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1
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Lu CY, Lin CP, Lee HL, Peng PJ, Huang SC, Chuang MR, Lin YJ. Epigenetic Perspectives and Their Prognostic Value in Early Recurrence After Hepatocellular Carcinoma Resection. Cancers (Basel) 2025; 17:769. [PMID: 40075616 PMCID: PMC11898875 DOI: 10.3390/cancers17050769] [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: 01/07/2025] [Revised: 02/06/2025] [Accepted: 02/14/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND/OBJECTIVES The post-hepatectomy survival of patients with hepatocellular carcinoma (HCC) faces challenges due to high recurrence rates, especially early recurrence (ER). We investigated DNA methylation in HCC and developed a methylation-based model for ER prediction (MER). METHODS We studied HCC patients with ER within a year post-hepatectomy, comparing them to those who remained recurrence-free (RF) for 5 years. In a testing set, we examined genome-wide methylation profiles to identify differences between ER and RF. Validation in an independent cohort confirmed candidate markers using real-time quantitative methylation-specific PCR (qMSP). We constructed MER by incorporating identified gene methylation, clinical information, and serum protein marker, and evaluated its predictive performance using ROC analysis and Cox regression. RESULTS Distinct signatures of hypermethylation and hypomethylation were observed between ER and RF, as well as between cirrhotic and non-cirrhotic groups. Significant aberrant methylation pathways, including FGFR signaling, the PI3K network, and the MAPK pathway, were observed in non-cirrhotic ER patients. Conversely, cirrhotic ER patients showed notable associations with Wnt/β-catenin signaling, cell adhesion, and migration mechanisms. Through qMSP analysis, we identified ER-associated genes, including BDNF, FOXL2, LMO7, NCAM1, NEIS3, PLA2G7, and LTB4R. MER demonstrated strong predictive ability for ER, with an AUC of 0.855, surpassing current indicators such as AFP, tumor size, and BCLC stage. Combining different predictors resulted in heightened AUC values. Importantly, the inclusion of MER yielded to the highest AUC of 0.952, underscoring the substantial contribution of MER to predictive accuracy. CONCLUSIONS This study discovered the involvement of aberrant DNA methylation in HCC with early recurrence. The MER outperforms clinicopathological predictors and achieves robust prediction capabilities in identifying patients at risk of ER.
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Affiliation(s)
- Chang-Yi Lu
- Department of Clinical Diagnostic Technology, EpiSante Biomedical Co., Ltd., Hsinchu 302, Taiwan; (C.-Y.L.)
| | - Ching-Pin Lin
- Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Hsiang-Lin Lee
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Pey-Jey Peng
- Department of Clinical Diagnostic Technology, EpiSante Biomedical Co., Ltd., Hsinchu 302, Taiwan; (C.-Y.L.)
| | - Shao-Chang Huang
- Department of Clinical Diagnostic Technology, EpiSante Biomedical Co., Ltd., Hsinchu 302, Taiwan; (C.-Y.L.)
| | - Meng-Rong Chuang
- Department of Clinical Diagnostic Technology, EpiSante Biomedical Co., Ltd., Hsinchu 302, Taiwan; (C.-Y.L.)
| | - Yih-Jyh Lin
- Division of General and Transplant Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Liver Cancer Collaborative Oncology Group, National Cheng Kung University Hospital, Tainan 704, Taiwan
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2
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Koch S. The transcription factor FOXQ1 in cancer. Cancer Metastasis Rev 2025; 44:22. [PMID: 39777582 PMCID: PMC11711781 DOI: 10.1007/s10555-025-10240-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/01/2025] [Indexed: 01/11/2025]
Abstract
FOXQ1 is a member of the large forkhead box (FOX) family of transcription factors that is involved in all aspects of mammalian development, physiology, and pathobiology. FOXQ1 has emerged as a major regulator of epithelial-to-mesenchymal transition and tumour metastasis in cancers, especially carcinomas of the digestive tract. Accordingly, FOXQ1 induction is recognised as an independent prognostic factor for worse overall survival in several types of cancer, including gastric and colorectal cancer. In this review article, I summarise new evidence on the role of FOXQ1 in cancer, with a focus on molecular mechanisms that control FOXQ1 levels and the regulation of FOXQ1 target genes. Unravelling the functions of FOXQ1 has the potential to facilitate the development of targeted treatments for metastatic cancers.
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Affiliation(s)
- Stefan Koch
- Wallenberg Centre for Molecular Medicine (WCMM), Linköping University, Linköping, Sweden.
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, BKV/MMV - Plan 13, Lab 1, 581 85, Linköping, Sweden.
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3
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Lu G, Du R, Lu L, Wang Q, Zhang M, Gu X, Feng N, Zhang S, Liu Y, Li J, Pei J. Macrophage-specific κ-OR knockout exacerbates inflammation in hypoxic pulmonary hypertension. Eur J Pharmacol 2025; 986:177152. [PMID: 39586395 DOI: 10.1016/j.ejphar.2024.177152] [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: 09/19/2024] [Revised: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 11/27/2024]
Abstract
Hypoxic pulmonary hypertension (HPH), a prevalent subtype of pulmonary arterial hypertension, is characterized by pulmonary vasoconstriction (HPV) and vascular remodeling, accompanied by inflammatory responses. Recent in vivo studies have shown a critical role of the κ-opioid receptor (κ-OR) in modulating the aforementioned pathological processes. Specifically, macrophage-specific κ-OR-knockout models have shown inflammatory response exacerbation with pulmonary hypertension and vascular remodeling. Conversely, the novel κ-OR agonist Q-U50, 488H inhibits inflammatory pathways, thereby attenuating pulmonary vasoconstriction and vascular remodeling. The present study revealed that hypoxia promoted macrophage infiltration and pulmonary artery smooth muscle cell proliferation. Moreover, under these conditions, macrophages secreted interleukin (IL)-6, which triggered the signal transducer and activator of transcription 3 (STAT3)/miR-153-3p signaling cascade. Herein, we identified miR-153-3p downregulated κ-OR gene expression, which is a key contributor to HPV and remodeling, it was identified as a pivotal regulator of κ-OR mRNA levels. The pharmacological activation of κ-OR inhibited IL-6 release from macrophages and disrupted the IL-6/STAT3/miR-153-3p pathway. This dual action of κ-OR activation mitigated pulmonary artery contraction and remodeling, thereby offering a protective mechanism against HPH. The present findings have delineated a novel negative feedback loop driving HPH pathogenesis and suggested that targeting the κ-OR-IL-6-STAT3-miR-153-3p axis represented a promising therapeutic strategy against HPH.
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MESH Headings
- Receptors, Opioid, kappa/genetics
- Receptors, Opioid, kappa/agonists
- Animals
- Macrophages/metabolism
- MicroRNAs/genetics
- STAT3 Transcription Factor/metabolism
- STAT3 Transcription Factor/genetics
- Interleukin-6/metabolism
- Interleukin-6/genetics
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/pathology
- Hypoxia/complications
- Hypoxia/genetics
- Mice
- Mice, Knockout
- Inflammation/genetics
- Inflammation/pathology
- Pulmonary Artery/pathology
- Signal Transduction
- Male
- Mice, Inbred C57BL
- Vascular Remodeling/drug effects
- Vascular Remodeling/genetics
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/pathology
- Cell Proliferation/drug effects
- Vasoconstriction/drug effects
- 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology
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Affiliation(s)
- Guofang Lu
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China; State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Rui Du
- Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Linhe Lu
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Qiaojuan Wang
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Min Zhang
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Xiaoming Gu
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Na Feng
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Shumiao Zhang
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Yali Liu
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China.
| | - Juan Li
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China.
| | - Jianming Pei
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China.
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4
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Dalkılıç S, Kadıoğlu Dalkılıç L, Uygur L, Timurkaan M, Gültürk B, Kaplan M. Bioinformatics analysis of colorectal cancer transcriptomic data reveals novel prognostic signature and potential biomarker genes. Scand J Gastroenterol 2024:1-12. [PMID: 39644158 DOI: 10.1080/00365521.2024.2437437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 11/15/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024]
Abstract
OBJECTIVE Colorectal cancer (CRC) is a type of digestive system cancer. At the molecular level, some factors, including genetic and epigenetic factors, as well as various signaling pathways such as oxidative stress and inflammation, play an active role in the onset of CRC. Genetic and epigenetic mutations, particularly in oncogenes and tumor suppressor genes, occur during colorectal adenocarcinoma development as a result of a change in gastrointestinal epithelial cell proliferation and self-renewal rates. This study aimed to determine the genes and molecular mechanisms that play a role in the emergence of this disease by analyzing the CRC data. MATERIAL AND METHODS Microarray data selected for bioinformatics analysis is Gene Expression data stored with the code GSE110224 in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Gene expression analysis, functional clustering analysis, enrichment analysis, and pathway analysis were performed using this data set. RESULTS Analysis of raw transcriptomic data revealed 1770 common DEGs in CRC. While the expression level of 769 of these genes increased, the expression level of 1001 genes decreased. A Protein-protein interaction (PPI) network was created from the first 25 genes with increased expression levels and 11 signature genes were identified. Increased expression of REG1A, MMP3, FOXQ1 and CEMIP genes and decreased expression of AQP8, CA1, CLDN8, PYY, CA4, CEACAM7 and SLC30A10 genes were observed. CONCLUSIONS This approach revealed a CRC-specific molecular profile and may provide some guidance for further investigation of potential biomarkers for diagnosis and prognosis prediction of CRC patients.
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Affiliation(s)
- Semih Dalkılıç
- Department of Biology and Molecular Biology and Genetics Program, Faculty of Science, Fırat University, Elazig, Türkiye
| | | | - Lütfü Uygur
- Department of Biology and Molecular Biology and Genetics Program, Faculty of Science, Fırat University, Elazig, Türkiye
| | - Mustafa Timurkaan
- Department of Internal Medicine, Fethi Sekin City Hospital, Elazig, Turkey
| | - Barış Gültürk
- Department of General Surgery, Medikal Hospital, Elazig, Turkey
| | - Mustafa Kaplan
- Department of Medical Parasitology, Faculty of Medicine, Faculty of Medicine, Elazig, Turkey
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5
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Wei R, Xie H, Zhou Y, Chen X, Zhang L, Bui B, Liu X. VCAN in the extracellular matrix drives glioma recurrence by enhancing cell proliferation and migration. Front Neurosci 2024; 18:1501906. [PMID: 39554845 PMCID: PMC11565936 DOI: 10.3389/fnins.2024.1501906] [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: 09/25/2024] [Accepted: 10/17/2024] [Indexed: 11/19/2024] Open
Abstract
Introduction Gliomas are the most prevalent primary malignant intracranial tumors, characterized by high rates of therapy resistance, recurrence, and mortality. A major factor contributing to the poor prognosis of gliomas is their ability to diffusely infiltrate surrounding and even distant brain tissues, rendering complete total resection almost impossible and leading to frequent recurrences. The extracellular matrix (ECM) plays a key role in the tumor microenvironment and may significantly influence glioma progression, recurrence, and therapeutic response. Methods In this study, we first identified the ECM and the Versican (VCAN), a key ECM protein, as critical contributors to glioma recurrence through a comprehensive analysis of transcriptomic data comparing recurrent and primary gliomas. Using single-cell sequencing, we revealed heterogeneous distribution patterns and extensive intercellular communication among ECM components. External sequencing and immunohistochemical (IHC) staining further validated that VCAN is significantly upregulated in recurrent gliomas and is associated with poor patient outcomes. Results Functional assays conducted in glioma cell lines overexpressing VCAN demonstrated that VCAN promotes cell proliferation and migration via the PI3K/Akt/AP-1 signaling pathway. Furthermore, inhibiting the PI3K/Akt pathway effectively blocked VCAN-mediated glioma progression. Conclusion These findings provide valuable insights into the mechanisms underlying glioma recurrence and suggest that targeting both VCAN and the PI3K/Akt pathway could represent a promising therapeutic strategy for managing recurrent gliomas.
