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Wu Y, Ge Y, Gan J, Jin Y, Cui Y, Zheng X, Yao X, Sun G. Mechanism of action for Troxerutin targeting the sialylation-related gene EGLN3 for the treatment of LUAD. Sci Rep 2025; 15:9298. [PMID: 40102484 PMCID: PMC11920082 DOI: 10.1038/s41598-025-92028-2] [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: 10/08/2024] [Accepted: 02/25/2025] [Indexed: 03/20/2025] Open
Abstract
Studies have demonstrated that sialylation changes play a vital part in lung adenocarcinoma (LUAD), yet the specific mechanism is uncertain. Hence, in the present research, we screened sialylation-related biomarkers in LUAD using the bioinformatic strategy, predicted the drugs and performed relevant experiments to explore their role in regulating LUAD. The TCGA-LUAD, GSE31210, and GSE13213 datasets were combined to form LUAD ensemble. The sialylation-related genes (SRGs) linked with LUAD prognosis were determined by univariate Cox regression analysis, and their expressions and mutations in LUAD were analyzed in GSCA database. Then, depending on the consistent clustering of prognostic SRGs, LUAD patients were divided into sialylation-related subgroups, followed by the investigation of survival, immunity, and clinical characteristics in the subgroups. LASSO regression analysis was further employed to identify prognostic gene signatures and to build a sialylation-related model to predict the prognosis of LUAD patients. The gene signature were validated using RT-qPCR and used for predicting target medicines using molecular docking to further investigate the potential therapies for LUAD patients. A total of 26 SRGs in LUAD ensemble were associated with prognosis, and LUAD samples were classified into two sialylation-related subgroups based on these SRGs. Intergroup comparisons revealed that patients in Cluster A had greater survival rates, as well as higher immune infiltration. The risk prognostic model built based on 6 prognostic gene signature was able to effectively predict the survival of LUAD patients. Finally, the experimental findings indicated that Troxerutin exhibits a strong binding energy to the sialylation-related gene EGLN3, which could greatly reduce the growth of LUAD by inhibiting the expression of EGLN3, thus limiting the capacity of LUAD cells in the proliferation, migration, and invasion. Troxerutin could target and lower the expression of sialylation-related gene EGLN3, reducing LUAD cells' ability to proliferate, migrate, and invade, making it an essential reference for LUAD prevention and treatment.
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Affiliation(s)
- Yanan Wu
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
| | - Yanlei Ge
- Department of Radiotherapy and Chemotherapy, Affiliated Hospital of North China University of Science and Technology, Tangshan, 063000, Hebei, China
- Department of Hebei Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China
- Department of Tangshan Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China
| | - Junqing Gan
- Department of Radiotherapy and Chemotherapy, Affiliated Hospital of North China University of Science and Technology, Tangshan, 063000, Hebei, China
- Department of Hebei Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China
- Department of Tangshan Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China
| | - Ye Jin
- Department of Hebei Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China
- Department of Tangshan Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China
- Clinical Medicine School, North China University of Science and Technology, Tangshan, 063000, Hebei, China
| | - Yishuang Cui
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
| | - Xuan Zheng
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
| | - Xuemin Yao
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
| | - Guogui Sun
- Department of Radiotherapy and Chemotherapy, Affiliated Hospital of North China University of Science and Technology, Tangshan, 063000, Hebei, China.
- Department of Hebei Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China.
- Department of Tangshan Key Laboratory of Medical-Industrial Intergration Precision Medicine, Tangshan, 063000, Hebei, China.
- School of Pharmacy, North China University of Science and Technology, Tangshan, 063210, Hebei, China.
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You J, Yu Q, Chen R, Li J, Zhao T, Lu Z. A prognostic model for lung adenocarcinoma based on cuproptosis and disulfidptosis related genes revealing the key prognostic role of FURIN. Sci Rep 2025; 15:6057. [PMID: 39972012 PMCID: PMC11840156 DOI: 10.1038/s41598-025-90653-5] [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: 11/01/2024] [Accepted: 02/14/2025] [Indexed: 02/21/2025] Open
Abstract
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Despite advances in treatment, the prognosis remains poor due to late diagnosis. Cuproptosis (driven by copper ion accumulation) and disulfidptosis (driven by disulfide bond accumulation) are novel forms of programmed cell death, closely linked to tumor initiation, progression, and resistance. However, the specific roles of these mechanisms in LUAD remain inadequately studied. This study integrated multi-omics data from TCGA and GEO databases to systematically evaluate the differential expression and prognostic significance of copper and disulfide-related genes (DCRGs), identify two DCRG molecular subtypes, and construct a DCRG scoring model based on four key genes. Multi-omics analysis results revealed that the DCRG score not only accurately predicts prognosis in LUAD patients but is also closely associated with immune cell infiltration patterns and EGFR inhibitor responses. RT-qPCR validated the high expression of FURIN and RHOV in LUAD cells, supporting their role as potential therapeutic targets. Further Mendelian randomization analysis confirmed the causal relationship between FURIN and LUAD development. These findings provide novel biomarkers for the prognosis evaluation of LUAD based on cuproptosis and disulfidptosis mechanisms and offer a theoretical basis for targeting FURIN in LUAD treatment.
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Affiliation(s)
- Jianhang You
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, China
| | - Qing Yu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, China
| | - Ronghui Chen
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, 350000, China
| | - Jianlin Li
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, China
| | - Tao Zhao
- Department of Central Laboratory, Shandong Provincial Key Medical and Health Laboratory of Perioperative Precise Anesthesia and Organ Protection Mechanism Research, Rizhao Key Laboratory of Basic Research on Anesthesia and Respiratory Intensive Care, The People's Hospital of Rizhao, Rizhao, 276826, Shandong, China.
- School of Anesthesiology, Shandong Second Medical University, Weifang, 261053, China.
| | - Zhong Lu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, China.
- Department of Oncology, School of Clinical Medicine, Affiliated Hospital of Shandong Second Medical University, Shandong Second Medical University, Weifang, 261053, Shandong, China.
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Zhao K, Sun T, Sun Q, Chen Z, Wang T, Yang J, Li L, Zhu Y, Liu X, Yang D, Lin B, Lu N. Nerve Growth Factor Signaling Promotes Nuclear Translocation of TRAF4 to Enhance Tumor Stemness and Metastatic Dormancy Via C-Jun-mediated IL-8 Autocrine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2414437. [PMID: 39716976 PMCID: PMC11831473 DOI: 10.1002/advs.202414437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/03/2024] [Indexed: 12/25/2024]
Abstract
Tumor necrosis factor receptor-associated factor 4 (TRAF4), an E3 ubiquitin ligase, is frequently overexpressed in tumors. Although its cytoplasmic role in tumor progression is well-documented, the precise mechanisms underlying its nuclear localization and functional contributions in tumor cells remain elusive. This study demonstrated a positive correlation between the expression of nuclear TRAF4 and both tumor grades and stemness signatures in human cancer tissues. Notably, reduced nuclear TRAF4 led to decreased stemness properties and metastatic dormancy of tumor cells. Conversely, restoring nuclear TRAF4 in TRAF4-knockout (TRAF4-KO) cells augmented these cellular capabilities. Within the nucleus, the TRAF domain of TRAF4 interacted with c-Jun, thereby stimulating its transcriptional activity. This interaction subsequently led to an enhancement of the promoter activity of interleukin-8 (IL-8), which is identified as a mediator of nuclear TRAF4-induced tumor dormancy. Additionally, activation of AKT signaling by nerve growth factor facilitated TRAF4 phosphorylation at Ser242, enhancing its interaction with 14-3-3θ and promoting its nuclear translocation. Importantly, pharmacological modulation of TRAF4 nuclear translocation is found to suppress tumor tumorigenicity and metastasis in tumor models. This study highlights the critical role of nuclear TRAF4 in regulating tumor stemness and dormancy, positioning it as a potential therapeutic target for metastatic and refractory cancers.
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Affiliation(s)
- Kai Zhao
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
| | - Tifan Sun
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
| | - Qiruo Sun
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
| | - Zhenzhong Chen
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
| | - Tiepeng Wang
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
- School of PharmacyNanjing University of Chinese Medicine138 Xianlin Rd.Nanjing210023China
| | - Jinming Yang
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
- Department of PharmacyThe Second Hospital of NanjingAffiliated Hospital to Nanjing University of Chinese MedicineNanjing210003China
| | - Lei Li
- Department of General SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjing210029China
| | - Yanan Zhu
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
| | - Xinye Liu
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
| | - Dawei Yang
- Department of PharmacyThe Second Hospital of NanjingAffiliated Hospital to Nanjing University of Chinese MedicineNanjing210003China
| | - Binyan Lin
- School of PharmacyNanjing University of Chinese Medicine138 Xianlin Rd.Nanjing210023China
| | - Na Lu
- State Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical University24 TongjiaxiangNanjing210009China
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Takano Y, Suzuki J, Nomura K, Fujii G, Zenkoh J, Kawai H, Kuze Y, Kashima Y, Nagasawa S, Nakamura Y, Kojima M, Tsuchihara K, Seki M, Kanai A, Matsubara D, Kohno T, Noguchi M, Nakaya A, Tsuboi M, Ishii G, Suzuki Y, Suzuki A. Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development. Nat Commun 2024; 15:10637. [PMID: 39639005 PMCID: PMC11621540 DOI: 10.1038/s41467-024-54671-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
The interaction of tumor cells and their microenvironment is thought to be a key factor in tumor development. We present spatial RNA profiles obtained from 30 lung adenocarcinoma patients at the non-invasive and later invasive stages. We use spatial transcriptome sequencing data in conjunction with in situ RNA profiling to conduct higher resolution analyses. The detailed examination of each case, as well as the subsequent computational analyses based on the observed diverse profiles, reveals that significant changes in the phenotypic appearances of tumor cells are frequently associated with changes in immune cell features. The phenomenon coincides with the induction of a series of cellular expression programs that enable tumor cells to transform and break through the immune cell barrier, allowing them to progress further. The study shows how lung tumors develop through interaction in their microenvironments.
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Affiliation(s)
- Yuma Takano
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
- Pharmaceutical Science Department, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan
| | - Jun Suzuki
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
- Department of General Thoracic Surgery, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Kotaro Nomura
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Gento Fujii
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Junko Zenkoh
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Hitomi Kawai
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yuta Kuze
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Yukie Kashima
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Satoi Nagasawa
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Yuka Nakamura
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
| | - Motohiro Kojima
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
| | - Katsuya Tsuchihara
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
| | - Masahide Seki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Akinori Kanai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Daisuke Matsubara
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Masayuki Noguchi
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Akihiro Nakaya
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Masahiro Tsuboi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Genichiro Ishii
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
| | - Ayako Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
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Feng X, Wu W, Liu F. AH-6809 mediated regulation of lung adenocarcinoma metastasis through NLRP7 and prognostic analysis of key metastasis-related genes. Front Pharmacol 2024; 15:1486265. [PMID: 39697539 PMCID: PMC11652142 DOI: 10.3389/fphar.2024.1486265] [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: 08/25/2024] [Accepted: 09/30/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Lung adenocarcinoma (LUAD) has become one of the leading causes of cancer-related deaths globally, with metastasis representing the most lethal stage of the disease. Despite significant advances in diagnostic and therapeutic strategies for LUAD, the mechanisms enabling cancer cells to breach the blood-brain barrier remain poorly understood. While genomic profiling has shed light on the nature of primary tumors, the genetic drivers and clinical relevance of LUAD metastasis are still largely unexplored. Objectives This study aims to investigate the genomic differences between brain-metastatic and non-brain-metastatic LUAD, identify potential prognostic biomarkers, and evaluate the efficacy of AH-6809 in modulating key molecular pathways involved in LUAD metastasis, with a focus on post-translational modifications (PTMs). Methods Genomic analyses were performed using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between brain-metastatic and non-metastatic LUAD samples were identified. Key gene modules were determined using Weighted Gene Co-expression Network Analysis (WGCNA), and their prognostic significance was assessed through Kaplan-Meier analysis. Cellular experiments, including CCK8 and qRT-PCR assays, were conducted to evaluate the anti-cancer effects of AH-6809 in LUAD cells. Apoptosis and inflammatory marker expression were assessed using immunofluorescence. Results Genomic analysis differentiated brain-metastatic from non-brain-metastatic LUAD and identified NLRP7, FIBCD1, and ELF5 as prognostic markers. AH-6809 significantly suppressed LUAD cell proliferation, promoted apoptosis, and modulated epithelial-mesenchymal transition (EMT) markers. These effects were reversed upon NLRP7 knockdown, highlighting its role in metastasis. Literature analysis further supported AH-6809's tumor-suppressive activity, particularly in NLRP7 knockdown cells, where it inhibited cell growth and facilitated apoptosis. AH-6809 was also found to affect SUMO1-mediated PTMs and downregulate EMT markers, including VIM and CDH2. NLRP7 knockdown partially reversed these effects. Immunofluorescence revealed enhanced apoptosis and inflammation in lung cancer cells, especially in NLRP7 knockdown cells treated with AH-6809. The regulatory mechanisms involve SUMO1-mediated post-translational modifications and NQO1. Further studies are required to elucidate the molecular mechanisms and assess the clinical potential of these findings. Conclusion These findings demonstrate the critical role of NLRP7 and associated genes in LUAD metastasis and suggest that AH-6809 holds promise as a potential therapeutic agent for brain-metastatic LUAD.
