, Cui Y, Tao Y, Li Y, Chen Y. TET2 stabilized by deubiquitinase USP21 ameliorates cigarette smoke-induced apoptosis in airway epithelial cells. iScience 2024; 27:109252. [PMID: 38439981 PMCID: PMC10910280 DOI: 10.1016/j.isci.2024.109252] [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: 05/21/2023] [Revised: 12/29/2023] [Accepted: 02/13/2024] [Indexed: 03/06/2024] Open
Abstract
DNA demethylase TET2 was related with lung function. However, the precise role of TET2 in cigarette smoke (CS)-induced apoptosis of airway epithelium cells, and the mechanisms involved, have yet to be elucidated. Here, we showed that CS decreased TET2 protein levels but had no significant effect on its mRNA levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients and CS-induced COPD mice model and even in airway epithelial cell lines. TET2 could inhibit CS-induced apoptosis of airway epithelial cell in vivo and in vitro. Moreover, we identified ubiquitin-specific protease 21 (USP21) as a deubiquitinase of TET2 in airway epithelial cells. USP21 interacted with TET2 and inhibited CSE-induced TET2 degradation. USP21 downregulated decreased TET2 abundance and further reduced the anti-apoptosis effect of TET2. Thus, we draw a conclusion that the USP21/TET2 axis is involved in CS-induced apoptosis of airway epithelial cells.
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Affiliation(s)
- Lijuan Luo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Diagnosis and Treatment center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan 410011, China
| | - Zihang Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Diagnosis and Treatment center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan 410011, China
| | - Tiao Li
- Department of Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xiangming Liu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Diagnosis and Treatment center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan 410011, China
| | - Yanan Cui
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Diagnosis and Treatment center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan 410011, China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yi Li
- Department of Infectious Disease Department, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Diagnosis and Treatment center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, Hunan 410011, China
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Sun W, Song J, Wu Q, Deng L, Zhang T, Zhang L, Hua Y, Cao Y, Hou L. Regulator of Ribosome Synthesis 1 (RRS1) Stabilizes GRP78 and Promotes Breast Cancer Progression. Molecules 2024; 29:1051. [PMID: 38474562 DOI: 10.3390/molecules29051051] [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: 02/03/2024] [Revised: 02/24/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Regulator of ribosome synthesis 1 (RRS1), a crucial regulatory factor in ribosome biogenesis, exerts a remarkable impact on the progression of breast cancer (BC). However, the exact mechanisms and pathways have not yet been fully elucidated. To investigate the impact of RRS1 on BC growth and metastasis, along with its underlying mechanisms. We discovered that RRS1 is overexpressed in BC tissues and cell lines. This study aims to regulate the level of RRS1 through lentiviral transfection technology to explore its potential function in BC cells. Knockdown of RRS1 resulted in the inhibition of cell proliferation, invasion, and migration, whereas overexpression had the opposite effects. We firstly identified the interaction between RRS1 and Glucose-Regulated Protein 78 (GRP78) using Co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis, providing evidences of co-localization and positive regulation between RRS1 and GRP78. We observed that RRS1 inhibited the degradation of GRP78 through the ubiquitin-proteasome pathway, resulting in the stabilization of GRP78. In addition, our findings suggested that RRS1 promoted BC progression by activating the GRP78-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. In conclusion, this newly discovered RRS1/GRP78 signaling axis provides a molecular and theoretical basis for further exploring the mechanisms of breast cancer invasion and metastasis.