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Affiliation(s)
- Ruolun Wei
- Department of Neurosurgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China
- Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA, United States
| | - Haoyun Xie
- Biochemistry and Molecular Biology, Georgetown University, Washington, DC, United States
| | - Yukun Zhou
- Department of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Xuhao Chen
- Department of Pathophysiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Liwei Zhang
- Department of Vascular Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China
| | - Brandon Bui
- Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA, United States
- Department of Human Biology, Stanford University, Stanford, CA, United States
| | - Xianzhi Liu
- Department of Neurosurgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China
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6
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Liu Y, Shao K, Yang W, Shen Q, Lu M, Shao Z, Chu S, Wang Y, Wang X, Chen X, Bai J, Wu X. Phosphorylated FOXQ1, a novel substrate of JNK1, inhibits sorafenib-induced ferroptosis by activating ETHE1 in hepatocellular carcinoma. Cell Death Dis 2024; 15:395. [PMID: 38839744 PMCID: PMC11153576 DOI: 10.1038/s41419-024-06789-1] [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: 07/05/2023] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant cancer with poor overall survival. The application of sorafenib is a major breakthrough in the treatment of HCC. In our study, FOXQ1 was significantly overexpressed in sorafenib-resistant HCC cells and suppressed sorafenib-induced ferroptosis. We found that phosphorylation of FOXQ1 at serine 248 is critical for the suppression of sorafenib-induced ferroptosis. Furthermore, as the upstream phosphorylation kinase of FOXQ1, JNK1, which is activated by sorafenib, can directly phosphorylate the serine 248 site of FOXQ1. Then, the phosphorylated FOXQ1 got a high affinity for the promoter of ETHE1 and activates its transcription. Further flow cytometry results showed that ETHE1 reduced intracellular lipid peroxidation and iron levels. Collectively, our study implicated the JNK1-FOXQ1-ETHE1 axis in HCC ferroptosis induced by sorafenib, providing mechanistic insight into sensitivity to sorafenib therapy of HCC.
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Affiliation(s)
- Yiwei Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Ke Shao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
- Department of General Surgery, The People's Hospital of Rugao, Affiliated Rugao Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Wendong Yang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Qi Shen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Mengru Lu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Zhiying Shao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Sufang Chu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
| | - Yuming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
| | - Xiaofeng Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
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7
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Wu J, Wu Y, Chen S, Guo Q, Shao Y, Liu C, Lin K, Wang S, Zhu J, Chen X, Ju X, Xia L, Wu X. PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/β-catenin signalling pathway. Oncogene 2024; 43:866-883. [PMID: 38297082 DOI: 10.1038/s41388-024-02943-3] [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: 07/06/2023] [Revised: 01/03/2024] [Accepted: 01/08/2024] [Indexed: 02/02/2024]
Abstract
Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/β-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/β-catenin pathway by stabilising FOXQ1 expression.
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Affiliation(s)
- Jiangchun Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Yong Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Siyu Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Qinhao Guo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Yang Shao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Chaohua Liu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Kailin Lin
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Simin Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Jun Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xiaojun Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xingzhu Ju
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Lingfang Xia
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xiaohua Wu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
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8
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Yu X, Zhang H, Li J, Gu L, Cao L, Gong J, Xie P, Xu J. Construction of a prognostic prediction model in liver cancer based on genes involved in integrin cell surface interactions pathway by multi-omics screening. Front Cell Dev Biol 2024; 12:1237445. [PMID: 38374893 PMCID: PMC10875080 DOI: 10.3389/fcell.2024.1237445] [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: 06/22/2023] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
Background: Liver cancer is a common malignant tumor with an increasing incidence in recent years. We aimed to develop a model by integrating clinical information and multi-omics profiles of genes to predict survival of patients with liver cancer. Methods: The multi-omics data were integrated to identify liver cancer survival-associated signal pathways. Then, a prognostic risk score model was established based on key genes in a specific pathway, followed by the analysis of the relationship between the risk score and clinical features as well as molecular and immunologic characterization of the key genes included in the prediction model. The function experiments were performed to further elucidate the undergoing molecular mechanism. Results: Totally, 4 pathways associated with liver cancer patients' survival were identified. In the pathway of integrin cell surface interactions, low expression of COMP and SPP1, and low CNVs level of COL4A2 and ITGAV were significantly related to prognosis. Based on above 4 genes, the risk score model for prognosis was established. Risk score, ITGAV and SPP1 were the most significantly positively related to activated dendritic cell. COL4A2 and COMP were the most significantly positively associated with Type 1 T helper cell and regulatory T cell, respectively. The nomogram (involved T stage and risk score) may better predict short-term survival. The cell assay showed that overexpression of ITGAV promoted tumorigenesis. Conclusion: The risk score model constructed with four genes (COMP, SPP1, COL4A2, and ITGAV) may be used to predict survival in liver cancer patients.
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Affiliation(s)
- Xiang Yu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Hao Zhang
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jinze Li
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lu Gu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lei Cao
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jun Gong
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ping Xie
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jian Xu
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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9
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Zhang X, Yu C, Zhao S, Wang M, Shang L, Zhou J, Ma Y. The role of tumor-associated macrophages in hepatocellular carcinoma progression: A narrative review. Cancer Med 2023; 12:22109-22129. [PMID: 38098217 PMCID: PMC10757104 DOI: 10.1002/cam4.6717] [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: 04/21/2023] [Revised: 11/04/2023] [Accepted: 11/07/2023] [Indexed: 12/31/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, with complex etiology and mechanism, and a high mortality rate. Tumor-associated macrophages (TAMs) are an important part of the HCC tumor microenvironment. Studies in recent years have shown that TAMs are involved in multiple stages of HCC and are related to treatment and prognosis in HCC. The specific mechanisms between TAMs and HCC are gradually being revealed. This paper reviews recent advances in the mechanisms associated with TAMs in HCC, concentrating on an overview of effects of TAMs on drug resistance in HCC and the signaling pathways linked with HCC, providing clues for the treatment and prognosis determination of HCC.
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Affiliation(s)
- Xinyi Zhang
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Chao Yu
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Siqi Zhao
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Min Wang
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Longcheng Shang
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Jin Zhou
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Yong Ma
- Department of General Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
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10
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Xia L, Feng M, Ren Y, Hao X, Jiao Q, Xu Q, Wang Y, Wang Q, Gong N. DSE inhibits melanoma progression by regulating tumor immune cell infiltration and VCAN. Cell Death Discov 2023; 9:373. [PMID: 37833287 PMCID: PMC10576081 DOI: 10.1038/s41420-023-01676-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/23/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
Dermatan sulfate epimerase (DSE) is a C5 epiminase that plays a key role in converting chondroitin sulfate into dermal sulfate. DSE is often upregulated during carcinogenesis of some types of cancer and can regulate growth factor signaling in cancer cells. However, the expression and function of DSE in human melanoma have not been reported. In this study, we investigated the influence of tumor-derived DSE in melanoma progression and the potential mechanism of their action. First, proteomic analysis of collected melanoma tissues revealed that DSE was significantly down-regulated in melanoma tissues. DSE silenced or overexpressed melanoma cells were constructed to detect the effect of DSE on melanoma cells, and it was found that the up-regulation of DSE significantly inhibited the proliferation, migration and invasion of melanoma cells. Data analysis and flow cytometry were used to evaluate the immune subpopulations in tumors, and it was found that the high expression of DSE was closely related to the invasion of killer immune cells. Mechanistically, DSE promoted the expression of VCAN, which inhibited the biological activity of melanoma cells. Together, these results suggest that DSE is downregulated in melanoma tissues, and that high expression of DSE can promote melanoma progression by inducing immune cell infiltration and VCAN expression.
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Affiliation(s)
- Lin Xia
- Department of Plastic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Maoxiao Feng
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, China
| | - Xiaodong Hao
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Qinlian Jiao
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - QinChen Xu
- Department of Clinical Laboratory, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, 250033, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Qin Wang
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, China.
| | - Ningji Gong
- Department of Emergency, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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11
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Lu G, Du R, Dong J, Sun Y, Zhou F, Feng F, Feng B, Han Y, Shang Y. Cancer associated fibroblast derived SLIT2 drives gastric cancer cell metastasis by activating NEK9. Cell Death Dis 2023; 14:421. [PMID: 37443302 PMCID: PMC10344862 DOI: 10.1038/s41419-023-05965-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 07/15/2023]
Abstract
The secretory properties of cancer-associated fibroblasts (CAFs) play predominant roles in shaping a pro-metastatic tumor microenvironment. The present study demonstrated that SLIT2, an axon guidance protein, produced by CAFs and promoted gastric cancer (GC) metastasis in two gastric cancer cell lines (AGS and MKN45) by binding to roundabout guidance receptor 1 (ROBO1). Mass-spectrometry analysis revealed that ROBO1 could interact with NEK9, a serine/threonine kinase. And their mutual binding activities were further enhanced by SLIT2. Domain analysis revealed the kinase domain of NEK9 was critical in its interaction with the intracellular domain (ICD) of ROBO1, and it also directly phosphorylated tripartite motif containing 28 (TRIM28) and cortactin (CTTN) in AGS and MKN45 cells. TRIM28 function as a transcriptional elongation factor, which directly facilitate CTTN activation. In addition, Bioinformatics analysis and experimental validation identified transcriptional regulation of STAT3 and NF-κB p100 by TRIM28, and a synergetic transcription of CTTN by STAT3 and NF-κB p100 was also observed in AGS and MKN45. Therefore, CAF-derived SLIT2 increased the expression and phosphorylation levels of CTTN, which induced cytoskeletal reorganization and GC cells metastasis. A simultaneous increase in the expression levels of NEK9, TRIM28 and CTTN was found in metastatic GC lesions compared with paired non-cancerous tissues and primary cancer lesions via IHC and Multiplex IHC. The analysis of the data from a cohort of patients with GC revealed that increased levels of NEK9, TRIM28 and CTTN were associated with a decreased overall survival rate. On the whole, these findings revealed the connections of CAFs and cancer cells through SLIT2/ROBO1 and inflammatory signaling, and the key molecules involved in this process may serve as potential biomarkers and therapeutic targets for GC.
