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Shi J, Zhu X, Yang JB. Advances and challenges in molecular understanding, early detection, and targeted treatment of liver cancer. World J Hepatol 2025; 17:102273. [PMID: 39871899 PMCID: PMC11736488 DOI: 10.4254/wjh.v17.i1.102273] [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: 10/14/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 01/06/2025] Open
Abstract
In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.
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Affiliation(s)
- Ji Shi
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Xu Zhu
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Jun-Bo Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, Guangdong Province, China.
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Li C, Zhang ED, Ye Y, Xiao Z, Huang H, Zeng Z. Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma. Sci Rep 2024; 14:14051. [PMID: 38890507 PMCID: PMC11189538 DOI: 10.1038/s41598-024-64907-7] [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: 12/31/2023] [Accepted: 06/14/2024] [Indexed: 06/20/2024] Open
Abstract
Mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a mitochondrial isoenzyme, supports the growth of cancer cells under glucose deficiency conditions in vitro. This study investigated the role and potential mechanism of PCK2 in the occurrence and development of Hepatocellular carcinoma (HCC). The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other databases distinguish the expression of PCK2 and verified by qRT-PCR and Western blotting. Kaplan-Meier was conducted to assess PCK2 survival in HCC. The potential biological function of PCK2 was verified by enrichment analysis and gene set enrichment analysis (GSEA). The correlation between PCK2 expression and immune invasion and checkpoint was found by utilizing Tumor Immune Estimation Resource (TIMER). Lastly, the effects of PCK2 on the proliferation and metastasis of hepatocellular carcinoma cells were evaluated by cell tests, and the expressions of Epithelial mesenchymal transformation (EMT) and apoptosis related proteins were detected. PCK2 is down-regulated in HCC, indicating a poor prognosis. PCK2 gene mutation accounted for 1.3% of HCC. Functional enrichment analysis indicated the potential of PCK2 as a metabolism-related therapeutic target. Subsequently, we identified several signaling pathways related to the biological function of PCK2. The involvement of PCK2 in immune regulation was verified and key immune checkpoints were predicted. Ultimately, after PCK2 knockdown, cell proliferation and migration were significantly increased, and N-cadherin and vimentin expression were increased. PCK2 has been implicated in immune regulation, proliferation, and metastasis of hepatocellular carcinoma, and is emerging as a novel predictive biomarker and metabolic-related clinical target.
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Affiliation(s)
| | | | - Youzhi Ye
- Kunming Medical University, Kunming, China
| | | | - Hanfei Huang
- The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, China.
| | - Zhong Zeng
- The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, China.
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Almalki WH, Almujri SS. The dual roles of circRNAs in Wnt/β-Catenin signaling and cancer progression. Pathol Res Pract 2024; 255:155132. [PMID: 38335783 DOI: 10.1016/j.prp.2024.155132] [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: 12/06/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 02/12/2024]
Abstract
Cancer, a complex pathophysiological condition, arises from the abnormal proliferation and survival of cells due to genetic mutations. Dysregulation of cell cycle control, apoptosis, and genomic stability contribute to uncontrolled growth and metastasis. Tumor heterogeneity, microenvironmental influences, and immune evasion further complicate cancer dynamics. The intricate interplay between circular RNAs (circRNAs) and the Wnt/β-Catenin signalling pathway has emerged as a pivotal axis in the landscape of cancer biology. The Wnt/β-Catenin pathway, a critical regulator of cell fate and proliferation, is frequently dysregulated in various cancers. CircRNAs, a class of non-coding RNAs with closed-loop structures, have garnered increasing attention for their diverse regulatory functions. This review systematically explores the intricate crosstalk between circRNAs and the Wnt/β-Catenin pathway, shedding light on their collective impact on cancer initiation and progression. The review explores the diverse mechanisms through which circRNAs modulate the Wnt/β-Catenin pathway, including sponging microRNAs, interacting with RNA-binding proteins, and influencing the expression of key components in the pathway. Furthermore, the review highlights specific circRNAs implicated in various cancer types, elucidating their roles as either oncogenic or tumour-suppressive players in the context of Wnt/β-Catenin signaling. The intricate regulatory networks formed by circRNAs in conjunction with the Wnt/β-Catenin pathway are discussed, providing insights into potential therapeutic targets and diagnostic biomarkers. This comprehensive review delves into the multifaceted roles of circRNAs in orchestrating tumorigenesis through their regulatory influence on the Wnt/β-Catenin pathway.
