|
1
|
Azad MG, Russell T, Gu X, Zhao X, Richardson V, Wijesinghe TP, Babu G, Guo X, Kaya B, Dharmasivam M, Deng Z, Richardson DR. NDRG1 and its Family Members: More than Just Metastasis Suppressor Proteins and Targets of Thiosemicarbazones. J Biol Chem 2025:110230. [PMID: 40378957 DOI: 10.1016/j.jbc.2025.110230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/19/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025] Open
Abstract
N-Myc downstream regulated gene-1 (NDRG1) and the other three members of this family (NDRG2, 3, and 4) play various functional roles in the cellular stress response, differentiation, migration, and development. These proteins are involved in regulating key signaling proteins and pathways that are often dysregulated in cancer, such as EGFR, PI3K/AKT, c-Met, and the Wnt pathway. NDRG1 is the primary, well-examined member of the NDRG family, and is generally characterized as a metastasis suppressor that inhibits the first step in metastasis, the epithelial-mesenchymal transition. While NDRG1 is well-studied, emerging evidence suggests NDRG2, NDRG3, and NDRG4 also play significant roles in modulating oncogenic signaling and cellular homeostasis. NDRG family members are regulated by multiple mechanisms, including transcriptional control by hypoxia-inducible factors, p53, and Myc, as well as post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Pharmacological targeting of the NDRG family is a therapeutic strategy against cancer. For instance, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have been extensively shown to up-regulate NDRG1 expression, leading to metastasis suppression and inhibition of tumor growth in multiple cancer models. Similarly, targeting NDRG2 demonstrates its pro-apoptotic and anti-proliferative effects, particularly in glioblastoma and colorectal cancer. This review provides a comprehensive analysis of the structural features, regulatory mechanisms, and biological functions of the NDRG family and their roles in cancer and neurodegenerative diseases. Additionally, NDRG1-4 are explored as therapeutic targets in oncology, focusing on recent advances in anti-cancer agents that induce the expression of these proteins. Implications for future research and clinical applications are also discussed.
Collapse
Affiliation(s)
- Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Tiffany Russell
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xuanling Gu
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xiao Zhao
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Vera Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Tharushi P Wijesinghe
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Golap Babu
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Xinnong Guo
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Busra Kaya
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Mahendiran Dharmasivam
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Zhao Deng
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| |
Collapse
|
|
2
|
Li H, Qiao L, Kong M, Fang H, Yan Z, Guo R, Guo W. Construction and validation of a prognostic signature based on microvascular invasion and immune-related genes in hepatocellular carcinoma. Sci Rep 2024; 14:26994. [PMID: 39506070 PMCID: PMC11541849 DOI: 10.1038/s41598-024-78467-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 10/31/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Microvascular invasion (MVI) is an independent risk factor of poor prognosis in hepatocellular carcinoma (HCC) and can be used to guide the diagnosis and treatment of HCC. The immune system serves as an integral role in the incidence and progression of HCC. However, the molecular biology correlation between MVI and tumor immunity and the value of combining the two parameters to predict patient prognosis and HCC response to treatment remain to be evaluated. RESULTS In this study, we used univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis to establish the MVI and immune-related gene index (MIRGPI) including eight genes. We demonstrated that the MIRGPI was an independent risk factor in predicting the prognosis of HCC. Subsequently, our research established a nomogram model combining pathologic characteristics and verified its good clinical application value. In addition, our study found that the TP53 gene had a higher mutation frequency and a lower degree of immune infiltration in the high-risk group. The low-risk group had higher sensitivity to immunotherapy, sorafenib, and TACE treatment, and the high-risk group had higher sensitivity to common chemotherapeutic agents. Finally, SEMA3C was found to facilitate the proliferation, migration and invasive ability of HCC by in vitro and in vivo experiments, and its mechanism may be associated with the activation of the NF-Κb/EMT signaling pathway. CONCLUSIONS In summary, the MIRGPI signature we developed is a reliable marker for the prediction of prognosis and treatment response, and is important for the prognostic assessment and individualized treatment of HCC.
Collapse
Affiliation(s)
- Hao Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Lixue Qiao
- Thyroid Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Minyu Kong
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Haoran Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Zhiping Yan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Key Laboratory for Hepatopathy and Transplantation Medicine, Zhengzhou, China
- Henan Engineering & Research Center for Diagnosis and Treatment of Hepatobiliary and Pancreatic Surgical Diseases, Zhengzhou, China
| | - Ran Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China.
- National Organ Transplantation Physician Training Center, Zhengzhou, China.
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450052, Henan, China.