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Affiliation(s)
- Xu Feng
- Department of Neurointerventional, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Wei Wu
- Department of Acupuncture, Jin Zhou Hospital of Traditional Chinese Medicine, Jinzhou, China
| | - Feifei Liu
- Department of Anesthesiology, The First Affiliated Hospital of Jinzhou MedicalUniversity, Jinzhou, China
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Cai K, Fu W, Liu H, Yang X, Wang Z, Zhao X. Leveraging Bioinformatics and Machine Learning for Identifying Prognostic Biomarkers and Predicting Clinical Outcomes in Lung Adenocarcinoma. Genes (Basel) 2024; 15:1497. [PMID: 39766765 PMCID: PMC11675206 DOI: 10.3390/genes15121497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/06/2024] [Accepted: 11/21/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: There exist significant challenges for lung adenocarcinoma (LUAD) due to its poor prognosis and limited treatment options, particularly in the advanced stages. It is crucial to identify genetic biomarkers for improving outcome predictions and guiding personalized therapies. Methods: In this study, we utilize a multi-step approach that combines principled sure independence screening, penalized regression methods and information gain to identify the key genetic features of the ultra-high dimensional RNA-sequencing data from LUAD patients. We then evaluate three methods of survival analysis: the Cox model, survival tree, and random survival forests (RSFs), to compare their predictive performance. Additionally, a protein-protein interaction network is used to explore the biological significance of identified genes. Results:DKK1 and TNS4 are consistently selected as significant predictors across all feature selection methods. The Kaplan-Meier method shows that high expression levels of these genes are strongly correlated with poorer survival outcomes, suggesting their potential as prognostic biomarkers. RSF outperforms Cox and survival tree methods, showing higher AUC and C-index values. The protein-protein interaction network highlights key nodes such as VEGFC and LAMA3, which play central roles in LUAD progression. Conclusions: Our findings provide valuable insights into the genetic mechanisms of LUAD. These results contribute to the development of more accurate prognostic tools and personalized treatment strategies for LUAD.
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Affiliation(s)
- Kaida Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing 210009, China
- Department of Statistics and Actuarial Science, School of Mathematics, Southeast University, Nanjing 211189, China; (W.F.); (H.L.); (X.Y.); (Z.W.); (X.Z.)
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Wenzhi Fu
- Department of Statistics and Actuarial Science, School of Mathematics, Southeast University, Nanjing 211189, China; (W.F.); (H.L.); (X.Y.); (Z.W.); (X.Z.)
| | - Hanwen Liu
- Department of Statistics and Actuarial Science, School of Mathematics, Southeast University, Nanjing 211189, China; (W.F.); (H.L.); (X.Y.); (Z.W.); (X.Z.)
| | - Xiaofang Yang
- Department of Statistics and Actuarial Science, School of Mathematics, Southeast University, Nanjing 211189, China; (W.F.); (H.L.); (X.Y.); (Z.W.); (X.Z.)
| | - Zhengyan Wang
- Department of Statistics and Actuarial Science, School of Mathematics, Southeast University, Nanjing 211189, China; (W.F.); (H.L.); (X.Y.); (Z.W.); (X.Z.)
| | - Xin Zhao
- Department of Statistics and Actuarial Science, School of Mathematics, Southeast University, Nanjing 211189, China; (W.F.); (H.L.); (X.Y.); (Z.W.); (X.Z.)
- Key Laboratory of Measurement and Control of Complex Systems of Engineering, Ministry of Education, Southeast University, Nanjing 210096, China
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Xu Y, Shen Y, Zhang C, Zheng L, Ji F, Chen J, Cheng S, Zheng Y. Exploring the Effect of Fidgetin-Like 1 on Colorectal Cancer Through Tissue Chip and In Vitro Experiments. Balkan Med J 2024; 41:491-498. [PMID: 39319820 PMCID: PMC11589218 DOI: 10.4274/balkanmedj.galenos.2024.2024-7-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024] Open
Abstract
Background Fidgetin-like 1 (FIGNL1) is extensively overexpressed in a variety of cancers. It facilitates non‑small cell lung cancer tumor cell proliferation and hepatocellular carcinoma formation due to abnormal DNA repair. Clinically relevant data indicates that its high expression is linked with the poor prognosis of patients with renal clear-cell carcinoma, low-grade gliomas, and hepatocellular carcinoma. Nevertheless, the scope of FIGNL1’s involvement in cancer, particularly colorectal cancer (CRC), remains unclear. Aims To investigate the function of FIGNL1 in CRC. Study Design Cell culture study. Methods The TCGA database and immunohistochemistry analysis were employed to investigate FIGNL1 expression in CRC tissue. A cell viability assay was performed using the Cell Counting Kit-8. The cell migration and invasion were evaluated using the transwell assay. Small interfering RNA (siRNA) transfection was conducted to knockdown FIGNL1 expression. Infection with FIGNL1 overexpression lentivirus was performed to promote FIGNL1 overexpression. The STRING database was employed for predicting protein interaction. Results FIGNL1 was substantially upregulated in human CRC tissues and was associated with TNM stages and lymph node metastasis in patients. The inhibition of CRC cell proliferation, migration, and invasion in Caco-2 cells was achieved by silencing FIGNL1 using siRNA. Additional investigations suggested that FIGNL1 overexpression could promote CRC cell proliferation, migration, and invasion via P38 signaling pathway activation in Colo-205 cells. Subsequent experiments demonstrated that FIGNL1-mediated P38 phosphorylation was contingent upon SPIDR interaction. Conclusion These results implied that FIGNL1 was a potential anticancer drug target, which also offered a novel strategy for future CRC treatment.
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Affiliation(s)
- Yunxing Xu
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Yucheng Shen
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Chen Zhang
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Liangfeng Zheng
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Feiyue Ji
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Jin Chen
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Shouliang Cheng
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
| | - Yu Zheng
- Clinic of Central Laboratory, Hai’an City People’s Hospital of Jiangsu Province, Hai’an Hospital Affiliated to Nantong University, Nantong, China
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Wu C, Ge W, Wu Y. Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 inhibitor, MI‑2, attenuates non‑small cell lung cancer cell proliferation, migration and invasion, and promotes apoptosis by suppressing the JNK/c‑JUN pathway. Oncol Lett 2024; 28:465. [PMID: 39119234 PMCID: PMC11306989 DOI: 10.3892/ol.2024.14598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/15/2024] [Indexed: 08/10/2024] Open
Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors are effective in attenuating the progression of several types of cancer. However, their role in lung cancer requires further investigation. Therefore, the present study aimed to explore the effect of the MALT1 inhibitor, MI-2, on the behavior of non-small cell lung cancer (NSCLC) cells and to uncover their possible underlying mechanism of action. The mRNA and protein expression levels of MALT1 were detected in the human normal lung epithelial cell line BEAS-2B, and the NSCLC cell lines, NCI-H1299, NCI-H1650, HCC827, A549 and NCI-H23. Subsequently, NCI-H1650 and A549 cells were treated with MI-2. Additionally, NCI-H1650 and A549 cells were co-treated with anisomycin, a c-JUN N-terminal kinase (JNK) pathway activator, with or without MI-2. The results illustrated that the mRNA and protein expression levels of MALT1 were significantly increased in NCI-H1299, NCI-H1650, A549 and NCI-H23 cells compared with those in BEAS-2B cells. Treatment of NCI-H1650 and A549 cells with MI-2 for 72 h reduced the optical density value as determined using the Cell Counting Kit-8 assay. Consistently, the 5-ethynyl-2'-deoxyuridine assay also showed that proliferation was reduced in MI-2-treated NSCLC cells. In addition, MI-2 downregulated B-cell lymphoma 2 (BCL2), and enhanced BCL2-associated X-protein expression and apoptotic rate in NCI-H1650 and A549 cells. These findings indicated that MI-2 could inhibit NCI-H1650 and A549 cell proliferation and promote apoptosis. Furthermore, treatment of cells with MI-2 only attenuated the migration and invasion of NCI-H1650 cells. Notably, MI-2 decreased the expression levels of phosphorylated (p)-JNK and p-c-JUN in NCI-H1650 and A549 cells, thus suggesting that MI-2 could suppress the JNK/c-JUN signaling pathway. However, NSCLC cell co-treatment with anisomycin (JNK pathway activator) reversed the effect of MI-2 on the proliferation, apoptosis and activation of the JNK/c-JUN pathway in NCI-H1650 and A549 cells. In conclusion, the present study demonstrated that the MALT1 inhibitor, MI-2, could suppress NSCLC cell proliferation, migration and invasion, and induce apoptosis via inactivating the JNK/c-JUN pathway.
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Affiliation(s)
- Chunyan Wu
- Department of Oncology, Baotou Central Hospital, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
| | - Wei Ge
- Department of Oncology, Baotou Central Hospital, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
| | - Yun Wu
- Department of Oncology, Baotou Central Hospital, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
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9
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Pan X, Chen H, Zhang L, Xie Y, Zhang K, Lian C, Wang X. Identification of a novel immunogenic death-associated model for predicting the immune microenvironment in lung adenocarcinoma from single-cell and Bulk transcriptomes. J Cancer 2024; 15:5165-5182. [PMID: 39247599 PMCID: PMC11375542 DOI: 10.7150/jca.98659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/02/2024] [Indexed: 09/10/2024] Open
Abstract
Background: Studies on immunogenic death (ICD) in lung adenocarcinoma are limited, and this study aimed to determine the function of ICD in LUAD and to construct a novel ICD-based prognostic model to improve immune efficacy in lung adenocarcinoma patients. Methods: The data for lung adenocarcinoma were obtained from the Cancer Genome Atlas (TCGA) database and the National Center for Biotechnology Information (GEO). The single-cell data were obtained from Bischoff P et al. To identify subpopulations, we performed descending clustering using TSNE. We collected sets of genes related to immunogenic death from the literature and identified ICD-related genes through gene set analysis of variance (GSVA) and weighted gene correlation network analysis (WGCNA). Lung adenocarcinoma patients were classified into two types using consistency clustering. The difference between the two types was analyzed to obtain differential genes. An immunogenic death model (ICDRS) was established using LASSO-Cox analysis and compared with lung adenocarcinoma models of other individuals. External validation was performed in the GSE31210 and GSE50081 cohorts. The efficacy of immunotherapy was assessed using the TIDE algorithm and the IMvigor210, GSE78220, and TCIA cohorts. Furthermore, differences in mutational profiles and immune microenvironment between different risk groups were investigated. Subsequently, ROC diagnostic curves and KM survival curves were used to screen ICDRS key regulatory genes. Finally, RT-qPCR was used to verify the differential expression of these genes. Results: Eight ICD genes were found to be highly predictive of LUAD prognosis and significantly correlated with it. Multivariate analysis showed that patients in the low-risk group had a higher overall survival rate than those in the high-risk group, indicating that the model was an independent predictor of LUAD. Additionally, ICDRS demonstrated better predictive ability compared to 11 previously published models. Furthermore, significant differences in biological function and immune cell infiltration were observed in the tumor microenvironment between the high-risk and low-risk groups. It is noteworthy that immunotherapy was also significant in both groups. These findings suggest that the model has good predictive efficacy. Conclusions: The ICD model demonstrated good predictive performance, revealing the tumor microenvironment and providing a new method for evaluating the efficacy of pre-immunization. This offers a new strategy for future treatment of lung adenocarcinoma.