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Affiliation(s)
- Guofang Lu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Rui Du
- Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Jiaqiang Dong
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Yi Sun
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Fenli Zhou
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Fan Feng
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Bin Feng
- Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Ying Han
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
| | - Yulong Shang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
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12
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Alqurashi YE, Al-Hetty HRAK, Ramaiah P, Fazaa AH, Jalil AT, Alsaikhan F, Gupta J, Ramírez-Coronel AA, Tayyib NA, Peng H. Harnessing function of EMT in hepatocellular carcinoma: From biological view to nanotechnological standpoint. ENVIRONMENTAL RESEARCH 2023; 227:115683. [PMID: 36933639 DOI: 10.1016/j.envres.2023.115683] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/08/2023] [Accepted: 03/11/2023] [Indexed: 05/08/2023]
Abstract
Management of cancer metastasis has been associated with remarkable reduction in progression of cancer cells and improving survival rate of patients. Since 90% of mortality are due to cancer metastasis, its suppression can improve ability in cancer fighting. The EMT has been an underlying cause in increasing cancer migration and it is followed by mesenchymal transformation of epithelial cells. HCC is the predominant kind of liver tumor threatening life of many people around the world with poor prognosis. Increasing patient prognosis can be obtained via inhibiting tumor metastasis. HCC metastasis modulation by EMT and HCC therapy by nanoparticles are discussed here. First of all, EMT happens during progression and advanced stages of HCC and therefore, its inhibition can reduce tumor malignancy. Moreover, anti-cancer compounds including all-trans retinoic acid and plumbaging, among others, have been considered as inhibitors of EMT. The EMT association with chemoresistance has been evaluated. Moreover, ZEB1/2, TGF-β, Snail and Twist are EMT modulators in HCC and enhancing cancer invasion. Therefore, EMT mechanism and related molecular mechanisms in HCC are evaluated. The treatment of HCC has not been only emphasized on targeting molecular pathways with pharmacological compounds and since drugs have low bioavailability, their targeted delivery by nanoparticles promotes HCC elimination. Moreover, nanoparticle-mediated phototherapy impairs tumorigenesis in HCC by triggering cell death. Metastasis of HCC and even EMT mechanism can be suppressed by cargo-loaded nanoparticles.
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Affiliation(s)
- Yaser E Alqurashi
- Department of Biology, College of Science Al-zulfi, Majmaah University, Al-Majmaah, 11952, Saudi Arabia
| | | | | | | | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, Pin Code 281406, U. P., India
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Ecuador; Epidemiology and Biostatistics Research Group, CES University, Colombia; Educational Statistics Research Group (GIEE), National University of Education, Ecuador
| | - Nahla A Tayyib
- Faculty of Nursing, Umm Al- Qura University, Makkah, Saudi Arabia
| | - Hu Peng
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
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13
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Luo HL, Chang YL, Liu HY, Wu YT, Sung MT, Su YL, Huang CC, Wang PC, Peng JM. VCAN Hypomethylation and Expression as Predictive Biomarkers of Drug Sensitivity in Upper Urinary Tract Urothelial Carcinoma. Int J Mol Sci 2023; 24:ijms24087486. [PMID: 37108649 PMCID: PMC10139123 DOI: 10.3390/ijms24087486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Versican (VCAN), also known as extracellular matrix proteoglycan 2, has been suggested as a potential biomarker in cancers. Previous research has found that VCAN is highly expressed in bladder cancer. However, its role in predicting outcomes for patients with upper urinary tract urothelial cancer (UTUC) is not well understood. In this study, we collected tissues from 10 patients with UTUC, including 6 with and 4 without lymphovascular invasion (LVI), a pathological feature that plays a significant role in determining metastasis. Results from RNA sequencing revealed that the most differentially expressed genes were involved in extracellular matrix organization. Using the TCGA database for clinical correlation, VCAN was identified as a target for study. A chromosome methylation assay showed that VCAN was hypomethylated in tumors with LVI. In our patient samples, VCAN expression was also found to be high in UTUC tumors with LVI. In vitro analysis showed that knocking down VCAN inhibited cell migration but not proliferation. A heatmap analysis also confirmed a significant correlation between VCAN and migration genes. Additionally, silencing VCAN increased the effectiveness of cisplatin, gemcitabine and epirubicin, thus providing potential opportunities for clinical application.
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Affiliation(s)
- Hao-Lun Luo
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Yin-Lun Chang
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Hui-Ying Liu
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Yen-Ting Wu
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Ming-Tse Sung
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Yu-Li Su
- Department of Hematology and Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Chun-Chieh Huang
- Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Pei-Chia Wang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Jei-Ming Peng
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
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14
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Xiang D, Gu M, Liu J, Dong W, Yang Z, Wang K, Fu J, Wang H. m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway. Cancer Lett 2023; 560:216144. [PMID: 36958694 DOI: 10.1016/j.canlet.2023.216144] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/25/2023] [Accepted: 03/21/2023] [Indexed: 03/25/2023]
Abstract
Hepatic leukemia factor (HLF) is aberrantly expressed in human malignancies. However, its role in regulating intrahepatic cholangiocarcinoma (ICC) remains unclear. This study aimed to define the role of HLF in ICC progression. Here, we showed that HLF expression is upregulated in ICC and predicts the poor prognosis in patients. Mechanistically, HLF activation in ICC is mediated by METTL3-dependent m6A methylation of the HLF mRNA. As per the results from the loss- or gain-of-function experiments, HLF promoted the self-renewal, tumorigenicity, proliferation and metastasis of ICC cells. RNA-seq and CUT&Tag analyses showed that frizzled-4 (FZD4) and forkhead box Q1 (FOXQ1) are target genes of HLF. Moreover, FOXQ1 transcriptionally activates METTL3 expression, forming a positive feedback loop, which subsequently activates WNT/β-catenin signaling and downstream tumor stemness. Furthermore, HLF expression was positively correlated with METTL3, IGF2BP3, FZD4 and FOXQ1 expression in ICC tissues in a large ICC cohort. The combined IHC panels exhibited a better prognostic value for patients with ICC than any of these components alone. In conclusions, these findings demonstrated that the METTL3/HLF/FOXQ1 regulatory circuit drove FZD4-mediated WNT/β-catenin activation in ICC progression, suggesting that targeting this axis could be novel therapeutic strategy for ICC.
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Affiliation(s)
- Daimin Xiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute(2), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, China
| | - Mingye Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute(2), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China
| | - Junyu Liu
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China
| | - Wei Dong
- Department of Pathology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China
| | - Zhishi Yang
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China
| | - Kui Wang
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China.
| | - Jing Fu
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, China.
| | - Hongyang Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute(2), Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Third Affiliated Hospital of Naval Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Shanghai, China.
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15
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Zheng J, Dou R, Zhang X, Zhong B, Fang C, Xu Q, Di Z, Huang S, Lin Z, Song J, Wang S, Xiong B. LINC00543 promotes colorectal cancer metastasis by driving EMT and inducing the M2 polarization of tumor associated macrophages. J Transl Med 2023; 21:153. [PMID: 36841801 PMCID: PMC9960415 DOI: 10.1186/s12967-023-04009-6] [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: 11/23/2022] [Accepted: 02/16/2023] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND The interaction between the tumor-microenvironment (TME) and the cancer cells has emerged as a key player in colorectal cancer (CRC) metastasis. A small proportion of CRC cells which undergo epithelial-mesenchymal transition (EMT) facilitate the reshaping of the TME by regulating various cellular ingredients. METHODS Immunohistochemical analysis, RNA immunoprecipitation (RIP), RNA Antisense Purification (RAP), dual luciferase assays were conducted to investigate the biological function and regulation of LINC00543 in CRC. A series in vitro and in vivo experiments were used to clarify the role of LINC00543 in CRC metastasis. RESULTS Here we found that the long non-coding RNA LINC00543, was overexpressed in colorectal cancer tissues, which correlated with advanced TNM stage and poorer prognosis of CRC patients. The overexpression of LINC00543 promoted tumorigenesis and metastasis of CRC cells by enhancing EMT and remodeling the TME. Mechanistically, LINC00543 blocked the transport of pre-miR-506-3p across the nuclear-cytoplasmic transporter XPO5, thereby reducing the production of mature miR-506-3p, resulting in the increase in the expression of FOXQ1 and induction of EMT. In addition, upregulation of FOXQ1 induced the expression of CCL2 that accelerated the recruitment of macrophages and their M2 polarization. CONCLUSIONS Our study showed that LINC00543 enhanced EMT of CRC cells through the pre-miR-506-3p/FOXQ1 axis. This resulted in the upregulation of CCL2, leading to macrophages recruitment and M2 polarization, and ultimately stimulating the progression of CRC.
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Affiliation(s)
- Jinsen Zheng
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Rongzhang Dou
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Xinyao Zhang
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Bo Zhong
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.49470.3e0000 0001 2331 6153Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China
| | - Chenggang Fang
- grid.49470.3e0000 0001 2331 6153Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China
| | - Qian Xu
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Ziyang Di
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Sihao Huang
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Zaihuan Lin
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Jialin Song
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071, Hubei, China.
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071, Hubei, China.
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16
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Liu QP, Chen YY, An P, Rahman K, Luan X, Zhang H. Natural products targeting macrophages in tumor microenvironment are a source of potential antitumor agents. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 109:154612. [PMID: 36610172 DOI: 10.1016/j.phymed.2022.154612] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/10/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Macrophages are one of the major cell types in the immune system and are closely related to tumor development, which can be polarized into M1 type with anti-tumor activity or M2 type with pro-tumor activity. The infiltration of more macrophages into tumor predicts poorer prognosis due to their more exhibition of M2 phenotype under the influence of many factors in the tumor microenvironment (TME). Therefore, reverse of M2 macrophage polarization in TME is conducive to the suppression of tumor deterioration and understanding the influencing factors of macrophage polarization is helpful to provide new ideas for the subsequent targeting macrophages for tumor therapy. PURPOSE This review summarizes the effects of TME on macrophage polarization and natural products against M2 macrophage polarization, which may provide some directions for tumor therapy. METHODS The search of relevant literature was conducted using the PubMed, Science Direct, CNKI and Web of Science databases with the search terms "macrophage", "tumor microenvironment", "natural product" and "tumor". RESULTS The mutual transformation of M1 and M2 phenotypes in macrophages is influenced by many factors. Tumor cells affect the polarization of macrophages by regulating the expression of genes and proteins and the secretion of cytokines. The expression of some genes or proteins in macrophages is also related to their own polarization. Many natural products can reverse M2 polarization of macrophages which has been summarized in this review. CONCLUSION Regulation of macrophage polarization in TME can inhibit tumor development, and natural products have the potential to impede tumor development by regulating macrophage polarization.