- Department of Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| |
Collapse
|
|
3
|
Li SN, Li MX, Guo WW, Zhang LR, Ding YH, Wu XJ. LINC02561 promotes metastasis in HCC via HIF1-α/NDRG1/UPF1 axis. Gene 2024; 896:148033. [PMID: 38013127 DOI: 10.1016/j.gene.2023.148033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/14/2023] [Accepted: 11/23/2023] [Indexed: 11/29/2023]
Abstract
In the entire world, hepatocellular carcinoma (HCC) is one of the most frequent cancers that lead to death. Experiments on the function of long non-coding RNAs in the emergence of malignancies, including HCC, are ongoing. As a crucial RNA monitoring mechanism in eucaryotic cells, nonsense-mediated mRNA decay (NMD) can recognize and destroy mRNAs, which has an premature termination codons (PTC) in the open reading frame to prevent harmful buildup of truncated protein products in the cells. Nonsense transcript regulator 1 (Up-frameshift suppressor 1, UPF1), as a highly conserved RNA helicase and ATPase, plays a key role in NMD. Our laboratory screened out the highly expressed lncRNA LINC02561 in HCC from the TCGA database. Further research found that LINC02561 enhanced the invasion and transition abilities of liver cancer cells by regulating the protein N-Myc downstream regulated 1 (NDRG1). Hypoxia inducible factor-1 (HIF-1α) can bonded to LINC02561 promoters under hypoxic conditions, thereby promoting the upregulation of LINC02561 expression in liver cancer cells. LINC02561 competes with NDRG1 mRNA to bind UPF1, thereby preventing the degradation of NDRG1 mRNA to facilitate NDRG1 protein level. Taken together, the HIF1α-LINC02561-UPF1-NDRG1 regulatory axis could be an entirely novel target of liver cancer-related treatment.
Collapse
Affiliation(s)
- Sheng-Nan Li
- China University of Mining and Technology, China
| | - Mei-Xiang Li
- China University of Mining and Technology, China
| | - Wen-Wen Guo
- The Affiliated Hospital of China University of Mining and Technology, Department of Radiation Oncology, Xuzhou Municipal First People's Hospital, Xuzhou 221002, China
| | | | - Yun-He Ding
- The Affiliated Hospital of China University of Mining and Technology, Department of Radiation Oncology, Xuzhou Municipal First People's Hospital, Xuzhou 221002, China
| | - Xiao-Jin Wu
- The Affiliated Hospital of China University of Mining and Technology, Department of Radiation Oncology, Xuzhou Municipal First People's Hospital, Xuzhou 221002, China.
| |
Collapse
|
|
4
|
Miao C, He X, Chen G, Kahlert UD, Yao C, Shi W, Su D, Hu L, Zhang Z. Seven oxidative stress-related genes predict the prognosis of hepatocellular carcinoma. Aging (Albany NY) 2023; 15:15050-15063. [PMID: 38097352 PMCID: PMC10781471 DOI: 10.18632/aging.205330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/06/2023] [Indexed: 01/07/2024]
Abstract
Predicting the prognosis of hepatocellular carcinoma (HCC) is a major medical challenge and of guiding significance for treatment. This study explored the actual relevance of RNA expression in predicting HCC prognosis. Cox's multiple regression was used to establish a risk score staging classification and to predict the HCC patients' prognosis on the basis of data in the Cancer Genome Atlas (TCGA). We screened seven gene biomarkers related to the prognosis of HCC from the perspective of oxidative stress, including Alpha-Enolase 1(ENO1), N-myc downstream-regulated gene 1 (NDRG1), nucleophosmin (NPM1), metallothionein-3, H2A histone family member X, Thioredoxin reductase 1 (TXNRD1) and interleukin 33 (IL-33). Among them we measured the expression of ENO1, NGDP1, NPM1, TXNRD1 and IL-33 to investigate the reliability of the multi-index prediction. The first four markers' expressions increased successively in the paracellular tissues, the hepatocellular carcinoma samples (from patients with better prognosis) and the hepatocellular carcinoma samples (from patients with poor prognosis), while IL-33 showed the opposite trend. The seven genes increased the sensitivity and specificity of the predictive model, resulting in a significant increase in overall confidence. Compared with the patients with higher-risk scores, the survival rates with lower-risk scores are significantly increased. Risk score is more accurate in predicting the prognosis HCC patients than other clinical factors. In conclusion, we use the Cox regression model to identify seven oxidative stress-related genes, investigate the reliability of the multi-index prediction, and develop a risk staging model for predicting the prognosis of HCC patients and guiding precise treatment strategy.