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Affiliation(s)
- Wenjing Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao 266011, China
| | - Junying Song
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao 266011, China
| | - Qinglan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao 266011, China
| | - Lin Deng
- Wanzhou District Center for Disease Control, Chongqing 404100, China
| | - Tenglong Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao 266011, China
| | - Li Zhang
- Experimental Center for Undergraduates of Pharmacy, School of Pharmacy, Qingdao University, Qingdao 266011, China
| | - Yanan Hua
- Chongqing Key Laboratory of Sichuan-Chongqing Co-Construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yi Cao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao 266011, China
| | - Lin Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Qingdao University, Qingdao 266011, China
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Bai J, Li Y, Cai L. Clinical implications of forkhead box M1, cyclooxygenase-2 , and glucose-regulated protein 78 in breast invasive ductal carcinoma. World J Clin Cases 2023; 11:7284-7293. [PMID: 37969442 PMCID: PMC10643068 DOI: 10.12998/wjcc.v11.i30.7284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/11/2023] [Accepted: 09/18/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Breast infiltrating ductal carcinoma (BIDC) represents the largest heterotypic tumor group, and an in-depth understanding of the pathogenesis of BIDC is key to improving its prognosis. AIM To analyze the expression profiles and clinical implications of forkhead box M1 (FOXM1), cyclooxygenase-2 (COX-2), and glucose-regulated protein 78 (GRP78) in BIDC. METHODS A total of 65 BIDC patients and 70 healthy controls who presented to our hospital between August 2019 and May 2021 were selected for analysis. The peripheral blood FOXM1, COX-2, and GRP78 levels in both groups were measured and the association between their expression profiles in BIDC was examined. Additionally, we investigated the diagnostic value of FOXM1, COX-2, and GRP78 in patients with BIDC and their correlations with clinicopathological features. Furthermore, BIDC patients were followed for 1 year to identify factors influencing patient prognosis. RESULTS The levels of FOXM1, COX-2, and GRP78 were significantly higher in BIDC patients compared to healthy controls (P < 0.05), and a positive correlation was observed among them (P < 0.05). Receiver operating characteristic analysis demonstrated that FOXM1, COX-2, and GRP78 had excellent diagnostic value in predicting the occurrence of BIDC (P < 0.05). Subsequently, we found significant differences in FOXM1, COX-2, and GRP78 levels among patients with different histological grades and metastasis statuses (with vs without) (P < 0.05). Cox analysis revealed that FOXM1, COX-2, GRP78, increased histological grade, and the presence of tumor metastasis were independent risk factors for prognostic death in BIDC (P < 0.001). CONCLUSION FOXM1, COX-2, and GRP78 exhibit abnormally high expression in BIDC, promoting malignant tumor development and closely correlating with prognosis. These findings hold significant research implications for the future diagnosis and treatment of BIDC.
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Affiliation(s)
- Jie Bai
- Department of Clinical Laboratory, Joint Logistics Support Unit 940 Hospital, Lanzhou 730030, Gansu Province, China
| | - Ying Li
- Department of Breast Surgery, The Fourth Hospital of Shijiazhuang, Shijiazhuang 050032, Hebei Province, China
| | - Li Cai
- Department of Pathology, Huai’an Maternal and Child Health Care Center, Huai’an 223002, Jiangsu Province, China
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Liu Y, Shen S, Yan Z, Yan L, Ding H, Wang A, Xu Q, Sun L, Yuan Y. Expression characteristics and their functional role of IGFBP gene family in pan-cancer. BMC Cancer 2023; 23:371. [PMID: 37088808 PMCID: PMC10124011 DOI: 10.1186/s12885-023-10832-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 04/11/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Insulin-like growth factor binding proteins (IGFBPs) are critical regulators of the biological activities of insulin-like growth factors. The IGFBP family plays diverse roles in different types of cancer, which we still lack comprehensive and pleiotropic understandings so far. METHODS Multi-source and multi-dimensional data, extracted from The Cancer Genome Atlas (TCGA), Oncomine, Cancer Cell Line Encyclopedia (CCLE), and the Human Protein Atlas (HPA) was used for bioinformatics analysis by R language. Immunohistochemistry and qRT-PCR were performed to validate the results of the database analysis results. Bibliometrics and literature review were used for summarizing the research progress of IGFBPs in the field of tumor. RESULTS The members of IGFBP gene family are differentially expressed in various cancer types. IGFBPs expression can affect prognosis of different cancers. The expression of IGFBPs expression is associated with multiple signal transduction pathways. The expression of IGFBPs is significantly correlated with tumor mutational burden, microsatellite instability, tumor stemness and tumor immune microenvironment. The qRT-PCR experiments verified the lower expression of IGFBP2 and IGFBP6 in gastric cancer and the lower expression of IGFBP6 in colorectal cancer. Immunohistochemistry validated a marked downregulation of IGFBP2 protein in gastric cancer tissues. The keywords co-occurrence analysis of IGFBP related publications in cancer showed relative research have been more concentrating on the potential of IGFBPs as tumor diagnostic and prognostic markers and developing cancer therapies. CONCLUSIONS These findings provide frontier trend of IGFBPs related research and new clues for identifying novel therapeutic targets for various cancers.