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Affiliation(s)
- Qiu-Ping Liu
- Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yu-Ying Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Pei An
- Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Khalid Rahman
- School of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores University, Liverpool, United Kingdom
| | - Xin Luan
- Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hong Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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17
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Erratum. Hepatology 2022; 76:1901. [PMID: 36218174 DOI: 10.1002/hep.32766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
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18
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Zangouei AS, Tolue Ghasaban F, Dalili A, Akhlaghipour I, Moghbeli M. MicroRNAs as the pivotal regulators of Forkhead box protein family during gastrointestinal tumor progression and metastasis. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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19
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Xiao Y, Li Y, Shi D, Wang X, Dai S, Yang M, Kong L, Chen B, Huang X, Lin C, Liao W, Xu B, Chen X, Wang L, Chen X, Ouyang Y, Liu G, Li H, Song L. MEX3C-Mediated Decay of SOCS3 mRNA Promotes JAK2/STAT3 Signaling to Facilitate Metastasis in Hepatocellular Carcinoma. Cancer Res 2022; 82:4191-4205. [PMID: 36112698 DOI: 10.1158/0008-5472.can-22-1203] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/02/2022] [Accepted: 09/13/2022] [Indexed: 12/24/2022]
Abstract
Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)-mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3'UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. SIGNIFICANCE This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.
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Affiliation(s)
- Yunyun Xiao
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yue Li
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dongni Shi
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaoqing Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuqin Dai
- Department of Medicinal Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Muwen Yang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lingzhi Kong
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Boyu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xinjian Huang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chuyong Lin
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wenting Liao
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Benke Xu
- Department of Human Anatomy, School of Basic Medical Sciences, Yangtze University, Jingzhou, China
| | - Xin Chen
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Lishuai Wang
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiangfu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Ouyang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guozhen Liu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, China
| | - Heping Li
- Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
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20
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Shan X, Hu P, Ni L, Shen L, Zhang Y, Ji Z, Cui Y, Guo M, Wang H, Ran L, Yang K, Wang T, Wang L, Chen B, Yao Z, Wu Y, Yu Q. Serine metabolism orchestrates macrophage polarization by regulating the IGF1-p38 axis. Cell Mol Immunol 2022; 19:1263-1278. [PMID: 36180780 PMCID: PMC9622887 DOI: 10.1038/s41423-022-00925-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 09/05/2022] [Indexed: 01/27/2023] Open
Abstract
Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK-STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.
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Affiliation(s)
- Xiao Shan
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Penghui Hu
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Lina Ni
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Long Shen
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Yanan Zhang
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Zemin Ji
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Yan Cui
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Meihua Guo
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Haoan Wang
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Liyuan Ran
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
- Shandong Provincial Hospital, School of Laboratory Animal and Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250021, Shandong, China
| | - Kun Yang
- Shandong Provincial Hospital, School of Laboratory Animal and Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250021, Shandong, China
| | - Ting Wang
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Lei Wang
- Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Bin Chen
- Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Zhi Yao
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
| | - Yingjie Wu
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China.
- Shandong Provincial Hospital, School of Laboratory Animal and Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250021, Shandong, China.
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA.
| | - Qiujing Yu
- Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China.
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21
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Wang MQ, Li YP, Xu M, Tian Y, Wu Y, Zhang X, Shi JJ, Dang SS, Jia XL. VCAN, expressed highly in hepatitis B virus-induced hepatocellular carcinoma, is a potential biomarker for immune checkpoint inhibitors. World J Gastrointest Oncol 2022; 14:1933-1948. [PMID: 36310697 PMCID: PMC9611428 DOI: 10.4251/wjgo.v14.i10.1933] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/23/2022] [Accepted: 09/12/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND As a proteoglycan, VCAN exists in the tumor microenvironment and regulates tumor proliferation, invasion, and metastasis, but its role in hepatocellular carcinoma (HCC) has not yet been elucidated.
AIM To investigate the expression and potential mechanism of action of VCAN in HCC.
METHODS Based on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, we explored the correlation between VCAN expression and clinical features, and analyzed the prognosis of patients with high and low VCAN expression. The potential mechanism of action of VCAN was explored by Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis. We also explored immune cell infiltration, immune checkpoint gene expression, and sensitivity of immune checkpoint [programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte antigen 4 (CTLA4)] inhibitor therapy in patients with different VCAN expression. VCAN mRNA expression and VCAN methylation in peripheral blood were tested in 100 hepatitis B virus (HBV)-related patients (50 HCC and 50 liver cirrhosis).
RESULTS VCAN was highly expressed in HCC tissues, which was associated with a poor prognosis in HCC patients. No significant difference was found in VCAN mRNA expression in blood between patients with HBV-related cirrhosis and those with HCC, but there was a significant difference in VCAN methylation between the two groups. The correlation between VCAN and infiltrations of several different tumor immune cell types (including B cells, CD8+ T cells, and eosinophils) was significantly different. VCAN was strongly related to immune checkpoint gene expression and tumor mutation burden, and could be a biomarker of sensitivity to immune checkpoint (PD1/CTLA4) inhibitors. In addition, VCAN mRNA expression was associated with hepatitis B e antigen, HBV DNA, white blood cells, platelets, cholesterol, and coagulation function.
CONCLUSION High VCAN level could be a possible biomarker for poor prognosis of HCC, and its immunomodulatory mechanism in HCC warrants investigation.
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Affiliation(s)
- Mu-Qi Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Meng Xu
- Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Yan Tian
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Yuan Wu
- Department of Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Juan-Juan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Xiao-Li Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
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22
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Dong Q, Yan L, Xu Q, Hu X, Yang Y, Zhu R, Xu Q, Yang Y, Wang B. Pan-cancer analysis of forkhead box Q1 as a potential prognostic and immunological biomarker. Front Genet 2022; 13:944970. [PMID: 36118871 PMCID: PMC9475120 DOI: 10.3389/fgene.2022.944970] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022] Open
Abstract
Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family involved in the occurrence and development of different tumors. However, the specific expression patterns and functions of FOXQ1 in pan-cancer remain unclear. Therefore, we collected the expression, mutation, and clinical information data of 33 tumors from The Cancer Genome Atlas database. Via public pan-cancer transcriptome data analysis, we found that FOXQ1 is differentially expressed in various tumors at tissue and cell levels, such as liver hepatocellular carcinoma, colon adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Kaplan–Meier and Cox analyses suggested that FOXQ1 expression was associated with poor overall survival of cutaneous melanoma and thymoma. Its expression was also associated with good disease-specific survival (DSS) in prostate adenocarcinoma but poor DSS in liver hepatocellular carcinoma. In addition, FOXQ1 expression was associated with poor disease-free survival of pancreatic adenocarcinoma. Moreover, FOXQ1 expression was closely related to the tumor mutational burden in 14 tumor types and microsatellite instability (MSI) in 8 tumor types. With an increase in stromal and immune cells, FOXQ1 expression was increased in breast invasive carcinoma, pancreatic adenocarcinoma, thyroid carcinoma, lung adenocarcinoma, and ovarian serous cystadenocarcinoma, while its expression was decreased in pancreatic adenocarcinoma, bladder urothelial carcinoma, and stomach adenocarcinoma. We also found that FOXQ1 expression was related to the infiltration of 22 immune cell types in different tumors (p < 0.05), such as resting mast cells and resting memory CD4 T cells. Last, FOXQ1 was coexpressed with 47 immune-related genes in pan-cancer (p < 0.05). In conclusion, FOXQ1 expression is closely related to prognosis, clinicopathological parameters, cancer-related pathway activity, the tumor mutational burden, MSI, the tumor microenvironment, immune cell infiltration, and immune-related genes and has the potential to be a diagnostic and prognostic biomarker as well as an immunotherapy target for tumors. Our findings provide important clues for further mechanistic research into FOXQ1.
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Affiliation(s)
- Qiguan Dong
- Department of Radiation Oncology, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group, Fushun, China
- *Correspondence: Qiguan Dong, ; Yuchao Yang, ; Bengang Wang,
| | - Lirong Yan
- Tumour Etiology and Screening Department of Cancer Institute and General Surgery, Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China
| | - Qingbang Xu
- Department of Pain Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianliang Hu
- Department of Breast Surgery, The 3rd People’s Hospital of Liaoyang, Liaoyang, China
| | - Yan Yang
- Department of Radiation Oncology, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group, Fushun, China
| | - Ruiwu Zhu
- Department of Thoracic Surgery, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group, Fushun, China
| | - Qian Xu
- Tumour Etiology and Screening Department of Cancer Institute and General Surgery, Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China
| | - Yuchao Yang
- Department of Neurology, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group, Fushun, China
- *Correspondence: Qiguan Dong, ; Yuchao Yang, ; Bengang Wang,
| | - Bengang Wang
- Department of Hepatobiliary Surgery, Institute of General Surgery, First Hospital of China Medical University, Shenyang, China
- *Correspondence: Qiguan Dong, ; Yuchao Yang, ; Bengang Wang,
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23
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Francisco AB, Li J, Farghli AR, Kanke M, Shui B, Munn PR, Grenier JK, Soloway PD, Wang Z, Reid LM, Liu J, Sethupathy P. Chemical, Molecular, and Single-nucleus Analysis Reveal Chondroitin Sulfate Proteoglycan Aberrancy in Fibrolamellar Carcinoma. CANCER RESEARCH COMMUNICATIONS 2022; 2:663-678. [PMID: 36923282 PMCID: PMC10010304 DOI: 10.1158/2767-9764.crc-21-0177] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/21/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022]
Abstract
Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with no effective therapeutic options. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer growth and/or metastasis. To bridge this knowledge gap, we assessed pathways relevant to proteoglycans, a major component of the extracellular matrix. We first analyzed gene expression data from FLC and nonmalignant liver tissue (n = 27) to identify changes in glycosaminoglycan (GAG) biosynthesis pathways and found that genes associated with production of chondroitin sulfate, but not other GAGs, are significantly increased by 8-fold. We then implemented a novel LC/MS-MS based method to quantify the abundance of different types of GAGs in patient tumors (n = 16) and found that chondroitin sulfate is significantly more abundant in FLC tumors by 6-fold. Upon further analysis of GAG-associated proteins, we found that versican (VCAN) expression is significantly upregulated at the mRNA and protein levels, the latter of which was validated by IHC. Finally, we performed single-cell assay for transposase-accessible chromatin sequencing on FLC tumors (n = 3), which revealed for the first time the different cell types in FLC tumors and also showed that VCAN is likely produced not only from FLC tumor epithelial cells but also activated stellate cells. Our results reveal a pathologic aberrancy in chondroitin (but not heparan) sulfate proteoglycans in FLC and highlight a potential role for activated stellate cells. Significance This study leverages a multi-disciplinary approach, including state-of-the-art chemical analyses and cutting-edge single-cell genomic technologies, to identify for the first time a marked chondroitin sulfate aberrancy in FLC that could open novel therapeutic avenues in the future.
