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Bates M, Mohamed BM, Lewis F, O'Toole S, O'Leary JJ. Biomarkers in high grade serous ovarian cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189224. [PMID: 39581234 DOI: 10.1016/j.bbcan.2024.189224] [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: 01/28/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Faye Lewis
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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2
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Orang A, Marri S, McKinnon RA, Petersen J, Michael MZ. Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study. Cancers (Basel) 2024; 16:2055. [PMID: 38893174 PMCID: PMC11171104 DOI: 10.3390/cancers16112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. METHODS The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs. RESULTS Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. CONCLUSIONS This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
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Affiliation(s)
- Ayla Orang
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Shashikanth Marri
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Ross A. McKinnon
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, SA 5042, Australia
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Wang H, Wang W. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening. Open Med (Wars) 2024; 19:20240919. [PMID: 38584823 PMCID: PMC10998672 DOI: 10.1515/med-2024-0919] [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: 09/11/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 04/09/2024] Open
Abstract
Background The disulfide stress-induced cell death known as disulfidptosis is characterized by the disintegration of cytoskeletal proteins and F-actin as a result of an excessive buildup of disulfides within the cell. The relationship between disulfidptosis-associated long non-coding RNA (lncRNA) in hepatocellular carcinoma (HCC) progression is still not clearly understood. In this article, we aim to explore the crucial role of lncRNA in HCC. Methods We initially obtained lncRNA related to HCC and clinical data from TCGA. The genes associated with disulfidptosis were identified through co-expression analysis, Cox regression, and Lasso regression. Additionally, we established a prognostic model for verification. Results The risk model constructed with disulfidptosis-related lncRNA has been confirmed to be a good predictor of high and low-risk groups of HCC patients through survival curves, independent prognostic analysis, concordance index (C-index), ROC curves, and Kaplan-Meier plots. We also discovered differences in the response to immune targets and anticancer drugs between the two groups of patients, with GDC0810, Osimertinib, Paclitaxel, and YK-4-279 being more effective for patients in the high-risk group. Conclusion In conclusion, we have developed a risk model that can guide future efforts to diagnose and treat HCC.
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Affiliation(s)
- Haojun Wang
- Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
- Capital Medical University, Beijing, 100071, China
| | - Wei Wang
- Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
- Capital Medical University, Beijing, 100071, China
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Hu W, Ma SL, Qiong L, Du Y, Gong LP, Pan YH, Sun LP, Wen JY, Chen JN, Guan XY, Shao CK. PPM1G promotes cell proliferation via modulating mutant GOF p53 protein expression in hepatocellular carcinoma. iScience 2024; 27:109116. [PMID: 38384839 PMCID: PMC10879691 DOI: 10.1016/j.isci.2024.109116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/25/2023] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p < 0.0001) and disease-free survival (p = 0.004) in HCC patients. Enhanced expression of PPM1G increases the cell proliferation rate, and knockdown of PPM1G led to a significant reduction in tumor volume in vivo. Further experiments illustrated that upregulated-PPM1G expression increased the protein expression of gain-of-function (GOF) mutant p53. Besides, the immunoprecipitation analysis revealed a direct interaction between PPM1G and GOF mutant p53. Collectively, PPM1G can be a powerful prognostic predictor and potential drug-target molecule.
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Affiliation(s)
- Wen Hu
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Shao-Lin Ma
- Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
| | - Liang Qiong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Yu Du
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Li-Ping Gong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Yu-Hang Pan
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Li-Ping Sun
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Jing-Yun Wen
- Department of Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Jian-Ning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [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: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Chen Y, Zhu Z, Ma T, Zhang L, Chen J, Jiang J, Lu C, Ding Y, Guan W, Yi N, Ren H. TP53 mutation-related senescence is an indicator of hepatocellular carcinoma patient outcomes from multiomics profiles. SMART MEDICINE 2023; 2:e20230005. [PMID: 39188277 PMCID: PMC11235654 DOI: 10.1002/smmd.20230005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/13/2023] [Indexed: 08/28/2024]
Abstract
TP53 mutation frequently occurs in hepatocellular carcinoma (HCC). Senescence also plays a vital role in the ongoing process of HCC. P53 is believed to regulate the advancement of senescence in HCC. However, the exact mechanism of TP53 mutation-related senescence remains unclear. In this study, we found the TP53 mutation was positively correlated with senescence in HCC, and the differential expressed genes were primarily located in macrophages. Our results proved that the risk score could have an independent and vital role in predicting the prognosis of HCC patients. In addition, HCC patients with a high risk score may most probably benefit from immune checkpoint block therapy. We also found the risk score is elevated in chemotherapy-treated HCC samples, with a high level of senescence-associated secretory phenotype. Finally, we validated the risk-score genes in the protein level and noticed the risk score is positively related with M2 polarization. Of note, we considered that the risk score under the TP53 mutation and senescence is a promising biomarker with the potential to aid in predicting prognosis, defining tumor environment characteristics, and assessing the benefits of immunotherapy for HCC patients.
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Affiliation(s)
- Yu‐Yan Chen
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Zheng‐Yi Zhu
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Tao Ma
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Lu Zhang
- Nanjing Drum Tower Hospital Clinical College of Jiangsu UniversityNanjingChina
| | - Jing Chen
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Jia‐Wei Jiang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Cui‐Hua Lu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Yi‐Tao Ding
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Wen‐Xian Guan
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Nan Yi
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Hao‐Zhen Ren
- Department of Hepatobiliary SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
- Department of General SurgeryAffiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
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Chu C, Liu D, Wang D, Hu S, Zhang Y. Identification and development of TP53 mutation-associated Long non-coding RNAs signature for optimized prognosis assessment and treatment selection in hepatocellular carcinoma. Int J Immunopathol Pharmacol 2023; 37:3946320231211795. [PMID: 37942552 PMCID: PMC10637161 DOI: 10.1177/03946320231211795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 10/17/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND The TP53 gene is estimated to be mutated in over 50% of tumors, with the majority of tumors exhibiting abnormal TP53 signaling pathways. However, the exploration of TP53 mutation-related LncRNAs in Hepatocellular carcinoma (HCC) remains incomplete. This study aims to identify such LncRNAs and enhance the prognostic accuracy for Hepatoma patients. MATERIAL AND METHODS Differential gene expression was identified using the "limma" package in R. Prognosis-related LncRNAs were identified via univariate Cox regression analysis, while a prognostic model was crafted using multivariate Cox regression analysis. Survival analysis was conducted using Kaplan-Meier curves. The precision of the prognostic model was assessed through ROC analysis. Subsequently, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were executed on the TCGA dataset via the TIDE database. Fractions of 24 types of immune cell infiltration were obtained from NCI Cancer Research Data Commons using deconvolution techniques. The protein expression levels encoded by specific genes were obtained through the TPCA database. RESULTS In this research, we have identified 85 LncRNAs associated with TP53 mutations and developed a corresponding signature referred to as TP53MLncSig. Kaplan-Meier analysis revealed a lower 3-year survival rate in high-risk patients (46.9%) compared to low-risk patients (74.2%). The accuracy of the prognostic TP53MLncSig was further evaluated by calculating the area under the ROC curve. The analysis yielded a 5-year ROC score of 0.793, confirming its effectiveness. Furthermore, a higher score for TP53MLncSig was found to be associated with an increased response rate to immune checkpoint blocker (ICB) therapy (p = .005). Patients possessing high-risk classification exhibited lower levels of P53 protein expression and higher levels of genomic instability. CONCLUSION The present study aimed to identify and validate LncRNAs associated with TP53 mutations. We constructed a prognostic model that can predict chemosensitivity and response to ICB therapy in HCC patients. This novel approach sheds light on the role of LncRNAs in TP53 mutation and provides valuable resources for analyzing patient prognosis and treatment selection.
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Affiliation(s)
- Chenghao Chu
- Department of General Surgery, Anqing First People's Hospital Affiliated to Anhui Medical University, Anqing, China
- Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Daoli Liu
- Department of General Surgery, Anqing First People's Hospital Affiliated to Anhui Medical University, Anqing, China
| | - Duofa Wang
- Department of General Surgery, Anqing First People's Hospital Affiliated to Anhui Medical University, Anqing, China
| | - Shuangjiu Hu
- Department of General Surgery, Anqing First People's Hospital Affiliated to Anhui Medical University, Anqing, China
| | - Yongwei Zhang
- Department of General Surgery, Anqing First People's Hospital Affiliated to Anhui Medical University, Anqing, China
- Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
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Shi L, Cao J, Lei X, Shi Y, Wu L. Multi-omics data identified TP53 and LRP1B as key regulatory gene related to immune phenotypes via EPCAM in HCC. Cancer Med 2022; 11:2145-2158. [PMID: 35150083 PMCID: PMC9119357 DOI: 10.1002/cam4.4594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/16/2022] Open
Abstract
Background Many studies showed that the prognosis of hepatocellular carcinoma (HCC) was significantly associated with the expressions of TP53 and LRP1B. However, the potential influence of the two genes on the malignant progression of HCC is still to be expounded. Methods According to the correlation analysis between immune cells and expression levels of TP53 and LRP1B, we filtered the immune cells to perform unsupervised clustering analysis. Integration of multi‐omic data analysis identified genetic alteration and epigenetic alteration. In addition, pathway analysis was used to explore the potential function of the differentially expressed mRNAs. According to the differentially expressed genes, we established an interaction network to seek the hub gene. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a prognosis model. Results The unsupervised clustering analysis showed that the cluster A1 showed the highest immune cell levels and the cluster B2 showed the lowest immune cell levels. Multi‐omics data analysis identified that somatic mutations, copy number variations, and DNA methylation levels had significant differences between cluster A1 and cluster B2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the upregulated mRNAs in the cluster A1 were mainly concentrated in T cell activation, external side of plasma membrane, receptor ligand activity, and cytokine−cytokine receptor interaction. Importantly, the EPCAM was identified as a critical node in the lncRNAs–miRNAs–mRNAs regulatory network correlated with the immune phenotypes. In addition, based on differentially expressed genes between cluster A1 and cluster B2, the prognostic model established by LASSO could predict the overall survival (OS) of HCC accurately. Conclusions The results indicated that the TP53 and LRP1B acted as the key genes in regulating the immune phenotypes of HCC via EPCAM.