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Affiliation(s)
- Xinyu Pan
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, The Department of Pulmonary Critical Care Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233030, China
- Department of Medical Imaging, Bengbu Medical University, Bengbu 233030, China
| | - Huili Chen
- Research Center of Clinical Laboratory Science, Bengbu Medical University, Bengbu, 233030, China
| | - Linxiang Zhang
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, The Department of Pulmonary Critical Care Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233030, China
| | - Yiluo Xie
- Department of Clinical Medicine, Bengbu Medical University, Bengbu, 233030, China
| | - Kai Zhang
- Department of Clinical Medicine, Bengbu Medical University, Bengbu, 233030, China
| | - Chaoqun Lian
- Research Center of Clinical Laboratory Science, Bengbu Medical University, Bengbu, 233030, China
| | - Xiaojing Wang
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, The Department of Pulmonary Critical Care Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233030, China
- Molecular Diagnosis Center, Joint Research Center for Regional Diseases of IHM, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233030, China
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Zhang Z, Zhang D, Su K, Wu D, Hu Q, Jin T, Ye T, Zhang R. NTSR1 promotes epithelial-mesenchymal transition and metastasis in lung adenocarcinoma through the Wnt/β-catenin pathway. Mutat Res 2024; 829:111877. [PMID: 39180939 DOI: 10.1016/j.mrfmmm.2024.111877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/26/2024] [Accepted: 07/30/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) patients are implicated in poor prognoses and increased mortality rates. Metastasis, as a leading cause of LUAD-related deaths, requires further investigation. Highly metastatic cancer cells often exhibit extensive characteristics of epithelial-mesenchymal transition (EMT). This study attempted to identify novel targets associated with LUAD metastasis and validate their specific molecular mechanisms. METHODS Bioinformatics was conducted to determine NTSR1 expression in LUAD and the enriched pathways. Immunohistochemical analysis was used to assess NTSR1 expression in LUAD tissue. qRT-PCR examined expressions of NTSR1 and Wnt/β-Catenin pathway-related genes in LUAD cells. Transwell assayed cell migration and invasion. Cell adhesion experiments were conducted to evaluate cell adhesion capacity. Western blot analysis was employed to examine expression of EMT, Wnt/β-Catenin pathway, and cell adhesion markers. RESULTS NTSR1 was upregulated in LUAD tissues and cells, and enriched in EMT pathway. Knockdown of NTSR1 reduced migration, invasion, and adhesion abilities in LUAD cells, and inhibited EMT progression and Wnt/β-Catenin pathway. Rescue experiments demonstrated that β-Catenin activator SKL2001 reversed repressive influence of NTSR1 knockdown on LUAD cell malignant phenotypes and EMT progression. CONCLUSION The data obtained in this study suggested that NTSR1 stimulated EMT and metastasis in LUAD via Wnt/β-Catenin pathway. This finding may provide options for overcoming LUAD metastasis.
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Affiliation(s)
- Zhihao Zhang
- Department of Cardiothoracic Surgery, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China.
| | - Dongliang Zhang
- Department of Cardiothoracic Surgery, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
| | - Kai Su
- Department of Cardiothoracic Surgery, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
| | - Dongqiang Wu
- Department of Cardiothoracic Surgery, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
| | - Qiqi Hu
- Human Resource Management Department, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
| | - Tianying Jin
- Department of Cardiothoracic Surgery, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
| | - Tingting Ye
- Medical Insurance Information Section, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
| | - Rongrong Zhang
- Department of Cardiothoracic Surgery, China Coast Guard Hospital ot the People's Armed Police Force, Jiaxing, Zhejiang 314001, China
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11
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Hong C, Meng Y, Qiu A, Zhang H, Yang L, Hong Y, Huang Y. Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway. BMB Rep 2024; 57:336-341. [PMID: 38919013 PMCID: PMC11289505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 03/25/2024] [Accepted: 05/30/2024] [Indexed: 06/27/2024] Open
Abstract
Lung cancer is one of the most significant malignancies, with both high morbidity and mortality. CDK10 is closely related to cancer progression and metastasis. However, its role in lung cancer radioresistance demands further clarification. In this study, we demonstrated that CDK10 was downregulated in lung cancer tissues, and CDK10 expression level was associated with the clinical prognosis in lung cancer patients. We also found that silencing CDK10 promoted lung cancer cell proliferation, migration, and radioresistance. We further verified that silencing CDK10 facilitated the activation of JNK/c-Jun signaling, and c-Jun depletion could reverse the effects of CDK10 knockdown in lung cancer cells. Our findings revealed that CDK10 plays an important role in cell growth and radioresistance by inhibiting JNK/c-Jun signaling pathway in lung cancer. Therefore, CDK10 might be a promising therapeutic target in lung cancer. [BMB Reports 2024; 57(7): 336-341].
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Affiliation(s)
- Chaojin Hong
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People
| | - Yimei Meng
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People
| | - Anchen Qiu
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People
| | - Haibo Zhang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People
| | - Liu Yang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People
| | - Yupeng Hong
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People
| | - Yumei Huang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People
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12
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Song XQ, Shao ZM. Identification of immune-related prognostic biomarkers in triple-negative breast cancer. Transl Cancer Res 2024; 13:1707-1720. [PMID: 38737702 PMCID: PMC11082668 DOI: 10.21037/tcr-23-1554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 02/29/2024] [Indexed: 05/14/2024]
Abstract
Background Triple-negative breast cancer (TNBC), a type of breast cancer, lacks immune-related markers that can be used for prognosis or prediction. Therefore, we created a predictive framework for TNBC using a risk assessment. Methods Our previous study group consisted of 360 individuals who were diagnosed with TNBC through pathology using RNA sequencing and had clinical data from Fudan University Shanghai Cancer Center (FUSCC). A risk scoring model was constructed using the Cox regression method with the least absolute shrinkage and selection operator (LASSO). A multivariate Cox regression analysis was utilized to develop the prediction model, which was then assessed using the consistency index and calibration plots. The validation cohort of The Cancer Genome Atlas (TCGA) TNBC confirmed the strength of the signatures' predictive value. Results The prognostic risk score model included 12 genes: TDO2, CHIT1, CARML2, HLA-C, ADIRF, C19orf33, CA8, AHNAK2, RHOV, OPLAH, THEM6, and NEBL. The receiver operator characteristic (ROC) curves for survivability values at 1, 3, and 5 years in the FUSCC TNBC cohort demonstrated area under the curve (AUC) values of 0.78, 0.83, and 0.75, respectively. These results indicated a high level of accuracy in predicting outcomes, which was further confirmed through validation using TCGA database. The patients in the high-risk group showed worse prognoses and lower levels of immune cell infiltration, specifically CD8+ T cells, than those in the low-risk group. Furthermore, the low-risk group exhibited a significant upregulation of genes that encode immune checkpoints, including CD274 and CTLA4, suggesting that immunotherapy may yield enhanced efficacy within this particular group. Conclusions In conclusion, the prognostic signature consisting of 12 genes can assist in the choice of immunotherapy for TNBC.
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Affiliation(s)
- Xiao-Qing Song
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhi-Ming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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13
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Liu F, Yang Y, Xu XS, Yuan M. MESBC: A novel mutually exclusive spectral biclustering method for cancer subtyping. Comput Biol Chem 2024; 109:108009. [PMID: 38219419 DOI: 10.1016/j.compbiolchem.2023.108009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 12/22/2023] [Accepted: 12/24/2023] [Indexed: 01/16/2024]
Abstract
Many soft biclustering algorithms have been developed and applied to various biological and biomedical data analyses. However, few mutually exclusive (hard) biclustering algorithms have been proposed, which could better identify disease or molecular subtypes with survival significance based on genomic or transcriptomic data. In this study, we developed a novel mutually exclusive spectral biclustering (MESBC) algorithm based on spectral method to detect mutually exclusive biclusters. MESBC simultaneously detects relevant features (genes) and corresponding conditions (patients) subgroups and, therefore, automatically uses the signature features for each subtype to perform the clustering. Extensive simulations revealed that MESBC provided superior accuracy in detecting pre-specified biclusters compared with the non-negative matrix factorization (NMF) and Dhillon's algorithm, particularly in very noisy data. Further analysis of the algorithm on real datasets obtained from the TCGA database showed that MESBC provided more accurate (i.e., smaller p-value) overall survival prediction in patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cancers when compared to the existing, gold-standard subtypes for lung cancers (integrative clustering). Furthermore, MESBC detected several genes with significant prognostic value in both LUAD and LUSC patients. External validation on an independent, unseen GEO dataset of LUAD showed that MESBC-derived clusters based on TCGA data still exhibited clear biclustering patterns and consistent, outstanding prognostic predictability, demonstrating robust generalizability of MESBC. Therefore, MESBC could potentially be used as a risk stratification tool to optimize the treatment for the patient, improve the selection of patients for clinical trials, and contribute to the development of novel therapeutic agents.
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Affiliation(s)
- Fengrong Liu
- Department of Statistics and Finance, University of Science and Technology of China, Hefei 230026, China
| | - Yaning Yang
- Department of Statistics and Finance, University of Science and Technology of China, Hefei 230026, China
| | | | - Min Yuan
- School of Public Health Administration, Anhui Medical University, Hefei 230032, China.
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14
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Shabangu CS, Su WH, Li CY, Yu ML, Dai CY, Huang JF, Chuang WL, Wang SC. Systematic integration of molecular and clinical approaches in HCV-induced hepatocellular carcinoma. J Transl Med 2024; 22:268. [PMID: 38475805 PMCID: PMC10935926 DOI: 10.1186/s12967-024-04925-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 01/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play a crucial role in gene expression and regulation, with dysregulation of miRNA function linked to various diseases, including hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). There is still a gap in understanding the regulatory relationship between miRNAs and mRNAs in HCV-HCC. This study aimed to investigate the function and effects of persistent HCV-induced miRNA expression on gene regulation in HCC. METHODS MiRNA array data were used to identify differentially expressed miRNAs and their targets, and miRNAs were analyzed via DIANA for KEGG pathways, gene ontology (GO) functional enrichment, and Ingenuity Pathways Analysis (IPA) for hepatotoxicity, canonical pathways, associated network functions, and interactive networks. RESULTS Seventeen miRNAs in L-HCV and 9 miRNAs in S-HCV were differentially expressed, and 5 miRNAs in L-HCV and 5 miRNAs in S-HCV were significantly expressed in liver hepatocellular carcinoma (LIHC) tumors. Grouped miRNA survival analysis showed that L-HCV miRNAs were associated with survival in LIHC, and miRNA‒mRNA targets regulated viral carcinogenesis and cell cycle alteration through cancer pathways in LIHC. MiRNA-regulated RCN1 was suppressed through miRNA-oncogene interactions, and suppression of RCN1 inhibited invasion and migration in HCC. CONCLUSION Persistent HCV infection induced the expression of miRNAs that act as tumor suppressors by inhibiting oncogenes in HCC. RCN1 was suppressed while miRNAs were upregulated, demonstrating an inverse relationship. Therefore, hsa-miR-215-5p, hsa-miR-10b-5p, hsa-let-7a-5p and their target RCN1 may be ideal biomarkers for monitoring HCV-HCC progression.
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Affiliation(s)
- Ciniso Sylvester Shabangu
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wen-Hsiu Su
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chia-Yang Li
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Chia-Yen Dai
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Jee-Fu Huang
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wan-Long Chuang
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shu-Chi Wang
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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Woo S, Strasser L. Atypical RhoUV GTPases in development and disease. Biochem Soc Trans 2024; 52:89-97. [PMID: 38314621 PMCID: PMC10903452 DOI: 10.1042/bst20230212] [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: 10/24/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/06/2024]
Abstract
RhoU and RhoV are members of the Rho family of small GTPases that comprise their own subfamily. RhoUV GTPases are classified as atypical due to the kinetics of their GTP/GDP binding cycles. They also possess unique N- and C-termini that regulate their subcellular localization and activity. RhoU and RhoV have been linked to cytoskeletal regulation, cell adhesion, and cell migration. They each exhibit distinct expression patterns during embryonic development and diseases such as cancer metastasis, suggesting they have specialized functions. In this review, we will discuss the known functions of RhoU and RhoV, with a focus on their roles in early development, organogenesis, and disease.
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Affiliation(s)
- Stephanie Woo
- Department of Molecular Cell Biology, University of California, Merced, CA, U.S.A
- Quantitative and Systems Biology Graduate Program, University of California, Merced, CA, U.S.A
| | - Leesa Strasser
- Department of Molecular Cell Biology, University of California, Merced, CA, U.S.A
- Quantitative and Systems Biology Graduate Program, University of California, Merced, CA, U.S.A
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16
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Miao Y, Liu J. Tumor-suppressive action of miR-30a-5p in lung adenocarcinoma correlates with ABL2 inhibition and PI3K/AKT pathway inactivation. Clin Transl Oncol 2024; 26:398-413. [PMID: 37479901 DOI: 10.1007/s12094-023-03255-w] [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: 02/01/2023] [Accepted: 06/14/2023] [Indexed: 07/23/2023]
Abstract
INTRODUCTION ABL2 contributes to the oncogenic potential of cancers, pointing to its inhibition as a possible strategy against malignant diseases. Bioinformatics prediction of upstream effector miR-30a-5p for ABL2 allowed us to hypothesize and then validate mechanistic actions of miR-30a-5p in lung adenocarcinoma (LUAD). MATERIALS AND METHODS The ABL2 expression in LUAD was analyzed in the TCGA data, clinical samples, and cell lines. The shRNA-mediated silencing of ABL2 was introduced to illustrate its effect on malignant phenotypes of LUAD cells. The binding affinity between ABL2 and miR-30a-5p was verified by luciferase activity and RNA pull-down assay. Ectopic expression, knockdown methods, and PI3K inhibitor LY294002 were used to investigate their effects on in vitro biological characteristics and in vivo tumor growth of LUAD cells. Using nude mouse lung adenocarcinoma in situ and brain metastasis models to validate the inhibitory effect of miR-30a-5p on LUAD by regulating the ABL2/PI3K/AKT signaling axis. RESULTS High expression of ABL2 and poor expression of miR-30a-5p were noticed in LUAD tissues and cell lines. Importantly, miR-30a-5p was demonstrated to target and downregulate ABL2, subsequently inactivating the PI3K/AKT pathway. miR-30a-5p inhibited the malignant phenotypes of LUAD cells by inhibiting ABL2 expression and inactivating the PI3K/AKT pathway. For in vivo experiments, miR-30a-5p was substantiated to thwart tumor tumorigenesis by regulating the ABL2/PI3K/AKT axis. In addition, miR-30a-5p suppresses the occurrence and development of in situ lung cancer and brain metastasis via the ABL2/PI3K/AKT signaling pathway. CONCLUSION This study underscores the inhibitory role of miR-30a-5p in LUAD through the ABL2/PI3K/AKT axis, which may be a viable target for LUAD treatment.
