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Zhang Z, Xu W, Ye K, Lv S, Wu J, Zhou Y. Piperlongumine inhibits renal cell carcinoma progression by modulating the DDX11-miR-15b-3p-DLD axis. Transl Androl Urol 2025; 14:897-912. [PMID: 40376520 PMCID: PMC12076233 DOI: 10.21037/tau-2025-11] [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: 01/05/2025] [Accepted: 04/01/2025] [Indexed: 05/18/2025] Open
Abstract
Background Piperlongumine (PL) is a natural alkaloid obtained from the long pepper and can inhibit the progression of various tumors. However, its role in renal cell carcinoma (RCC) remains unclear. Thus, the purpose of this study was to determine whether PL can suppress RCC progression and to clarify the related mechanisms. Methods Cell Counting Kit-8 (CCK-8) and colony formation assays were applied to characterize the effect of PL in RCC cell proliferation; meanwhile, cellular reactive oxygen species (ROS), Fe2+ level, and mitochondrial membrane potential (MMP) assays were used to determine PL's role in mitochondrial homeostasis. Immunofluorescence experiments using MitoTracker red was applied to visualize the morphology of mitochondria. Western blotting and coimmunoprecipitation (Co-IP) and RNA immunoprecipitation (RNA-IP) assays were used to examine PL's regulation of DDX11 expression via miR-15b-3p. In addition, a xenograft mouse model was created to clarify the effect of DDX11 overexpression on RCC progression with or without PL treatment. Results We found that PL inhibited RCC cell proliferation in a dose-dependent manner by interfering with the mitochondrial homeostasis of RCC cells. In terms of mechanism, RNA sequencing showed that PL decreased the expression of DDX11, inhibited the maturation of miR-15b-3p, and further increased the level of dihydrolipoamide dehydrogenase (DLD) to disrupt the mitochondrial homeostasis of RCC cells. In addition, the vivo xenograft mouse model showed that DDX11 plays a stimulatory role in PL-induced RCC inhibition. Conclusions Our study demonstrated that DDX11 contributes to PL-induced RCC inhibition by modulating the miR-15b-3p-DLD axis.
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Affiliation(s)
- Zhenghao Zhang
- Clinical Laboratory, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Wenfang Xu
- Clinical Laboratory, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Kewen Ye
- Clinical Laboratory, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Shanmei Lv
- Clinical Laboratory, Shaoxing People’s Hospital, Shaoxing, China
| | - Jintao Wu
- Clinical Laboratory, Shaoxing People’s Hospital, Shaoxing, China
| | - Yadi Zhou
- Clinical Laboratory, Affiliated Hospital of Shaoxing University, Shaoxing, China
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Song P, Shen N, Wu Z, He S. Baicalein Inhibits Tumor Property of Hepatocellular Carcinoma Cells Through the Inactivation of the E2F Transcription Factor 1/Mediator Complex Subunit 7 Axis. Chem Biol Drug Des 2025; 105:e70063. [PMID: 39935236 DOI: 10.1111/cbdd.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 01/16/2025] [Accepted: 01/28/2025] [Indexed: 02/13/2025]
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis. Baicalein, a natural compound, can regulate multiple cellular processes in various cancer types. In this study, we investigated the role of baicalein in regulating HCC and explored its potential mechanism. The expression of mediator complex subunit 7 (MED7) and E2F transcription factor 1 (E2F1) was analyzed by quantitative real-time polymerase chain reaction or Western blotting assay. Cell proliferation was assessed by cell colony formation assay and 5-ethynyl-2'-deoxyuridine assay. Cell migration was analyzed by transwell assay and wound-healing assay. Cell invasion was analyzed by transwell assay. Angiogenic ability of HCC cells was assessed by tube formation assay. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to validate the association between E2F1 and MED7. The xenograft mouse model assay was conducted to determine the effects of baicalein and E2F1 overexpression on tumor formation. Immunohistochemistry assay was used to determine positive expression rates of proteins. Upregulation of MED7 and E2F1 expression was observed in both HCC tissues and cells. Knockdown of MED7 suppressed HCC cell proliferation, migration, invasion, and tube formation. Transcriptional activation of MED7 by E2F1 was demonstrated in HCC cells. Overexpression of MED7 mitigated the effects induced by E2F1 depletion in HCC cells. Additionally, baicalein treatment effectively inhibited the tumor property of HCC cells by decreasing E2F1 expression in both in vitro and in vivo models. Baicalein inhibited the tumor property of HCC cells through the inactivation of the E2F1/MED7 axis, highlighting its potential clinical application in the treatment of HCC.