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Affiliation(s)
- Liang Shi
- Department of Clinical Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.,Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jie Cao
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin Lei
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yifen Shi
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lili Wu
- Department of Clinical Blood Transfusion, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.,Department of Clinical Laboratory, The Central Hospital of Wenzhou, Wenzhou, China
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Huang DP, Liao MM, Tong JJ, Yuan WQ, Peng DT, Lai JP, Zeng YH, Qiu YJ, Tong GD. Construction of a genome instability-derived lncRNA-based risk scoring system for the prognosis of hepatocellular carcinoma. Aging (Albany NY) 2021. [PMID: 34799469 DOI: 10.1863/aging.203698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023]
Abstract
Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, genome instability-associated lncRNAs (GILncRNAs) and their performance in clinical prognostic significance in hepatocellular carcinoma (HCC) are rarely reported. Our study constructed a computational framework integrating somatic mutation information and lncRNA expression profiles of HCC genome and we identified 88 GILncRNAs of HCC. Function enrichment analysis revealed that GILncRNAs were involved in various metabolism processes and genome instability of cancer. A genome instability-derived lncRNA-based gene signature (GILncSig) was constructed using training set data. The performance of GILncSig for outcome prediction was validated in testing set and The Cancer Genome Atlas (TCGA) set. The multivariate cox regression analysis and stratification analysis demonstrated GILncSig could serve as an independent prognostic factor for the overall survival of HCC patients. The time-dependent Receiver Operating Characteristic (ROC) curve illustrated GILncSig outperformed two recently published lncRNA signatures for overall survival prediction. The combination of GILncSig and tumor protein p53 (TP53) mutation status exhibited better prognostic performance in survival evaluation compared to TP53 mutation status alone. AC145343.1 was further validated to be a risk factor for HCC in vitro among GILncSig. Overall, our study provided a novel approach for identification of genome instability-associated lncRNAs and established an independent risk score system for outcome prediction of HCC patients, which provided a new insight for exploring in-depth mechanism and potential therapy strategy.
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Affiliation(s)
- Dan-Ping Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Mian-Mian Liao
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China.,College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510403, Guangdong, China
| | - Jing-Jing Tong
- The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde 528300, Guangdong Province, China
| | - Wei-Qu Yuan
- Department of Acupuncture, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - De-Ti Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Lai
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Yi-Hao Zeng
- College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510403, Guangdong, China
| | - Yi-Jun Qiu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510403, Guangdong Province, China
| | - Guang-Dong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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10
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Huang DP, Liao MM, Tong JJ, Yuan WQ, Peng DT, Lai JP, Zeng YH, Qiu YJ, Tong GD. Construction of a genome instability-derived lncRNA-based risk scoring system for the prognosis of hepatocellular carcinoma. Aging (Albany NY) 2021; 13:24621-24639. [PMID: 34799469 PMCID: PMC8660619 DOI: 10.18632/aging.203698] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 10/25/2021] [Indexed: 12/25/2022]
Abstract
Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, genome instability-associated lncRNAs (GILncRNAs) and their performance in clinical prognostic significance in hepatocellular carcinoma (HCC) are rarely reported. Our study constructed a computational framework integrating somatic mutation information and lncRNA expression profiles of HCC genome and we identified 88 GILncRNAs of HCC. Function enrichment analysis revealed that GILncRNAs were involved in various metabolism processes and genome instability of cancer. A genome instability-derived lncRNA-based gene signature (GILncSig) was constructed using training set data. The performance of GILncSig for outcome prediction was validated in testing set and The Cancer Genome Atlas (TCGA) set. The multivariate cox regression analysis and stratification analysis demonstrated GILncSig could serve as an independent prognostic factor for the overall survival of HCC patients. The time-dependent Receiver Operating Characteristic (ROC) curve illustrated GILncSig outperformed two recently published lncRNA signatures for overall survival prediction. The combination of GILncSig and tumor protein p53 (TP53) mutation status exhibited better prognostic performance in survival evaluation compared to TP53 mutation status alone. AC145343.1 was further validated to be a risk factor for HCC in vitro among GILncSig. Overall, our study provided a novel approach for identification of genome instability-associated lncRNAs and established an independent risk score system for outcome prediction of HCC patients, which provided a new insight for exploring in-depth mechanism and potential therapy strategy.
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Affiliation(s)
- Dan-Ping Huang
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Mian-Mian Liao
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
- College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510403, Guangdong, China
| | - Jing-Jing Tong
- The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde 528300, Guangdong Province, China
| | - Wei-Qu Yuan
- Department of Acupuncture, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - De-Ti Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Lai
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Yi-Hao Zeng
- College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510403, Guangdong, China
| | - Yi-Jun Qiu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510403, Guangdong Province, China
| | - Guang-Dong Tong
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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11
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Duan X, Cai Y, He T, Shi X, Zhao J, Zhang H, Shen Y, Zhang H, Zhang H, Duan W, Jiang B, Mao X. The effect of the TP53 and RB1 mutations on the survival of hepatocellular carcinoma patients with different racial backgrounds. J Gastrointest Oncol 2021; 12:1786-1796. [PMID: 34532128 DOI: 10.21037/jgo-21-312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 07/02/2021] [Indexed: 12/18/2022] Open
Abstract
Background Racial disparities in the survival of patients with hepatocellular carcinoma (HCC) exist. Gene mutations have a profound effect on carcinogenesis, are easily affected by environment and etiology factors, and may result in survival divergences among patients with different racial backgrounds. This report explores the effects of gene mutations on the survival of American Caucasians and Asian patients. Methods The sequencing and clinical data of 336 HCC patients were obtained from The Cancer Genome Atlas (TCGA) database. The sequencing data was subject to gene mutation profiling, and an analysis of immune cell infiltration was conducted. A multivariate analysis was performed to assess the independent effects of gene mutations on patients' overall survival (OS) and disease-free survival (DFS). Results Asian HCC patients had a significantly higher level of TP53 mutation frequency than Caucasian HCC patients (Asian vs. Caucasian, 39% vs. 23%; P=0.003). The TP53 mutation was associated with shorter OS [hazard ratio (HR), 2.33; 95% confidence interval (CI), 1.36-3.97; P=0.002] and DFS (HR, 2.2; 95% CI, 1.38-3.51; P<0.001) in Caucasian HCC patients, but had no effect on Asian HCC patients' survival. Compared to Asian HCC patients, Caucasian HCC patients with the TP53 mutation had a decreased proportion of infiltrating M2 macrophages and activating natural killer (NK) cells, and an increased proportion of follicular helper T cells. The RB1 mutation was associated with shorter OS (HR, 3.37; 95% CI, 1.73-6.57; P<0.001) in Asian HCC patients, and shorter DFS (HR, 2.11; 95% CI, 1.15-3.88; P=0.017) in Caucasian HCC patients. Asian HCC patients with the RB1 mutation had a decreased proportion of infiltrating CD8 T cells. Conclusions The effects of the TP53 and RB1 mutations on survival differ among Asian and Caucasian HCC patients.
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Affiliation(s)
- Xiaohui Duan
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Yi Cai
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | | | | | | | - Hui Zhang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Yao Shen
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Hongjian Zhang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Heng Zhang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Wenbin Duan
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Bo Jiang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Xianhai Mao
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
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12
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Huo J, Wu L, Zang Y. Construction and Validation of a Reliable Six-Gene Prognostic Signature Based on the TP53 Alteration for Hepatocellular Carcinoma. Front Oncol 2021; 11:618976. [PMID: 34178618 PMCID: PMC8222811 DOI: 10.3389/fonc.2021.618976] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/14/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood. MATERIAL AND APPROACH This study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan-Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis. RESULTS A prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression. CONCLUSION Our study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.
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Affiliation(s)
- Junyu Huo
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liqun Wu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yunjin Zang
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
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13
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A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma. J Pers Med 2021; 11:jpm11050332. [PMID: 33922244 PMCID: PMC8145764 DOI: 10.3390/jpm11050332] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/13/2021] [Accepted: 04/20/2021] [Indexed: 01/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug-gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.
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14
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Yu M, Xu W, Jie Y, Pang J, Huang S, Cao J, Gong J, Li X, Chong Y. Identification and validation of three core genes in p53 signaling pathway in hepatitis B virus-related hepatocellular carcinoma. World J Surg Oncol 2021; 19:66. [PMID: 33685467 PMCID: PMC7938465 DOI: 10.1186/s12957-021-02174-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/18/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common cancer and the leading cause is persistent hepatitis B virus (HBV) infection. We aimed to identify some core genes and pathways for HBV-related HCC. METHODS Gene expression profiles of GSE62232, GSE121248, and GSE94660 were available from Gene Expression Omnibus (GEO). The GSE62232 and GSE121248 profiles were the analysis datasets and GSE94660 was the validation dataset. The GEO2R online tool and Venn diagram software were applied to analyze commonly differentially expressed genes between HBV-related HCC tissues and normal tissues. Then, functional enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genome (KEGG) as well as the protein-protein interaction (PPI) network was conducted. The overall survival rates and the expression levels were detected by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA). Next, gene set enrichment analysis (GSEA) was performed to verify the KEGG pathway analysis. Furthermore, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to validate the levels of these three core genes in tumor tissues and adjacent non-tumor liver tissues from 12 HBV related HCC patients, HBV-associated liver cancer cell lines and normal liver cell lines, and HepG2 with p53 knockdown or deletion, respectively. RESULTS Fifteen highly expressed genes associated with significantly worse prognoses were selected and CCNB1, CDK1, and RRM2 in the p53 signaling pathway were identified as core genes. GSEA results showed that samples highly expressing three core genes were all enriched in the p53 signaling pathway in a validation dataset (P < 0.0001). The expression of these three core genes in tumor tissue samples was higher than that in relevant adjacent non-tumor liver tissues (P < 0.0001). Furthermore, we also found that the above genes were highly expressed in liver cancer cell lines compared with normal liver cells. In addition, we found that the expression of these three core genes in p53 knockdown or knockout HCC cell lines was lower than that in negative control HCC cell lines (P < 0.05). CONCLUSIONS CCNB1, CDK1, and RRM2 were enriched in the p53 signaling pathway and could be potential biomarkers and therapeutic targets for HBV-related HCC.
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Affiliation(s)
- Mingxue Yu
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Wenli Xu
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Yusheng Jie
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Jiahui Pang
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Siqi Huang
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Jing Cao
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Jiao Gong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China
| | - Xinhua Li
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China.
| | - Yutian Chong
- Department of Infectious Diseases and Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China.
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15
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Han H, Desert R, Das S, Song Z, Athavale D, Ge X, Nieto N. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020; 73:933-951. [PMID: 32371195 PMCID: PMC7502511 DOI: 10.1016/j.jhep.2020.04.033] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.
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Affiliation(s)
- Hui Han
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Suite 1020N, MC 787, Chicago, IL 60612, USA.