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Affiliation(s)
- Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
| | - Salem Salman Almujri
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Aseer, Saudi Arabia
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Shi DM, Dong SS, Zhou HX, Song DQ, Wan JL, Wu WZ. Genomic and transcriptomic profiling reveals key molecules in metastatic potentials and organ-tropisms of hepatocellular carcinoma. Cell Signal 2023; 104:110565. [PMID: 36539000 DOI: 10.1016/j.cellsig.2022.110565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/04/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022]
Abstract
Metastasis is a landmark event for rapid postsurgical relapse and death of HCC patients. Although distinct genomic and transcriptomic profiling of HCC metastasis had been reported previously, the causal relationships of somatic mutants, mRNA levels and metastatic potentials were difficult to be established in clinic. Therefore, 11 human HCC cell lines and 7 monoclonal derivatives with definite metastatic potentials and tropisms were subjected to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). TP53, MYO5A, ROS1 and ARID2 were the prominent mutants of metastatic drivers in HCC cells. During HCC clonal evaluation, TP53, MYO5A and ROS1 mutations occurred in the early stage, EXT2 and NIN in the late stage. NF1 mutant was unique in lung tropistic cell lines, RNF126 mutant in lymphatic tropistic ones. PER1, LMO2, GAS7, NR4A3 expression levels were positively associated with relapse-free survival (RFS) of HCC patients. The integrative analysis revealed 58 genes exhibited both somatic mutation and dysregulated mRNA levels in high metastatic cells. Altogether, metastatic drivers could accumulate gradually at different stages during HCC progression, some drivers might modulate HCC metastatic potentials and the others regulate metastatic tropisms.
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Affiliation(s)
- Dong-Min Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China; Department of Medical Oncology, Changzheng Hospital, Shanghai, People's Republic of China
| | - Shuang-Shuang Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Hong-Xing Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Dong-Qiang Song
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jin-Liang Wan
- Department of Medical Oncology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Wei-Zhong Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
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A Novel Prognostic Four-Gene Signature of Breast Cancer Identified by Integrated Bioinformatics Analysis. DISEASE MARKERS 2022; 2022:5925982. [PMID: 35265226 PMCID: PMC8898848 DOI: 10.1155/2022/5925982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/20/2021] [Accepted: 12/27/2021] [Indexed: 11/20/2022]
Abstract
Molecular analysis facilitates the prediction of overall survival (OS) of breast cancer and decision-making of the treatment plan. The current study was designed to identify new prognostic genes for breast cancer and construct an effective prognostic signature with integrated bioinformatics analysis. Differentially expressed genes in breast cancer samples from The Cancer Genome Atlas (TCGA) dataset were filtered by univariate Cox regression analysis. The prognostic model was optimized by the Akaike information criterion and further validated using the TCGA dataset (n = 1014) and Gene Expression Omnibus (GEO) dataset (n = 307). The correlation between the risk score and clinical information was assessed by univariate and multivariate Cox regression analyses. Functional pathways in relation to high-risk and low-risk groups were analyzed using gene set enrichment analysis (GSEA). Four prognostic genes (EXOC6, GPC6, PCK2, and NFATC2) were screened and used to construct a prognostic model, which showed robust performance in classifying the high-risk and low-risk groups. The risk score was significantly related to clinical features and OS. We identified 19 functional pathways significantly associated with the risk score. This study constructed a new prognostic model with a high prediction performance for breast cancer. The four-gene prognostic signature could serve as an effective tool to predict prognosis and assist the management of breast cancer patients.