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Affiliation(s)
- Pinghui Song
- Department of General Surgery, Shaanxi 215 Hospital of Nuclear Industry, Xianyang City, Shaanxi, China
| | - Naiying Shen
- Department of General Surgery, Shaanxi 215 Hospital of Nuclear Industry, Xianyang City, Shaanxi, China
| | - Zhongkun Wu
- Department of General Surgery, Shaanxi 215 Hospital of Nuclear Industry, Xianyang City, Shaanxi, China
| | - Sha He
- Department of Interventional, Shaanxi 215 Hospital of Nuclear Industry, Xianyang City, Shaanxi, China
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Wu HY, Cao SY, Xu ZG, Wang T, Ji GW, Wang K. Construction of a radiogenomic signature based on endoplasmic reticulum stress for predicting prognosis and systemic combination therapy response in hepatocellular carcinoma. BMC Cancer 2025; 25:131. [PMID: 39849389 PMCID: PMC11756198 DOI: 10.1186/s12885-025-13433-4] [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: 09/28/2024] [Accepted: 01/02/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. Various factors in the tumor environment (TME) can lead to the activation of endoplasmic reticulum stress (ERS), thereby affecting the occurrence and development of tumors. The objective of our study was to develop and validate a radiogenomic signature based on ERS to predict prognosis and systemic combination therapy response. METHODS Using data from The Cancer Genome Atlas Program (TCGA) as a training cohort and data from International cancer genome consortium (ICGC) as a testing cohort. Univariate Cox regression and multivariate Cox regression analysis were used to identify prognostic-related genes and construct a model. HCC single-cell data obtained from Gene Expression Omnibus (GEO) were used to map gene signatures and explore inter-cellular signaling communications. Finally, a radiogenomic signature was used to predict the objective response rate (ORR) and overall survival (OS). RESULTS A total of four gene signatures related to ERS, including Stanniocalcin-2 (STC2), Melanoma-Associated Antigen 3 (MAGEA3), BR Serine/Threonine-Protein Kinase 2 (BRSK2), DEAD/H-Box Helicase 11 (DDX11) were identified. Macrophages were significantly different between high-risk and low-risk groups. The high-risk group showed higher targeting programmed cell death-1 (PD-1) and mutated tumor protein p53 (TP53) scores. Drug sensitivity analysis found that most sensitive drugs target the phosphatidylinositol 3-kinase/ mechanistic target of rapamycin (PI3K/mTOR) signaling pathway. Further research revealed the expression of STC2 in the endothelial cells (ECs), particularly plasmalemma vesicle associated protein (PLVAP) + ECs, and may regulate the reprogramming and function of macrophages. Furthermore, we identified nine radiomic features and established a radiogenomic signature based on ERS that can predict prognosis and response to systemic combination therapy. This signature can guide systemic combination therapy for patients with unresectable HCC. CONCLUSIONS We established an ERS prognostic model that can predict patient prognosis. We also found that ERS is closely related to the TME and is mainly manifested in the interaction between tumor-associated endothelial cells (TAEs) and tumor-associated macrophages (TAMs). Moreover, we constructed a radiogenomic signature based on the ERS. This signature can guide subsequent combination therapy for patients with unresectable HCC.
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Affiliation(s)
- Huai-Yu Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China
- NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, People's Republic of China
| | - Shu-Ya Cao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China
- NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, People's Republic of China
| | - Zheng-Gang Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China
- NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, People's Republic of China
| | - Tian- Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China
- NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, People's Republic of China
| | - Gu-Wei Ji
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China.
- NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, People's Republic of China.
| | - Ke Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, People's Republic of China.
- NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, People's Republic of China.