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16
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Oncoprotein 18 is necessary for malignant cell proliferation in bladder cancer cells and serves as a G3-specific non-invasive diagnostic marker candidate in urinary RNA. PLoS One 2020; 15:e0229193. [PMID: 32614890 PMCID: PMC7332083 DOI: 10.1371/journal.pone.0229193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/15/2020] [Indexed: 12/28/2022] Open
Abstract
Background Urine-based diagnostics indicated involvement of oncoprotein 18 (OP18) in bladder cancer. In cell culture models we investigated the role of OP18 for malignant cell growth. Methods We analyzed 113 urine samples and investigated two human BCa cell lines as a dual model: RT-4 and ECV-304, which represented differentiated (G1) and poorly differentiated (G3) BCa. We designed specific siRNA for down-regulation of OP18 in both cell lines. Phenotypes were characterized by cell viability, proliferation, and expression of apoptosis-related genes. Besides, sensitivity to cisplatin treatment was evaluated. Results Analysis of urine samples from patients with urothelial BCa revealed a significant correlation of the RNA-ratio OP18:uroplakin 1A with bladder cancer. High urinary ratios were mainly found in moderately to poorly differentiated tumors (grade G2-3) that were muscle invasive (stage T2-3), whereas samples from patients with more differentiated non-invasive BCa (G1) showed low OP18:UPK1A RNA ratios. Down-regulation of OP18 expression in ECV-304 shifted its phenotype towards G1 state. Further, OP18-directed siRNA induced apoptosis and increased chemo-sensitivity to cisplatin. Conclusions This study provides conclusive experimental evidence for the link between OP18-derived RNA as a diagnostic marker for molecular staging of BCa in non-invasive urine-based diagnostics and the patho-mechanistic role of OP18 suggesting this gene as a therapeutic target.
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17
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Li H, Yu J, Wu Y, Shao B, Wei X. In situ antitumor vaccination: Targeting the tumor microenvironment. J Cell Physiol 2020; 235:5490-5500. [PMID: 32030759 DOI: 10.1002/jcp.29551] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 01/07/2020] [Indexed: 02/05/2023]
Abstract
Tumor microenvironment is known to play important roles in tumor progression. Many therapies, targeting the tumor microenvironment, are designed and applied in the clinic. One of these approaches is in situ antitumor therapy. This way, bacteria, antibodies, plasmid DNA, viruses, and cells are intratumorally delivered into the tumor site as "in-situ antitumor vaccine," which seeks to enhance immunogenicity and generate systemic T cell responses. In addition, this intratumoral therapy can alter the tumor microenvironment from immunosuppressive to immunostimulatory while limiting the risk of systemic exposure and associated toxicity. Contemporarily, promising preclinical results and some initial success in clinical trials have been obtained after intratumoral therapy.
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Affiliation(s)
- Hanwen Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Jiayun Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Yongyao Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Bin Shao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Xiawei Wei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
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18
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Zhao E, Shen Y, Amir M, Farris AB, Czaja MJ. Stathmin 1 Induces Murine Hepatocyte Proliferation and Increased Liver Mass. Hepatol Commun 2020; 4:38-49. [PMID: 31909354 PMCID: PMC6939544 DOI: 10.1002/hep4.1447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/20/2019] [Indexed: 12/15/2022] Open
Abstract
The endogenous cellular signals that initiate the transition of hepatocytes from quiescence to proliferation remain unclear. The protein stathmin 1 (STMN1) is highly expressed in dividing cells, including hepatocytes, and functions to promote cell mitosis through physical interactions with tubulin and microtubules that regulate mitotic spindle formation. The recent finding that STMN1 mediates the resistance of cultured hepatocytes to oxidant stress led to an examination of the expression and function of this protein in the liver in vivo. STMN1 messenger RNA (mRNA) and protein were essentially undetectable in normal mouse liver but increased markedly in response to oxidant injury from carbon tetrachloride. Similarly, levels of STMN1 mRNA and protein were increased in human livers from patients with acute fulminant hepatic failure. To determine STMN1 function in the liver in vivo, mice were infected with a control or Stmn1-expressing adenovirus. Stmn1 expression induced spontaneous liver enlargement with a doubling of the liver to body weight ratio. The increase in liver mass resulted, in part, from hepatocellular hypertrophy but mainly from an induction of hepatocyte proliferation. STMN1 expression led to marked increases in the numbers of 5-bromo-2'-deoxyuridine-positive and mitotic hepatocytes and hepatic nuclear levels of cyclins and cyclin-dependent kinases. STMN1-induced hepatocyte proliferation was followed by an apoptotic response and a return of the liver to its normal mass. Conclusion: STMN1 promotes entry of quiescent hepatocytes into the cell cycle. STMN1 expression by itself in the absence of any reduction in liver mass is sufficient to stimulate a hepatic proliferative response that significantly increases liver mass.
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Affiliation(s)
- Enpeng Zhao
- Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNY
| | - Yang Shen
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGA
| | - Muhammad Amir
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGA
| | - Alton B. Farris
- Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaGA
| | - Mark J. Czaja
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGA
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19
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Hao C, Cui Y, Chang S, Huang J, Birkin E, Hu M, Zhi X, Li W, Zhang L, Cheng S, Jiang WG. OPN promotes the aggressiveness of non-small-cell lung cancer cells through the activation of the RON tyrosine kinase. Sci Rep 2019; 9:18101. [PMID: 31792339 PMCID: PMC6889187 DOI: 10.1038/s41598-019-54843-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022] Open
Abstract
Osteopontin (OPN) is identified as a diagnostic and prognostic biomarker of tumor progression and metastasis. In non-small-cell lung cancer (NSCLC), the functions of OPN have not been well characterized. The current study sought to investigate the clinical implications of OPN expression in NSCLC and the role of OPN in the aggressiveness of the lung cancer cells. Using a proteomics approach, we identified that phospho-RON (p-RON) was one of the most remarkably up-regulated proteins in OPN-overexpressing cells. The levels of OPN and RON transcripts were unveiled as independent prognostic indicators of survival in NSCLC (p = 0.001). Higher levels of OPN, RON and p-RON proteins were observed in tumor tissues. Knock down of the OPN gene suppressed the migration and invasion abilities of the A549 lung cancer cells which endogenously expresses OPN. While ectopic expression of OPN in the SK-MES-1 lung cancer cells increased levels of cellular invasion and migration. In addition, these changes were accompanied by a phosphorylated activation of RON. Small-molecule inhibition of RON or siRNA silencing of RON significantly reduced OPN-induced migration and invasion of lung cancer cells and had an inhibitory effect on the OPN-mediated cell epithelial-mesenchymal transition. Our study suggests that in NSCLC, the aberrant expression of OPN can be considered as an independent survival indicator and is associated with disease progression. OPN plays a crucial role in promoting migration and invasion properties of lung cancer cells through its phosphorylation activation of the RON signaling pathway, implying its potential as a therapeutic target in the treatment of NSCLC.
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Affiliation(s)
- Chengcheng Hao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yuxin Cui
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK
| | - Siyuan Chang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China
| | - Jing Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China
| | - Emily Birkin
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK
| | - Mu Hu
- Department of Thoracic Surgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xiuyi Zhi
- Department of Thoracic Surgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Wenbin Li
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lijian Zhang
- Department of Thoracic Surgery, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Beijing, 100142, P.R. China
| | - Shan Cheng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China.
| | - Wen G Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China.
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
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20
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Zhang D, Dai L, Yang Z, Wang X, LanNing Y. Association of STMN1 with survival in solid tumors: A systematic review and meta-analysis. Int J Biol Markers 2019; 34:108-116. [PMID: 30966849 DOI: 10.1177/1724600819837210] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The prognostic value of Stathmin 1 (STMN1) in malignant solid tumors remains controversial. Thus, we conducted this meta-analysis to summarize the potential value of STMN1 as a biomarker for predicting overall survival in patients with solid tumor. METHODS We systematically searched eligible studies in PubMed, Web of Science, and EMBASE from the establishment date of these databases to September 2018. Hazard ratio (HR) and its 95% confidence interval (CI) was used to assess the association between STMN1 expression and overall survival. RESULTS A total of 25 studies with 4625 patients were included in this meta-analysis. Our combined results showed that high STMN1 expression was associated with poor overall survival in solid tumors (HR = 1.85, 95% CI 1.55, 2.21). In general, our subgroup and sensitivity analyses demonstrated that our combined results were stable and reliable. However, from the results of the subgroups we found that high STMN1 expression was not related to overall survival in colorectal cancer and endometrial cancer anymore, suggesting that much caution should be taken to interpret our combined result, and more studies with large sample sizes are required to further explore the prognostic value of STMN1 expression in the specific type of tumors, especially colorectal cancer and endometrial cancer. CONCLUSIONS STMN1 could serve as a prognostic biomarker and could be developed as a valuable therapeutic target for patients with solid tumors. However, due to the limitations of the present meta-analysis, this conclusion should be taken with caution. Further studies adequately designed are required to confirm our findings.
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Affiliation(s)
- Dan Zhang
- 1 Department of General Surgery, Lanzhou University Second Clinical Medical College, Lanzhou University, Lanzhou, China.,2 Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu Province, China
| | - Lizhen Dai
- 3 Department of Obstetrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - ZengXi Yang
- 1 Department of General Surgery, Lanzhou University Second Clinical Medical College, Lanzhou University, Lanzhou, China.,2 Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu Province, China
| | - XiChen Wang
- 1 Department of General Surgery, Lanzhou University Second Clinical Medical College, Lanzhou University, Lanzhou, China.,2 Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu Province, China
| | - Yin LanNing
- 1 Department of General Surgery, Lanzhou University Second Clinical Medical College, Lanzhou University, Lanzhou, China.,2 Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu Province, China
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Wang X, Zhou Z, Zhang T, Wang M, Xu R, Qin S, Zhang S. Overexpression of miR-664 is associated with poor overall survival and accelerates cell proliferation, migration and invasion in hepatocellular carcinoma. Onco Targets Ther 2019; 12:2373-2381. [PMID: 30992673 PMCID: PMC6445241 DOI: 10.2147/ott.s188658] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. This study aimed to investigate the expression patterns of microRNA-664 (miR-664) in HCC tissues and cells, and assess its clinical significance and functional role in HCC. Patients and methods One hundred and thirty-four paired HCC and non-cancerous tissues were collected from patients who underwent surgery in Qianfoshan Hospital affiliated to Shandong University (Shandong, China) between 2009 and 2012. Expression of miR-664 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Prognostic value of miR-664 in HCC was evaluated using Kaplan–Meier survival analysis and Cox regression analysis. Cell proliferation was analyzed using the CCK-8 assay, and cell migration and invasion of HCC cells was evaluated by the Transwell assay. Results Expression of miR-664 was significantly upregulated in HCC tissues and cells when compared with the normal controls (all P<0.05). MiR-664 expression was associated with lymph node metastasis, TNM stage and differentiation (all P<0.05) in the HCC patients. High miR-664 expression predicted poor overall survival (log-rank P=0.004) and acted as an independent prognostic factor (HR =1.945, 95% CI=1.078–3.508, P=0.027). According to cell experiments, the upregulation of miR-664 could promote, whereas the downregulation of miR-664 could inhibit proliferation, migration and invasion of HCC cells (all P<0.05). SIVA1 was predicted as a direct target gene of miR-664 in HCC. Conclusion All data indicated that overexpression of miR-664 is associated with poor prognosis of HCC patients, and may enhance tumor progression of HCC by targeting SIVA1. MiR-664 may be a candidate therapeutic target for HCC treatment.