Collapse
Affiliation(s)
- Chen Miao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiao He
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ulf D. Kahlert
- Molecular and Experimental Surgery, Clinic for General-, Visceral-, Vascular and Transplant Surgery, Faculty of Medicine and University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Chenchen Yao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenjie Shi
- Molecular and Experimental Surgery, Clinic for General-, Visceral-, Vascular and Transplant Surgery, Faculty of Medicine and University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China
- Department of Pathology and Clinical Laboratory, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Liang Hu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Zhihong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
5
|
Badwei N. Molecular Clues for Prediction of Hepatocellular Carcinoma Recurrence After Liver Transplantation. J Clin Exp Hepatol 2023; 13:804-812. [PMID: 37693263 PMCID: PMC10482986 DOI: 10.1016/j.jceh.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/15/2023] [Indexed: 09/12/2023] Open
Abstract
Recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) is one of the commonest causes of cancer-related mortality. Thus, advances in the HCC molecular features have paid researchers great attention to identifying the different risk factors that could aid in liver cancer initiation and progression for earlier prediction of post-operative HCC recurrence risk. Our review has focused on the possible molecular onco-drivers' for HCC recurrence post-LT that may represent diagnostic/prognostic tools and scoring models for the proper selection of LT candidates with HCC.
Collapse
Affiliation(s)
- Nourhan Badwei
- Tropical Medicine, Gastroenterology and Hepatology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
6
|
Cheng Q, Ning S, Zhu L, Zhang C, Jiang S, Hao Y, Zhu J. NDRG1 facilitates self-renewal of liver cancer stem cells by preventing EpCAM ubiquitination. Br J Cancer 2023; 129:237-248. [PMID: 37165202 PMCID: PMC10338678 DOI: 10.1038/s41416-023-02278-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/25/2023] [Accepted: 04/12/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Portal vein tumour thrombus (PVTT) is the main pathway of HCC intrahepatic metastasis and is responsible for the poor prognosis of patients with HCC. However, the molecular mechanisms underlying PVTT vascular metastases have not been fully elucidated. METHODS NDRG1 expression was assessed by immunohistochemistry and immunoblotting in clinical specimens obtained from curative surgery. The functional relevance of NDRG1 was evaluated using sphere formation and animal models of tumorigenicity and metastasis. The relationship between NDRG1 and EpCAM was explored using molecular biological techniques. RESULTS NDRG1 protein was upregulated in HCC samples compared to non-tumorous tissues. Furthermore, NDRG1 expression was enhanced in the PVTT samples. Our functional study showed that NDRG1 was required for the self-renewal of tumour-initiating/cancer stem cells (CSCs). In addition, NDRG1 knockdown inhibited the proliferation and migration of PVTT-1 cells in vitro and in vivo. NDRG1 was found to stabilise the functional tumour-initiating cell marker EpCAM through protein-protein interactions and inhibition of EpCAM ubiquitination. CONCLUSION Our findings suggest that NDRG1 enhances CSCs expansion, PVTT formation and growth capability through the regulation of EpCAM stability. NDRG1 may be a promising target for the treatment of patients with HCC and PVTT.
Collapse
Affiliation(s)
- Qian Cheng
- Department of Hepatobiliary Surgery, Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, 100044, Beijing, China.
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
| | - Shanglei Ning
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Shandong, China
| | - Lei Zhu
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Changlu Zhang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Shaodong Jiang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yajing Hao
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, 100044, Beijing, China.
| |
Collapse
|
|
7
|
Shen J, Gao H, Li B, Huang Y, Shi Y. The integration of machine learning and multi-omics analysis provides a powerful approach to screen aging-related genes and predict prognosis and immunotherapy efficacy in hepatocellular carcinoma. Aging (Albany NY) 2023; 15:6848-6864. [PMID: 37517087 PMCID: PMC10415564 DOI: 10.18632/aging.204876] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/15/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly malignant tumor with high incidence and mortality rates. Aging-related genes are closely related to the occurrence and development of cancer. Therefore, it is of great significance to evaluate the prognosis of HCC patients by constructing a model based on aging-related genes. METHOD Non-negative matrix factorization (NMF) clustering analysis was used to cluster the samples. The correlation between the risk score and immune cells, immune checkpoints, and Mismatch Repair (MMR) was evaluated through Spearman correlation test. Real Time Quantitative PCR (RT-qPCR) and immunohistochemistry were used to validate the expression levels of key genes in tissue and cells for the constructed model. RESULT By performing NMF clustering, we were able to effectively group the liver cancer samples into two distinct clusters. Considering the potential correlation between aging-related genes and the prognosis of liver cancer patients, we used aging-related genes to construct a prognostic model. Spearman correlation analysis showed that the model risk score was closely related to MMR and immune checkpoint expression. Drug sensitivity analysis also provided guidance for the clinical use of chemotherapy drugs. RT-qPCR showed that TFDP1, NDRG1, and FXR1 were expressed at higher levels in different liver cancer cell lines compared to normal liver cells. CONCLUSION In summary, we have developed an aging-related model to predict the prognosis of hepatocellular carcinoma and guide clinical drug treatment for different patients.