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Affiliation(s)
- Adam B Francisco
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Jine Li
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.,Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Alaa R Farghli
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Matt Kanke
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Bo Shui
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Paul R Munn
- Genomics Innovation Hub, Biotechnology Resource Center, Cornell University, Ithaca, New York
| | - Jennifer K Grenier
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York.,Genomics Innovation Hub, Biotechnology Resource Center, Cornell University, Ithaca, New York
| | - Paul D Soloway
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
| | - Zhangjie Wang
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Lola M Reid
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Jian Liu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
| | - Praveen Sethupathy
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York
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24
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Castaneda M, den Hollander P, Mani SA. Forkhead Box Transcription Factors: Double-Edged Swords in Cancer. Cancer Res 2022; 82:2057-2065. [PMID: 35315926 PMCID: PMC9258984 DOI: 10.1158/0008-5472.can-21-3371] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 02/12/2022] [Accepted: 03/14/2022] [Indexed: 01/07/2023]
Abstract
A plethora of treatment options exist for cancer therapeutics, but many are limited by side effects and either intrinsic or acquired resistance. The need for more effective targeted cancer treatment has led to the focus on forkhead box (FOX) transcription factors as possible drug targets. Forkhead factors such as FOXA1 and FOXM1 are involved in hormone regulation, immune system modulation, and disease progression through their regulation of the epithelial-mesenchymal transition. Forkhead factors can influence cancer development, progression, metastasis, and drug resistance. In this review, we discuss the various roles of forkhead factors in biological processes that support cancer as well as their function as pioneering factors and their potential as targetable transcription factors in the fight against cancer.
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Affiliation(s)
- Maria Castaneda
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Petra den Hollander
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sendurai A. Mani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Corresponding Author: Sendurai A. Mani, Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Suite 910, Houston, TX 77030-3304. Phone: 713-792-9638; E-mail:
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25
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Kato K, Fukai M, Hatanaka KC, Takasawa A, Aoyama T, Hayasaka T, Matsuno Y, Kamiyama T, Hatanaka Y, Taketomi A. Versican Secreted by Cancer-Associated Fibroblasts is a Poor Prognostic Factor in Hepatocellular Carcinoma. Ann Surg Oncol 2022; 29:7135-7146. [PMID: 35543908 DOI: 10.1245/s10434-022-11862-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 04/20/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is highly recurrent. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, promote malignancy; however, the mechanisms underlying their actions are obscure. We aimed to identify CAF-specific proteins in HCC and determine whether they could be potential therapeutic targets. METHODS Using comprehensive proteomic analysis of CAFs and noncancerous fibroblasts (NFs) primary-cultured from resected HCC specimens from the same patients, CAF-specific proteins were identified. Immunohistochemistry for versican (VCAN) was performed on cancerous tissues obtained from 239 patients with HCC. Conditioned medium from CAFs transfected with siRNA for VCAN was analyzed in vitro. RESULTS CAFs significantly promoted HCC cell proliferation, migration, and invasion (p < 0.01, 0.01, and 0.01, respectively) compared with NFs. VCAN was upregulated in CAFs, and its stromal level correlated with poor differentiation (p = 0.009) and positive vascular invasion (p = 0.003). Stromal VCAN level was also associated with significantly lower overall (p = 0.002) and relapse-free (p < 0.001) survival rates. It also independently predicted prognosis and recurrence. VCAN-knockdown CAFs significantly suppressed HCC cell migration and invasion compared with negative control. CONCLUSIONS VCAN secreted from CAFs promoted malignant transformation of HCC cells and has potential as a new therapeutic target in HCC.
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Affiliation(s)
- Koichi Kato
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kanako C Hatanaka
- Center for Development of Advanced Diagnostics (C-DAD), Hokkaido University Hospital, Sapporo, Japan.,Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takahiro Hayasaka
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoshihiro Matsuno
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yutaka Hatanaka
- Center for Development of Advanced Diagnostics (C-DAD), Hokkaido University Hospital, Sapporo, Japan.,Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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26
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Tellez-Gabriel M, Tekpli X, Reine TM, Hegge B, Nielsen SR, Chen M, Moi L, Normann LS, Busund LTR, Calin GA, Mælandsmo GM, Perander M, Theocharis AD, Kolset SO, Knutsen E. Serglycin Is Involved in TGF-β Induced Epithelial-Mesenchymal Transition and Is Highly Expressed by Immune Cells in Breast Cancer Tissue. Front Oncol 2022; 12:868868. [PMID: 35494005 PMCID: PMC9047906 DOI: 10.3389/fonc.2022.868868] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 03/21/2022] [Indexed: 12/03/2022] Open
Abstract
Serglycin is a proteoglycan highly expressed by immune cells, in which its functions are linked to storage, secretion, transport, and protection of chemokines, proteases, histamine, growth factors, and other bioactive molecules. In recent years, it has been demonstrated that serglycin is also expressed by several other cell types, such as endothelial cells, muscle cells, and multiple types of cancer cells. Here, we show that serglycin expression is upregulated in transforming growth factor beta (TGF-β) induced epithelial-mesenchymal transition (EMT). Functional studies provide evidence that serglycin plays an important role in the regulation of the transition between the epithelial and mesenchymal phenotypes, and it is a significant EMT marker gene. We further find that serglycin is more expressed by breast cancer cell lines with a mesenchymal phenotype as well as the basal-like subtype of breast cancers. By examining immune staining and single cell sequencing data of breast cancer tissue, we show that serglycin is highly expressed by infiltrating immune cells in breast tumor tissue.
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Affiliation(s)
- Marta Tellez-Gabriel
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Xavier Tekpli
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Trine M. Reine
- Department of Interphase Genetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Beate Hegge
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Stephanie R. Nielsen
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Meng Chen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Line Moi
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
- Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway
| | - Lisa Svartdal Normann
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Research and Innovation, Vestre Viken Hospital Trust, Drammen, Norway
| | - Lill-Tove R. Busund
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
- Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Gunhild M. Mælandsmo
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Maria Perander
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Achilleas D. Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | | | - Erik Knutsen
- Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway
- Centre for Clinical Research and Education, University Hospital of North Norway, Tromsø, Norway
- *Correspondence: Erik Knutsen,
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27
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Dituri F, Gigante G, Scialpi R, Mancarella S, Fabregat I, Giannelli G. Proteoglycans in Cancer: Friends or Enemies? A Special Focus on Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14081902. [PMID: 35454809 PMCID: PMC9024587 DOI: 10.3390/cancers14081902] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/04/2022] [Accepted: 04/08/2022] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Proteoglycans affect multiple molecular and cellular processes during the progression of solid tumors with a highly desmoplastic stroma, such as HCC. Due to their role in enhancing or limiting the traits of cancer cells underlying their aggressiveness, such as proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and stemness, these macromolecules could be exploited as molecular targets or therapeutic agents. Proteoglycans, such as biglycan, versican, syndecan-1, glypican-3, and agrin, promote HCC cell proliferation, EMT, and angiogenesis, while endostatin and proteoglycan 4 were shown to impair cancer neovascularization or to enhance the sensitivity of HCC cells to drugs, such as sorafenib and regorafenib. Based on this evidence, interventional strategies involving the use of humanized monoclonal antibodies, T cells engineered with chimeric antigen receptors, or recombinant proteins mimicking potentially curative proteoglycans, are being employed or may be adopted in the near future for the treatment of HCC. Abstract Proteoglycans are a class of highly glycosylated proteins expressed in virtually all tissues, which are localized within membranes, but more often in the pericellular space and extracellular matrix (ECM), and are involved in tissue homeostasis and remodeling of the stromal microenvironment during physiological and pathological processes, such as tissue regeneration, angiogenesis, and cancer. In general, proteoglycans can perform signaling activities and influence a range of physical, chemical, and biological tissue properties, including the diffusivity of small electrolytes and nutrients and the bioavailability of growth factors. While the dysregulated expression of some proteoglycans is observed in many cancers, whether they act as supporters or limiters of neoplastic progression is still a matter of controversy, as the tumor promoting or suppressive function of some proteoglycans is context dependent. The participation of multiple proteoglycans in organ regeneration (as demonstrated for the liver in hepatectomy mouse models) and in cancer suggests that these molecules actively influence cell growth and motility, thus contributing to key events that characterize neoplastic progression. In this review, we outline the main roles of proteoglycans in the physiology and pathology of cancers, with a special mention to hepatocellular carcinoma (HCC), highlighting the translational potential of proteoglycans as targets or therapeutic agents for the treatment of this disease.
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Affiliation(s)
- Francesco Dituri
- National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.G.); (R.S.); (S.M.); (G.G.)
- Correspondence:
| | - Gianluigi Gigante
- National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.G.); (R.S.); (S.M.); (G.G.)
| | - Rosanna Scialpi
- National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.G.); (R.S.); (S.M.); (G.G.)
| | - Serena Mancarella
- National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.G.); (R.S.); (S.M.); (G.G.)
| | - Isabel Fabregat
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBEREHD and University of Barcelona, L’Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Gianluigi Giannelli
- National Institute of Gastroenterology Saverio de Bellis, IRCCS Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.G.); (R.S.); (S.M.); (G.G.)
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Rashid MU, Lao Y, Spicer V, Coombs KM. Zika Virus Infection of Sertoli Cells Alters Protein Expression Involved in Activated Immune and Antiviral Response Pathways, Carbohydrate Metabolism and Cardiovascular Disease. Viruses 2022; 14:v14020377. [PMID: 35215967 PMCID: PMC8878972 DOI: 10.3390/v14020377] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 11/29/2022] Open
Abstract
Zika virus (ZIKV), a re-emerging virus, causes congenital brain abnormalities and Guillain–Barré syndrome. It is mainly transmitted by Aedes mosquitoes, but infections are also linked to sexual transmissions. Infectious ZIKV has been isolated, and viral RNA has been detected in semen over a year after the onset of initial symptoms, but the mode of long-term persistence is not yet understood. ZIKV can proliferate in human Sertoli cells (HSerC) for several weeks in vitro, suggesting that it might be a reservoir for persistent ZIKV infection. This study determined proteomic changes in HSerC during ZIKV infections by TMT-mass spectrometry analysis. Levels of 4416 unique Sertoli cell proteins were significantly altered at 3, 5, and 7 days after ZIKV infection. The significantly altered proteins include enzymes, transcription regulators, transporters, kinases, peptidases, transmembrane receptors, cytokines, ion channels, and growth factors. Many of these proteins are involved in pathways associated with antiviral response, antigen presentation, and immune cell activation. Several immune response pathway proteins were significantly activated during infection, e.g., interferon signaling, T cell receptor signaling, IL-8 signaling, and Th1 signaling. The altered protein levels were linked to predicted activation of immune response in HSerC, which was predicted to suppress ZIKV infection. ZIKV infection also affected the levels of critical regulators of gluconeogenesis and glycolysis pathways such as phosphoglycerate mutase, phosphoglycerate kinase, and enolase. Interestingly, many significantly altered proteins were associated with cardiac hypertrophy, which may induce heart failure in infected patients. In summary, our research contributes to a better understanding of ZIKV replication dynamics and infection in Sertoli cells.
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Affiliation(s)
- Mahamud-ur Rashid
- Department of Medical Microbiology and Infectious Diseases, The University of Manitoba, Room 543 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada;
- Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada; (Y.L.); (V.S.)
- Correspondence:
| | - Ying Lao
- Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada; (Y.L.); (V.S.)
| | - Victor Spicer
- Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada; (Y.L.); (V.S.)
| | - Kevin M. Coombs
- Department of Medical Microbiology and Infectious Diseases, The University of Manitoba, Room 543 Basic Medical Sciences Building, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada;
- Manitoba Centre for Proteomics & Systems Biology, Room 799, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada; (Y.L.); (V.S.)