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Affiliation(s)
- Xianming Wang
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
| | - Zhengtong Zhou
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
| | - Tao Zhang
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
| | - Minghai Wang
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
| | - Rongwei Xu
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
| | - Shiyong Qin
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
| | - Shuguang Zhang
- Department of General Surgery, Qianfoshan Hospital Affiliated to Shandong University, Shandong 250014, China, ;
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Long J, Wang A, Bai Y, Lin J, Yang X, Wang D, Yang X, Jiang Y, Zhao H. Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma. EBioMedicine 2019; 42:363-374. [PMID: 30885723 PMCID: PMC6491941 DOI: 10.1016/j.ebiom.2019.03.022] [Citation(s) in RCA: 243] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 03/07/2019] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC. METHODS We investigated TP53 mutation status and RNA expression in different populations and platforms and developed an immune prognostic model (IPM) based on immune-related genes that were differentially expressed between TP53WT and TP53MUT HCC samples. Then, the influence of the IPM on the immune microenvironment in HCC was comprehensively analysed. FINDINGS TP53 mutation resulted in the downregulation of the immune response in HCC. Thirty-seven of the 312 immune response-related genes were differentially expressed based on TP53 mutation status. An IPM was established and validated based on 865 patients with HCC to differentiate patients with a low or high risk of poor survival. A nomogram was also established for clinical application. Functional enrichment analysis showed that the humoral immune response and immune system diseases pathway represented the major function and pathway, respectively, related to the IPM genes. Moreover, we found that the patients in the high-risk group had higher fractions of T cells follicular helper, T cells regulatory (Tregs) and macrophages M0 and presented higher expression of CTLA-4, PD-1 and TIM-3 than the low-risk group. INTERPRETATION TP53 mutation is strongly related to the immune microenvironment in HCC. Our IPM, which is sensitive to TP53 mutation status, may have important implications for identifying subgroups of HCC patients with low or high risk of unfavourable survival. FUND: This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten Thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), and the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001).
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Affiliation(s)
- Junyu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, China
| | - Yi Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dongxu Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | | | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Menyhárt O, Nagy Á, Győrffy B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. ROYAL SOCIETY OPEN SCIENCE 2018; 5:181006. [PMID: 30662724 PMCID: PMC6304123 DOI: 10.1098/rsos.181006] [Citation(s) in RCA: 336] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 11/08/2018] [Indexed: 05/03/2023]
Abstract
Background: Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets. Methods: The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, n = 371; Affymetrix arrays, n = 91; Illumina gene chips, n = 135) by uni- and multivariate Cox regression and Mann-Whitney U-test, separately for Asian and Caucasian patients. Results: One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at p < 0.05. After multiple testing correction BIRC5 (p = 1.9 × 10-10), CDC20 (p = 2.5 × 10-9) and PLK1 (p = 3 × 10-9) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage (p = 0.0018) and expression of CENPH (p = 0.0038) and CDK4 (p = 0.038). KIF18A was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts (p = 0.003 and p = 0.025, respectively). Conclusion: Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.
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Affiliation(s)
- Otília Menyhárt
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | - Ádám Nagy
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
| | - Balázs Győrffy
- 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
- Author for correspondence: Balázs Győrffy e-mail:
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Increased Trimethylation of histone H3K36 associates with biliary differentiation and predicts poor prognosis in resectable hepatocellular carcinoma. PLoS One 2018; 13:e0206261. [PMID: 30356299 PMCID: PMC6200274 DOI: 10.1371/journal.pone.0206261] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/09/2018] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Trimethylation of histone H3K36 (H3K36me3), an epigenetic marker of transcription-associated histone modification and stem cell regulation, is expressed in a variety of human cancers. This study elucidated the prognostic significance of H3K36me3 in patients with resectable hepatocellular carcinoma (HCC). METHODS Expression of H3K36me3 was retrospectively evaluated through immunohistochemistry in 152 surgically resected primary HCCs. RESULTS In nontumorous liver parenchyma, H3K36Me3 was detected in bile ducts but not in hepatocytes. H3K36me3 was positive in 104 (68.4%) of the HCCs. Positivity for H3K36me3 was associated with high level of serum α-fetoprotein (>200 ng/mL, P = 0.0148), high tumor grade (P = 0.0017), and high tumor stage (P = 0.0008). Patients with H3K36me3-positive tumors were more likely to have lower 5-year disease-free survival and 5-year overall survival than those with H3K36me3-negative tumors (P = 0.0484 and P = 0.0213, respectively). Multivariate analysis showed that H3K36me3 positivity was an independent predictor of high tumor grade (P = 0.0475) and high tumor stage (P = 0.0114) and thus contributed to poor prognosis. Furthermore, H3K36me3 positivity was significantly correlated with the expression of biliary markers cytokeratin 19 (CK19) and hepatocyte nuclear factor 1β (HNF1β) (P < 0.0001 and P = 0.0005, respectively). Combinatorial analysis revealed that CK19 and HNF1β expression individually exerted additive prognostic adverse effects on HCCs with H3K36me3 positivity. CONCLUSIONS Our study indicates that H3K36me3 positivity is associated with the expression of biliary markers and is a crucial predictor of poor prognosis in resectable HCC.
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Sun T, Li P, Sun D, Bu Q, Li G. Prognostic value of osteopontin in patients with hepatocellular carcinoma: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e12954. [PMID: 30412113 PMCID: PMC6221565 DOI: 10.1097/md.0000000000012954] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE The prognostic value of tissue and serum osteopontin (OPN) in hepatocellular carcinoma (HCC) remain controversial. The aim of present meta-analysis was to evaluate the prognostic value of OPN in patients with HCC. METHODS Eligible studies were systematically searched by PubMed, EMBASE, and Google scholar. A meta-analysis of 12 studies included 2117 cases was performed to estimate the association between OPN level and overall survival (OS), disease-free survival (DFS) in HCC patients. Subgroup analyses were also performed in the meta-analysis. RESULTS The pooled data of studies showed that high OPN level was significantly associated with poor OS (hazard ratios [HR] 1.84; 95% confidence intervals [CI] 1.54-2.20; P = .000) and DFS (HR 1.67; 95% CI 1.40-1.98; P = .000) in HCC. Furthermore, in subgroup analysis, high tissue based OPN by immunohistochemistry detection and serum-based OPN by enzyme-linked immunosorbent assay (ELISA) detection were both significantly associated with OS (tissue: HR 1.88; 95% CI 1.53-2.31; P < .0001; serum: HR 2.38; 95% CI 1.58-3.59; P < .0001). Simultaneously, we also found that OPN expression was positively associated with stage (odds ratios [OR] 5.68; 95% CI 3.443-7.758), tumor size (Size≤5 cm vs >5 cm; OR 2.001; 95% CI1.036-3.867). CONCLUSION The current evidence indicates that OPN could serve as a prognostic biomarker and a potential therapeutic target for HCC.
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Affiliation(s)
| | - Peng Li
- Department of Breast and Thyroid Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Diwen Sun
- Department of Breast and Thyroid Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Qingao Bu
- Department of Breast and Thyroid Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Guoqiang Li
- Department of Breast and Thyroid Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, China
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Tan HT, Chung MCM. Label-Free Quantitative Phosphoproteomics Reveals Regulation of Vasodilator-Stimulated Phosphoprotein upon Stathmin-1 Silencing in a Pair of Isogenic Colorectal Cancer Cell Lines. Proteomics 2018; 18:e1700242. [PMID: 29460479 DOI: 10.1002/pmic.201700242] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 02/10/2018] [Indexed: 02/06/2023]
Abstract
In this communication, we present the phosphoproteome changes in an isogenic pair of colorectal cancer cell lines, viz., the poorly metastatic HCT-116 and the highly metastatic derivative E1, upon stathmin-1 (STMN1) knockdown. The aim was to better understand how the alterations of the phosphoproteins in these cells are involved in cancer metastasis. After the phosphopeptides were enriched using the TiO2 HAMMOC approach, comparative proteomics analysis was carried out using sequential window acquisition of all theoretical mass spectra-MS. Following bioinformatics analysis using MarkerView and OneOmics platforms, we identified a list of regulated phosphoproteins that may play a potential role in signaling, maintenance of cytoskeletal structure, and focal adhesion. Among these phosphoproteins, was the actin cytoskeleton regulator protein, vasodilator-stimulated phosphoprotein (VASP), where its change in phosphorylation status was found to be concomitant with STMN1-associated roles in metastasis. We further showed that silencing of stathmin-1 altered the expression, subcellular localization and phosphorylation status of VASP, which suggested that it might be associated with remodeling of the cell cytoskeleton in colorectal cancer metastasis.
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Affiliation(s)
- Hwee Tong Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maxey Ching Ming Chung
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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27
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Yurong L, Biaoxue R, Wei L, Zongjuan M, Hongyang S, Ping F, Wenlong G, Shuanying Y, Zongfang L. Stathmin overexpression is associated with growth, invasion and metastasis of lung adenocarcinoma. Oncotarget 2018; 8:26000-26012. [PMID: 27494889 PMCID: PMC5432233 DOI: 10.18632/oncotarget.11006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 07/09/2016] [Indexed: 01/17/2023] Open
Abstract
Stathmin has been investigated as a tumor biomarker because it appear to be associated with tumorigenesis; however, the effect of stathmin in lung adenocarcinoma (LAC) remains poorly understood. The purpose of this study was to examine the expression of stathmin in lung adenocarcinoma, and to disclose the relationship between them. The expression of stathmin was examined by RT-PCR, IHC and Western blot. Furthermore, small interfering RNA (shRNA)-mediated silencing of stathmin was employed in LAC cells to investigate cell proliferation, invasion and apoptosis. In this study, we showed that overexpression of stathmin was significantly associated with poorly differentiated, lymph node metastasis and advance TNM stages of lung adenocarcinoma. And silencing of stathmin expression inhibited the proliferation, migration and invasion of lung adenocarcinoma PC-9 cells, and retarded the growth of PC-9 cells xenografts in nude mice. Additionally, the anticarcinogenic efficacy of stathmin silencing might be involved in P38 and MMP2 signaling pathways. In conclusion, these results showed that stathmin expression was significantly up-regulated in LAC, which may act as a biomarker for LAC. Furthermore, silence of stathmin inhibiting LAC cell growth indicated that stathmin may be a promising molecular target for LAC therapy.