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Affiliation(s)
- Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Shixuan Shen
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Lirong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Hanxi Ding
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ang Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China.
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Yan CY, Zhao ML, Wei YN, Zhao XH. Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities. Mol Ther Oncolytics 2023; 28:212-229. [PMID: 36860815 PMCID: PMC9969274 DOI: 10.1016/j.omto.2023.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.
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Affiliation(s)
- Chun-Yan Yan
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Meng-Lu Zhao
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Ya-Nan Wei
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Xi-He Zhao
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
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Du J, Tao Q, Liu Y, Huang Z, Jin H, Lin W, Huang X, Zeng J, Zhao Y, Liu L, Xu Q, Han X, Chen L, Chen XL, Wen Y. Assessment of the targeted effect of Sijunzi decoction on the colorectal cancer microenvironment via the ESTIMATE algorithm. PLoS One 2022; 17:e0264720. [PMID: 35303006 PMCID: PMC8932555 DOI: 10.1371/journal.pone.0264720] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 02/15/2022] [Indexed: 11/18/2022] Open
Abstract
Objective Sijunzi decoction (SJZD) was used to treat patients with colorectal cancer (CRC) as an adjuvant method. The aim of the study was to investigate the therapeutic targets and pathways of SJZD towards the tumor microenvironment of CRC via network pharmacology and the ESTIMATE algorithm. Methods The ESTIMATE algorithm was used to calculate immune and stromal scores to predict the level of infiltrating immune and stromal cells. The active targets of SJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and UniProt database. The core targets were obtained by matching the differentially expressed genes in CRC tissues and the targets of SJZD. Then, GO, KEGG and validation in TCGA were carried out. Results According to the ESTIMATE algorithm and survival analysis, the median survival time of the low stromal score group was significantly higher than that of the high stromal score group (P = 0.018), while the patients showed no significant difference of OS between different immune groups (P = 0.19). A total of 929 genes were upregulated and 115 genes were downregulated between the stromal score groups (|logFC| > 2, adjusted P < 0.05); 357 genes were upregulated and 472 genes were downregulated between the immune score groups. The component-target network included 139 active components and 52 related targets. The core targets were HSPB1, SPP1, IGFBP3, and TGFB1, which were significantly associated with poor prognosis in TCGA validation. GO terms included the response to hypoxia, the extracellular space, protein binding and the TNF signaling pathway. Immunoreaction was the main enriched pathway identified by KEGG analysis. Conclusion The core genes (HSPB1, SPP1, IGFBP3 and TGFB1) affected CRC development and prognosis by regulating hypoxia, protein binding and epithelial-mesenchymal transition in the extracellular matrix.