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Zeng Z, Cao Z, Tang Y. Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data. BMC Cancer 2020; 20:1037. [PMID: 33115417 PMCID: PMC7594443 DOI: 10.1186/s12885-020-07529-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Background The E2F family of transcription factor 2 (E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma (HCC) remains unknown. Our study aimed to investigate the role and clinical significance of E2F2 in HCC. Methods HCC raw data were extracted from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression were applied to analyze the relationship between the expression of E2F2 and clinicopathologic characteristics. Cox regression and Kaplan-Meier were employed to evaluate the correlation between clinicopathologic features and survival. The biological function of E2F2 was annotated by Gene Set Enrichment Analysis (GSEA). Results The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominently correlated with histologic grade (OR = 2.62 for G3–4 vs. G1–2, p = 1.80E-05), clinical stage (OR = 1.74 for III-IV vs. I-II, p = 0.03), T (OR = 1.64 for T3–4 vs.T1–2, p = 0.04), tumor status (OR = 1.88 for with tumor vs. tumor free, p = 3.79E-03), plasma alpha fetoprotein (AFP) value (OR = 3.18 for AFP ≥ 400 vs AFP<20, p = 2.16E-04; OR = 2.50 for 20 ≤ AFP<400 vs AFP<20, p = 2.56E-03). Increased E2F2 had an unfavorable OS (p = 7.468e− 05), PFI (p = 3.183e− 05), DFI (p = 0.001), DSS (p = 4.172e− 05). Elevated E2F2 was independently bound up with OS (p = 0.004, hazard ratio [HR] = 2.4 (95% CI [1.3–4.2])), DFI (P = 0.029, hazard ratio [HR] = 2.0 (95% CI [1.1–3.7])) and PFI (P = 0.005, hazard ratio [HR] = 2.2 (95% CI [1.3–3.9])). GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype. Conclusions Elevated E2F2 can be a promising independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signaling pathway, ubiquitin-mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participates in the initial and progression of HCC.
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Affiliation(s)
- Zhili Zeng
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Zebiao Cao
- Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Ying Tang
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, no.12, Airport Road, Sanyuanli Street, Baiyun District, Guangzhou, 510405, Guangdong, China.
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Wang Y, Argiles-Castillo D, Kane EI, Zhou A, Spratt DE. HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance. J Cell Sci 2020; 133:133/7/jcs228072. [PMID: 32265230 DOI: 10.1242/jcs.228072] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases play a critical role in various cellular pathways, including but not limited to protein trafficking, subcellular localization, innate immune response, viral infections, DNA damage responses and apoptosis. To date, 28 HECT E3 ubiquitin ligases have been identified in humans, and recent studies have begun to reveal how these enzymes control various cellular pathways by catalyzing the post-translational attachment of ubiquitin to their respective substrates. New studies have identified substrates and/or interactors with different members of the HECT E3 ubiquitin ligase family, particularly for E6AP and members of the neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) family. However, there still remains many unanswered questions about the specific roles that each of the HECT E3 ubiquitin ligases have in maintaining cellular homeostasis. The present Review discusses our current understanding on the biological roles of the HECT E3 ubiquitin ligases in the cell and how they contribute to disease development. Expanded investigations on the molecular basis for how and why the HECT E3 ubiquitin ligases recognize and regulate their intracellular substrates will help to clarify the biochemical mechanisms employed by these important enzymes in ubiquitin biology.