- Children’s Hospital Research Institute of Manitoba, Room 513, John Buhler Research Centre, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada
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29
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Papadas A, Cicala A, Kraus SG, Arauz G, Tong A, Deming D, Asimakopoulos F. Versican in Tumor Progression, Tumor–Host Interactions, and Cancer Immunotherapy. BIOLOGY OF EXTRACELLULAR MATRIX 2022:93-118. [DOI: 10.1007/978-3-030-99708-3_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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30
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Tan J, Liu B, Zhou L, Gao J, Wang XK, Liu Y, Wang JR. LncRNA TUG1 promotes bladder cancer malignant behaviors by regulating the miR-320a/FOXQ1 axis. Cell Signal 2021; 91:110216. [PMID: 34920123 DOI: 10.1016/j.cellsig.2021.110216] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Growing evidence has showed long noncoding RNAs (lncRNAs) play critical roles in bladder cancer (BC) progression. LncRNA taurine upregulated gene 1 (TUG1) was involved in the development of human malignancies. However, the intrinsic and concrete molecular mechanisms of TUG1 in BC remain largely unknown. METHODS Expression patterns of TUG1, miR-320a and FOXQ1 in BC tissues and cell lines were measured using qRT-PCR and western blot, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. The capacity of cell migration and invasion was evaluated using wound healing and transwell assay. Tumor xenograft assay was performed to further validate the role of TUG1 in BC progression. Dual luciferase reporter assay and FISH analysis were employed to verify the TUG1/miR-320a/FOXQ1 regulatory network. RESULTS TUG1 was significantly higher expression in BC specimens and cell lines. TUG1 knockdown suppressed BC cells malignant behaviors in vitro and inhibited tumor growth and metastasis in vivo, while TUG1 overexpression promoted BC cells malignant behaviors in vitro. However, the function of miR-320a was opposite to that of TUG1, and miR-320a inhibitor partially eliminated the inhibitory effect of TUG1 knockdown on the malignant behavior of BC cells. As a microRNA sponge, TUG1 actively elevated FOXQ1 expression to sponge miR-320a and subsequently promoted BC cells malignant phenotypes. CONCLUSION TUG1 may have great potential as therapeutic target for BC, since TUG1 silencing inhibited cell proliferation, migration and invasion in BC, while promoted cell apoptosis, by regulating the miR-320a/FOXQ1 axis.
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Affiliation(s)
- Jing Tan
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Bin Liu
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Lei Zhou
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Jun Gao
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xin-Kun Wang
- Department of Andrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Yuan Liu
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Jin-Rong Wang
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
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31
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Wu G, Yang Y, Zhu Y, Li Y, Zhai Z, An L, Liu M, Zheng Y, Wang Y, Zhou Y, Guo Q. Comprehensive Analysis to Identify the Epithelial-Mesenchymal Transition-Related Immune Signatures as a Prognostic and Therapeutic Biomarkers in Hepatocellular Carcinoma. Front Surg 2021; 8:742443. [PMID: 34722623 PMCID: PMC8554059 DOI: 10.3389/fsurg.2021.742443] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/13/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with the high rates of the morbidity and mortality due to the lack of the effective prognostic model for prediction. Aim: To construct a risk model composed of the epithelial–mesenchymal transition (EMT)-related immune genes for the assessment of the prognosis, immune infiltration status, and chemosensitivity. Methods: We obtained the transcriptome and clinical data of the HCC samples from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) databases. The Pearson correlation analysis was applied to identify the differentially expressed EMT-related immune genes (DE-EMTri-genes). Subsequently, the univariate Cox regression was introduced to screen out the prognostic gene sets and a risk model was constructed based on the least absolute shrinkage and selection operator-penalized Cox regression. Additionally, the receiver operating characteristic (ROC) curves were plotted to compare the prognostic value of the newly established model compared with the previous model. Furthermore, the correlation between the risk model and survival probability, immune characteristic, and efficacy of the chemotherapeutics were analyzed by the bioinformatics methods. Results: Six DE-EMTri-genes were ultimately selected to construct the prognostic model. The area under the curve (AUC) values for 1-, 2-, and 3- year were 0.773, 0.721, and 0.673, respectively. Stratified survival analysis suggested that the prognosis of the low-score group was superior to the high-score group. Moreover, the univariate and multivariate analysis indicated that risk score [hazard ratio (HR) 5.071, 95% CI 3.050, 8.432; HR 4.396, 95% CI 2.624, 7.366; p < 0.001] and stage (HR 2.500, 95% CI 1.721, 3.632; HR 2.111, 95% CI 1.443, 3.089; p < 0.001) served as an independent predictive factors in HCC. In addition, the macrophages, natural killer (NK) cells, and regulatory T (Treg) cells were significantly enriched in the high-risk group. Finally, the patients with the high-risk score might be more sensitive to cisplatin, doxorubicin, etoposide, gemcitabine, and mitomycin C. Conclusion: We established a reliable EMTri-genes-based prognostic signature, which may hold promise for the clinical prediction.
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Affiliation(s)
- Guozhi Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Yuan Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Yu Zhu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Department of Hematology, the First Hospital of Lanzhou University, Lanzhou, China
| | - Yemao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Zipeng Zhai
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Lina An
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Min Liu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
| | - Qinghong Guo
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Gansu Key Laboratory of Gastroenterology, Lanzhou University, Lanzhou, China
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HIPK3 Circular RNA Promotes Metastases of HCC Through Sponging miR-338-3p to Induce ZEB2 Expression. Dig Dis Sci 2021; 66:3439-3447. [PMID: 33247421 DOI: 10.1007/s10620-020-06688-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 10/21/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Upregulation of circHIPK3 has been observed in several kinds of malignancies. However, the mechanisms of circHIPK3 in HCC metastases remains unclear. We investigated the role and the mechanisms of circHIPK3 in the development of HCC. METHODS HCC tissues and paired adjacent non-tumor tissues of surgical patients were used to evaluate circHIPK3 expression. A series of biological experiments had been taken to evaluate the pro-metastatic ability of circHIPK3 during HCC development in vitro and in vivo. The potential mechanisms of circHIPK3 in HCC development were identified by RT-qPCR, Western blot, RIP, and luciferase reporter assays. RESULTS CircHIPK3 expression is significantly upregulated during HCC development. Overexpression of circHIPK3 promotes cell migration, invasion, and metastases in vitro and in vivo. CircHIPK3 promoted HCC metastases by sponging miR-338-3p to regulate EMT-associated proteins E-cadherin, vimentin, and ZEB2 expression. CONCLUSION CircHIPK3 plays a regulatory role in metastatic HCC by sponging miR-338-3p to induce ZEB2 expression, thus promoting EMT procession.
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Traditional Chinese medicine for prevention and treatment of hepatocellular carcinoma: A focus on epithelial-mesenchymal transition. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2021; 19:469-477. [PMID: 34538644 DOI: 10.1016/j.joim.2021.08.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/21/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant cancers worldwide. Epithelial-mesenchymal transition (EMT), which endows epithelial cells with mesenchymal properties, plays an important role in the early stages of metastasis. Conventional cancer therapies have promising effects, but issues remain, such as high rates of metastasis and drug resistance. Thus, exploring and evaluating new therapies is an urgent need. Traditional Chinese medicines (TCMs) have been acknowledged for their multi-target and coordinated intervention effects against HCC. Accumulating evidence indicates that TCM can inhibit the malignancy of cells and the progression of EMT in HCC. However, studies on the effects of TCM on EMT in HCC are scarce. In this review, we summarized recent developments in anti-EMT TCMs and formulae, focusing on their underlying pharmacological mechanisms, to provide a foundation for further research on the exact mechanisms through which TCM affects EMT in HCC.
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Alatan H, Chen Y, Zhou J, Wang L. Extracellular Matrix-Related Hubs Genes Have Adverse Effects on Gastric Adenocarcinoma Prognosis Based on Bioinformatics Analysis. Genes (Basel) 2021; 12:1104. [PMID: 34356118 PMCID: PMC8303807 DOI: 10.3390/genes12071104] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/07/2021] [Accepted: 07/17/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric adenocarcinoma (GAC) is the most frequent type of stomach cancer, characterized by high heterogeneity and phenotypic diversity. Although many novel strategies have been developed for treating GAC, recurrence and metastasis rates are still high. Therefore, it is necessary to screen new potential biomarkers correlated with prognosis and novel molecular targets. Gene expression profiles were obtained from the from NCBI Gene Expression Omnibus (GEO) database. We conduct an integrated analysis using the online Venny website to explore candidate hub genes between differentially expressed genes (DEGs) of two datasets. Gene ontology (GO) and Kyoto Encyclopedia 18 of Genes and Genomes (KEGG) pathway enrichment analysis found that extracellular matrix plays an important role in GAC. In addition, we applied protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes (STRING) and visualized with Cytoscape software. Furthermore, we employed Cytoscape software to analyze the interactive relationship of candidate gene for further analysis. We found that ECM related proteins played an important role in GAC, and 15 hub genes were extracted from 123 DEGs genes. There were four hub genes (bgn, vcan, col1a1 and timp1) predicted to be associated with poor prognosis among the 15 hub genes.
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Affiliation(s)
- Husile Alatan
- School of Basic Medicine, Hangzhou Normal University, Hangzhou 311121, China; (H.A.); (Y.C.)
- NS Bio Japan Co., Ltd., Akita 0130205, Japan
| | - Yinwei Chen
- School of Basic Medicine, Hangzhou Normal University, Hangzhou 311121, China; (H.A.); (Y.C.)
| | - Jinghua Zhou
- School of Basic Medicine, Hangzhou Normal University, Hangzhou 311121, China; (H.A.); (Y.C.)
| | - Li Wang
- School of Basic Medicine, Hangzhou Normal University, Hangzhou 311121, China; (H.A.); (Y.C.)
- Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, Graduate University for Advanced Studies (SOKENDAI), Hayama 2400193, Kanagawa, Japan
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35
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Birkhoff JC, Huylebroeck D, Conidi A. ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises. Genes (Basel) 2021; 12:1037. [PMID: 34356053 PMCID: PMC8304685 DOI: 10.3390/genes12071037] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/15/2022] Open
Abstract
After its publication in 1999 as a DNA-binding and SMAD-binding transcription factor (TF) that co-determines cell fate in amphibian embryos, ZEB2 was from 2003 studied by embryologists mainly by documenting the consequences of conditional, cell-type specific Zeb2 knockout (cKO) in mice. In between, it was further identified as causal gene causing Mowat-Wilson Syndrome (MOWS) and novel regulator of epithelial-mesenchymal transition (EMT). ZEB2's functions and action mechanisms in mouse embryos were first addressed in its main sites of expression, with focus on those that helped to explain neurodevelopmental and neural crest defects seen in MOWS patients. By doing so, ZEB2 was identified in the forebrain as the first TF that determined timing of neuro-/gliogenesis, and thereby also the extent of different layers of the cortex, in a cell non-autonomous fashion, i.e., by its cell-intrinsic control within neurons of neuron-to-progenitor paracrine signaling. Transcriptomics-based phenotyping of Zeb2 mutant mouse cells have identified large sets of intact-ZEB2 dependent genes, and the cKO approaches also moved to post-natal brain development and diverse other systems in adult mice, including hematopoiesis and various cell types of the immune system. These new studies start to highlight the important adult roles of ZEB2 in cell-cell communication, including after challenge, e.g., in the infarcted heart and fibrotic liver. Such studies may further evolve towards those documenting the roles of ZEB2 in cell-based repair of injured tissue and organs, downstream of actions of diverse growth factors, which recapitulate developmental signaling principles in the injured sites. Evident questions are about ZEB2's direct target genes, its various partners, and ZEB2 as a candidate modifier gene, e.g., in other (neuro)developmental disorders, but also the accurate transcriptional and epigenetic regulation of its mRNA expression sites and levels. Other questions start to address ZEB2's function as a niche-controlling regulatory TF of also other cell types, in part by its modulation of growth factor responses (e.g., TGFβ/BMP, Wnt, Notch). Furthermore, growing numbers of mapped missense as well as protein non-coding mutations in MOWS patients are becoming available and inspire the design of new animal model and pluripotent stem cell-based systems. This review attempts to summarize in detail, albeit without discussing ZEB2's role in cancer, hematopoiesis, and its emerging roles in the immune system, how intense ZEB2 research has arrived at this exciting intersection.