Collapse
Affiliation(s)
- Jiahui Shen
- Department of Pharmacy, Huzhou Maternity and Child Health Care Hospital, Huzhou, China
| | - Han Gao
- Department of Stomatology, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Bowen Li
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yan Huang
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yinfang Shi
- Department of Stomatology, First Affiliated Hospital of Huzhou University, Huzhou, China
| |
Collapse
|
|
8
|
Jia Q, Tan Y, Li Y, Wu Y, Wang J, Tang F. JUN-induced super-enhancer RNA forms R-loop to promote nasopharyngeal carcinoma metastasis. Cell Death Dis 2023; 14:459. [PMID: 37479693 PMCID: PMC10361959 DOI: 10.1038/s41419-023-05985-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 07/23/2023]
Abstract
Oncogenic super-enhancers (SEs) generate noncoding enhancer/SE RNAs (eRNAs/seRNAs) that exert a critical function in malignancy through powerful regulation of target gene expression. Herein, we show that a JUN-mediated seRNA can form R-loop to regulate target genes to promote metastasis of nasopharyngeal carcinoma (NPC). A combination of global run-on sequencing, chromatin-immunoprecipitation sequencing, and RNA sequencing was used to screen seRNAs. A specific seRNA associated with NPC metastasis (seRNA-NPCM) was identified as a transcriptional regulator for N-myc downstream-regulated gene 1 (NDRG1). JUN was found to regulate seRNA-NPCM through motif binding. seRNA-NPCM was elevated in NPC cancer tissues and highly metastatic cell lines, and promoted the metastasis of NPC cells in vitro and in vivo. Mechanistically, the 3' end of seRNA-NPCM hybridizes with the SE region to form an R-loop, and the middle segment of seRNA-NPCM binds to heterogeneous nuclear ribonucleoprotein R (hnRNPR) at the promoter of distal gene NDRG1 and neighboring gene tribbles pseudokinase 1 (TRIB1). These structures promote chromatin looping and long-distance chromatin interactions between SEs and promoters, thus facilitating NDRG1 and TRIB1 transcription. Furthermore, the clinical analyses showed that seRNA-NPCM and NDRG1 were independent prognostic factors for NPC patients. seRNA-NPCM plays a critical role in orchestrating target gene transcription to promote NPC metastasis.
Collapse
Affiliation(s)
- Qunying Jia
- Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, 410013, Changsha, China
| | - Yuan Tan
- Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, 410013, Changsha, China
| | - Yuejin Li
- Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, 410013, Changsha, China
| | - Yao Wu
- Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, 410013, Changsha, China
- Department of Ophthalmology and Otolaryngology, The First Hospital of Hunan University of Chinese Medicine, 410208, Changsha, China
| | - Jing Wang
- Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, 410013, Changsha, China
| | - Faqin Tang
- Hunan Key Laboratory of Oncotarget Gene and Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, 410013, Changsha, China.
| |
Collapse
|
|
9
|
Liu Y, Shen B, Huang T, Wang J, Jiang J. Construction and validation of 3-genes hypoxia-related prognostic signature to predict the prognosis and therapeutic response of hepatocellular carcinoma patients. PLoS One 2023; 18:e0288013. [PMID: 37406019 DOI: 10.1371/journal.pone.0288013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 06/19/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment. METHODS Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints. RESULTS A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype. CONCLUSIONS The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.
Collapse
Affiliation(s)
- Yunxun Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Bingbing Shen
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Ting Huang
- Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Jianguo Wang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Jianxin Jiang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| |
Collapse
|
|
10
|
Zheng P, Wu Y, Wang Y, Hu F. Disulfiram suppresses epithelial-mesenchymal transition (EMT), migration and invasion in cervical cancer through the HSP90A/NDRG1 pathway. Cell Signal 2023; 109:110771. [PMID: 37329997 DOI: 10.1016/j.cellsig.2023.110771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/01/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
Disulfiram (DSF) has proven to be a promising anti-tumor drug in preclinical studies. However, its anti-cancer mechanism has not yet been elucidated. As an activator in tumor metastasis, N-myc downstream regulated gene-1 (NDRG1) is involved in multiple oncogenic signaling pathways and is upregulated by cell differentiation signals in various cancer cell lines. DSF treatment results in a significant reduction in NDRG1, while down-regulated NDRG1 has a pronounced effect on invading cancer cells, as shown in our previous work. Here, in vitro and in vivo experiments confirm that DSF contributes to regulating tumor growth, EMT, and the migration and invasion of cervical cancer. Furthermore, our results show DSF binds to the ATP-binding pocket in the N-terminal domain of HSP90A, thereby affecting the expression of its client protein NDRG1. To our knowledge, this is the first report of DSF binding to HSP90A. In conclusion, this study sheds light on the molecular mechanism by which DSF inhibits tumor growth and metastasis through the HSP90A/NDRG1/β-catenin pathway in cervical cancer cells. These findings provide novel insights into the mechanism underlying DSF function in cancer cells.