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Affiliation(s)
- Yaya Wang
- College of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, Shanxi, China 710054.,Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Diana Argiles-Castillo
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Emma I Kane
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Anning Zhou
- College of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, Shanxi, China 710054
| | - Donald E Spratt
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
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Liu H, Zhao P, Jin X, Zhao Y, Chen Y, Yan T, Wang J, Wu L, Sun Y. A 9‑lncRNA risk score system for predicting the prognosis of patients with hepatitis B virus‑positive hepatocellular carcinoma. Mol Med Rep 2019; 20:573-583. [PMID: 31115573 PMCID: PMC6579967 DOI: 10.3892/mmr.2019.10262] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 12/28/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and can be induced by hepatitis B virus (HBV) infection. The aim of the present study was to screen prognosis‑associated long noncoding RNAs (lncRNAs) and construct a risk score system for the disease. The RNA‑sequencing data of patients with HCC (including 100 HCC samples and 26 normal samples) were extracted from The Cancer Genome Atlas (TCGA) database. In addition, GSE55092, GSE19665 and GSE10186 datasets were downloaded from the Gene Expression Omnibus database. Combined with weighted gene co‑expression network analysis, the identification and functional annotation of stable modules was performed. Using the MetaDE package, the consensus differentially expressed RNAs (DE‑RNAs) were analyzed. To construct a risk score system, prognosis‑associated lncRNAs and the optimal lncRNA combination were separately analyzed by survival and penalized packages. Finally, pathway enrichment analysis for the nodes in an lncRNA‑mRNA network was conducted via Gene Set Enrichment Analysis. A total of four stable modules and 3,051 consensus DE‑RNAs were identified. The stable modules were significantly associated with the histological grades of HCC, tumor, node and metastasis stage, pathological stage, recurrence and exposure to radiation therapy. A 9‑lncRNA optimal combination [DiGeorge syndrome critical region gene 9, glucosidase, β, acid 3 (GBA3), HLA complex group 4, N‑acetyltransferase 8B, neighbor of breast cancer 1 gene 2, prostate androgen‑regulated transcript 1, ret finger protein like 1 antisense RNA 1, solute carrier family 22 member 18 antisense and T‑cell leukemia/lymphoma 6] was selected from the 14 prognosis‑associated lncRNAs, and was further supported by the validation dataset, GSE10186. The lncRNA‑mRNA co‑expression network revealed lncRNA GBA3 as a positive regulator of phosphoenolpyruvate carboxykinase 2, an important enzyme in the metabolic pathway of gluconeogenesis. A risk score system was established based on the optimal 9 lncRNAs, which may be valuable for predicting the prognosis of patients with HBV‑positive HCC and improving understanding of mechanisms associated with the pathogenesis of this disease. On the contrary, a larger, independent cohort of patients is required to further validate the risk‑score system.
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Affiliation(s)
- Honghong Liu
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Ping Zhao
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Xueyuan Jin
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Yanling Zhao
- Department of Pharmacy, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Yongqian Chen
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Tao Yan
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Jianjun Wang
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Liang Wu
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Yongqiang Sun
- Integrative Medical Center, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
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Wu Y, Xia R, Dai C, Yan S, Xie T, Liu B, Gan L, Zhuang Z, Huang Q. Dexamethasone inhibits the proliferation of tumor cells. Cancer Manag Res 2019; 11:1141-1154. [PMID: 30774442 PMCID: PMC6362917 DOI: 10.2147/cmar.s187659] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Objective Dexamethasone (DEX) is a glucocorticoid that is commonly used in clinics. Previously, DEX has been shown to inhibit the function of immune system; however, DEX is often used to treat side reactions, such as nausea and vomiting caused by chemotherapy in clinics. Therefore, it is necessary to study the role of DEX in the treatment of cancer. Methods The effects of DEX on HepG2 were studied in vitro by Cell Counting Kit-8 method, cell cycle, and scratch test. The transplanted tumor model of HepG2 was established in nude mice to study the anti-tumor effect of DEX in vivo. In addition, in order to study the effect of DEX on the immune system, we also established a transplanted tumor model of 4T1 in normal immunized mice to study treatment effect and mechanism of DEX in mice of normal immune function. Results The results showed that DEX inhibited the proliferation of HepG2 in vitro and in vivo, affecting the cycle and migration of HepG2 cells, and the expression of c-Myc and the activation of mTOR signaling pathway were inhibited. The expression of key enzymes related to glucose metabolism is altered, especially that of phosphoenolpyruvate carboxykinase2 (PCK2). In normal immunized mice, DEX also inhibits the proliferation of tumor cells 4T1, while the proportion of CD4+CD45+T cells and CD8+CD45+ T cells in CD45+ cells in the lymph nodes upregulated, the proportion of Treg cells in CD4+ T cells downregulated in lymph nodes, and the proportion of MDSCs in tumor tissues downregulated. Conclusion DEX can inhibit tumor cells in vitro and in vivo. The mechanism is to inhibit the activation of mTOR signaling pathway by inhibiting the expression of c-Myc, further affecting the expression of key enzymes involved in glucose metabolism, especially PCK2. In addition, DEX has an inhibitory effect on the immune system, which may be the reason why DEX still has anti-tumor effect in normal mice.