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Affiliation(s)
- Lin Yurong
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Rong Biaoxue
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Li Wei
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Ming Zongjuan
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Shi Hongyang
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Fang Ping
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Gao Wenlong
- Department of Statistics and Epidemiology, Medical College, Lanzhou University, Lanzhou, China
| | - Yang Shuanying
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Li Zongfang
- Department of Elderly Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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Rong B, Nan Y, Liu H, Gao W. Increased stathmin correlates with advanced stage and poor survival of non-small cell lung cancer. Cancer Biomark 2018; 19:35-43. [PMID: 28282798 DOI: 10.3233/cbm-160239] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Previous studies show that overexpression of stathmin involved in the malignant biological behavior of lung cancer. This investigation is to disclose the expression status of stathmin in non-small cell lung cancer (NSCLC) and its clinical value for the diagnosis and prognosis to lung cancer. METHODS The expression of stathmin in cells and tissues of NSCLC was examined using immunohistochemistry (IHC), in-situ hybridization (ISH), and Western blot. The correlation between stathmin expression and survival of lung cancer patients was evaluated by a Kaplan-Meier method and the multiple regression analysis. RESULTS NSCLC tissues and cells showed an overexpression of stathmin compared with normal lung tissues and cells (p< 0.05). And the expression level of stathmin was significantly associated with lung adenocarcinoma (LAC) (p< 0.05), lymphatic invasion (p< 0.05) and advanced stages of NSCLC (p< 0.05). Moreover, overexpression of stathmin predicted a reduced survival (p<0.05). CONCLUSION Increased stathmin correlated with pathologic grade, lymphatic invasion, advanced stage and poor survival of NSCLC, which indicated that stathmin could serve as a potential biomarker of NSCLC.
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Affiliation(s)
- Biaoxue Rong
- Department of Respiratory Medicine, First Affiliated Hospital, Xi'an Medical University, Xi'an 710077, Shaanxi, China
| | - Yandong Nan
- Department of Respiratory Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hua Liu
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Wenlong Gao
- Institute of Epidemiology and Health Statistics, School of Public Health, Lanzhou University, Lanzhou, Gansu, China
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Buczak K, Ori A, Kirkpatrick JM, Holzer K, Dauch D, Roessler S, Endris V, Lasitschka F, Parca L, Schmidt A, Zender L, Schirmacher P, Krijgsveld J, Singer S, Beck M. Spatial Tissue Proteomics Quantifies Inter- and Intratumor Heterogeneity in Hepatocellular Carcinoma (HCC). Mol Cell Proteomics 2018; 17:810-825. [PMID: 29363612 PMCID: PMC5880102 DOI: 10.1074/mcp.ra117.000189] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 01/19/2018] [Indexed: 01/17/2023] Open
Abstract
The interpatient variability of tumor proteomes has been investigated on a large scale but many tumors display also intratumoral heterogeneity regarding morphological and genetic features. It remains largely unknown to what extent the local proteome of tumors intrinsically differs. Here, we used hepatocellular carcinoma as a model system to quantify both inter- and intratumor heterogeneity across human patient specimens with spatial resolution. We defined proteomic features that distinguish neoplastic from the directly adjacent nonneoplastic tissue, such as decreased abundance of NADH dehydrogenase complex I. We then demonstrated the existence of intratumoral variations in protein abundance that re-occur across different patient samples, and affect clinically relevant proteins, even in the absence of obvious morphological differences or genetic alterations. Our work demonstrates the suitability and the benefits of using mass spectrometry-based proteomics to analyze diagnostic tumor specimens with spatial resolution. Data are available via ProteomeXchange with identifier PXD007052.
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Affiliation(s)
- Katarzyna Buczak
- From the ‡European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
| | - Alessandro Ori
- From the ‡European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.,§Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Joanna M Kirkpatrick
- §Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.,¶European Molecular Biology Laboratory, Proteomics Core Facility, Heidelberg, Germany
| | - Kerstin Holzer
- ‖Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Daniel Dauch
- **Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.,‡‡Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Stephanie Roessler
- ‖Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Volker Endris
- ‖Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Felix Lasitschka
- ‖Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Luca Parca
- From the ‡European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
| | | | - Lars Zender
- **Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.,‡‡Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.,§§Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Peter Schirmacher
- ‖Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jeroen Krijgsveld
- ¶European Molecular Biology Laboratory, Proteomics Core Facility, Heidelberg, Germany.,‖‖European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephan Singer
- From the ‡European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany; .,‖Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Beck
- From the ‡European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany; .,European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany
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30
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Aronova A, Min IM, Crowley MJP, Panjwani SJ, Finnerty BM, Scognamiglio T, Liu YF, Whitsett TG, Garg S, Demeure MJ, Elemento O, Zarnegar R, Fahey TJ. STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro. Ann Surg Oncol 2017; 25:792-800. [PMID: 29214451 DOI: 10.1245/s10434-017-6296-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype. METHODS STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing. RESULTS Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G0/G1, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls. CONCLUSIONS STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.
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Affiliation(s)
- Anna Aronova
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA.
| | - Irene M Min
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Michael J P Crowley
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Suraj J Panjwani
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Brendan M Finnerty
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Theresa Scognamiglio
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Yi-Fang Liu
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | | | - Shipra Garg
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Olivier Elemento
- Department of Physiology and Biophysics, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA
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Biaoxue R, Hua L, Tian F, Wenlong G. Increased stathmin in serum as a potential tumor marker for lung adenocarcinoma. Jpn J Clin Oncol 2017; 47:342-349. [PMID: 28158640 DOI: 10.1093/jjco/hyx005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 01/16/2017] [Indexed: 11/12/2022] Open
Abstract
Background Stathmin has been found to be involved in malignant tumors; the aim of this study was to investigate the relationship between serum stathmin and clinico-pathological features of lung cancer. Methods In three lung cancer cell lines, stathmin expression and its secretion level in the supernatant were examined by Western blot and enzyme-linked immunosorbent assay (ELISA). Expression of stathmin was examined by immunohistochemistry in 48 lung cancer tissues, and serum stathmin expression level was examined by ELISA in 96 patients with lung cancer and 82 normal individuals. Sensitivity and specificity of serum stathmin were determined by receiver operator characteristic curve (ROC). Results In the three cell lines and their supernatant, stathmin levels were higher than those in 16 HBE cell line. Lung cancer tissues expressed higher level stathmin more frequently than normal lung tissue (P < 0.05). Serum stathmin level was significantly higher in the patients with lung cancer than in normal individuals (P < 0.001). Increased stathmin level in cancer tissue and serum were significantly associated with adenocarcinoma histology, lymph node metastasis and advanced stage. The threshold level of serum stathmin for distinguishing lung cancer from normal individuals was 1.86 ng/ml. The sensitivity and specificity were 93.7% and 91.5%, respectively. Conclusions Measurement of serum stathmin level could be a potential biomarker for lung cancer, especically those of adenocarcinoma, with lymph node metastasis and at advanced clinical stages.
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Affiliation(s)
- Rong Biaoxue
- Department of Respiratory Medicine, First Affiliated Hospital, Xi'an Medical University, Xi'an
| | - Liu Hua
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou
| | - Fu Tian
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining
| | - Gao Wenlong
- Institute of Epidemiology and Health Statistics, School of Public Health, Lanzhou University, Lanzhou, China
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He B, Yin J, Gong S, Gu J, Xiao J, Shi W, Ding W, He Y. Bioinformatics analysis of key genes and pathways for hepatocellular carcinoma transformed from cirrhosis. Medicine (Baltimore) 2017; 96:e6938. [PMID: 28640074 PMCID: PMC5484182 DOI: 10.1097/md.0000000000006938] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE We aimed to identify some pivotal genes and pathways for hepatocellular carcinoma (HCC) transformation from cirrhosis and explore potential targets for treatment of the disease. METHODS The GSE17548 microarray data were downloaded from Gene Expression Omnibus database, and 37 samples (20 cirrhosis and 17 HCC samples) were used for analysis. The differentially expressed genes (DEGs) in HCC tissues were compared with those in cirrhosis tissues and analyzed using the limma package. Gene ontology-biological process and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed using ClueGO and CluePedia tool kits, and the key KEGG pathway was analyzed using the R package pathview. The regulatory factor miRNA of DEGs was extracted from 3 verified miRNAs-target databases using the multiMiR R package. Moreover, a protein-protein interaction (PPI) network was constructed using the Cytoscape software. RESULTS DEGs including cyclin-dependent Kinase 1 (CDK1), PDZ-binding kinase (PBK), ribonucleotide reductase M2 (RRM2), and abnormal spindle homolog, and microcephaly-associated drosophila (ASPM) were the hub proteins with higher degrees in the PPI network. The cell cycle pathway (CDK1 enriched) and p53 signaling pathway (CDK1 and RRM2 enriched) were significantly enriched by DEGs. CONCLUSION CDK1, PBK, RRM2, and ASPM may be key genes for HCC transformation from cirrhosis. Furthermore, cell cycle and p53 signaling pathways may play vital mediatory roles; CDK1 may play crucial roles in HCC transformed from cirrhosis via cell cycle and p53 signaling pathways, and RRM2 might be involved in HCC transformed from cirrhosis via the p53 signaling pathway.
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Affiliation(s)
- Bosheng He
- Department of Radiology, the Second Affiliated Hospital of Nantong University
| | - Jianbing Yin
- Department of Radiology, the Second Affiliated Hospital of Nantong University
| | - Shenchu Gong
- Department of Radiology, the Second Affiliated Hospital of Nantong University
| | - Jinhua Gu
- Department of Pathophysiology, Nantong University Medical School
| | - Jing Xiao
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University
| | - Weixiang Shi
- Department of Radiology, the Second Affiliated Hospital of Nantong University
| | - Wenbin Ding
- Department of Radiology, the Second Affiliated Hospital of Nantong University
| | - Ying He
- Department of Ultrasound, the Tumor Hospital of Nantong University, Nantong, Jiangsu, China
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Zhao J, Zhang M, He P, Zhao J, Chen Y, Qi J, Wang Y. Proteomic analysis of oridonin-induced apoptosis in multiple myeloma cells. Mol Med Rep 2017; 15:1807-1815. [PMID: 28259901 DOI: 10.3892/mmr.2017.6213] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 12/13/2016] [Indexed: 11/06/2022] Open
Abstract
Oridonin is a diterpenoid compound isolated from the medicinal herb Rabdosia rubescens, and has shown marked antitumor effects against different types of cancer. However, the definitive systematic molecular mechanism underlying the antitumor activity of oridonin in multiple myeloma remains to be elucidated. In the present study, cell viability and cytotoxicity were examined to determine the appropriate concentration for proteomic investigation. In addition, cell apoptosis was evaluated using flow cytometry and transmission electron microscopy. A proteomic investigation using a two‑dimensional electrophoresis system and mass spectrometry was performed to identify and characterize the global proteome of the apoptosis induced by oridonin. Of the proteins identified, seven were involved in the anticancer effects of oridonin. Regulation of the expression and function of target proteins, stathmin, dihydrofolate reductase and pyruvate dehydrogenase E1β, may be potential, therapeutic strategies to effectively treat multiple myeloma. These findings provide novel information on the molecular mechanisms underlying the anticancer properties of oridonin in multiple myeloma.