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Shodry S, Hasan YTN, Ahdi IR, Ulhaq ZS. Gene targets with therapeutic potential in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4543-4547. [PMID: 39678796 PMCID: PMC11577361 DOI: 10.4251/wjgo.v16.i12.4543] [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: 06/27/2024] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 11/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Syifaus Shodry
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Yuliono Trika Nur Hasan
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Iwal Reza Ahdi
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Zulvikar Syambani Ulhaq
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency Republic of Indonesia, Cibinong 16911, Indonesia
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Yang G, Shi X, Zhang M, Wang K, Tian X, Wang X. DEAD/H-box helicase 11 is transcriptionally activated by Yin Yang-1 and accelerates oral squamous cell carcinoma progression. Cell Biol Int 2024; 48:1731-1742. [PMID: 39090819 DOI: 10.1002/cbin.12228] [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: 01/13/2024] [Revised: 05/28/2024] [Accepted: 07/12/2024] [Indexed: 08/04/2024]
Abstract
Oral squamous cell carcinoma (OSCC) is the most common oral malignancy. DEAD/H-box helicase 11 (DDX11), a DNA helicase, has been implicated in the progression of several cancers. Yet, the precise function of DDX11 in OSCC is poorly understood. The DDX11 expression in OSCC cells and normal oral keratinocytes was evaluated in the Gene Expression Omnibus database (GSE146483 and GSE31853). SCC-4 and CAL-27 cells expressing doxycycline-inducible DDX11 or DDX11 shRNA were generated by lentiviral infection. The role of DDX11 in OSCC cells was determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry assay, TUNEL staining, and western blot. The effects of DDX11 on tumor growth were explored in a xenograft nude mouse model. The relationship between DDX11 and transcription factor Yin Yang-1 (YY1) was researched using the dual luciferase report assay and chromatin immunoprecipitation assay. DDX11 expression was significantly upregulated in OSCC cells. Knockdown of DDX11 inhibited cell proliferation, induced cell cycle arrest, and suppressed PI3K-AKT pathway, while DDX11 overexpression showed opposite effects. The number of apoptotic cells was increased in DDX11 silenced cells. DDX11 upregulation or knockdown accelerated or suppressed tumor growth in vivo, respectively. Moreover, the YY1 bound and activated the DDX11 promoter, resulting in increasing DDX11 expression. Forced expression DDX11 reversed the anticancer effects of YY1 silencing on OSCC cells. DDX11 has tumor-promoting function in OSCC and is transcriptionally regulated by YY1, indicating that DDX11 may serve as a potential target for the OSCC treatment.
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Affiliation(s)
- Guang Yang
- Department of Oral & Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Oral & Maxillofacial Surgery, The First Hospital of Qiqihar, Qiqihar, China
| | - Xin Shi
- Department of Oral & Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Meixia Zhang
- Department of Oral & Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kaiwen Wang
- Department of Medical Affairs, The First Hospital of Qiqihar, Qiqihar, China
| | - Xin Tian
- Office of Academic Affairs, Qiqihar University, Qiqihar, China
| | - Xiaofeng Wang
- Department of Oral & Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Wang B, Liu Y, Liao Z, Wu H, Zhang B, Zhang L. EZH2 in hepatocellular carcinoma: progression, immunity, and potential targeting therapies. Exp Hematol Oncol 2023; 12:52. [PMID: 37268997 PMCID: PMC10236851 DOI: 10.1186/s40164-023-00405-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/15/2023] [Indexed: 06/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death. The accumulation of genetic and epigenetic changes is closely related to the occurrence and development of HCC. Enhancer of zeste homolog 2 (EZH2, a histone methyltransferase) is suggested to be one of the principal factors that mediates oncogenesis by acting as a driver of epigenetic alternation. Recent studies show that EZH2 is widely involved in proliferation and metastasis of HCC cells. In this review, the functions of EZH2 in HCC progression, the role of EZH2 in tumor immunity and the application of EZH2-related inhibitors in HCC therapy are summarized.
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Affiliation(s)
- Bohan Wang
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhibin Liao
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haofeng Wu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lei Zhang
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Department of Hepatobiliary Surgery, Shanxi Tongji Hospital, Tongji Medical College, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University, Huazhong University of Science and Technology, Taiyuan, 030032, China.
- Key Laboratory of Hepatobiliary and Pancreatic Diseases of Shanxi Province (Preparatory), Shanxi Tongji Hospital, Tongji Medical College, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University, Huazhong University of Science and Technology, Taiyuan, 030032, China.