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Affiliation(s)
- Yajun Miao
- Department of Oncology, Nantong First People's Hospital, Nantong, 226000, People's Republic of China
| | - Jun Liu
- Department of Chemotherapy, Affiliated Hospital of Nantong University, No.20, Xisi Road, Chongchuan District, Nantong, 226001, Jiangsu Province, People's Republic of China.
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Huang H, Wang S, Guan Y, Ren J, Liu X. Molecular basis and current insights of atypical Rho small GTPase in cancer. Mol Biol Rep 2024; 51:141. [PMID: 38236467 DOI: 10.1007/s11033-023-09140-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 12/11/2023] [Indexed: 01/19/2024]
Abstract
Atypical Rho GTPases are a subtype of the Rho GTPase family that are involved in diverse cellular processes. The typical Rho GTPases, led by RhoA, Rac1 and Cdc42, have been well studied, while relative studies on atypical Rho GTPases are relatively still limited and have great exploration potential. With the increase in studies, current evidence suggests that atypical Rho GTPases regulate multiple biological processes and play important roles in the occurrence and development of human cancers. Therefore, this review mainly discusses the molecular basis of atypical Rho GTPases and their roles in cancer. We summarize the sequence characteristics, subcellular localization and biological functions of each atypical Rho GTPase. Moreover, we review the recent advances and potential mechanisms of atypical Rho GTPases in the development of multiple cancers. A comprehensive understanding and extensive exploration of the biological functions of atypical Rho GTPases and their molecular mechanisms in tumors will provide important insights into the pathophysiology of tumors and the development of cancer therapeutic strategies.
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Affiliation(s)
- Hua Huang
- Center of Excellence for Environmental Safety and Biological Effects, Faculty of Environment and Life, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing University of Technology, Beijing, 100124, China
| | - Sijia Wang
- Center of Excellence for Environmental Safety and Biological Effects, Faculty of Environment and Life, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing University of Technology, Beijing, 100124, China
| | - Yifei Guan
- Center of Excellence for Environmental Safety and Biological Effects, Faculty of Environment and Life, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing University of Technology, Beijing, 100124, China
| | - Jing Ren
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing, 100853, China.
| | - Xinhui Liu
- Center of Excellence for Environmental Safety and Biological Effects, Faculty of Environment and Life, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing University of Technology, Beijing, 100124, China.
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, China.
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Yang H, Wei Z, Song Y, Du K, Yin N, Lu H, Li B, Hou L, Xing P, Chen L, Wang C, Xie S. NUAK1 promotes tumor metastasis through upregulating slug transcription in esophageal squamous cell carcinoma. Cancer Cell Int 2023; 23:258. [PMID: 37919754 PMCID: PMC10621130 DOI: 10.1186/s12935-023-03101-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 10/16/2023] [Indexed: 11/04/2023] Open
Abstract
BACKGROUND Metastasis is still a major cause of poor pathological outcome and prognosis in esophageal squamous cell carcinoma (ESCC) patients. NUAK1 has been reported highly expressed in many human cancers and is associated with the poor prognosis of cancer patients. However, the role of NUAK1 and its underlying signaling mechanism in ESCC metastasis remain unclear. METHODS Expression of NUAK1 in ESCC was detected by real-time quantitative RT-PCR (qRT-PCR), Western blotting and immunohistochemical staining. MTT, colony formation, wound-healing and transwell assays were used to determine the role NUAK1 in vitro. Metastasis was evaluated by use of an experimental pulmonary metastasis model in BALB/c-nu/nu mice. The mechanisms were assessed by using coimmunoprecipitation, immunofluorescence and dual-luciferase reporter gene experiments. RESULTS NUAK1 was highly expressed in ESCC tissues compared with the adjacent normal esophageal epithelial tissues. Moreover, the elevated expression of NUAK1 positively correlated with tumor invasion depth, lymph node metastasis, pathological TNM stage, and poor survival in ESCC patients. Further experiments showed that NUAK1 overexpression did not change the cell viability and colony formation of ESCC cells, while remarkably promoted the migration and invasion in vitro and experimental pulmonary metastasis in vivo. Mechanistically, NUAK1 enhanced the transcription level of Slug, which enhanced the migratory and invasive capability of ESCC cells. Consistently, silencing Slug almost completely diminished the migration and invasion of NUAK1-overexpressing ESCC cells. Further studies demonstrated that NUAK1 upregulated the transcription activity of Slug through activating the JNK/c-Jun pathway. CONCLUSION These results demonstrated that NUAK1 promoted the metastasis of ESCC cells through activating JNK/c-Jun/Slug signaling, indicating NUAK1 is a promising therapeutic target for metastatic ESCC.
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Affiliation(s)
- Huiru Yang
- School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Zhen Wei
- School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Yifan Song
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Kexin Du
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Nannan Yin
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Hong Lu
- Department of Oncology, Huaihe Hospital of Henan University, Kaifeng, 475004, Henan, China
| | - Bingbing Li
- Department of Oncology, Huaihe Hospital of Henan University, Kaifeng, 475004, Henan, China
| | - Lili Hou
- School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Panfei Xing
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China
| | - Liang Chen
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China.
| | - Chaojie Wang
- The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China.
| | - Songqiang Xie
- School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China.
- The Academy for Advanced Interdisciplinary Studies, Henan University, N. Jinming Ave., Kaifeng, 475004, Henan, China.
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Qin Q, Peng B. Prognostic significance of the rho GTPase RHOV and its role in tumor immune cell infiltration: a comprehensive pan-cancer analysis. FEBS Open Bio 2023; 13:2124-2146. [PMID: 37596964 PMCID: PMC10626275 DOI: 10.1002/2211-5463.13698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/10/2023] [Accepted: 08/17/2023] [Indexed: 08/21/2023] Open
Abstract
Ras homolog gene family member V (RHOV) is an atypical Rho GTPase that participates in various important cellular processes. Although RHOV has been identified to play an oncogenic role in lung cancer and triple-negative breast cancer, its role in other types of tumors remains unknown. In this study, we investigated the expression of RHOV in pan-cancer analysis using The Cancer Genome Atlas (TCGA) and Gene-Tissue Expression datasets. RHOV mRNA levels were dysregulated in several types of tumors. RHOV expression was identified as an independent prognostic factor in 7 of 33 types of tumors; however, the relationship varied according to tumor type. Higher RHOV expression was associated with a favorable prognosis in kidney renal cell carcinoma and prostate adenocarcinoma, for which RHOV expression was downregulated, whereas RHOV expression was associated with a poor prognosis for patients with adenoid cystic carcinoma, lung adenocarcinoma, pancreatic ductal adenocarcinoma, skin cutaneous melanoma, and uveal melanoma with upregulated RHOV expression. Furthermore, RHOV expression was associated with various clinicopathological parameters in these tumors. RHOV expression showed varied associations with different types of tumor-infiltrating immune cells and demonstrated a potential impact on the response to immunotherapy depending on the cancer type. Additionally, functional enrichment analysis of RHOV-related genes demonstrated a role in a wide range of developmental and immune-related processes. This study provides valuable insights into the role of RHOV in pan-cancer development, indicating its role as a tumor suppressor or oncogene according to the cancer type and tumor microenvironment.
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Affiliation(s)
- Qin Qin
- Department of OncologyJingzhou Hospital Affiliated to Yangtze UniversityChina
| | - Bing Peng
- Department of OncologyThe Second People's Hospital of JingmenChina
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20
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Zhang G, Gao Z, Guo X, Ma R, Wang X, Zhou P, Li C, Tang Z, Zhao R, Gao P. CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages. J Clin Invest 2023; 133:e166224. [PMID: 37707957 PMCID: PMC10617780 DOI: 10.1172/jci166224] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 09/08/2023] [Indexed: 09/16/2023] Open
Abstract
The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.
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21
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Liao Y, Wu C, Li Y, Wen J, Zhao D. MIF is a critical regulator of mononuclear phagocytic infiltration in hepatocellular carcinoma. iScience 2023; 26:107273. [PMID: 37520719 PMCID: PMC10371853 DOI: 10.1016/j.isci.2023.107273] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 05/03/2023] [Accepted: 06/28/2023] [Indexed: 08/01/2023] Open
Abstract
Immunotherapy targeting tumor-associated macrophages (TAMs) is a promising approach to treating cancer. However, the limited drug targets and ambiguous mechanisms impede the development of clinical immunotherapy strategies. To elucidate the underlying processes involved in mononuclear phagocyte (MNP) infiltration and phenotypic changes in hepatocellular carcinoma (HCC), we integrated single-cell RNA-sequencing data from 100,030 cells derived from patients with HCC and healthy individuals and compared the phenotypes and origins of the MNPs in the tumor core, tumor periphery, adjacent normal tissue, and healthy liver samples. Using machine learning and multi-omics analyses, we identified 445 infiltration-associated genes and potential drug targets affecting this process. Through in vitro experiments, we found that the expression of macrophage migration inhibitory factor (MIF) is the upstream regulator of secreted phosphoprotein 1 (SPP1) and promote migration in TAMs. Our findings also indicate that MIF promotes tumor metastasis and invasion and is a promising potential target for treating HCC.
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Affiliation(s)
- Yunxi Liao
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
| | - Chenyang Wu
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
| | - Yang Li
- Department of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Jinhua Wen
- Department of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Dongyu Zhao
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
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22
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Deng X, Chen X, Luo Y, Que J, Chen L. Intratumor microbiome derived glycolysis-lactate signatures depicts immune heterogeneity in lung adenocarcinoma by integration of microbiomic, transcriptomic, proteomic and single-cell data. Front Microbiol 2023; 14:1202454. [PMID: 37664112 PMCID: PMC10469687 DOI: 10.3389/fmicb.2023.1202454] [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: 04/08/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
Introduction Microbiome plays roles in lung adenocarcinoma (LUAD) development and anti-tumor treatment efficacy. Aberrant glycolysis in tumor might promote lactate production that alter tumor microenvironment, affecting microbiome, cancer cells and immune cells. We aimed to construct intratumor microbiome score to predict prognosis of LUAD patients and thoroughly investigate glycolysis and lactate signature's association with LUAD immune cell infiltration. Methods The Cancer Genome Atlas-LUAD (TCGA-LUAD) microbiome data was downloaded from cBioPortal and analyzed to examine its association with overall survival to create a prognostic scoring model. Gene Set Enrichment Analysis (GSEA) was used to find each group's major mechanisms involved. Our study then investigated the glycolysis and lactate pattern in LUAD patients based on 19 genes, which were correlated with the tumor microenvironment (TME) phenotypes and immunotherapy outcomes. We developed a glycolysis-lactate risk score and signature to accurately predict TME phenotypes, prognosis, and response to immunotherapy. Results Using the univariate Cox regression analysis, the abundance of 38 genera were identified with prognostic values and a lung-resident microbial score (LMS) was then developed from the TCGA-LUAD-microbiome dataset. Glycolysis hallmark pathway was significantly enriched in high-LMS group and three distinct glycolysis-lactate patterns were generated. Patients in Cluster1 exhibited unfavorable outcomes and might be insensitive to immunotherapy. Glycolysis-lactate score was constructed for predicting prognosis with high accuracy and validated in external cohorts. Gene signature was developed and this signature was elevated in epithelial cells especially in tumor mass on single-cell level. Finally, we found that the glycolysis-lactate signature levels were consistent with the malignancy of histological subtypes. Discussion Our study demonstrated that an 18-microbe prognostic score and a 19-gene glycolysis-lactate signature for predicting prognosis of LUAD patients. Our LMS, glycolysis-lactate score and glycolysis-lactate signature have potential roles in precision therapy of LUAD patients.