Collapse
Affiliation(s)
- Peng Zheng
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China.
| | - Yaoqin Wu
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yuqiong Wang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Fan Hu
- Third Institute of Oceanography Ministry of Natural Resources, Xiamen 361005, China.
| |
Collapse
|
|
11
|
Pommergaard HC. Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma. APMIS 2023; 131 Suppl 146:1-39. [PMID: 37186326 DOI: 10.1111/apm.13309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
|
|
12
|
Wong SL, Kardia E, Vijayan A, Umashankar B, Pandzic E, Zhong L, Jaffe A, Waters SA. Molecular and Functional Characteristics of Airway Epithelium under Chronic Hypoxia. Int J Mol Sci 2023; 24:ijms24076475. [PMID: 37047450 PMCID: PMC10095024 DOI: 10.3390/ijms24076475] [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: 03/03/2023] [Revised: 03/20/2023] [Accepted: 03/24/2023] [Indexed: 04/14/2023] Open
Abstract
Localized and chronic hypoxia of airway mucosa is a common feature of progressive respiratory diseases, including cystic fibrosis (CF). However, the impact of prolonged hypoxia on airway stem cell function and differentiated epithelium is not well elucidated. Acute hypoxia alters the transcription and translation of many genes, including the CF transmembrane conductance regulator (CFTR). CFTR-targeted therapies (modulators) have not been investigated in vitro under chronic hypoxic conditions found in CF airways in vivo. Nasal epithelial cells (hNECs) derived from eight CF and three non-CF participants were expanded and differentiated at the air-liquid interface (26-30 days) at ambient and 2% oxygen tension (hypoxia). Morphology, global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility and ion transport) of basal stem cells and differentiated cultures were assessed. hNECs expanded at chronic hypoxia, demonstrating epithelial cobblestone morphology and a similar proliferation rate to hNECs expanded at normoxia. Hypoxia-inducible proteins and pathways in stem cells and differentiated cultures were identified. Despite the stem cells' plasticity and adaptation to chronic hypoxia, the differentiated epithelium was significantly thinner with reduced barrier integrity. Stem cell lineage commitment shifted to a more secretory epithelial phenotype. Motile cilia abundance, length, beat frequency and coordination were significantly negatively modulated. Chronic hypoxia reduces the activity of epithelial sodium and CFTR ion channels. CFTR modulator drug response was diminished. Our findings shed light on the molecular pathophysiology of hypoxia and its implications in CF. Targeting hypoxia can be a strategy to augment mucosal function and may provide a means to enhance the efficacy of CFTR modulators.
Collapse
Affiliation(s)
- Sharon L Wong
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Egi Kardia
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Abhishek Vijayan
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Bala Umashankar
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Elvis Pandzic
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW 2052, Australia
| | - Ling Zhong
- Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052, Australia
| | - Adam Jaffe
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW 2052, Australia
| | - Shafagh A Waters
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
- Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW 2052, Australia
| |
Collapse
|
|
13
|
Han F, Cao D, Zhu X, Shen L, Wu J, Chen Y, Xu Y, Xu L, Cheng X, Zhang Y. Construction and validation of a prognostic model for hepatocellular carcinoma: Inflammatory ferroptosis and mitochondrial metabolism indicate a poor prognosis. Front Oncol 2023; 12:972434. [PMID: 36686830 PMCID: PMC9850107 DOI: 10.3389/fonc.2022.972434] [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: 07/15/2022] [Accepted: 12/15/2022] [Indexed: 01/07/2023] Open
Abstract
Background An increasing number of innovations have been discovered for treating hepatocellular carcinoma (HCC or commonly called HCC) therapy, Ferroptosis and mitochondrial metabolism are essential mechanisms of cell death. These pathways may act as functional molecular biomarkers that could have important clinical significance for determining individual differences and the prognosis of HCC. The aim of this study was to construct a stable and reliable comprehensive model of genetic features and clinical factors associated with HCC prognosis. Methods In this study, we used RNA-sequencing (fragments per kilobase of exon model per million reads mapped value) data from the Cancer Genome Atlas (TCGA) database to establish a prognostic model. We enrolled 104 patients for further validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses (KEGG) analysis were used for the functional study of differentially expressed genes. Pan-cancer analysis was performed to evaluate the function of the Differentially Expressed Genes (DEGs). Thirteen genes were identified by univariate and least absolute contraction and selection operation (LASSO) Cox regression analysis. The prognostic model was visualized using a nomogram. Results We found that eight genes, namely EZH2, GRPEL2, PIGU, PPM1G, SF3B4, TUBG1, TXNRD1 and NDRG1, were hub genes for HCC and differentially expressed in most types of cancer. EZH2, GRPEL2 and NDRG1 may indicate a poor prognosis of HCC as verified by tissue samples. Furthermore, a gene set variation analysis algorithm was created to analyze the relationship between these eight genes and oxidative phosphorylation, mitophagy, and FeS-containing proteins, and it showed that ferroptosis might affect inflammatory-related pathways in HCC. Conclusion EZH2, GRPEL2, NDRG1, and the clinical factor of tumor size, were included in a nomogram for visualizing a prognostic model of HCC. This nomogram based on a functional study and verification by clinical samples, shows a reliable performance of patients with HCC.