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Ren Z, Zhang J, Zheng D, Luo Y, Song Z, Chen F, Li A, Liu X. Identification of Prognosis-Related Oxidative Stress Model with Immunosuppression in HCC. Biomedicines 2023; 11:695. [PMID: 36979675 PMCID: PMC10045103 DOI: 10.3390/biomedicines11030695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/10/2023] [Accepted: 02/19/2023] [Indexed: 03/03/2023] Open
Abstract
For hepatocellular carcinoma (HCC) patients, we attempted to establish a new oxidative stress (OS)-related prognostic model for predicting prognosis, exploring immune microenvironment, and predicting the immunotherapy response. Significantly differently expressed oxidative stress-related genes (DEOSGs) between normal and HCC samples from the Cancer Genome Atlas (TCGA) were screened, and then based on weighted gene coexpression network analysis (WGCNA), HCC-related hub genes were discovered. Based on the least absolute shrinkage and selection operator (LASSO) and cox regression analysis, a prognostic model was developed. We validated the prognostic model's predictive power using an external validation cohort: the International Cancer Genome Consortium (ICGC).Then a nomogram was determined. Furthermore, we also examined the relationship of the risk model and clinical characteristics as well as immune microenvironment. 434 DEOSGs, comprising 62 downregulated and 372 upregulated genes (p < 0.05 and |log2FC| ≥ 1), and 257 HCC-related hub genes were recognized in HCC. Afterward, we built a five-DEOSG (LOX, CYP2C9, EIF2B4, EZH2, and SRXN1) prognostic risk model. Using the nomogram, the risk model was shown to have good prognostic value. Compared to the low risk group, HCC patients with high risk had poorer outcomes, worse pathological grades, and advanced tumor stages (p < 0.05). There were significant increases in LOX, EIF2B4, EZH2, and SRXN1 expression in HCC samples, while CYP2C9 expression was decreased. Finally, Real-time PCR (RT-qPCR) confirmed the mRNA expressions of five genes (CYP2C9, EIF2B4, EZH2, SRXN1, LOX) in HCC cell lines. Our study constructed a prognostic OS-related model with strong predictive power and potential as an immunosuppressive biomarker for HCC leading to improving prediction and providing new insights for HCC immunotherapy.
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Affiliation(s)
- Zhixuan Ren
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Jiakang Zhang
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Dayong Zheng
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Yue Luo
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Zhenghui Song
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Fengsheng Chen
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Aimin Li
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
| | - Xinhui Liu
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
- Cancer Center, Southern Medical University, Guangzhou 510315, China
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Li J, Wang J, Wang Y, Zhao X, Su T. E2F1 combined with LINC01004 super-enhancer to promote hepatocellular carcinoma cell proliferation and metastasis. Clin Epigenetics 2023; 15:17. [PMID: 36721155 PMCID: PMC9887888 DOI: 10.1186/s13148-023-01428-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 01/13/2023] [Indexed: 02/01/2023] Open
Abstract
INTRODUCTION Super-enhancer-associated lncRNAs play important roles in the occurrence and development of malignant tumors, including hepatocellular carcinoma (HCC). OBJECTIVES The current work aimed to identify and characterize super-enhancer-associated lncRNAs in the pathogenesis of HCC. METHODS H3K27ac ChIP-seq data from HepG2 cell line and two HCC tissues were used to identify super-enhancer-associated lncRNAs in HCC. JQ-1 treatment and CRISPR-dCas9 system were performed to confirm super-enhancer activity. Quantitative real-time PCR (qPCR), ChIP-qPCR, and dual-luciferase reporter system assay demonstrated the regulation of E2F1 on super-enhancer. Functional loss experiment was used to identify the function of LINC01004. RESULTS In this study, we identified and characterized LINC01004, a novel super-enhancer-associated lncRNA, as a crucial oncogene in HCC. LINC01004 was upregulated in liver cancer tissues and was associated with poor patient prognosis. Moreover, LINC01004 promoted cell proliferation and metastasis of HCC. The binding of E2F1 to the super-enhancer could promote the transcription of LINC01004, while the inhibition of super-enhancer activity decreased LINC01004 expression. CONCLUSION This finding might provide mechanistic insights into the molecular mechanisms underlying hepatocarcinogenesis and the biological function of super-enhancer. LINC01004 can serve as a potential therapeutic target for HCC patient.