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Affiliation(s)
| | | | | | - Jun Que
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Liang Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Zhang L, Liu Y, Zhuang JG, Guo J, Li YT, Dong Y, Song G. Identification of key genes and biological pathways in lung adenocarcinoma by integrated bioinformatics analysis. World J Clin Cases 2023; 11:5504-5518. [PMID: 37637684 PMCID: PMC10450371 DOI: 10.12998/wjcc.v11.i23.5504] [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: 05/19/2023] [Revised: 06/29/2023] [Accepted: 07/25/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND The objectives of this study were to identify hub genes and biological pathways involved in lung adenocarcinoma (LUAD) via bioinformatics analysis, and investigate potential therapeutic targets. AIM To determine reliable prognostic biomarkers for early diagnosis and treatment of LUAD. METHODS To identify potential therapeutic targets for LUAD, two microarray datasets derived from the Gene Expression Omnibus (GEO) database were analyzed, GSE3116959 and GSE118370. Differentially expressed genes (DEGs) in LUAD and normal tissues were identified using the GEO2R tool. The Hiplot database was then used to generate a volcanic map of the DEGs. Weighted gene co-expression network analysis was conducted to cluster the genes in GSE116959 and GSE118370 into different modules, and identify immune genes shared between them. A protein-protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes database, then the CytoNCA and CytoHubba components of Cytoscape software were used to visualize the genes. Hub genes with high scores and co-expression were identified, and the Database for Annotation, Visualization and Integrated Discovery was used to perform enrichment analysis of these genes. The diagnostic and prognostic values of the hub genes were calculated using receiver operating characteristic curves and Kaplan-Meier survival analysis, and gene-set enrichment analysis was conducted. The University of Alabama at Birmingham Cancer data analysis portal was used to analyze relationships between the hub genes and normal specimens, as well as their expression during tumor progression. Lastly, validation of protein expression was conducted on the identified hub genes via the Human Protein Atlas database. RESULTS Three hub genes with high connectivity were identified; cellular retinoic acid binding protein 2 (CRABP2), matrix metallopeptidase 12 (MMP12), and DNA topoisomerase II alpha (TOP2A). High expression of these genes was associated with a poor LUAD prognosis, and the genes exhibited high diagnostic value. CONCLUSION Expression levels of CRABP2, MMP12, and TOP2A in LUAD were higher than those in normal lung tissue. This observation has diagnostic value, and is linked to poor LUAD prognosis. These genes may be biomarkers and therapeutic targets in LUAD, but further research is warranted to investigate their usefulness in these respects.
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Affiliation(s)
- Lin Zhang
- Department of Critical Medicine, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
| | - Yuan Liu
- Department of Critical Medicine, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
| | - Jian-Guo Zhuang
- Department of Internal Medicine, Xiongxian Hospital of Traditional Chinese Medicine, Baoding 071800, Hebei Province, China
| | - Jie Guo
- Second Department of Respiratory Medicine, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
| | - Yan-Tao Li
- Department of Critical Medicine, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
| | - Yan Dong
- Department of Critical Medicine, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
| | - Gang Song
- Second Department of Respiratory Medicine, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
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Li G, Zhang H, Lai H, Liang G, Huang J, Zhao F, Xie X, Peng C. Erianin: A phytoestrogen with therapeutic potential. Front Pharmacol 2023; 14:1197056. [PMID: 37608888 PMCID: PMC10440559 DOI: 10.3389/fphar.2023.1197056] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 07/03/2023] [Indexed: 08/24/2023] Open
Abstract
Erianin, a phytoestrogen with therapeutic potential, is one of the major active components of Dendrobll caulis. Erianin has a variety of pharmacological effects, such as anti-tumor, anti-inflammatory, anti-diabetic retinopathy, anti-psoriasis, and antibacterial effects. Especially, in regard to the anti-tumor effect of erianin, the underlying molecular mechanism has been partly clarified. In fact, the numerous pharmacological actions of erianin are complex and interrelated, mainly including ERK1/2, PI3K/Akt, JAK2/STAT3, HIF-1α/PD-L1, PPT1/mTOR, JNK/c-Jun, and p38 MAPK signal pathway. However, on account of the poor water solubility and the low bioavailability of erianin, greatly affected and limited its further development and application. And it is worthwhile and meaningful to explore more extensive pharmacological effects and mechanisms, clarify pharmacokinetics, and synthesize the derivatives of erianin. Conclusively, in this paper, the pharmacological effects of erianin and its mechanism, pharmacokinetics, and derivatives studies were reviewed, in order to provide a reference for the development and application of erianin.
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Affiliation(s)
- Gangmin Li
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Huiqiong Zhang
- Safety Evaluation Center, Sichuan Institute for Drug Control (Sichuan Testing Center of Medical Devices), Chengdu, China
| | - Hui Lai
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Gang Liang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Jiang Huang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Fulan Zhao
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xiaofang Xie
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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25
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Pan L, Mulaw MA, Gout J, Guo M, Zarrin H, Schwarz P, Baumann B, Seufferlein T, Wagner M, Oswald F. RBPJ Deficiency Sensitizes Pancreatic Acinar Cells to KRAS-Mediated Pancreatic Intraepithelial Neoplasia Initiation. Cell Mol Gastroenterol Hepatol 2023; 16:783-807. [PMID: 37543088 PMCID: PMC10520364 DOI: 10.1016/j.jcmgh.2023.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND AND AIMS Development of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC, and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis. METHODS Conditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for acinar-to-ductal metaplasia together with immunohistology and comprehensive transcriptional profiling by RNA sequencing. RESULTS We identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT-driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of pancreatic intraepithelial neoplasia lesions with massive fibrotic stroma formation. Interestingly, RNA-sequencing data revealed a transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression. CONCLUSIONS Our findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.
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Affiliation(s)
- Leiling Pan
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Medhanie A Mulaw
- Unit for Single-cell Genomics, Medical Faculty, Ulm University, Ulm, Germany
| | - Johann Gout
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Min Guo
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Hina Zarrin
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Peggy Schwarz
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Bernd Baumann
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Thomas Seufferlein
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Martin Wagner
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
| | - Franz Oswald
- Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany.
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Hua L, Wu J, Ge J, Li X, You B, Wang W, Hu B. Identification of lung adenocarcinoma subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes. Front Cell Dev Biol 2023; 11:1060086. [PMID: 37234773 PMCID: PMC10206047 DOI: 10.3389/fcell.2023.1060086] [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: 10/02/2022] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Background: Lung adenocarcinoma (LUAD) is the most common variant of non-small cell lung cancer (NSCLC) across the world. Recently, the rapid development of immunotherapy has brought a new dawn for LUAD patients. Closely related to the tumor immune microenvironment and immune cell functions, more and more new immune checkpoints have been discovered, and various cancer treatment studies targeting these novel immune checkpoints are currently in full swing. However, studies on the phenotype and clinical significance of novel immune checkpoints in LUAD are still limited, and only a minority of patients with LUAD can benefit from immunotherapy. Methods: The LUAD datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the immune checkpoints score of each sample were calculated based on the expression of the 82 immune checkpoints-related genes (ICGs). The weighted gene co-expression network analysis (WGCNA) was used to obtain the gene modules closely related to the score and two different LUAD clusters were identified based on these module genes by the Non-negative Matrix Factorization (NMF) Algorithm. The differentially expressed genes between the two clusters were further used to construct a predictive signature for prognosis, immune features, and the response to immunotherapy for LUAD patients through a series of regression analyses. Results: A new immune checkpoints-related signature was finally established according to the expression of 7 genes (FCER2, CD200R1, RHOV, TNNT2, WT1, AHSG, and KRTAP5-8). This signature can stratify patients into high-risk and low-risk groups with different survival outcomes and sensitivity to immunotherapy, and the signature has been well validated in different clinical subgroups and validation cohorts. Conclusion: We constructed a novel immune checkpoints-related LUAD risk assessment system, which has a good predictive ability and significance for guiding immunotherapy. We believe that these findings will not only aid in the clinical management of LUAD patients but also provide some insights into screening appropriate patients for immunotherapy.
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Affiliation(s)
- Linbin Hua
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jiyue Wu
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jiashu Ge
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xin Li
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Bin You
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Bin Hu
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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Wu S, Sun Z, Guo Z, Li P, Mao Q, Tang Y, Chen H, Peng H, Wang S, Cao Y. The effectiveness of blood-activating and stasis-transforming traditional Chinese medicines (BAST) in lung cancer progression-a comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116565. [PMID: 37172918 DOI: 10.1016/j.jep.2023.116565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/20/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Blood-activating and stasis-transforming traditional Chinese medicines (BAST) are a class of herbs that have the effect of dilating blood vessels and dispersing stagnation. Modern pharmaceutical research has demonstrated that they are capable of improving hemodynamics and micro-flow, resist thrombosis and promote blood flow. BAST contain numerous active ingredients, which can theoretically regulate multiple targets at the same time and have a wide range of pharmacological effects in the treatment of diseases including human cancers. Clinically, BAST have minimal side effects and can be used in combination with Western medicine to improve patients' quality of life, lessen adverse effects and minimize the risk of recurrence and metastasis of cancers. AIM OF THE REVIEW We aimed to summarize the research progression of BAST on lung cancer in the past five years and present a prospect for the future. Particularly, this review further analyzes the effects and molecular mechanisms that BAST inhibit the invasion and metastasis of lung cancer. MATERIALS AND METHODS Relevant studies about BSAT were collected from PubMed and Web of science. RESULTS Lung cancer is one of the malignant tumors with the highest mortality rate. Most patients with lung cancer are diagnosed at an advanced stage and are highly susceptible to metastasis. Recent studies have shown that BAST, a class of traditional Chinese medicine (TCM) with the function of opening veins and dispersing blood stasis, significantly improve hemodynamics and microcirculation, prevent thrombosis and promote blood flow, and thereby inhibiting the invasion and metastasis of lung cancer. In the current review, we analyzed 51 active ingredients extracted from BAST. It was found that BAST and their active ingredients contribute to the prevention of invasion and metastasis of lung cancer through multiple mechanisms, such as regulation of EMT process, specific signaling pathway and metastasis-related genes, tumor blood vessel formation, immune microenvironment and inflammatory response of tumors. CONCLUSIONS BSAT and its active ingredients have showed promising anticancer activity and significantly inhibit the invasion and metastasis of lung cancer. A growing number of studies have realized their potential clinical significance in the therapy of lung cancer, which will provide substantial evidences for the development of new TCM for lung cancer therapy.
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Affiliation(s)
- Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zhe Sun
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zehuai Guo
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Peiqin Li
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Qianqian Mao
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yang Tang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Hongyu Chen
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Huiting Peng
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Sisi Wang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yang Cao
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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Li Z, Jiang D, Liu F, Li Y. Involvement of ZDHHC9 in lung adenocarcinoma: regulation of PD-L1 stability via palmitoylation. In Vitro Cell Dev Biol Anim 2023; 59:193-203. [PMID: 37002491 DOI: 10.1007/s11626-023-00755-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/20/2023] [Indexed: 04/03/2023]
Abstract
Palmitoylation is a post-translational modification occurring on cysteine residues, which process is catalyzed by a family of zinc finger Asp-His-His-Cys (DHHC) domain-containing (ZDHHC) protein acyltransferases. As a family member, ZDHHC9 plays a crucial role in varied malignancies by regulating protein stability via protein substrate palmitoylation. Based on the bioinformatic analysis of GEO gene microarray GSE75037 (|log2 fold change|> 1, P < 0.05), ZDHHC9 was defined as a significantly upregulated gene in lung adenocarcinoma (LUAD), which was also confirmed in our collected clinical specimens. It is necessary to explore the biological function of ZDHHC9 in LUAD cells. The follow-up functional experiments revealed that ZDHHC9 deficiency inhibited proliferation, migration, and invasion, while stimulated apoptosis in HCC827 cells. Besides, these malignant phenotypes could be accelerated by ZDHHC9 overexpression in A549. Moreover, we revealed that ZDHHC9 knockdown could promote PD-L1 protein degradation by reducing its palmitoylation level. The reduction of PD-L1 protein level could enhance anti-tumor immunity and inhibit the growth of LUAD cells. Therefore, our study uncovers the tumor-promoting role of ZDHHC9 in LUAD via regulating PD-L1 stability through palmitoylation, highlighting ZDHHC9 as a novel therapeutic target for LUAD.
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Zhang Z, Li X, Wang Y, Wei Y, Wei X. Involvement of inflammasomes in tumor microenvironment and tumor therapies. J Hematol Oncol 2023; 16:24. [PMID: 36932407 PMCID: PMC10022228 DOI: 10.1186/s13045-023-01407-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/08/2023] [Indexed: 03/19/2023] Open
Abstract
Inflammasomes are macromolecular platforms formed in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns, whose formation would cause maturation of interleukin-1 (IL-1) family members and gasdermin D (GSDMD), leading to IL-1 secretion and pyroptosis respectively. Several kinds of inflammasomes detecting different types of dangers have been found. The activation of inflammasomes is regulated at both transcription and posttranscription levels, which is crucial in protecting the host from infections and sterile insults. Present findings have illustrated that inflammasomes are involved in not only infection but also the pathology of tumors implying an important link between inflammation and tumor development. Generally, inflammasomes participate in tumorigenesis, cell death, metastasis, immune evasion, chemotherapy, target therapy, and radiotherapy. Inflammasome components are upregulated in some tumors, and inflammasomes can be activated in cancer cells and other stromal cells by DAMPs, chemotherapy agents, and radiation. In some cases, inflammasomes inhibit tumor progression by initiating GSDMD-mediated pyroptosis in cancer cells and stimulating IL-1 signal-mediated anti-tumor immunity. However, IL-1 signal recruits immunosuppressive cell subsets in other cases. We discuss the conflicting results and propose some possible explanations. Additionally, we also summarize interventions targeting inflammasome pathways in both preclinical and clinical stages. Interventions targeting inflammasomes are promising for immunotherapy and combination therapy.