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Affiliation(s)
- Judith C. Birkhoff
- Department of Cell Biology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (J.C.B.); (D.H.)
| | - Danny Huylebroeck
- Department of Cell Biology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (J.C.B.); (D.H.)
- Department of Development and Regeneration, Unit Stem Cell and Developmental Biology, Biomedical Sciences Group, KU Leuven, 3000 Leuven, Belgium
| | - Andrea Conidi
- Department of Cell Biology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (J.C.B.); (D.H.)
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36
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Xia Q, Shu Z, Ye T, Zhang M. Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma. Front Genet 2020; 11:595699. [PMID: 33365048 PMCID: PMC7750531 DOI: 10.3389/fgene.2020.595699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022] Open
Abstract
As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is the fifth major cause of cancer-associated mortality worldwide. In 90% of cases, HCC develops in the context of liver cirrhosis and chronic hepatitis B virus (HBV) infection is an important etiology for cirrhosis and HCC, accounting for 53% of all HCC cases. To understand the underlying mechanisms of the dynamic chain reactions from normal to HBV infection, from HBV infection to liver cirrhosis, from liver cirrhosis to HCC, we analyzed the blood lncRNA expression profiles from 38 healthy control samples, 45 chronic hepatitis B patients, 46 liver cirrhosis patients, and 46 HCC patients. Advanced machine-learning methods including Monte Carlo feature selection, incremental feature selection (IFS), and support vector machine (SVM) were applied to discover the signature associated with HCC progression and construct the prediction model. One hundred seventy-one key HCC progression-associated lncRNAs were identified and their overall accuracy was 0.823 as evaluated with leave-one-out cross validation (LOOCV). The accuracies of the lncRNA signature for healthy control, chronic hepatitis B, liver cirrhosis, and HCC were 0.895, 0.711, 0.870, and 0.826, respectively. The 171-lncRNA signature is not only useful for early detection and intervention of HCC, but also helpful for understanding the multistage tumorigenic processes of HCC.
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Affiliation(s)
- Qi Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, China.,Zhejiang University, Hangzhou, China
| | - Zheyue Shu
- Zhejiang University, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Ting Ye
- Zhejiang University, Hangzhou, China
| | - Min Zhang
- Zhejiang University, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
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37
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Li M, Chen L, Gao Y, Li M, Wang X, Qiang L, Wang X. Recent advances targeting C-C chemokine receptor type 2 for liver diseases in monocyte/macrophage. Liver Int 2020; 40:2928-2936. [PMID: 33025657 DOI: 10.1111/liv.14687] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/21/2020] [Accepted: 10/01/2020] [Indexed: 12/12/2022]
Abstract
Liver plays a critical role in metabolism, nutrient storage and detoxification. Emergency signals or appropriate immune response leads to pathological inflammation and breaks the steady state when liver dysfunction appears, which makes body more susceptible to chronic liver infection, autoimmune diseases and tumour. Compelling proof has illustrated the non-redundant importance of C-C chemokine receptor type 2 (CCR2), one of G-protein-coupled receptors, in different diseases. Selectively expressed on the surface of cells, CCR2 is involved in various signalling pathways and regulates the migration of cells. Especially, a peculiar role of CCR2 has been identified within decades in the onset and progression of hepatic diseases, which led to particular focusing on CCR2 as a new therapeutic and diagnostic target for non-alcoholic fatty liver disease and hepatocellular carcinoma. In this review, we discuss the effect of CCR2 in monocytes/macrophages on liver diseases. The application and translation of the decades of discoveries into therapies promise novel approaches in the treatment of liver disease.
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Affiliation(s)
- Min Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Liu Chen
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue Gao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mengyuan Li
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.,Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.,Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Lei Qiang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoping Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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38
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Papadas A, Arauz G, Cicala A, Wiesner J, Asimakopoulos F. Versican and Versican-matrikines in Cancer Progression, Inflammation, and Immunity. J Histochem Cytochem 2020; 68:871-885. [PMID: 32623942 PMCID: PMC7711242 DOI: 10.1369/0022155420937098] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/04/2020] [Indexed: 12/16/2022] Open
Abstract
Versican is an extracellular matrix proteoglycan with key roles in multiple facets of cancer development, ranging from proliferative signaling, evasion of growth-suppressor pathways, regulation of cell death, promotion of neoangiogenesis, and tissue invasion and metastasis. Multiple lines of evidence implicate versican and its bioactive proteolytic fragments (matrikines) in the regulation of cancer inflammation and antitumor immune responses. The understanding of the dynamics of versican deposition/accumulation and its proteolytic turnover holds potential for the development of novel immune biomarkers as well as approaches to reset the immune thermostat of tumors, thus promoting efficacy of modern immunotherapies. This article summarizes work from several laboratories, including ours, on the role of this central matrix proteoglycan in tumor progression as well as tumor-immune cell cross-talk.
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Affiliation(s)
- Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
- Cellular & Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI
| | - Garrett Arauz
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Joshua Wiesner
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
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39
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Tang H, Zheng J, Bai X, Yue KL, Liang JH, Li DY, Wang LP, Wang JL, Guo Q. Forkhead Box Q1 Is Critical to Angiogenesis and Macrophage Recruitment of Colorectal Cancer. Front Oncol 2020; 10:564298. [PMID: 33330033 PMCID: PMC7734287 DOI: 10.3389/fonc.2020.564298] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/23/2020] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis and the tumor microenvironment (TME) play important roles in tumorigenesis. Forkhead box Q1 (FOXQ1) is a well-established oncogene in multiple tumors, including colorectal cancer (CRC); however, whether FOXQ1 contributes to angiogenesis and TME modification in CRC remains largely uncharacterized. Here, we demonstrate an essential role of FOXQ1-induced angiogenesis and macrophage recruitment in CRC that is related to its ability to promote the migration of endothelial cells and macrophages through activation of the EGF/PDGF pathway and the Twist1/CCL2 axis. We also provide evidence showing that the clinical significance between FOXQ1, Twist1, CCL2, and macrophage infiltration is associated with reduced 8-year survival in CRC patients. Our findings suggest FOXQ1 plays critical roles in the malignancy and progression of CRC, Therefore, FOXQ1 may serve as a therapeutic target for inhibiting angiogenesis and reducing macrophage recruitment in CRC.
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Affiliation(s)
- Hui Tang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Ji Zheng
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
- Genetic Testing Center, Qingdao Women and Children’s Hospital, Qingdao, China
| | - Xuan Bai
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Ke-Lin Yue
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jian-Hua Liang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Dan-Yang Li
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Lin-Ping Wang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jin-Li Wang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Qiang Guo
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
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Qin S, Jiang J, Lu Y, Nice EC, Huang C, Zhang J, He W. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther 2020; 5:228. [PMID: 33028808 PMCID: PMC7541492 DOI: 10.1038/s41392-020-00313-5] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/25/2020] [Accepted: 08/30/2020] [Indexed: 02/07/2023] Open
Abstract
Resistance to cancer therapy is a major barrier to cancer management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance, the latter of which is the focus that will be discussed here. Such non-mutational processes are largely driven by tumor cell plasticity, which renders tumor cells insusceptible to the drug-targeted pathway, thereby facilitating the tumor cell survival and growth. The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial-mesenchymal transition, acquisition properties of cancer stem cells, and trans-differentiation potential during drug exposure. From observations in various cancers, this concept provides an opportunity for investigating the nature of anticancer drug resistance. Over the years, our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased. This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs, which are likely to improve patient outcomes in clinical practice.
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Affiliation(s)
- Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China
| | - Yi Lu
- School of Medicine, Southern University of Science and Technology Shenzhen, Shenzhen, Guangdong, 518055, People's Republic of China
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China.
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Road, 611137, Chengdu, People's Republic of China.
| | - Jian Zhang
- School of Medicine, Southern University of Science and Technology Shenzhen, Shenzhen, Guangdong, 518055, People's Republic of China.
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, People's Republic of China.
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
- Chongqing Key Laboratory for Disease Proteomics, Chongqing, People's Republic of China.
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41
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Islam S, Watanabe H. Versican: A Dynamic Regulator of the Extracellular Matrix. J Histochem Cytochem 2020; 68:763-775. [PMID: 33131383 DOI: 10.1369/0022155420953922] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural macromolecule of the extracellular matrix in the brain and large blood vessels. In contrast, versican is transiently expressed at high levels during development and under pathological conditions when the extracellular matrix dramatically changes, including in the inflammation and repair process. There are many reports showing the upregulation of versican in cancer, which correlates with cancer aggressiveness. Versican has four classical splice variants, and all the variants contain G1 and G3 domains at N- and C-termini, respectively. There are two glycosaminoglycan attachment domains CSα and CSβ. The largest V0 variant contains both CSα and CSβ, V1 contains CSβ, V2 contains CSα, and the shortest G3 variant has neither of them. Versican degradation is initiated by cleavage at a site in the CSβ domain by ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases. The N-terminal fragment containing the G1 domain has been reported to exert various biological functions, although its mechanisms of action have not yet been elucidated. In this review, we describe the role of versican in inflammation and cancer and also address the biological function of versikine.