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Affiliation(s)
- Jingxuan Li
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Jiying Wang
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Yanping Wang
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Xueyan Zhao
- grid.452757.60000 0004 0644 6150Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Tao Su
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Cai C, Peng X, Zhang Y. Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression. Bioengineered 2021; 12:7007-7019. [PMID: 34551671 PMCID: PMC8806772 DOI: 10.1080/21655979.2021.1965441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The purpose of the current study was to investigate the biological function of cell division cycle-associated protein 7 (CDCA7) on ovarian cancer (OC) progression and analyze the molecular mechanism of CDCA7 on OC cellular processes and angiogenesis. CDCA7 expression in OC tissues and adjacent normal tissues was obtained from Gene Expression Profiling Interactive Analysis (GEPIA) and in various cancer cell lines was obtained from Cancer Cell Line Encyclopedia (CCLE). Moreover, CDCA7 expression in adjacent normal tissues and tumor tissues of OC patients as well as in normal ovarian epithelial cells (NOEC) and ovarian cancer cells (OVCAR3, SKOV3, CAOV-3, A2780) was further confirmed via Western blot assay and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, Immunohistochemistry (IHC) was also applied for determination of CDCA7 expression in tissues of OC patients. Then, SKOV3 cells were introduced with shRNA-CDCA7 for functional experiments. GeneMANIA database analysis and coimmunoprecipitation (Co-IP) assay verified the interaction between CDCA7 and enhancer of zeste homolog 2 (EZH2) to probe the potential mechanism. CDCA7 expression was elevated in tumor tissues of OC patients and OC cell lines. CDCA7 silencing restrained the proliferative, migrative and invasive capacities and arrested cell cycle of OC cells. In addition, CDCA7 knockdown induced a weaker in vitro angiogenesis of HUVECs. Mechanistically, CDCA7 interacted with EZH2. Downregulation of CDCA7 arrested angiogenesis by suppressing EZH2 expression. To sum up, the current study revealed the impact and potential mechanism of CDCA7 on OC cellular processes, developing a promising molecular target for OC therapies.
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Affiliation(s)
- Chunyan Cai
- Department Of Gynaecology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xing Peng
- Department Of Gynaecology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Yumei Zhang
- Department Of Gynaecology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
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Park JS, Lee ME, Jang WS, Rha KH, Lee SH, Lee J, Ham WS. The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity. Cancers (Basel) 2021; 13:cancers13112574. [PMID: 34073906 PMCID: PMC8197413 DOI: 10.3390/cancers13112574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/13/2021] [Accepted: 05/20/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary DDX11, a helicase involved in sister chromatid cohesion, was identified as a significant biomarker of aggressive renal cell carcinoma (RCC) in our previous studies. In this study, we evaluated the molecular pathways through which DDX11 is involved in RCC cell survival. Furthermore, we assessed the sensitivity of poly (ADP-ribose) polymerase (PARP) inhibitors, which have not been used in RCC treatment, in association with DDX11 expression. DDX11-deficient RCC inhibited RCC proliferation, caused defects in segregation, and increased apoptosis. DDX11-deficient RCC was associated with increased sensitivity to PARP inhibition. DDX11 could be a novel therapeutic and prognostic biomarker for RCC patients, and this study is the first to suggest the use of PARP inhibitors in DDX11-deficient RCC patients. Abstract Genes associated with the DEAD-box helicase DDX11 are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with DDX11-specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of DDX11 knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. DDX11 knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. DDX11-deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, DDX11 could determine PARP inhibitor sensitivity in RCC. DDX11 could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.
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Affiliation(s)
- Jee Soo Park
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
- Department of Urology, Sorokdo National Hospital, Goheung 59562, Korea
| | - Myung Eun Lee
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
| | - Won Sik Jang
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
| | - Koon Ho Rha
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
| | - Seung Hwan Lee
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
| | - Jongsoo Lee
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
| | - Won Sik Ham
- Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (K.H.R.); (S.H.L.); (J.L.)
- Correspondence: ; Tel.: +82-10-6242-7938; Fax: +82-2-312-2538
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The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer. Genes (Basel) 2021; 12:genes12030395. [PMID: 33802088 PMCID: PMC8000936 DOI: 10.3390/genes12030395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
DDX11/ChlR1 is a super-family two iron–sulfur cluster containing DNA helicase with roles in DNA replication and sister chromatid cohesion establishment, and general chromosome architecture. Bi-allelic mutations of the DDX11 gene cause a rare hereditary disease, named Warsaw breakage syndrome, characterized by a complex spectrum of clinical manifestations (pre- and post-natal growth defects, microcephaly, intellectual disability, heart anomalies and sister chromatid cohesion loss at cellular level) in accordance with the multifaceted, not yet fully understood, physiological functions of this DNA helicase. In the last few years, a possible role of DDX11 in the onset and progression of many cancers is emerging. Herein we summarize the results of recent studies, carried out either in tumoral cell lines or in xenograft cancer mouse models, suggesting that DDX11 may have an oncogenic role. The potential of DDX11 DNA helicase as a pharmacological target for novel anti-cancer therapeutic interventions, as inferred from these latest developments, is also discussed.
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