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Affiliation(s)
- Jing Zhao
- Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Mei Zhang
- Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Pengcheng He
- Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Junjie Zhao
- Department of Genetics and Molecular Biology, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jun Qi
- Institute of Xi'an Blood Bank, Shaanxi Blood Center, Xi'an, Shaanxi 710061, P.R. China
| | - Yuan Wang
- Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Wu L, Bai X, Xie Y, Yang Z, Yang X, Lin J, Zhu C, Wang A, Zhang H, Miao R, Wu Y, Robson SC, Zhao Y, Sang X, Zhao H. MetastamiRs: A promising choice for antihepatocellular carcinoma nucleic acid drug development. Hepatol Res 2017; 47:80-94. [PMID: 27138942 DOI: 10.1111/hepr.12737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 04/18/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.
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Affiliation(s)
- Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xue Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Yang
- Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoyu Miao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yan Wu
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Simon C Robson
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yi Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Biaoxue R, Hua L, Wenlong G, Shuanying Y. Overexpression of stathmin promotes metastasis and growth of malignant solid tumors: a systemic review and meta-analysis. Oncotarget 2016; 7:78994-79007. [PMID: 27806343 PMCID: PMC5346693 DOI: 10.18632/oncotarget.12982] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/22/2016] [Indexed: 01/08/2023] Open
Abstract
Stathmin has been investigated to be involved in development and progress of malignant tumors. This study was to clarify the relationship between expression of stathmin and tumors and assess its clinical significance. We identified 25 studies with a total of 3,571 individuals from the electronic bibliographic databases and strictly evaluated the quality and heterogeneity of included studies. We analysed the relationship between expression of stathmin and clinical characteristics by the fixed-effects and random-effects of meta-analysis and constructed a summary receiver-operator characteristic curve to estimate the test characteristics. The results showed that patients with cancer displayed a higher stathmin expression than those of non-cancer individuals (OR, 0.31), and overexpression of stathmin correlated with tumor cell differentiation (OR, 0.73), lymph node invasion (OR, 0.80) and high TNM stage (OR, 0.67). The pooled sensitivity of stathmin for distinguishing malignant tumors was 0.73 and the specificity was 0.77. The maximum balance joint for sensitivity and specificity (the Q-value) was 0.7566 and the area under the curve (AUC) was 0.8234. In conclusion, these results showed that overexpression of stathmin intimately correlated with malignant behavior of tumors, suggesting it could be a risk factor of malignant tumors. Stathmin had great sensitivity and specificity indicated it should be a significant molecular biomarker for malignant tumors.
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Affiliation(s)
- Rong Biaoxue
- Department of Respiratory Medicine, First Affiliated Hospital, Xi'an Medical University, Xi'an, China
| | - Liu Hua
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, China
| | - Gao Wenlong
- Department of Statistics and Epidemiology, Medical College, Lanzhou University, Lanzhou, China
| | - Yang Shuanying
- Department of Respiratory Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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36
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Liu J, Li W, Deng M, Liu D, Ma Q, Feng X. Immunohistochemical Determination of p53 Protein Overexpression for Predicting p53 Gene Mutations in Hepatocellular Carcinoma: A Meta-Analysis. PLoS One 2016; 11:e0159636. [PMID: 27428001 PMCID: PMC4948819 DOI: 10.1371/journal.pone.0159636] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Whether increased expression of the tumor suppressor protein p53 indicates a p53 gene mutation in hepatocellular carcinoma (HCC) remains unclear. We conducted a meta-analysis to determine whether p53 protein overexpression detected by immunohistochemistry (IHC) offers a diagnostic prediction for p53 gene mutations in HCC patients. METHODS Systematic literature searches were conducted with an end date of December 2015. A meta-analysis was performed to estimate the diagnostic accuracy of IHC-determined p53 protein overexpression in the prediction of p53 gene mutations in HCC. Sensitivity, subgroup, and publication bias analyses were also conducted. RESULTS Thirty-six studies were included in the meta-analysis. The results showed that the overall sensitivity and specificity for IHC-determined p53 overexpression in the diagnostic prediction of p53 mutations in HCC were 0.83 (95% CI: 0.80-0.86) and 0.74 (95% CI: 0.71-0.76), respectively. The summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.65 (95% CI: 2.21-3.18) and 0.36 (95% CI: 0.26-0.50), respectively. The diagnostic odds ratio (DOR) of IHC-determined p53 overexpression in predicting p53 mutations ranged from 0.56 to 105.00 (pooled, 9.77; 95% CI: 6.35-15.02), with significant heterogeneity between the included studies (I2 = 40.7%, P = 0.0067). Moreover, subgroup and sensitivity analyses did not alter the results of the meta-analysis. However, potential publication bias was present in the current meta-analysis. CONCLUSION The upregulation of the tumor suppressor protein p53 was indeed linked to p53 gene mutations. IHC determination of p53 overexpression can predict p53 gene mutations in HCC patients.
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Affiliation(s)
- Jiangbo Liu
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, PR China
- * E-mail: (JL); (XF)
| | - Wei Li
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Miao Deng
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
| | - Dechun Liu
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Xiaoshan Feng
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
- * E-mail: (JL); (XF)
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Cheung PFY, Yip CW, Ng LWC, Lo KW, Chow C, Chan KF, Cheung TT, Cheung ST. Comprehensive characterization of the patient-derived xenograft and the paralleled primary hepatocellular carcinoma cell line. Cancer Cell Int 2016; 16:41. [PMID: 27279800 PMCID: PMC4898407 DOI: 10.1186/s12935-016-0322-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 06/03/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive cancer with high mortality and morbidity worldwide. The limited clinically relevant model has impeded the development of effective HCC treatment strategy. Patient-derived xenograft (PDX) models retain most of the characteristics of original tumors and were shown to be highly predictive for clinical outcomes. Notably, primary cell line models allow in-depth molecular characterization and high-throughput analysis. Combined usage of the two models would provide an excellent tool for systematic study of therapeutic strategies. Here, we comprehensively characterized the novel PDX and the paralleled primary HCC cell line model. METHODS Tumor tissues were collected from HCC surgical specimens. HCC cells were sorted for in vivo PDX and in vitro cell line establishment by the expression of hepatic cancer stem cell marker to enhance cell viability and the rate of success on subsequent culture. The PDX and its matching primary cell line were authenticated and characterized in vitro and in vivo. RESULTS Among the successful cases for generating PDXs and primary cells, HCC40 is capable for both PDX and primary cell line establishment, which were then further characterized. The novel HCC40-PDX and HCC40-CL exhibited consistent phenotypic characteristics as the original tumor in terms of HBV protein and AFP expressions. In common with HCC40-PDX, HCC40-CL was tumorigenic in immunocompromised mice. The migration ability in vitro and metastatic properties in vivo echoed the clinical feature of venous infiltration. Genetic profiling by short tandem repeat analysis and p53 mutation pattern consolidated that both the HCC40-PDX and HCC40-CL models were derived from the HCC40 clinical specimen. CONCLUSIONS The paralleled establishment of PDX and primary cell line would serve as useful models in comprehensive studies for HCC pathogenesis and therapeutics development for personalized treatment.
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Affiliation(s)
- Phyllis F Y Cheung
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China ; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi Wai Yip
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China ; Department of Surgery, The University of Hong Kong, Hong Kong, China ; Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan
| | - Linda W C Ng
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Chit Chow
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Kui Fat Chan
- Department of Pathology, Tuen Mun Hospital, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Siu Tim Cheung
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China ; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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Li J, Hu G, Kong F, Wu K, Song K, He J, Sun W. Elevated STMN1 Expression Correlates with Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma. Pathol Oncol Res 2015; 21:1013-20. [PMID: 25791566 DOI: 10.1007/s12253-015-9930-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 03/05/2015] [Indexed: 01/09/2023]
Abstract
STMN1 is a cytosolic phosphoprotein that not only participates in cell division, but also plays an important role in other microtubule-dependent processes, such as cell motility. Furthermore, STMN1 acts as a "relay protein" in several intracellular signaling pathways that influence cell growth and differentiation. Thus, STMN1 is likely to support cellular processes essential for tumor progression: survival and migration. Indeed, elevated STMN1 expression has been reported in various types of human malignancies and is correlated with poor prognosis in these human malignancies. However, the clinical and prognostic significance of STMN1 in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, we assessed STMN1 in PDAC in this retrospective study. We first examined STMN1 expression in PDAC tissues from 27 cases and matched adjacent non-cancerous tissues by quantitative polymerase chain reaction (PCR) and western blot analyses. Next, immunohistochemistry was used to evaluate STMN1 expression in 87 archived paraffin-embedded PDAC specimens. STMN1 mRNA and protein expression levels were to a large extent up-regulated in PDAC tissue compared with their adjacent non-cancerous tissues. Moreover, STMN1 expression was closely correlated with histological differentiation, lymphatic metastasis, and TNM stage (P = 0.023, 0.047, and 0.014, respectively). In addition, PDAC patients with higher STMN1 expression died sooner than those with lower STMN1 expression (P < 0.01). Multivariate analysis demonstrated that STMN1 expression was an independent prognostic factor for PDAC patients (P < 0.01). Herein, we provide the first evidence that up-regulated STMN1 may contribute to tumor progression and poor prognosis in PDAC patients and may serve as a novel prognostic marker.