Collapse
Affiliation(s)
- Fang Han
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Dan Cao
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China,College of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, Zhejiang, China
| | - Xin Zhu
- Hepatobiliary and Pancreatic Surgery Department, Shaoxing Peoples’s Hospital, Shaoxing, Zhejiang, China
| | - Lianqiang Shen
- Department of General Surgery, The First People’s Hospital of Linping District, Hangzhou, Hangzhou, Zhejiang, China
| | - Jia Wu
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Yizhen Chen
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China,Clincal Dept. Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Youyao Xu
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China,Clincal Dept. Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Linwei Xu
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Xiangdong Cheng
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Yuhua Zhang
- Hepatobiliary and Pancreatic Surgery Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China,Clincal Dept. Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China,*Correspondence: Yuhua Zhang,
| |
Collapse
|
|
14
|
Gao B, Wang Y, Lu S. Construction and validation of a novel signature based on epithelial-mesenchymal transition-related genes to predict prognosis and immunotherapy response in hepatocellular carcinoma by comprehensive analysis of the tumor microenvironment. Funct Integr Genomics 2022; 23:6. [PMID: 36536232 PMCID: PMC9763151 DOI: 10.1007/s10142-022-00933-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022]
Abstract
Immunotherapy has yielded encouraging results in the treatment of advanced hepatocellular carcinoma (HCC). However, the relationship between epithelial-mesenchymal transition (EMT) and immunotherapy for HCC has not been adequately explained. In this study, we comprehensively analyzed a bulk RNA sequence dataset of 365 HCC patients in The Cancer Genome Atlas (TCGA) dataset. Subsequently, we constructed a prognostic signature based on 6 EMT-related genes and divided 365 HCC patients into high- and low-risk groups. The predictive efficacy of the signature was well validated in different clinical subgroups and in two independent external datasets. We further explored the relationship between prognostic signature and immunotherapy response in terms of immune cell infiltration, somatic mutations, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint-associated gene expression, single-nucleotide variants (SNV) neoantigens, cancer testicular antigens (CTA) scores, and tumor immune dysfunction and exclusion (TIDE) scores. We validated the predictive efficacy of prognostic signature for immunotherapy response using external independent immunotherapy data. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to validate EMT-related gene overexpression in HCC tissue samples. Prognostic signature was an independent risk factor affecting the prognosis of HCC patients and has shown superiority in predicting patient survival compared to other clinical factors. Compared with the low-risk group, the proportion of Activated_CD4_T_cell, Type_2_T_helper_cel, and macrophages were higher in the tumor microenvironment of HCC patients in the high-risk group, while the Activated_CD8_T_cell and CD56bright_natural_killer_cell proportions were lower. The prognostic signature was positively correlated with TMB scores, MSI scores, SNV neoantigens scores, expression levels of immune checkpoint-related genes, and TIDE scores, and patients in the high-risk group were more suitable for immunotherapy. qRT-PCR confirms overexpression of 6 EMT-related genes in HCC tissues for the construction of prognostic signature. Our novel prognostic signature can effectively predict the prognosis and immunotherapy response of HCC patients. In the future, it will be an effective tool for physicians to screen suitable immunotherapy populations and improve response rates and overall survival (OS).
Collapse
Affiliation(s)
- Biao Gao
- School of Medicine, Nankai University, Tianjin, 300300, China
| | - Yafei Wang
- School of Medicine, Nankai University, Tianjin, 300300, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 10058, China. .,Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 10058, China. .,Key Laboratory of Digital Hepetobiliary Surgery PLA, Beijing, 10058, China.
| |
Collapse
|
|
15
|
NDRG1 in Cancer: A Suppressor, Promoter, or Both? Cancers (Basel) 2022; 14:cancers14235739. [PMID: 36497221 PMCID: PMC9737586 DOI: 10.3390/cancers14235739] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
N-myc downregulated gene-1 (NDRG1) has been variably reported as a metastasis suppressor, a biomarker of poor outcome, and a facilitator of disease progression in a range of different cancers. NDRG1 is poorly understood in cancer due to its context-dependent and pleiotropic functions. Within breast cancer, NDRG1 is reported to be either a facilitator of, or an inhibitor of tumour progression and metastasis. The wide array of roles played by NDRG1 are dependent on post-translational modifications and subcellular localization, as well as the cellular context, for example, cancer type. We present an update on NDRG1, and its association with hallmarks of cancer such as hypoxia, its interaction with oncogenic proteins such as p53 as well its role in oncogenic and metastasis pathways in breast and other cancers. We further comment on its functional implications as a metastasis suppressor and promoter, its clinical relevance, and discuss its therapeutic targetability in different cancers.