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Affiliation(s)
- Jiaxin Du
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Quyuan Tao
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Liu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhanming Huang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - He Jin
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenjia Lin
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinying Huang
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingyan Zeng
- Shenzhen Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongchang Zhao
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lingyu Liu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qian Xu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue Han
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lixia Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin-lin Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
- * E-mail: (XC); (YW)
| | - Yi Wen
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- * E-mail: (XC); (YW)
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Identification of Aging-Related Genes Associated with Prognostic Value and Immune Microenvironment Characteristics in Diffuse Large B-Cell Lymphoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3334522. [PMID: 35069971 PMCID: PMC8777392 DOI: 10.1155/2022/3334522] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/11/2021] [Accepted: 12/24/2021] [Indexed: 12/11/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a complex invasive tumour that occurs mainly among the elderly. Therefore, we analysed the relationship between ageing-related genes (AG) and DLBCL prognosis. Datasets related to DLBCL and human AGs were downloaded and screened from the Gene Expression Omnibus (GEO) database and HAGR website, respectively. LASSO and Cox regression were used to analyse AGs in the dataset and construct an AG predictive model related to DLBCL prognosis. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment were used to analyse the function of the AG predictive model. The immune microenvironment and immune cell infiltration in DLBCL and their relationship with the AG prediction model were also analysed. After the analysis, 118 AGs were identified as genes related to DLBCL prognosis. Using the LASSO and Cox regression analyses, 9 AGs (PLAU, IL7R, MYC, S100B, IGFBP3, NR3C1, PTK2, TBP, and CLOCK) were used to construct an AG prognostic model. In the training and verification sets, this model exhibited excellent predictive ability for the prognosis of patients with DLBCL who have different clinical characteristics. Further analysis revealed that the high- and low-risk groups of the AG prognostic model were significantly correlated with immune cell infiltration and tumour microenvironment in DLBCL. Functional enrichment analysis also showed that the genes in the AG model were associated with immune-related functions and pathways. In conclusion, we constructed an AG model with a strong predictive function in DLBCL, with the ability to predict the prognosis of patients with different clinical features. This model provides new ideas and potential therapeutic targets for the study of the pathogenesis of DLBCL.
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Qin Q, Fang DL, Zhou W, Meng Y, Wei J. Classification and immune invasion analysis of breast cancer based on m6A genes. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1418. [PMID: 34733970 PMCID: PMC8506726 DOI: 10.21037/atm-21-3404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/11/2021] [Indexed: 12/16/2022]
Abstract
Background Breast cancer (BRCA) shows genetic, epigenetic, and phenotypic diversity. Methylation of N6-methyladenosine (m6A) affects the occurrence, development, and therapeutic efficacy of BRCA. However, the characteristics and prognostic value of m6A in BRCA remain unclear. We aimed to classify and construct a scoring system for the m6A regulatory gene in BRCA, and to explore its potential mechanisms. Methods In this study, we selected 23 m6A regulatory genes and analyzed their genetic variation in BRCA, including copy number variation (CNV) data, expression differences, mutations, gene types, and correlations between genes. Survival curves were drawn by the Kaplan-Meier method, and a log-rank P<0.05 was considered statistically significant. The partitioning around medoids (PAM) algorithm was used for molecular subtype analysis of m6A, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to quantify the relative infiltration levels of various immune cell subgroups, and a scoring system was built based on principal component analysis (PCA). Results In BRCA, m6A regulatory gene mutation frequency is not high, while that of CNV mutation is high, which is related to gene expression and closely related to prognosis. In this study, we identified 3 different m6A subtypes, which are closely related to the level of immune cell infiltration. We further constructed an m6A score system, in which lower scores were correlated with low tumor mutation burden (TMB), later clinical staging, programmed cell death 1 ligand 1 (PD-L1) expression, and triple-negative breast cancer (TNBC). Conclusions This study highlights the diversity and complexity of the role of m6A in BRCA. The classification of BRCA based on the m6A regulatory gene can help us understand the characteristics of BRCA and help develop individualized immunotherapy regimens.