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Affiliation(s)
- Jian Li
- Department of PET center, Xiangya Hospital, Central South University, Changsha, China
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Cong WM, Wu MC. New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges. Cancer Lett 2015; 368:14-19. [PMID: 26276723 DOI: 10.1016/j.canlet.2015.07.043] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/17/2015] [Accepted: 07/18/2015] [Indexed: 02/09/2023]
Abstract
Primary liver cancer (PLC) is one of the most common malignancies worldwide with increasing incidence and accounts for the third leading cause of cancer-related mortality. Traditional morphopathology primarily emphasizes qualitative diagnosis of PLC, which is not sufficient to resolve the major concern of increasing the long-term treatment efficacy of PLC in clinical management for the modern era. Since the beginning of the 21st century, molecular pathology has played an active role in the investigation of the evaluation of the metastatic potential of PLC, detection of drug targets, prediction of recurrence risks, analysis of clonal origins, evaluation of the malignancy trend of precancerous lesions, and determination of clinical prognosis. As a result, many new progresses have been obtained, and new strategies of molecular-pathological diagnosis have been formed. Moreover, the new types of pathobiological diagnosis indicator systems for PLC have been preliminarily established. These achievements provide valuable molecular pathology-based guide for clinical formulation of individualized therapy programs for PLC. This review article briefly summarizes some relevant progresses of molecular-pathological diagnosis of PLC from the perspective of clinical translational application other than basic experimental studies.
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Affiliation(s)
- Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
| | - Meng-Chao Wu
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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Chen H, Zhang T, Sheng Y, Zhang C, Peng Y, Wang X, Zhang C. Methylation Profiling of Multiple Tumor Suppressor Genes in Hepatocellular Carcinoma and the Epigenetic Mechanism of 3OST2 Regulation. J Cancer 2015; 6:740-9. [PMID: 26185536 PMCID: PMC4504110 DOI: 10.7150/jca.11691] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 05/12/2015] [Indexed: 12/28/2022] Open
Abstract
DNA methylation is considered as a significant mechanism that silences tumor suppressor genes (TSGs) and could be used in the early diagnosis of cancer. Histone modifications often work together with DNA methylation; however, how these epigenetic alterations regulate TSGs remains unclear. Here, we determined the methylation status of ten TSGs (3OST2, ppENK, CHFR, LKB1, THBS1, HIC1, SLIT2, EDNRB, COX2, and CLDN7) in hepatocellular carcinoma (HCC) and corresponding noncancerous tissues. Methylation profiling revealed that four genes had very high frequencies of methylation in HCCs, but interestingly, similar high frequencies were also detected in corresponding noncancerous tissues (97.9% vs 95.8% for SLIT2, 93.8% vs 81.3% for EDNRB, 66.7% vs 85.4% for HIC1, and 56.3% vs 56.3% for ppENK, P > 0.05). Only the 3OST2 gene was frequently methylated in HCCs and there was significant difference between HCCs and corresponding noncancerous tissues (68.8% vs 37.5%, P < 0.05). 5-aza-2'-deoxycytidine (5-Aza-CdR) or trichostatin A (TSA) alone could partially reverse 3OST2 methylation, and their combination resulted in complete reversal. UHRF1 and histone H3R8me2s were both enriched on the hypermethylated 3OST2 promoter, but H3R8me2a was not. After 5-Aza-CdR or TSA treatment, the UHRF1 and H3R8me2s enrichment was decreased, while H3R8me2a enrichment increased. We demonstrated that 3OST2 methylation may play a critical role in the earliest steps of hepatocarcinogenesis and is directly regulated by UHRF1. Furthermore, H3R8me2s acted as a repressive mark, while H3R8me2a was correlated with 3OST2 transcriptional activity.
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Affiliation(s)
- Haiyan Chen
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China ; 2. Department of Pathology, Shandong Provincial Chest Hospital, Jinan 250012, P. R. China
| | - Tingguo Zhang
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China
| | - Yan Sheng
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China
| | - Cheng Zhang
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China
| | - Yunfei Peng
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China
| | - Xiao Wang
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China
| | - Cuijuan Zhang
- 1. Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, P. R. China
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Lin H, Lin D, Xiong XS. Roles of human papillomavirus infection and stathmin in the pathogenesis of sinonasal inverted papilloma. Head Neck 2015; 38:220-4. [PMID: 25224680 DOI: 10.1002/hed.23864] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The purpose of this study was to investigate roles of human papillomavirus (HPV) infection and stathmin in sinonasal inverted papilloma (SNIP). METHODS HPV DNA detection was performed by the fluorescence-based polymerase chain reaction (PCR) method. Stathmin protein expression was investigated by the immunohistochemistry method and mRNA expression of stathmin, Kif2a, and cyclin D1 were assessed by real-time PCR in SNIP and control subjects. RESULTS The positive rate of HPV DNA detected in SNIP was about 53.6% (15 of 28). Recurrent cases showed a higher rate of HPV infection compared with initial cases and higher Krouse stage (T3 + T4) cases showed higher rate of HPV infection than lower Krouse stage (T1 + T2) cases. Stronger expression of stathmin, Kif2a, and cyclin D1 were observed in SNIP, especially HPV(+) SNIP. CONCLUSION HPV infection was closely associated with recurrence and progression of SNIP. Stathmin is a valuable prognostic marker and could be considered as a therapeutic target in patients with SNIP.
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Affiliation(s)
- Hai Lin
- Department of Otorhinolaryngology, Eye and ENT Hospital of Fudan University, Shanghai, China.,Department of Otorhinolaryngology, Fuzhou General Hospital, Fuzhou, Fujian, China
| | - Dong Lin
- Department of Biology and Chemical Engineering, Fuqing Branch of Fujian Normal University, Fuqing, Fujian, China
| | - Xi-Sheng Xiong
- Department of Pathology, Fuzhou General Hospital, Fuzhou, Fujian, China
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Amaddeo G, Cao Q, Ladeiro Y, Imbeaud S, Nault JC, Jaoui D, Gaston Mathe Y, Laurent C, Laurent A, Bioulac-Sage P, Calderaro J, Zucman-Rossi J. Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. Gut 2015; 64:820-9. [PMID: 25021421 PMCID: PMC4392232 DOI: 10.1136/gutjnl-2013-306228] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 05/14/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features. METHODS Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied. RESULTS HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1). CONCLUSIONS Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients.
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Affiliation(s)
- Giuliana Amaddeo
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Qian Cao
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Yannick Ladeiro
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Sandrine Imbeaud
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Jean-Charles Nault
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | | | | | | | - Alexis Laurent
- Assistance Publique-Hôpitaux de Paris, digestive, hepatobiliary and liver transplantation, CHU Henri Mondor, Créteil, France,IMRB—Inserm U955 Equipe n. 18 “Virologie moleculaire et immunologie –Physiopathologie et therapeutique des Hépatites virales chroniques”, Créteil, France
| | - Paulette Bioulac-Sage
- Inserm, UMR-1053; Université Victor Segalen Bordeaux 2, Bordeaux, France,Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, France
| | - Julien Calderaro
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France,Department of Pathology, CHU Henri Mondor, Créteil, France
| | - Jessica Zucman-Rossi
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France,Hopital Europeen Georges Pompidou, Paris, France
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Huang WJ, Jeng YM, Lai HS, Fong IU, Sheu FYB, Lai PL, Yuan RH. Expression of hypoxic marker carbonic anhydrase IX predicts poor prognosis in resectable hepatocellular carcinoma. PLoS One 2015; 10:e0119181. [PMID: 25738958 PMCID: PMC4349857 DOI: 10.1371/journal.pone.0119181] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 01/11/2015] [Indexed: 02/07/2023] Open
Abstract
Carbonic anhydrase IX (CA-IX), a hypoxia marker, correlates with tumor progression in a variety of human cancers. However, the role of CA-IX in hepatocellular carcinomas (HCCs) remains largely unknown. We examined the expression of 277 unifocal, resectable, primary HCC tumors using immunohistochemistry. The CA-IX protein was expressed in 110 of the 227 (48.5%) HCC tumors. The expression of CA-IX correlated with younger age (P = 0.0446), female sex (P = 0.0049), high serum α-fetoprotein levels (P<1x10-6), larger tumor size (P = 0.0031), high tumor grade P<1x10-6) and high tumor stage (P = 1.5x10-6). Patients with HCC tumors that expressed CA-IX were more likely to have lower 5-year disease-free survival (DFS; P = 0.0001) and 5-year overall survival (OS; P<1x10-6). The multivariate analysis indicated that CA-IX expression was an independent predictor for high tumor stage (P = 0.0047) and DFS (P = 0.0456), and a borderline predictor for OS (P = 0.0762). Furthermore, CA-IX expression predicted poor DFS and OS in patients with high tumor stage (P = 0.0004 and P<1x10-6, respectively). Interestingly, CA-IX expression might contribute to the worse prognosis of female patients with advanced HCCs. Our study indicates the expression of the CA-IX protein is a crucial predictor of poor prognosis in resectable HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage.
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Affiliation(s)
- Wei-Ju Huang
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
- Department of Nursing, Hsin-Sheng College of Medical Care and Management, No. 418, Gaoping Section, Zhongfeng Road, Longtan Township, Taoyuan County, 32544, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
- Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Hong-Shiee Lai
- Departments of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Iok-U Fong
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Fang-Yu Bonnie Sheu
- Department of Biomedical Science, University of Illinois College of Medicine, 1601 Parkview Ave, Rockford, IL, 61107, United States of America
| | - Po-Lin Lai
- Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Ray-Hwang Yuan
- Departments of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
- Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10051, Taiwan
- * E-mail:
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Zheng F, Liao YJ, Cai MY, Liu TH, Chen SP, Wu PH, Wu L, Bian XW, Guan XY, Zeng YX, Yuan YF, Kung HF, Xie D. Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets. PLoS Genet 2015; 11:e1004873. [PMID: 25693145 PMCID: PMC4334495 DOI: 10.1371/journal.pgen.1004873] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 11/04/2014] [Indexed: 12/31/2022] Open
Abstract
Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.