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Affiliation(s)
- Yuantao Wu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Soochow, China,
| | - Rui Xia
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Soochow, China,
| | - Chungang Dai
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow, China
| | - Suji Yan
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow, China
| | - Tao Xie
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow, China
| | - Bing Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow, China
| | - Lei Gan
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Soochow, China,
| | - Zhixiang Zhuang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Soochow, China,
| | - Qiang Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow, China
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Krist DT, Foote PK, Statsyuk AV. UbFluor: A Fluorescent Thioester to Monitor HECT E3 Ligase Catalysis. ACTA ACUST UNITED AC 2017; 9:11-37. [PMID: 28253433 DOI: 10.1002/cpch.17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
HECT E3 ubiquitin ligases (∼28 are known) are associated with many phenotypes in eukaryotes and are important drug targets. However, assays used to screen for small molecule inhibitors of HECT E3s are complex and require ATP, Ub, E1, E2, and HECT E3 enzymes, producing three covalent thioester enzyme intermediates E1∼Ub, E2∼Ub, and HECT E3∼Ub (where ∼ indicates a thioester bond), and mixtures of polyubiquitin chains. To reduce the complexity of the assay, we developed a novel class of fluorescent probes, UbFluor, that act as mechanistically relevant pseudosubstrates of HECT E3s. These probes undergo a direct transthiolation reaction with the catalytic cysteine of HECT E3s, producing the catalytically active HECT E3∼Ub thioester accompanied by fluorophore release. Thus, a fluorescence polarization assay can continuously monitor UbFluor consumption by HECT E3s, and changes in UbFluor consumption rendered by biochemical point mutations or small molecule modulation of HECT E3 activity. © 2017 by John Wiley & Sons, Inc.
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Affiliation(s)
- David T Krist
- Northwestern University, Department of Chemistry, Chemistry of Life Processes Institute, Evanston, Illinois
| | - Peter K Foote
- Northwestern University, Department of Chemistry, Chemistry of Life Processes Institute, Evanston, Illinois
| | - Alexander V Statsyuk
- Northwestern University, Department of Chemistry, Chemistry of Life Processes Institute, Evanston, Illinois
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11
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Vert A, Castro J, Ribó M, Benito A, Vilanova M. A nuclear-directed human pancreatic ribonuclease (PE5) targets the metabolic phenotype of cancer cells. Oncotarget 2017; 7:18309-24. [PMID: 26918450 PMCID: PMC4951290 DOI: 10.18632/oncotarget.7579] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/11/2016] [Indexed: 12/18/2022] Open
Abstract
Ribonucleases represent a new class of antitumor RNA-damaging drugs. However, many wild-type members of the vertebrate secreted ribonuclease family are not cytotoxic because they are not able to evade the cytosolic ribonuclease inhibitor. We previously engineered the human pancreatic ribonuclease to direct it to the cell nucleus where the inhibitor is not present. The best characterized variant is PE5 that kills cancer cells through apoptosis mediated by the p21WAF1/CIP1 induction and the inactivation of JNK. Here, we have used microarray-derived transcriptional profiling to identify PE5 regulated genes on the NCI/ADR-RES ovarian cancer cell line. RT-qPCR analyses have confirmed the expression microarray findings. The results show that PE5 cause pleiotropic effects. Among them, it is remarkable the down-regulation of multiple genes that code for enzymes involved in deregulated metabolic pathways in cancer cells.