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Affiliation(s)
- Qiang Qin
- Department of Hematology, Baise People's Hospital, Baise, China.,Department of Breast and Thyroid Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Da Lang Fang
- Department of Breast and Thyroid Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Weijie Zhou
- Clinical Laboratory, Baise People's Hospital, Baise, China
| | - Yuhua Meng
- Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan, China
| | - Jie Wei
- Department of Hematology, Baise People's Hospital, Baise, China
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Rai R, Kennedy AL, Isingizwe ZR, Javadian P, Benbrook DM. Similarities and Differences of Hsp70, hsc70, Grp78 and Mortalin as Cancer Biomarkers and Drug Targets. Cells 2021; 10:cells10112996. [PMID: 34831218 PMCID: PMC8616428 DOI: 10.3390/cells10112996] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/17/2022] Open
Abstract
Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, hsc70, Grp78 and Mortalin members of the HSP70 family encoded by HSPA1, HSPA8, HSPA5 and HSPA9 genes, respectively. Methods: Literature reviews were conducted using HSPA1, HSPA5, HSPA8 and HSPA9 gene or protein names or synonyms combined with biological or cancer-relevant terms. Ingenuity Pathway Analysis was used to identify and compare profiles of proteins that directly bind individual chaperones and their associated pathways. TCGA data was probed to identify associations of hsc70 with cancer patient survival. ClinicalTrials.gov was used to identify HSP70 family studies. Results: The chaperones have similar protein folding functions. Their different cellular effects are determined by co-chaperones and client proteins combined with their intra- and extra-cellular localizations. Their upregulation is associated with worse patient prognosis in multiple cancers and can stimulate tumor immune responses or drug resistance. Their inhibition selectively kills cancer over healthy cells. Conclusions: Differences in Hsp70, hsc70, Grp78 and mortalin provide opportunities to calibrate HSP70 inhibitors for individual cancers and combination therapies.
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Affiliation(s)
- Rajani Rai
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (P.J.)
| | - Amy L. Kennedy
- Pathology Department, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Zitha Redempta Isingizwe
- Pharmaceutical Sciences Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Pouya Javadian
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (P.J.)
| | - Doris Mangiaracina Benbrook
- Gynecologic Oncology Section, Obstetrics and Gynecology Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (P.J.)
- Pathology Department, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
- Pharmaceutical Sciences Department, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
- Correspondence: ; Tel.: +1-405-271-5523
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Insulin-Like Growth Factor Binding Protein-3 Exerts Its Anti-Metastatic Effect in Aerodigestive Tract Cancers by Disrupting the Protein Stability of Vimentin. Cancers (Basel) 2021; 13:cancers13051041. [PMID: 33801272 PMCID: PMC7958122 DOI: 10.3390/cancers13051041] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/29/2022] Open
Abstract
Simple Summary Local invasion and distal metastasis are the main causes of cancer-related death and the poor prognosis of patients with aerodigestive tract cancers. Therefore, understanding the biology of invasion and metastasis is important for the development of effective therapeutic strategies. The present study shows that insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the migration and invasion of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells in vitro and the development of metastasized tumors in vivo. Mechanistic studies suggest vimentin as a cellular target for the antimetastatic effect of IGFBP-3. These results contribute to a better understanding on the regulation of metastasis of cancer cells, providing the rationale to utilize IGFBP-3 as an effective therapeutic strategy targeting migration and metastasis of aerodigestive tract cancers. Abstract The proapoptotic, antiangiogenic, and antimetastatic activities of insulin-like growth factor binding protein-3 (IGFBP-3) through IGF-dependent or -independent mechanisms have been suggested in various types of human cancers. However, a mechanistic explanation of and downstream targets involved in the antimetastatic effect of IGFBP-3 is still lacking. In this study, by applying various in vitro and in vivo models, we show that IGFBP-3 suppresses migration and invasion of human head and neck squamous carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cells. Silencing IGFBP-3 expression elevated the migration and invasion of NSCLC and HNSCC cells in vitro and their local invasion and metastasis in vivo, whereas overexpression of IGFBP-3 decreased such prometastatic changes. Local invasion of 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC tumors was consistently significantly potentiated in Igfbp3 knockout mice compared with that in wild-type mice. Mechanistically, IGFBP-3 disrupted the protein stability of vimentin via direct binding and promoting its association with the E3 ligase FBXL14, causing proteasomal degradation. The C-terminal domain of IGFBP-3 and the head domain of vimentin are essential for their interaction. These results provide a molecular framework for IGFBP-3′s IGF-independent antimetastatic and antitumor activities.
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