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Affiliation(s)
- Fang Zheng
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Yi-Ji Liao
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mu-Yan Cai
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tian-Hao Liu
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Shu-Peng Chen
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Pei-Hong Wu
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Tumor Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Long Wu
- Department of Clinical Oncology, People’s Hospital, Wuhan University, Wuhan, China
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xin-Yuan Guan
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
| | - Yi-Xin Zeng
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yun-Fei Yuan
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hsiang-Fu Kung
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- State Key Laboratory of Oncology in South China, the Chinese University of Hong Kong, Hong Kong, China
| | - Dan Xie
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- * E-mail:
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Overexpression of stathmin 1 is a poor prognostic biomarker in non-small cell lung cancer. J Transl Med 2015; 95:56-64. [PMID: 25384122 DOI: 10.1038/labinvest.2014.124] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 07/15/2014] [Accepted: 08/12/2014] [Indexed: 01/03/2023] Open
Abstract
Stathmin 1 (STMN1), a major microtubule-depolymerizing protein, is involved in cell cycle progression and cell motility. However, the clinical significance of STMN1 expression in non-small cell lung cancer (NSCLC) has not been determined. The expression pattern of STMN1 mRNA was analyzed by quantitative real-time PCR (qRT-PCR) in 37 cases of NSCLC and in the corresponding non-tumor tissue samples. Furthermore, immunohistochemistry was performed to detect STMN1 protein expression in 113 primary NSCLC tissues. The functional role of STMN1 in lung cancer cell lines was evaluated by small interfering RNA-mediated depletion followed by analyses of cell proliferation and invasion. We found that the STMN1 mRNA and protein levels in NSCLC tissues were significantly higher than those in the corresponding non-tumor tissues (P<0.001). In addition, increased STMN1 expression was correlated with poor tumor differentiation (P<0.001), large tumor size (P=0.022), advanced N stage (P=0.033), and advanced TNM stage (P<0.001). Kaplan-Meier analysis indicates that NSCLC patients with higher STMN1 expression showed significantly worse survival. Moreover, multivariate analysis indicates that higher STMN1 protein expression was an independent prognostic factor of disease-specific survival (HR 2.247, 95%CI 1.320-3.825, P=0.003). Finally, the knockdown of STMN1 in lung cancer cells resulted in a decrease in cellular proliferation and invasion. Our findings suggest that STMN1 may have an important role in NSCLC progression and could serve as a potential prognostic marker for patients with NSCLC.
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Song Y, Mu L, Han X, Liu X, Fu S. siRNA targeting stathmin inhibits invasion and enhances chemotherapy sensitivity of stem cells derived from glioma cell lines. Acta Biochim Biophys Sin (Shanghai) 2014; 46:1034-40. [PMID: 25348735 DOI: 10.1093/abbs/gmu099] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Glioma is one of the most highly angiogenic tumors, and glioma stem cells (GSCs) are responsible for resistance to chemotherapy and radiotherapy, as well as recurrence after operation. Stathmin is substantial for mitosis and plays an important role in proliferation and migration of glioma-derived endothelial cells. However, the relationship between stathmin and GSCs is incompletely understood. Here we isolated GSCs from glioma cell lines U87MG and U251, and then used siRNA targeting stathmin for silencing. We showed that silencing of stathmin suppressed the proliferation, increased the apoptosis rate, and arrested the cell cycle at G2/M phase in GSCs. Silencing of stathmin in GSCs also resulted in inhibited the migration/invasion as well as the capability of vasculogenic mimicry. The susceptibility of GSCs to temozolomide was also enhanced by stathmin silencing. Our findings suggest stathmin as a potential target in GSCs for glioma treatment.
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Affiliation(s)
- Yuwen Song
- Department of Neurosurgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Luyan Mu
- Department of Neurosurgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Xuezhe Han
- Neurosurgery and Vascular Biology Program, Children's Hospital Boston/Harvard Medical School, Boston, MA 02115, USA
| | - Xiaoqian Liu
- Department of Neurosurgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Songbin Fu
- Department of Genetics, Harbin Medical University, Harbin 150081, China
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Zhao E, Amir M, Lin Y, Czaja MJ. Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. PLoS One 2014; 9:e109750. [PMID: 25285524 PMCID: PMC4186850 DOI: 10.1371/journal.pone.0109750] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 09/10/2014] [Indexed: 12/11/2022] Open
Abstract
Stathmin 1 performs a critical function in cell proliferation by regulating microtubule polymerization. This proliferative function is thought to explain the frequent overexpression of stathmin in human cancer and its correlation with a bad prognosis. Whether stathmin also functions in cell death pathways is unclear. Stathmin regulates microtubules in part by binding free tubulin, a process inhibited by stathmin phosphorylation from kinases including c-Jun N-terminal kinase (JNK). The involvement of JNK activation both in stathmin phosphorylation, and in hepatocellular resistance to oxidative stress, led to an examination of the role of stathmin/JNK crosstalk in oxidant-induced hepatocyte death. Oxidative stress from menadione-generated superoxide induced JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes. A stathmin knockdown sensitized hepatocytes to both apoptotic and necrotic cell death from menadione without altering levels of oxidant generation. The absence of stathmin during oxidative stress led to JNK overactivation that was the mechanism of cell death as a concomitant knockdown of JNK1 or JNK2 blocked death. Hepatocyte death from JNK overactivation was mediated by the effects of JNK on mitochondria. Mitochondrial outer membrane permeabilization occurred in stathmin knockdown cells at low concentrations of menadione that triggered apoptosis, whereas mitochondrial β-oxidation and ATP homeostasis were compromised at higher, necrotic menadione concentrations. Stathmin therefore mediates hepatocyte resistance to death from oxidative stress by down regulating JNK and maintaining mitochondrial integrity. These findings demonstrate a new mechanism by which stathmin promotes cell survival and potentially tumor growth.
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Affiliation(s)
- Enpeng Zhao
- Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Muhammad Amir
- Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Yu Lin
- Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Mark J. Czaja
- Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
- * E-mail:
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Meta-analysis of the prognostic and diagnostic significance of serum/plasma osteopontin in hepatocellular carcinoma. J Clin Gastroenterol 2014; 48:806-14. [PMID: 24247813 DOI: 10.1097/mcg.0000000000000018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOALS The aim of this study was to perform a meta-analysis to evaluate the prognostic and diagnostic significance of serum/plasma osteopontin (OPN) in hepatocellular carcinoma (HCC). BACKGROUND The prognostic and diagnostic value of serum/plasma OPN) in HCC remain controversial. STUDY Eligible studies were identified through a systematic literature search. A meta-analysis of 8 studies (4 for prognosis and 4 for diagnosis, 1399 patients) was performed to estimate the association between serum/plasma-based OPN elevation and overall survival (OS) and disease-free survival (DFS) in HCC patients, and to evaluate the accuracy of plasma OPN and α-fetoprotein (AFP) in the diagnosis of HCC. Subgroup analyses were also performed in the meta-analysis. RESULTS We found that serum/plasma-based OPN elevation was significantly associated with poor OS (HR, 1.96; 95% CI, 1.47-2.61; P<0.00001) and DFS (HR, 1.80; 95% CI, 1.43-2.26; P<0.00001) in HCC. The summary estimates for plasma OPN and AFP in diagnosing HCC in the studies included were as follows: sensitivity, 88% (95% CI, 84%-91%) versus 68% (95% CI, 63%-73%); specificity, 87% (95% CI, 83%-90%) versus 97% (95% CI, 94%-99%); diagnostic odds ratio, 62.87 (95% CI, 10.90-362.60) versus 49.09 (95% CI, 11.36-212.10); and area under SROS, 0.91 (95% CI, 0.85-0.97) versus 0.68 (95% CI, 0.45-1.03). CONCLUSIONS The current evidence indicates that serum/plasma-based OPN seems to have significant predictive ability for estimating survival in HCC, and plasma OPN has a comparable accuracy to AFP for the diagnosis of HCC, although the diagnostic value of plasma OPN for early or AFP-negative HCC remains to be assessed by further studies.
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Yuan RH, Lai HS, Hsu HC, Lai PL, Jeng YM. Expression of bile duct transcription factor HNF1β predicts early tumor recurrence and is a stage-independent prognostic factor in hepatocellular carcinoma. J Gastrointest Surg 2014; 18:1784-94. [PMID: 25052070 DOI: 10.1007/s11605-014-2596-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 07/11/2014] [Indexed: 01/31/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) frequently exhibits biliary differentiation, which is typically overlooked. Hepatocyte nuclear factor 1β (HNF1β), a bile duct-specific transcription factor expressed in bile ducts but not in the normal hepatocytes, is also expressed in HCC. MATERIALS AND METHODS The expression of HNF1β and the biliary differentiation marker cytokeratin 19 (CK19) were retrospectively evaluated using immunohistochemistry in 159 surgically resected primary HCCs. RESULTS A significant correlation was observed between HNF1β protein expression and younger age (p = 0.0293), high serum α-fetoprotein levels (p = 6 × 10(-4)), and high tumor grade (p = 0.0255). However, HNF1β expression exhibited no correlation with tumor stage. Patients with HCCs and HNF1β expression were more likely to exhibit early tumor recurrence (ETR; p = 0.0048) and a lower 5-year survival rate (p = 0.0001). A multivariate analysis indicated HNF1β expression as an independent prognostic factor in HCC (p = 0.0048). A combinatorial analysis revealed additive adverse effects of HNF1β when concomitant with CK19 expression and p53 mutation. Furthermore, HNF1β expression can predict poor prognosis in patients with ETR. CONCLUSION Our results indicated that HNF1β expression is a crucial predictor of poor prognosis in HCC and is independent of tumor stage. Moreover, concomitant HNF1β and CK19 expressions exhibited additive adverse effects in HCC, confirming that HCC with biliary differentiation has a poor prognosis.
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Affiliation(s)
- Ray-Hwang Yuan
- Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10051, Taiwan, Republic of China
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Lu Y, Liu C, Xu YF, Cheng H, Shi S, Wu CT, Yu XJ. Stathmin destabilizing microtubule dynamics promotes malignant potential in cancer cells by epithelial-mesenchymal transition. Hepatobiliary Pancreat Dis Int 2014; 13:386-94. [PMID: 25100123 DOI: 10.1016/s1499-3872(14)60038-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Stathmin is a ubiquitous cytosolic regulatory phosphoprotein and is overexpressed in different human malignancies. The main physiological function of stathmin is to interfere with microtubule dynamics by promoting depolymerization of microtubules or by preventing polymerization of tubulin heterodimers. Stathmin plays important roles in regulating many cellular functions as a result of its microtubule-destabilizing activity. Currently, the critical roles of stathmin in cancer cells, as well as in lymphocytes have been valued. This review discusses stathmin and microtubule dynamics in cancer development, and hypothesizes their possible relationship with epithelial-mesenchymal transition (EMT). DATA SOURCES A PubMed search using such terms as "stathmin", "microtubule dynamics", "epithelial-mesenchymal transition", "EMT", "malignant potential" and "cancer" was performed to identify relevant studies published in English. More than 100 related articles were reviewed. RESULTS The literature clearly documented the relationship between stathmin and its microtubule-destabilizing activity of cancer development. However, the particular mechanism is poorly understood. Microtubule disruption is essential for EMT, which is a crucial process during cancer development. As a microtubule-destabilizing protein, stathmin may promote malignant potential in cancer cells by initiating EMT. CONCLUSIONS We propose that there is a stathmin-microtubule dynamics-EMT (S-M-E) axis during cancer development. By this axis, stathmin together with its microtubule-destabilizing activity contributes to EMT, which stimulates the malignant potential in cancer cells.
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Affiliation(s)
- Yu Lu
- Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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