Collapse
|
|
16
|
Xu S, Gao R, Zhou Y, Yang Y, Zhang Y, Li Q, Luo C, Liu SM. Clinical Diagnostic and Prognostic Potential of NDRG1 and NDRG2 in Hepatocellular Carcinoma Patients. Front Oncol 2022; 12:862216. [PMID: 35795037 PMCID: PMC9252526 DOI: 10.3389/fonc.2022.862216] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022] Open
Abstract
Background Primary liver cancer is still the most common lethal malignancy. The N-myc downstream-regulated gene family (NDRG1–4) is a group of multifunctional proteins associated with carcinogenesis. However, systematic evaluation of the diagnostic and prognostic values of NDRG1 or NDRG2 expression in liver cancer is poorly investigated. Method The gene expression matrix of liver hepatocellular carcinoma (LIHC) was comprehensively analyzed by the “limma” and “Dseq2” R packages. The Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to identify the biological functional differences. A single-sample GSEA (ssGSEA) was conducted to quantify the extent of immune cell infiltration. Finally, the clinical and prognostic information of LIHC patients was systematically investigated using Kaplan–Meier analysis and logistic and Cox regression analysis. Results Compared with normal tissues, NDRG1 expression was higher, whereas NDRG2 expression was lower in tumor tissues (P <0.001). The area under the receiver operator characteristic curve (AUROC) of NDRG1 and NDRG2 for LIHC was 0.715 and 0.799, respectively. Kaplan–Meier analysis revealed that NDRG1 and NDRG2 were independent clinical prognostic biomarkers for the overall survival (OS, P = 0.001 and 2.9e−06), progression-free interval (PFI, P = 0.028 and 0.005) and disease-specific survival (DSS, P = 0.027 and P <0.001). The C-indexes and calibration plots of the nomogram suggest that NDRG1 and NDRG2 have an effective predictive performance for OS (C-index: 0.676), DSS (C-index: 0.741) and PFI (C-index: 0.630) of liver cancer patients. The mutation rate of NDRG1 in liver cancer reached up to 14%, and DNA methylation levels of NDRG1 and NDRG2 promoters correlated significantly with clinical prognosis. Conclusions The mRNA expression and DNA methylation of NDRG superfamily members have the potential for LIHC diagnosis and prognosis via integrative analysis from multiple cohorts.
Collapse
Affiliation(s)
- Shaohua Xu
- Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ruihuan Gao
- Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yidan Zhou
- Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ying Yang
- Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qianyuan Li
- The First College of Clinical Medical Science, Three Gorges University, Hubei, China
| | - Chunhua Luo
- The First College of Clinical Medical Science, Three Gorges University, Hubei, China
| | - Song-Mei Liu
- Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Song-Mei Liu,
| |
Collapse
|
|
17
|
Huang L, Guan S, Feng L, Wei J, Wu L. Integrated analysis identified NPNT as a potential key regulator in tumor metastasis of hepatocellular carcinoma. Gene 2022; 825:146436. [PMID: 35304239 DOI: 10.1016/j.gene.2022.146436] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/12/2022] [Accepted: 03/11/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the lethal malignancies worldwide. Tumor metastasis is the main cause of HCC related death. Although progress has been made in the mechanism study of HCC in the past decades, the underlying mechanism of HCC metastasis has not been fully illustrated. In the present study, bioinformatic analysis including weighted gene co-expression network analysis (WGCNA), differentially expressed gene analysis, and gene enrichment analysis were applied to discover genes correlated with HCC metastasis. Immunohistochemistry (IHC) assays were applied to detect the expression of NPNT in HCC samples. Cell transfection, wound healing, matrigel transwell assays, and western blot assays were utilized to evaluate the effects of NPNT on cell migration and invasion and signaling pathway variation. We found that NPNT was up-regulated in HCC tumor tissues compared with normal tissues. Especially, NPNT was highly expressed in metastatic tumor compared with non-metastatic HCC tumors. Down-regulation of NPNT via siRNA transfection inhibited cell migration, invasion, and FAK/PI3K/AKT signaling pathway in HCC. Our results demonstrate that NPNT is a potential key regulator in HCC metastasis.