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Affiliation(s)
- Ziqi Zhang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xue Li
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yang Wang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yuquan Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xiawei Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
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Spotlight on CYP4B1. Int J Mol Sci 2023; 24:ijms24032038. [PMID: 36768362 PMCID: PMC9916508 DOI: 10.3390/ijms24032038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to tissue-specific toxicities. Similar to other members of the CYP4 family, CYP4B1 has the ability to hydroxylate fatty acids and fatty alcohols. Structural insights into the enigmatic role of CYP4B1 with functions in both, xenobiotic and endobiotic metabolism, as well as its unusual heme-binding characteristics are now possible by the recently solved crystal structures of native rabbit CYP4B1 and the p.E310A variant. Importantly, CYP4B1 does not play a major role in hepatic P450-catalyzed phase I drug metabolism due to its predominant extra-hepatic expression, mainly in the lung. In addition, no catalytic activity of human CYP4B1 has been observed owing to a unique substitution of an evolutionary strongly conserved proline 427 to serine. Nevertheless, association of CYP4B1 expression patterns with various cancers and potential roles in cancer development have been reported for the human enzyme. This review will summarize the current status of CYP4B1 research with a spotlight on its roles in the metabolism of endogenous and exogenous compounds, structural properties, and cancer association, as well as its potential application in suicide gene approaches for targeted cancer therapy.
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Jie Y, Wu J, An D, Li M, He H, Wang D, Gu A, E M. Molecular characterization based on tumor microenvironment-related signatures for guiding immunotherapy and therapeutic resistance in lung adenocarcinoma. Front Pharmacol 2023; 14:1099927. [PMID: 36726580 PMCID: PMC9884810 DOI: 10.3389/fphar.2023.1099927] [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: 11/16/2022] [Accepted: 01/03/2023] [Indexed: 01/19/2023] Open
Abstract
Background: Although the role of tumor microenvironment in lung adenocarcinoma (LUAD) has been explored in a number of studies, the value of TME-related signatures in immunotherapy has not been comprehensively characterized. Materials and Methods: Consensus clustering was conducted to characterize TME-based molecular subtypes using transcription data of LUAD samples. The biological pathways and immune microenvironment were assessed by CIBERSORT, ESTIMATE, and gene set enrichment analysis. A TME-related risk model was established through the algorithms of least absolute shrinkage and selection operator (Lasso) and stepwise Akaike information criterion (stepAIC). Results: Four TME-based molecular subtypes including C1, C2, C3, and C4 were identified, and they showed distinct overall survival, genomic characteristics, DNA methylation pattern, immune microenvironment, and biological pathways. C1 had the worst prognosis and high tumor proliferation rate. C3 and C4 had higher enrichment of anti-tumor signatures compared to C1 and C2. C4 had evidently low enrichment of epithelial-mesenchymal transition (EMT) signature and tumor proliferation rate. C3 was predicted to be more sensitive to immunotherapy compared with other subtypes. C1 is more sensitive to chemotherapy drugs, including Docetaxel, Vinorelbine and Cisplatin, while C3 is more sensitive to Paclitaxel. A five-gene risk model was constructed, which showed a favorable performance in three independent datasets. Low-risk group showed a longer overall survival, more infiltrated immune cells, and higher response to immunotherapy than high-risk group. Conclusion: This study comprehensively characterized the molecular features of LUAD patients based on TME-related signatures, demonstrating the potential of TME-based signatures in exploring the mechanisms of LUAD development. The TME-related risk model was of clinical value to predict LUAD prognosis and guide immunotherapy.
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Affiliation(s)
- Yamin Jie
- Department of Radiation Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jianing Wu
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dongxue An
- Department of Radiation Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Man Li
- Department of Endoscopy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hongjiang He
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Duo Wang
- Department of Neurology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Anxin Gu
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Mingyan E
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Zhang D, Zhao Y. Identification of natural killer cell associated subtyping and gene signature to predict prognosis and drug sensitivity of lung adenocarcinoma. Front Genet 2023; 14:1156230. [PMID: 37091780 PMCID: PMC10119412 DOI: 10.3389/fgene.2023.1156230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/20/2023] [Indexed: 04/25/2023] Open
Abstract
Introduction: This research explored the immune characteristics of natural killer (NK) cells in lung adenocarcinoma (LUAD) and their predictive role on patient survival and immunotherapy response. Material and methods: Molecular subtyping of LUAD samples was performed by evaluating NK cell-associated pathways and genes in The Cancer Genome Atlas (TCGA) dataset using consistent clustering. 12 programmed cell death (PCD) patterns were acquired from previous study. Riskscore prognostic models were constructed using Least absolute shrinkage and selection operator (Lasso) and Cox regression. The model stability was validated in Gene Expression Omnibus database (GEO). Results: We classified LUAD into three different molecular subgroups based on NK cell-related genes, with the worst prognosis in C1 patients and the optimal in C3. Homologous Recombination Defects, purity and ploidy, TMB, LOH, Aneuploidy Score, were the most high-expressed in C1 and the least expressed in C3. ImmuneScore was the highest in C3 type, suggesting greater immune infiltration in C3 subtype. C1 subtypes had higher TIDE scores, indicating that C1 subtypes may benefit less from immunotherapy. Generally, C3 subtype presented highest PCD patterns scores. With four genes, ANLN, FAM83A, RHOV and PARP15, we constructed a LUAD risk prediction model with significant differences in immune cell composition, cell cycle related pathways between the two risk groups. Samples in C1 and high group were more sensitive to chemotherapy drug. The score of PCD were differences in high- and low-groups. Finally, we combined Riskscore and clinical features to improve the performance of the prediction model, and the calibration curve and decision curve verified that the great robustness of the model. Conclusion: We identified three stable molecular subtypes of LUAD and constructed a prognostic model based on NK cell-related genes, maybe have a greater potential for application in predicting immunotherapy response and patient prognosis.
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Affiliation(s)
- Dexin Zhang
- Respiratory Department of the Second Affiliated Hospital of Xi’an Jiaotong University Medical College, Xi’an, China
- *Correspondence: Dexin Zhang,
| | - Yujie Zhao
- Regional Marketing Department, Yuce Biotechnology Co, Ltd., Dabaihui Center, Shenzhen, China
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Gao S, Zhang X, Liu J, Ji F, Zhang Z, Meng Q, Zhang Q, Han X, Wu H, Yin Y, Lv Y, Shi W. Icariin Induces Triple-Negative Breast Cancer Cell Apoptosis and Suppresses Invasion by Inhibiting the JNK/c-Jun Signaling Pathway. Drug Des Devel Ther 2023; 17:821-836. [PMID: 36969705 PMCID: PMC10038011 DOI: 10.2147/dddt.s398887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/04/2023] [Indexed: 03/29/2023] Open
Abstract
Background Breast cancer is a common cancer worldwide. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by a poor prognosis. Icariin (ICA) is a flavonoid glycoside purified from the natural product Epimedium, which is reported to exert an inhibitory effect on a variety of cancers. However, molecular mechanisms behind ICA suppressed TNBC remain elusive. Methods The curative effects of ICA on TNBC cells and potential targets were predicted by network pharmacology and molecular biology methods screening, and the mechanism of inhibition was explained through in vitro experiments such as cell function determination, Western blot analysis, molecular docking verification, etc. Results This study showed that ICA inhibits TNBC cell functions such as proliferation, migration, and invasion in a dose-dependent manner. ICA could induce redox-induced apoptosis in TNBC cell, as shown by ROS upregulation. As a result of network pharmacology, ICA was predicted to be able to inhibit the MAPK signaling pathway. ICA treatment inhibited the expression of JNK and c-Jun and downregulated the antiapoptotic gene cIAP-2. Our results suggested that ICA could induce apoptosis by inducing an excessive accumulation of ROS in cells and suppress TNBC cell invasion via the JNK/c-Jun signaling pathway. Conclusion We demonstrated that ICA can effectively inhibit cell proliferation and induced apoptosis of TNBC cells. In addition, ICA could inhibit TNBC cell invasion through the JNK/c-Jun signaling pathway. The above suggests that ICA may become a potential drug for TNBC.
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Affiliation(s)
- Shenghan Gao
- The College of Life Sciences, Northwest University, Xi’an, 710069People’s Republic of China
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Xinyu Zhang
- The College of Life Sciences, Northwest University, Xi’an, 710069People’s Republic of China
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Jie Liu
- Clinical Medical Center, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Fuqing Ji
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Zhihao Zhang
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Qingjie Meng
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Qi Zhang
- The College of Life Sciences, Northwest University, Xi’an, 710069People’s Republic of China
| | - Xiaogang Han
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - He Wu
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Yulong Yin
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
| | - Yonggang Lv
- Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
- Correspondence: Yonggang Lv, Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China, Email
| | - Wenzhen Shi
- Clinical Medical Center, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China
- Wenzhen Shi, Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, School of Life Sciences and Medicine, Northwest University, Xi’an, People’s Republic of China, Tel +8615037916770, Email
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Zhu YP, Deng HT, Wang X, Rahat MA, Sun S, Zhang QZ. Cuproptosis-related molecular subtypes direct T cell exhaustion phenotypes and therapeutic strategies for patients with lung adenocarcinoma. Front Pharmacol 2023; 14:1146468. [PMID: 37113755 PMCID: PMC10126426 DOI: 10.3389/fphar.2023.1146468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/29/2023] [Indexed: 04/29/2023] Open
Abstract
Background: T cell exhaustion (TEX) heterogeneity leads to unfavorable immunotherapeutic responses in patients with cancer. Classification of TEX molecular phenotypes is pivotal to overcoming TEX and improving immunotherapies in the clinical setting. Cuproptosis is a novel form of programmed cell death associated with tumor progression. However, the relation between cuproptosis-related genes (CuRGs) and the different TEX phenotypes has not been investigated in lung adenocarcinoma (LUAD). Methods: Unsupervised hierarchical clustering and principal component analysis (PCA) algorithm were performed to determine CuRGs-related molecular subtypes and scores for patients with LUAD. The tumor immune microenvironment (TIME) landscape in these molecular subtypes and scores was estimated using ESTIMATE and ssGSEA algorithms. Furthermore, TEX characteristics and phenotypes were evaluated in distinct molecular subtypes and scores through GSVA and Spearman correlation analysis. Finally, TIDE scores, immunophenoscore, pRRophetic, GSE78220, and IMvigor210 datasets were employed to appraise the distinguishing capacity of CuRGscore in immunotherapy and pharmacotherapy effectiveness. Results: We identified three CuRGclusters, three geneClusters, and CuRGscore based on 1012 LUAD transcriptional profiles from five datasets. Compared with other molecular subtypes, CuRGcluster B, geneCluster C, and low-CuRGscore group with good prognosis presented fewer TEX characteristics, including immunosuppressive cells infiltration and TEX-associated gene signatures, signal pathways, checkpoint genes, transcription and inflammatory factors. These molecular subtypes were also responsive in distinguishing TEX phenotype in the terminal, GZMK+, and OXPHOS- TEX subtypes, but not the TCF7+ TEX subtype. Notably, copper importer and exporter, SLC31A1 and ATP7B, were remarkably associated with four TEX phenotypes and nine checkpoint genes such as PDCD1, CTLA4, HAVCR2, TIGIT, LAG3, IDO1, SIGLEC7, CD274, PDCD1LG2, indicating that cuproptosis was involved in the development of TEX and immunosuppressive environment in patients with LUAD. Moreover, CuRGscore was significantly related to the TIDE score, immunophenoscore, and terminal TEX score (Spearman R = 0.62, p < 0.001) to effectively predict immunotherapy and drug sensitivity in both training and external validation cohorts. Conclusion: Our study demonstrated the extensive effect of cuproptosis on TEX. CuRGs-related molecular subtypes and scores could illuminate the heterogeneity of TEX phenotype as reliable tools in predicting prognosis and directing more effective immunotherapeutic and chemotherapeutic strategies for patients with LUAD.