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Affiliation(s)
- Anna Vert
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Jessica Castro
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Marc Ribó
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Antoni Benito
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
| | - Maria Vilanova
- Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Girona, Spain.,Institut d'Investigació Biomèdica de Girona Josep Trueta, (IdIBGi), Girona, Spain
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12
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Choe KN, Nicolae CM, Constantin D, Imamura Kawasawa Y, Delgado-Diaz MR, De S, Freire R, Smits VA, Moldovan GL. HUWE1 interacts with PCNA to alleviate replication stress. EMBO Rep 2016; 17:874-86. [PMID: 27146073 DOI: 10.15252/embr.201541685] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 04/05/2016] [Indexed: 02/01/2023] Open
Abstract
Defects in DNA replication, DNA damage response, and DNA repair compromise genomic stability and promote cancer development. In particular, unrepaired DNA lesions can arrest the progression of the DNA replication machinery during S-phase, causing replication stress, mutations, and DNA breaks. HUWE1 is a HECT-type ubiquitin ligase that targets proteins involved in cell fate, survival, and differentiation. Here, we report that HUWE1 is essential for genomic stability, by promoting replication of damaged DNA We show that HUWE1-knockout cells are unable to mitigate replication stress, resulting in replication defects and DNA breakage. Importantly, we find that this novel role of HUWE1 requires its interaction with the replication factor PCNA, a master regulator of replication fork restart, at stalled replication forks. Finally, we provide evidence that HUWE1 mono-ubiquitinates H2AX to promote signaling at stalled forks. Altogether, our work identifies HUWE1 as a novel regulator of the replication stress response.
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Affiliation(s)
- Katherine N Choe
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Claudia M Nicolae
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Daniel Constantin
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Yuka Imamura Kawasawa
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Maria Rocio Delgado-Diaz
- Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna Tenerife, Spain
| | - Subhajyoti De
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA Molecular Oncology Program, University of Colorado Cancer Center, Aurora, CO, USA
| | - Raimundo Freire
- Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna Tenerife, Spain
| | - Veronique Aj Smits
- Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, La Laguna Tenerife, Spain
| | - George-Lucian Moldovan
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
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Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer 2015; 15:653-67. [PMID: 26493646 DOI: 10.1038/nrc4017] [Citation(s) in RCA: 224] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis.
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Affiliation(s)
- Jens U Marquardt
- Department of Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Snorri S Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Zhao H, Yang F, Shen W, Wang Y, Li X, You J, Zhou Q. Pazopanib diminishes non-small cell lung cancer (NSCLC) growth and metastases in vivo. Thorac Cancer 2015; 6:133-40. [PMID: 26273349 PMCID: PMC4448486 DOI: 10.1111/1759-7714.12138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Accepted: 05/07/2014] [Indexed: 11/30/2022] Open
Abstract
Background Anti-angiogenesis has been demonstrated to have a critical role in lung cancer pathogenesis. Here, we characterized the effect of the small-molecule angiogenesis inhibitor pazopanib on non-small cell lung cancer (NSCLC) cells. Methods NSCLC cells were tested for viability and migration after incubation with varying concentrations of pazopanib. Further, the phosphorylation status of extracellular signal-regulated kinase, protein kinase B, and MEK were assessed in vitro. For in vivo testing, mice grafted with NSCLC cell lines L9981 and A549 were treated orally with pazopanib. Results Pazopanib inhibits signaling pathways in tumor cells, thus blocking NSCLC cell growth and migration in vitro and inducing tumor cell arrest at G0/G1 phase. We show that pazopanib could inhibit tumor cell growth, decrease metastases, and prolong survival in two mouse xenograft models of human NSCLC. Conclusion These preclinical studies of pazopanib show the possibility of clinical application and, ultimately, improvement in patient outcome.
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Affiliation(s)
- Honglin Zhao
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
| | - Fan Yang
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
| | - Wang Shen
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
| | - Yuli Wang
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
| | - Xuebing Li
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
| | - Jiacong You
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
| | - Qinghua Zhou
- Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital Tianjin, China
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