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Affiliation(s)
- Shamima Islam
- Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Japan
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Japan
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42
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Abstract
Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
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Affiliation(s)
- Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
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Zhao C, Yuan G, Jiang Y, Xu J, Ye L, Zhan W, Wang J. Capn4 contributes to tumor invasion and metastasis in gastric cancer via activation of the Wnt/β-catenin/MMP9 signalling pathways. Exp Cell Res 2020; 395:112220. [PMID: 32777225 DOI: 10.1016/j.yexcr.2020.112220] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 07/03/2020] [Accepted: 08/03/2020] [Indexed: 02/07/2023]
Abstract
Capn4, a small regulatory subunit of the calpain proteolytic system, functions as a potential tumor promoter in several cancers. However, the biological functions and molecular mechanisms of Capn4 in gastric cancer (GC) remain poorly understood. In the current study, we found that upregulation of Capn4 was detected frequently in GC tissues, and was associated with significantly worse survival among the GC patients. Multivariate analyses revealed that abundance of Capn4 was an independent predictive marker for the poor prognosis of GC. Further, Capn4 knockdown notably suppressed GC invasion and metastasis in vitro. Consistently, a xenograft assay showed that silencing of Capn4 in GC cells suppressed their dissemination to lung tissue in vivo. Moreover, our results indicated that Capn4 promotes gastric cancer metastasis by increasing MMP9 expression, and demonstrated that MMP9 is crucial for the pro-metastasis role of Capn4 in GC cells. Further investigation revealed that Capn4 regulated MMP9 expression via activation of Wnt/β-catenin signaling pathway. Mechanistically, we found that Capn4 can decreased β-catenin ubiquitination to enhance the protein stability of β-catenin in GC cells. Collectively, Capn4 has a central role in gastric cancer metastasis, which could be a potential diagnostic and therapeutic target for GC.
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Affiliation(s)
- Chuanwen Zhao
- Department of General Surgery, Jiujiang First People's Hospital, Jiujiang, Jiangxi 332000, China
| | - Guohui Yuan
- Department of Hepatopancreatobiliary Surgery, Jiujiang First People's Hospital, Jiujiang, Jiangxi 332000, China
| | - Yuemei Jiang
- Department of prosthodontics, The Affiliated Stomatological Hospital of Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Jianfeng Xu
- Department of Hepatopancreatobiliary Surgery, Jiujiang First People's Hospital, Jiujiang, Jiangxi 332000, China
| | - Lin Ye
- Department of General Surgery, Jiujiang First People's Hospital, Jiujiang, Jiangxi 332000, China
| | - Wenhui Zhan
- Department of Maxillofacial Surgery, The Affiliated Stomatological Hospital of Jiujiang University, Jiujiang, Jiangxi 332000, China.
| | - Junfu Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
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Zhong Q, Fang Y, Lai Q, Wang S, He C, Li A, Liu S, Yan Q. CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:132. [PMID: 32653013 PMCID: PMC7353816 DOI: 10.1186/s13046-020-01637-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 07/01/2020] [Indexed: 02/08/2023]
Abstract
Background Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC. Methods The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice. Results Decreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. Conclusions CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.
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Affiliation(s)
- Qian Zhong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yuxin Fang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China
| | - Qiuhua Lai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China
| | - Shanci Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China
| | - Chengcheng He
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Qun Yan
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 1838th North Guangzhou Avenue, Guangzhou, 510515, China.
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Cao MX, Zhang WL, Yu XH, Wu JS, Qiao XW, Huang MC, Wang K, Wu JB, Tang YJ, Jiang J, Liang XH, Tang YL. Interplay between cancer cells and M2 macrophages is necessary for miR-550a-3-5p down-regulation-mediated HPV-positive OSCC progression. J Exp Clin Cancer Res 2020; 39:102. [PMID: 32493454 PMCID: PMC7268480 DOI: 10.1186/s13046-020-01602-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 05/22/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Human papillomavirus (HPV)-positive oral squamous cell carcinoma (OSCC) is increasing worldwide with typically higher grade and stage, while better prognosis. microRNAs (miRNAs) has been shown to play a critical role in cancer, however, their role in HPV-positive OSCC progression remains unclear. METHODS miRNA microarray was performed to identify differentially expressed miRNAs. qRT-PCR and FISH were performed to determine the relative expression of miR-550a-3-5p. CCK-8, Flow cytometry, Wound healing, Cell invasion assays and xenograft experiments were conducted to analyze the biological roles of miR-550a-3-5p. Tumor-associated macrophages (TAMs) generation, co-culturing of cancer cells with TAMs, Western blot, Dual-luciferase reporter gene assay, Immunohistochemistry and animal studies were performed to explore the mechanisms underlying the functions of miR-550a-3-5p. RESULTS We identified 19 miRNAs differentially expressed in HPV-positive OSCC specimens and miR-550a-3-5p was down-regulated. The low expression of miR-550a-3-5p correlated with higher tumor size and nodal metastasis of HPV-positive OSCC patients. Then, we found that miR-550a-3-5p suppressed the migration, invasion and EMT of HPV-positive OSCC cells dependent on decreasing M2 macrophages polarization. Moreover, miR-550a-3-5p, down-regulated by E6 oncoprotein, inhibited M2 macrophages polarization by YAP/CCL2 signaling, which in turn abrogating EMT program in HPV-positive OSCC cells. In addition, in both xenografts and clinical HPV-positive OSCC samples, miR-550a-3-5p levels were inversely associated with YAP, CCL2 expressions and the number of M2 macrophages. CONCLUSIONS E6/miR-550a-3-5p/YAP/CCL2 signaling induces M2 macrophages polarization to enhance EMT and progression, revealing a novel crosstalk between cancer cells and immune cells in HPV-positive OSCC microenvironment.
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Affiliation(s)
- Ming-Xin Cao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Wei-Long Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Xiang-Hua Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Jia-Shun Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Xin-Wei Qiao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Mei-Chang Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Ke Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Jing-Biao Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, China
| | - Jian Jiang
- Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, Sichuan, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China.
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China.
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Gong Z, Yu J, Yang S, Lai PBS, Chen GG. FOX transcription factor family in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2020; 1874:188376. [PMID: 32437734 DOI: 10.1016/j.bbcan.2020.188376] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/13/2020] [Accepted: 05/07/2020] [Indexed: 02/06/2023]
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process, involving the progressive accumulation of molecular alterations and transcriptomic alterations. The Forkhead-box (FOX) transcription factor family is characterized by its unique DNA binding domain (FKH or winged-helix domain). Human FOX family consists of about 17 subfamilies, at least 43 members. Some of them are liver-enriched transcription factors, suggesting that they may play a crucial role in the development or/and functions of the liver. Dysregulation of FOX transcription factors may contribute to the pathogenesis of HCC because they can activate or suppress the expression of various tumor-related molecules, and pinpoint different molecular and cellular events. Here we summarized, analyzed and discussed the status and the functions of the human FOX family of transcription factors in HCC, aiming to help the further development of them as potential therapeutic targets or/and diagnostic/prognostic markers for HCC.
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Affiliation(s)
- Zhongqin Gong
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Jianqing Yu
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Shucai Yang
- Department of Clinical Laboratory, Pingshan District people's Hospital of Shenzhen, Shenzhen, China
| | - Paul B S Lai
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
| | - George G Chen
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
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Wencong M, Jinghan W, Yong Y, Jianyang A, Bin L, Qingbao C, Chen L, Xiaoqing J. FOXK1 Promotes Proliferation and Metastasis of Gallbladder Cancer by Activating AKT/mTOR Signaling Pathway. Front Oncol 2020; 10:545. [PMID: 32363163 PMCID: PMC7180204 DOI: 10.3389/fonc.2020.00545] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 03/26/2020] [Indexed: 01/10/2023] Open
Abstract
Gallbladder cancer (GBC) is one of the most lethal malignancies worldwide, with extremely poor prognosis. Recently, forkhead box k1 (FOXK1), a member of the FOX transcription factor family, has been reported to be correlated with tumor progression in multiple malignancies. However, the role of FOXK1 in GBC has not been elucidated. In this study, we demonstrated that the expression level of FOXK1 was elevated in human GBC tissues and associated with increased liver metastasis, poor histological differentiation, advanced TNM stage, and shorter overall survival. Knockdown of FOXK1 expression inhibited GBC cells proliferation and metastasis. Consistently, overexpression of FOXK1 promoted GBC cells progression. Mechanical investigations verified that knockdown of FOXK1 could lead to G1/S cell cycle arrest through downregulating CDK4, CDK6, cyclin D1, and cyclin E1. And FOXK1 could regulate the expression of epithelial–mesenchymal transition (EMT) related proteins E-cad, N-cad, and Vimentin. Moreover, we found that FOXK1 could regulate the activation of Akt/mTOR signaling pathway. In addition, AKT special inhibitor MK-2206 could abolish the proliferation and metastasis discrepancy between FOXK1 overexpression GBC cells and control cells, which suggested the tumorpromoting effect of FOXK1 may be partially related with the activations of Akt/mTOR signaling pathway. Collectively, our results suggested that FOXK1 promotes GBC cells progression and represent a novel prognostic biomarker and potential therapeutic target in GBC.
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Affiliation(s)
- Ma Wencong
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Wang Jinghan
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Yu Yong
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Ao Jianyang
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Li Bin
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Cheng Qingbao
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Liu Chen
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Jiang Xiaoqing
- Department of Biliary Tract Surgery I, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
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Papadas A, Asimakopoulos F. Versican in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1272:55-72. [PMID: 32845502 DOI: 10.1007/978-3-030-48457-6_4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Versican is an extracellular matrix proteoglycan with nonredundant roles in diverse biological and cellular processes, ranging from embryonic development to adult inflammation and cancer. Versican is essential for cardiovascular morphogenesis, neural crest migration, and skeletal development during embryogenesis. In the adult, versican acts as an inflammation "amplifier" and regulator of immune cell activation and cytokine production. Increased versican expression has been observed in a wide range of malignant tumors and has been associated with poor patient outcomes. The main sources of versican production in the tumor microenvironment include accessory cells (myeloid cells and stromal components) and, in some contexts, the tumor cells themselves. Versican has been implicated in several classical hallmarks of cancer such as proliferative signaling, evasion of growth suppressor signaling, resistance to cell death, angiogenesis, and tissue invasion and metastasis. More recently, versican has been implicated in escape from tumor immune surveillance, e.g., through dendritic cell dysfunction. Versican's multiple contributions to benign and malignant biological processes are further diversified through the generation of versican-derived bioactive proteolytic fragments (matrikines), with versikine being the most studied to date. Versican and versican-derived matrikines hold promise as targets in the management of inflammatory and malignant conditions as well as in the development of novel predictive and prognostic biomarkers.
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Affiliation(s)
- Athanasios Papadas
- Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA. .,University of Wisconsin-Madison, Cellular and Molecular Pathology Program, Madison, WI, USA.
| | - Fotis Asimakopoulos
- Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA
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Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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Zhu X, Luo W, Bei C, Kong J, Zhang S, Fu Y, Li D, Tan S. Correlations between chromobox homolog 8 and key factors of epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Cell Int 2019; 19:340. [PMID: 31889893 PMCID: PMC6916084 DOI: 10.1186/s12935-019-1063-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/09/2019] [Indexed: 02/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC. Methods A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis. Results We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues. Conclusions Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.
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Affiliation(s)
- Xiaonian Zhu
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
| | - Wei Luo
- 2Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, 637000 Sichuan People's Republic of China
| | - Chunhua Bei
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
| | - Juan Kong
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
| | - Shidong Zhang
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
| | - Yuanyuan Fu
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
| | - Di Li
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
| | - Shengkui Tan
- 1Department of Epidemiology and Health Statistics, School of Public Health, Guilin Medical University, 109 Huancheng North Road 2, Guilin, 541004 Guangxi People's Republic of China
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