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Affiliation(s)
- Yi-Pan Zhu
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Hui-Ting Deng
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Nankai University, Tianjin, China
| | - Xiuyu Wang
- Department of Neurosurgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Michal A. Rahat
- Immunotherapy Laboratory, Carmel Medical Center, and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Shupeng Sun
- Department of Neurosurgery, Tianjin Huanhu Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Qiang-Zhe Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
- *Correspondence: Qiang-Zhe Zhang,
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Liu J, Liu Z, Yan W, Yang H, Fang S, Deng S, Wen Y, Shen P, Li Y, Hou R, Liu X, Huang T, Li R, Zheng D, Liu Z, Fang W. ENKUR recruits FBXW7 to ubiquitinate and degrade MYH9 and further suppress MYH9-induced deubiquitination of β-catenin to block gastric cancer metastasis. MedComm (Beijing) 2022; 3:e185. [PMID: 36448053 PMCID: PMC9697592 DOI: 10.1002/mco2.185] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/27/2022] Open
Abstract
ENKUR was shown as a suppressor in some tumors. However, the biological role of ENKUR on gastric cancer (GC) and its related molecular mechanisms is not clear. Here, we first observed that ENKUR significantly inhibited cell migration, invasion, and metastasis in GC. The molecular basis showed β-catenin-mediated epithelial-mesenchymal transition (EMT) signaling was inactivated in ENKUR-overexpressing GC cells. In addition, ENKUR knockdown markedly restored cell migration and invasion. Subsequently, ENKUR bound to MYH9 and decreased its protein expression by recruiting E3 ubiquitin ligase FBXW7 to form an ubiquitinated degradation complex. The downregulated MYH9 protein weakened the recruitment of the deubiquitinase USP2 and thus promoted the degradation of β-catenin protein, which finally suppressed EMT signaling. Finally, the oncogenic transcription factor c-Jun bound to ENKUR promoter and reduced its expression in GC. In clinical samples, decreased ENKUR expression promoted the unfavorable prognosis of GC. Our data proved the vital role of ENKUR on suppressing cell migration, invasion, and metastasis and demonstrated its potential as a therapeutic target for GC.
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Affiliation(s)
- Jiahao Liu
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Zhan Liu
- Department of GastroenterologyHunan People's HospitalChangshaP.R. China
| | - Weiwei Yan
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Huiling Yang
- School of PharmacyGuangdong Medical UniversityDongguanP.R. China
| | - Shiyi Fang
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
- School of Public HealthUniversity of South ChinaHengyangP. R. China
| | - Shuting Deng
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Yinghao Wen
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Peng Shen
- Oncology DepartmentNanfang HospitalSouthern Medical UniversityGuangzhouP.R. China
| | - Yonghao Li
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Rentao Hou
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Xiong Liu
- Oncology DepartmentNanfang HospitalSouthern Medical UniversityGuangzhouP.R. China
| | - Tao Huang
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Rong Li
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Dayong Zheng
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
| | - Zhen Liu
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
- Key Laboratory of Protein Modification and DegradationBasic School of Guangzhou Medical UniversityGuangzhouP. R. China
| | - Weiyi Fang
- Cancer Center, Integrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouP. R. China
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Wu G, Feng D, Zhang Z, Zhang G, Zhang W. Establishment of lung adenocarcinoma classification and risk model based on necroptosis-related genes. Front Genet 2022; 13:1037011. [PMID: 36452156 PMCID: PMC9702361 DOI: 10.3389/fgene.2022.1037011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/26/2022] [Indexed: 03/14/2024] Open
Abstract
Lung adenocarcinoma (LUAD) is the most widely known histological subtype of lung cancer. Its classification is significant for the characteristic evaluation of patients. The aim of this research is to assess the categorization of LUAD and its risk model based on necroptosis and to investigate its potential regulatory mechanisms for diagnosing and treating LUAD. According to the expression profile data along with the clinical information related to LUAD from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we constructed a consistency matrix through consistency clustering, and used the ConsensusClusterPlus as the measurement distance to cluster and subtype the samples, and performed gene set enrichment analysis and immune infiltration analysis. Least absolute shrinkage and selection operator (Lasso) regression was utilized for obtaining prognostic significant necroptosis phenotype-related genes. Finally, we measured each patient's riskscore (RS) and build a risk model, and predicted the effect of immunotherapy for different groups of risk factors in the model. Three molecular subtypes of LUAD were obtained by cluster analysis of necroptosis-related genes in LUAD samples. Compared with C1, C3 had a better prognosis and higher immune cell infiltration. The prognosis of the C1 subtype was poor and had a high clinical grade. The proportion of Stage II, Stage III, and Stage IV was much more in comparison with that of the other two subtypes. TP53 gene had a high mutation frequency in the C1 subtype. Gene Set Enrichment Analysis (GSEA) indicated that the aberrant pathways in the C1 and C3 subtypes mainly included some cell cycle-related pathways. In addition, seven genes were identified as related genes of necroptosis phenotype affecting prognosis. High RS had a poor prognosis, while low RS had a good prognosis. The RS was verified to have a strong ability to predict survival. LUAD can be classified by the genes linked with cell necrosis and apoptosis. The difference among various types is helpful to deepen the understanding of LUAD. In addition, a risk model was constructed based. In conclusion, this study provides potential detection targets and treatment methods for LUAD from a new perspective.
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Affiliation(s)
- Guodong Wu
- Department of Thoracic and Cardiovascular Surgery, The First Hospital of Fangshan District, Beijing, China
| | - Dingwei Feng
- Department of Thoracic Surgery, Beijing Yanhua Hospital, Beijing, China
| | - Ziyu Zhang
- Department of Thoracic and Cardiovascular Surgery, The First Hospital of Fangshan District, Beijing, China
| | - Gao Zhang
- Department of Thoracic and Cardiovascular Surgery, The First Hospital of Fangshan District, Beijing, China
| | - Wei Zhang
- Department of Thoracic and Cardiovascular Surgery, The First Hospital of Fangshan District, Beijing, China
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Wang X, Liu Y, Ding Y, Feng G. CAMSAP2 promotes colorectal cancer cell migration and invasion through activation of JNK/c-Jun/MMP-1 signaling pathway. Sci Rep 2022; 12:16899. [PMID: 36207462 PMCID: PMC9546856 DOI: 10.1038/s41598-022-21345-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
CAMSAP2 has been reported to act as an oncogene in hepatocellular carcinoma. However, the expression CAMSAP2 and its potential roles in colorectal cancer remain unclear. In this study, qRT-PCR and immunoblotting analysis were used to detect the mRNA and protein levels of CAMSAP2 in colorectal cancer tissues and cell lines. Wound-healing, transwell migration and invasion assay were performed to determine whether CAMSAP2 promotes the capabilities of migration and invasion of colorectal cancer cells. The results showed that CAMSAP2 was highly elevated in colorectal cancer tissues and cell lines. Moreover, the high CAMSAP2 expression was positively correlated with tumor invasion depth, lymph node metastasis, distant metastasis, and the poor prognosis of colorectal cancer. Additionally, ectopic expression of CAMSAP2 in colorectal cancer cells promoted the migration and invasion in vitro and enhanced the lung metastasis in nude mice. Conversely, silencing CAMSAP2 resulted in an opposite phenomenon. By gain- and loss-of function experiments, we demonstrated that MMP-1 was a substantial downstream target of CAMSAP2, and it played a crucial role in regulating the migration and invasion induced by CAMSAP2 in colorectal cancer cells. Mechanistically, CAMSAP2 promoted the activation of JNK/c-Jun signaling pathway and subsequently upregulated the transcription activity of MMP-1. Taken together, our findings demonstrated that CAMSAP2 promoted colorectal cancer cell migration, invasion and metastasis through activation of JNK/c-Jun/MMP-1 signaling pathway, indicating CAMSAP2 is a promising therapeutic target for the treatment of metastatic colorectal cancer patients.
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Affiliation(s)
- Xiaojuan Wang
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 473 Hanzheng Street, Wuhan, 430000, Hubei, China
| | - Yumin Liu
- Department of Obstetrics and Gynecology, Wuhan Hankou Hospital, Wuhan, 430010, Hubei, China
| | - Yawen Ding
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 473 Hanzheng Street, Wuhan, 430000, Hubei, China
| | - Gang Feng
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 473 Hanzheng Street, Wuhan, 430000, Hubei, China.
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He M, Wu G, Wang Z, Ren K, Yang Z, Xue Q. Development and validation of a TRP-related gene signature for overall survival prediction in lung adenocarcinoma. Front Genet 2022; 13:905650. [PMID: 36186485 PMCID: PMC9521679 DOI: 10.3389/fgene.2022.905650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/25/2022] [Indexed: 11/29/2022] Open
Abstract
The transient receptor potential (TRP) channel is a type of channel protein widely distributed in peripheral and central nervous systems. Genes encoding TRP can be regulated by natural aromatic substances and serve as a therapeutic target for many diseases. However, the role of TRP-related genes in lung adenocarcinoma (LUAD) remains unclear. In this study, we used data from TCGA to screen and identify 17 TRP-related genes that are differentially expressed between LUAD and normal lung tissues. Based on these differentially expressed genes (DEGs), we classified all patients with LUAD into two subtypes. Significant differences in prognosis, clinical features, and immune cell infiltration characteristics were observed between the two subtypes. Subsequently, a prognostic signature with 12 genes was established by applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, and all patients with LUAD were classified into low- and high-risk groups. Patients with LUAD in the low-risk group had a significantly longer survival time than those in the high-risk group (p < 0.001), which was confirmed by LUAD data from the GSE72094 and GSE68571 validation datasets. Combined with clinical characteristics, the risk score was found to be an independent predictor of overall survival (OS) in patients with LUAD. Additionally, patients with high TRP scores exhibited poorer clinical characteristics and immune status while showing a sensitive response to chemotherapeutic agents. In conclusion, the TRP score is a promising biomarker for determining the prognosis, molecular subtype, tumor microenvironment, and guiding personalized treatment in patients with LUAD.
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Affiliation(s)
- Min He
- Medical College of Nantong University, Nantong, Jiangsu, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Gujie Wu
- Medical College of Nantong University, Nantong, Jiangsu, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Ziheng Wang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Kuan Ren
- Medical College of Nantong University, Nantong, Jiangsu, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Zheng Yang
- Cardiothoracic Surgery Department, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- *Correspondence: Qun Xue, ; Zheng Yang,
| | - Qun Xue
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- *Correspondence: Qun Xue, ; Zheng Yang,
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Tu J, Tang M, Li G, Chen L, Huang Y. Molecular Typing Based on Oxidative Stress Genes and Establishment of Prognostic Characteristics of 7 Genes in Lung Adenocarcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9683819. [PMID: 36148413 PMCID: PMC9485712 DOI: 10.1155/2022/9683819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/25/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022]
Abstract
Oxidative stress could maintain different biological processes in human cancer. However, the effect of oxidative stress on lung adenocarcinoma (LUAD) should be studied. This study analyzed the expression and clinical importance of oxidative stress in LUAD in detail. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were employed for obtaining LUAD expression profiles. Based on oxidative stress-related genes, molecular subtypes substantially correlated with the LUAD prognosis were discovered with ConsensusClusterPlus. Differentially expressed genes (DEGs) among subtypes were found using the Limma software package. Least absolute shrinkage and selection operator- (Lasso-) Cox analysis was employed to create the polygenic risk model. RiskScore and clinically relevant features were used to create nomograms. By utilizing oxidative stress-related genes and reliable clustering, stable molecular subtypes were first discovered. The prognosis, clinical characteristics, route characteristics, and immunological characteristics of these three molecular subtypes were all different. Subsequently, by using differential expression genes among molecular subtypes and Lasso, 7 main genes linked with the oxidative stress phenotype were discovered. A prognostic risk model was also built on the basis of major genes associated with the oxidative stress phenotype. The model demonstrated a high level of resilience and was unaffected by clinical-pathological features. It played a stable predictive role in independent datasets. Ultimately, to improve the prognosis model and survival prediction, RiskScore (RS) was combined with clinicopathological variables, and a decision tree model was used. The model exhibited a high prediction accuracy as well as the ability to predict survival. This research found that oxidative stress-related genes have a major involvement in the onset and progression of LUAD and that they may influence LUAD susceptibility to immunotherapy and standard chemotherapy. Furthermore, the identified risk models for 7 genes linked with oxidative stress exhibited could assist clinical treatment decisions and prognosis prediction. The classifier could be used as a molecular diagnostic tool for assessing LUAD patients' prognosis risk.
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Affiliation(s)
- Jing Tu
- Department of Pulmonary and Critical Care Medicine, Chongqing General Hospital, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China
| | - Min Tang
- Department of Oncology, Chongqing General Hospital, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China
| | - Guoqing Li
- Department of Pulmonary and Critical Care Medicine, Chongqing General Hospital, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China
| | - Liang Chen
- Intensive Care Unit, Chongqing General Hospital, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China
| | - Yong Huang
- Department of Pulmonary and Critical Care Medicine, Chongqing General Hospital, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China
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Xu Y, Wang Y, Liang L, Song N. Single-cell RNA sequencing analysis to explore immune cell heterogeneity and novel biomarkers for the prognosis of lung adenocarcinoma. Front Genet 2022; 13:975542. [PMID: 36147484 PMCID: PMC9486955 DOI: 10.3389/fgene.2022.975542] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/22/2022] [Indexed: 01/17/2023] Open
Abstract
Background: Single-cell RNA sequencing is necessary to understand tumor heterogeneity, and the cell type heterogeneity of lung adenocarcinoma (LUAD) has not been fully studied.Method: We first reduced the dimensionality of the GSE149655 single-cell data. Then, we statistically analysed the subpopulations obtained by cell annotation to find the subpopulations highly enriched in tumor tissues. Monocle was used to predict the development trajectory of five subpopulations; beam was used to find the regulatory genes of five branches; qval was used to screen the key genes; and cellchart was used to analyse cell communication. Next, we used the differentially expressed genes of TCGA-LUAD to screen for overlapping genes and established a prognostic risk model through univariate and multivariate analyses. To identify the independence of the model in clinical application, univariate and multivariate Cox regression were used to analyse the relevant HR, 95% CI of HR and p value. Finally, the novel biomarker genes were verified by qPCR and immunohistochemistry.Results: The single-cell dataset GSE149655 was subjected to quality control, filtration and dimensionality reduction. Finally, 23 subpopulations were screened, and 11-cell subgroups were annotated in 23 subpopulations. Through the statistical analysis of 11 subgroups, five important subgroups were selected, including lung epithelial cells, macrophages, neuroendocrine cells, secret cells and T cells. From the analysis of cell trajectory and cell communication, it is found that the interaction of five subpopulations is very complex and that the communication between them is dense. We believe that these five subpopulations play a very important role in the occurrence and development of LUAD. Downloading the TCGA data, we screened the marker genes of these five subpopulations, which are also the differentially expressed genes in tumorigenesis, with a total of 462 genes, and constructed 10 gene prognostic risk models based on related genes. The 10-gene signature has strong robustness and can achieve stable prediction efficiency in datasets from different platforms. Two new molecular markers related to LUAD, HLA-DRB5 and CCDC50, were verified by qPCR and immunohistochemistry. The results showed that HLA-DRB5 expression was negatively correlated with the risk of LUAD, and CCDC50 expression was positively correlated with the risk of LUAD.Conclusion: Therefore, we identified a prognostic risk model including CCL20, CP, HLA-DRB5, RHOV, CYP4B1, BASP1, ACSL4, GNG7, CCDC50 and SPATS2 as risk biomarkers and verified their predictive value for the prognosis of LUAD, which could serve as a new therapeutic target.
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Affiliation(s)
| | | | | | - Nan Song
- *Correspondence: Leilei Liang, ; Nan Song,
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Identification of Cigarette Smoking-Related Novel Biomarkers in Lung Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9170722. [PMID: 35769670 PMCID: PMC9234045 DOI: 10.1155/2022/9170722] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 01/01/2023]
Abstract
Objective The aims of this study were to screen the gene mutations that are able to predict the risk of cigarette smoking-related lung adenocarcinoma (LUAD) and to evaluate its prognostic significance. Methods Clinical data and genetic information were retrieved from the TCGA database, and the patients with LUAD were divided into three groups including never smoking, light smoking, and heavy smoking according to cigarette smoking dose. Differentially mutated genes (DMGs) of each group were analyzed. At the same time, the function of DMGs in three smoking groups was evaluated by GO function and KEGG pathway analysis. The driver genes and protein variation effect of DMGs were performed to further screen key genes. The survival characteristics of the gene expression and mutation of those genes were analyzed and plotted to visualize by the Kaplan-Meier model. Result The DMGs for different smoking doses were identified. The driver and deleterious mutation in the DMGs were screened and gene interaction network was constructed. The DMGs with driver mutations and deleterious mutations that were associated with the overall survival in the heavy smoking patients were considered as the candidate genes for novel markers of smoking-related LUAD. The final novel risk factor gene was identified as MYH7 and the high express of MYH7 in LUAD correlation with patients' gender, lymph node metastasis, T stage, and clinical stage. Conclusions In summary, it can be concluded that MYH7 is a novel biomarker for heavy smoking-related LUAD and it is significantly correlated with the prognosis of lung cancer and is related to the clinical characteristics of lung cancer.
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Gong X, Li N, Sun C, Li Z, Xie H. A Four-Gene Prognostic Signature Based on the TEAD4 Differential Expression Predicts Overall Survival and Immune Microenvironment Estimation in Lung Adenocarcinoma. Front Pharmacol 2022; 13:874780. [PMID: 35600867 PMCID: PMC9114646 DOI: 10.3389/fphar.2022.874780] [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: 02/13/2022] [Accepted: 04/08/2022] [Indexed: 12/24/2022] Open
Abstract
Background: TEA domain transcription factor 4 (TEAD4) is a member of the transcriptional enhancer factor (TEF) family of transcription factors, which is studied to be linked to the tumorigenesis and progression of various forms of cancers, including lung adenocarcinoma (LUAD). However, the specific function of this gene in the progression of LUAD remains to be explored. Method: A total of 19 genes related to the Hippo pathway were analyzed to identify the significant genes involved in LUAD progression. The TCGA-LUAD data (n = 585) from public databases were mined, and the differentially expressed genes (DEGs) in patients with the differential level of TEAD4 were identified. The univariate Cox regression, zero LASSO regression coefficients, and multivariate Cox regression were performed to identify the independent prognostic signatures. The immune microenvironment estimation in the two subgroups, including immune cell infiltration, HLA family genes, and immune checkpoint genes, was assessed. The Gene Set Enrichment Analysis (GSEA) and GO were conducted to analyze the functional enrichment of DEGs between the two risk groups. The potential drugs for the high-risk subtypes were forecasted via the mode of action (moa) module of the connectivity map (CMap) database. Results:TEAD4 was found to be significantly correlated with poor prognosis in LUAD-patients. A total of 102 DEGs in TEAD4-high vs. TEAD4-low groups were identified. Among these DEGs, four genes (CPS1, ANLN, RHOV, and KRT6A) were identified as the independent prognostic signature to conduct the Cox risk model. The immune microenvironment estimation indicated a strong relationship between the high TEAD4 expression and immunotherapeutic resistance. The GSEA and GO showed that pathways, including cell cycle regulation, were enriched in the high-risk group, while immune response-related and metabolism biological processes were enriched in the low-risk group. Several small molecular perturbagens targeting CFTR or PLA2G1B, by the mode of action (moa) modules of the glucocorticoid receptor agonist, cyclooxygenase inhibitor, and NFkB pathway inhibitor, were predicted to be suited for the high-risk subtypes based on the high TEAD4 expression. Conclusion: The current study revealed TEAD4 is an immune regulation–related predictor of prognosis and a novel therapeutic target for LUAD.
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Affiliation(s)
- Xiaoxia Gong
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, China
| | - Ning Li
- Cardiovascular Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Chen Sun
- Hematology Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Zhaoshui Li
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Hao Xie
- School of Life Science and Technology, MOE Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, China
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Wang R, Liu H, Dong M, Huang D, Yi J. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis. Open Med (Wars) 2022; 17:826-840. [PMID: 35582196 PMCID: PMC9055259 DOI: 10.1515/med-2022-0428] [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: 09/12/2021] [Revised: 12/07/2021] [Accepted: 01/03/2022] [Indexed: 12/25/2022] Open
Abstract
This study aims to explore the function and mechanism of exosomal circ_0000519 in non-small cell lung cancer (NSCLC) development. Expression of circ_0000519, microRNA (miR)-1258, and Ras homolog gene family V (RHOV) in serum samples of NSCLC patients or cell lines were examined via quantitative reverse transcription-polymerase chain reaction and Western blotting. The function of circ_0000519 was evaluated through 5-ethynyl-2′-deoxyuridine (EdU) staining, colony formation, transwell, Western blotting, xenograft, and immunohistochemistry analyses. The binding relationship was evaluated by a dual-luciferase reporter assay and RNA pull-down assay. Results showed that circ_0000519 abundance was enhanced in the serum samples of NSCLC patients and cells. circ_0000519 knockdown suppressed the cell growth by decreasing the colony-formation ability and Cyclin D1 expression and inhibited cell metastasis via reducing migration, invasion, and levels of Vimentin and matrix metalloproteinase 9 (MMP9). circ_0000519 overexpression promoted cell growth and metastasis. circ_0000519 was carried by exosomes and knockdown of exosomal circ_0000519 suppressed the cell growth and metastasis. miR-1258 was downregulated in NSCLC cells and targeted by circ_0000519. RHOV was targeted by miR-1258 and upregulated in the NSCLC cells. miR-1258 knockdown or RHOV overexpression attenuated the influence of exosomal circ_0000519 knockdown on cell growth and metastasis. Exosomal circ_0000519 knockdown decreased xenograft tumor growth. Collectively, the knockdown of exosomal circ_0000519 repressed the cell growth and metastasis in NSCLC through the miR-1258/RHOV axis, which provided a new insight into NSCLC development and treatment.
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Affiliation(s)
- Rui Wang
- Department of Oncology, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Hongliu Liu
- Department of Oncology, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Mingqiang Dong
- Department of Oncology, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Dan Huang
- Department of Health Care for Cadres, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
| | - Jun Yi
- Department of Cardiothoracic Surgery, Jingmen No. 1 People's Hospital, Jingmen, Hubei, China
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Aspenström P. The Role of Fast-Cycling Atypical RHO GTPases in Cancer. Cancers (Basel) 2022; 14:cancers14081961. [PMID: 35454871 PMCID: PMC9029563 DOI: 10.3390/cancers14081961] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary For many years, cancer-associated mutations in RHO GTPases were not identified and observations suggesting roles for RHO GTPases in cancer were sparse. Instead, RHO GTPases were considered primarily to regulate cell morphology and cell migration, processes that rely on the dynamic behavior of the cytoskeleton. This notion is in contrast to the RAS proteins, which are famous oncogenes and found to be mutated at high incidence in human cancers. Recent advancements in the tools for large-scale genome analysis have resulted in a paradigm shift and RHO GTPases are today found altered in many cancer types. This review article deals with the recent views on the roles of RHO GTPases in cancer, with a focus on the so-called fast-cycling RHO GTPases. Abstract The RHO GTPases comprise a subfamily within the RAS superfamily of small GTP-hydrolyzing enzymes and have primarily been ascribed roles in regulation of cytoskeletal dynamics in eukaryotic cells. An oncogenic role for the RHO GTPases has been disregarded, as no activating point mutations were found for genes encoding RHO GTPases. Instead, dysregulated expression of RHO GTPases and their regulators have been identified in cancer, often in the context of increased tumor cell migration and invasion. In the new landscape of cancer genomics, activating point mutations in members of the RHO GTPases have been identified, in particular in RAC1, RHOA, and CDC42, which has suggested that RHO GTPases can indeed serve as oncogenes in certain cancer types. This review describes the current knowledge of these cancer-associated mutant RHO GTPases, with a focus on how their altered kinetics can contribute to cancer progression.
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Affiliation(s)
- Pontus Aspenström
- Rudbeck Laboratory, Department of Immunology, Genetics and Pathology (IGP), Uppsala University, SE-751 85 Uppsala, Sweden
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Sun L, Ding S, Luo Q, Wang P, Yang X, Wu L, Chen Y, Zheng X, Zhang H, Yuan L, Ruan S, Xie C. Taxus wallichiana var. chinensis (Pilg.) Florin Aqueous Extract Suppresses the Proliferation and Metastasis in Lung Carcinoma via JAK/STAT3 Signaling Pathway. Front Pharmacol 2021; 12:736442. [PMID: 34867344 PMCID: PMC8635059 DOI: 10.3389/fphar.2021.736442] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/30/2021] [Indexed: 11/23/2022] Open
Abstract
As one of the most common neoplasms globally, lung cancer (LC) is the leading cause of cancer-related mortality. Recurrence and metastasis negatively influencing therapeutic efficacy and overall survival demand new strategies in LC treatment. The advantages of TCM are increasingly highlighted. In this study, we obtained the major chemical components and their ratios in the aqueous extract of Taxus wallichiana var. chinensis (Pilg.) Florin (AETW) by UPLC-Q/TOF-MS/MS detection. The CCK-8 assay revealed that AETW could selectively inhibit the growth of A549 and HCC827 cells in a dose-dependent manner with little effect on normal human lung cells. Moreover, both in vitro and in vivo experiments showed that AETW was able to suppress the capacities of cell migration and invasion and downregulate the EMT and the JAK/STAT3 signaling pathway. To further probe into the molecular mechanism, the overexpression of STAT3 was performed into LC cells with AETW treatment, which counteracted the inhibitory effect on malignant behaviors of A549 and HCC827 cells with the decline in the expressions of p-JAK and p-STAT3. Taken together, we propose that AETW may inhibit the proliferation and metastasis by inactivating the JAK/STAT3 axis.
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Affiliation(s)
- Leitao Sun
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Shuning Ding
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qi Luo
- Qingbo Community Health Service Center of Shangcheng District, Hangzhou, China
| | - Peipei Wang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiao Yang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Linqin Wu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yangfan Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xueer Zheng
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Hang Zhang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Yuan
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shanming Ruan
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Changsheng Xie
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
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