Collapse
Affiliation(s)
- Lingkun Huang
- Medical College, Guangxi University, Nanning 530004, China
| | - Shuzhen Guan
- Medical College, Guangxi University, Nanning 530004, China
| | - Lin Feng
- Department of Pathology, the first Medical Center of PLA General Hospital, Beijing, China
| | - Jinrui Wei
- Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Lichuan Wu
- Medical College, Guangxi University, Nanning 530004, China.
| |
Collapse
|
|
18
|
Villodre ES, Hu X, Eckhardt BL, Larson R, Huo L, Yoon EC, Gong Y, Song J, Liu S, Ueno NT, Krishnamurthy S, Pusch S, Tripathy D, Woodward WA, Debeb BG. NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis. J Natl Cancer Inst 2022; 114:579-591. [PMID: 34893874 PMCID: PMC9002276 DOI: 10.1093/jnci/djab222] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/13/2021] [Accepted: 11/30/2021] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive. METHODS To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariable Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided. RESULTS We generated new sublines that exhibited a distinct propensity to metastasize to the brain. NDRG1-high-expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher's exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [95% CI] = 1.20 to 4.29, P = .009) and breast cancer-specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17, 95% CI = 1.10 to 4.30, P = .03) and breast cancer-specific survival rates (HR = 2.27, 95% CI = 1.05 to 4.92, P = .04). CONCLUSIONS We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.
Collapse
Affiliation(s)
- Emilly S Villodre
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoding Hu
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bedrich L Eckhardt
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Richard Larson
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lei Huo
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ester C Yoon
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Gong
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Juhee Song
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shuying Liu
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Savitri Krishnamurthy
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stefan Pusch
- German Cancer Consortium Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
- Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany
| | - Debu Tripathy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wendy A Woodward
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bisrat G Debeb
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
19
|
Yin X, Yu H, He XK, Yan SX. Prognostic and biological role of the N-Myc downstream-regulated gene family in hepatocellular carcinoma. World J Clin Cases 2022; 10:2072-2086. [PMID: 35321174 PMCID: PMC8895174 DOI: 10.12998/wjcc.v10.i7.2072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/24/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The N-Myc downstream-regulated gene (NDRG) family is comprised of four members (NDRG1-4) involved in various important biological processes. However, there is no systematic evaluation of the prognostic of the NDRG family in hepatocellular carcinoma (HCC).
AIM To analyze comprehensively the biological role of the NDRG family in HCC.
METHODS The NDRG family expression was explored using The Cancer Genome Atlas. DNA methylation interactive visualization database was used for methylation analysis of the NDRG family. The NDRG family genomic alteration was assessed using the cBioPortal. Single-sample Gene Set Enrichment Analysis was used to determine the degree of immune cell infiltration in tumors.
RESULTS NDRG1 and NDRG3 were up-regulated in HCC, while NDRG2 was down-regulated. Consistent with expression patterns, high expression of NDRG1 and NDRG3 was associated with poor survival outcomes (P < 0.05). High expression of NDRG2 was associated with favorable survival (P < 0.005). An NDRG-based signature that statistically stratified the prognosis of the patients was constructed. The percentage of genetic alterations in the NDRG family varied from 0.3% to 11.0%, and the NDRG1 mutation rate was the highest. NDRG 1-3 expression was associated with various types of infiltrated immune cells. Gene ontology analysis revealed that organic acid catabolism was the most important biological process related to the NDRG family. Gene Set Enrichment Analysis showed that metabolic, proliferation, and immune-related gene sets were enriched during NDRG1 and NDRG3 high expression and NDRG2 low expression.
CONCLUSION Overexpression of NDRG1 and NDRG3 and down-expression of NDRG2 are correlated with poor overall HCC prognosis. Our results may provide new insights into the indispensable role of NDRG1, 2, and 3 in the development of HCC and guide a promising new strategy for treating HCC.
Collapse
Affiliation(s)
- Xin Yin
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Hao Yu
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xing-Kang He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Sen-Xiang Yan
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| |
Collapse
|
|
20
|
Shi X, Cen Y, Shan L, Tian L, Zhu E, Yuan H, Li X, Liu Y, Wang B. N-myc downstream regulated gene 1 suppresses osteoblast differentiation through inactivating Wnt/β-catenin signaling. Stem Cell Res Ther 2022; 13:53. [PMID: 35120575 PMCID: PMC8817551 DOI: 10.1186/s13287-022-02714-5] [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: 07/12/2021] [Accepted: 12/24/2021] [Indexed: 11/22/2022] Open
Abstract
Background N-myc downstream regulated gene 1 (NDRG1) plays a role in a variety of biological processes including differentiation of osteoclasts. However, it is not known if and how NDRG1 regulates osteogenic differentiation of marrow stromal progenitor cells. Methods Gene expression profiling analysis was performed to study the expression level of Ndrg1 during osteogenic and adipogenic differentiation. Gain-of-function and/or loss-of function experiments were carried out to study the role of NDRG1 in the proliferation and differentiation of marrow stromal progenitor cells and the mechanism underlying the function was investigated. Finally, in vivo transfection of Ndrg1 siRNA was done and its effect on osteogenic and adipogenic differentiation in mice was explored. Results Gene expression profiling analysis revealed that NDRG1 level was regulated during osteogenic and adipogenic differentiation of progenitor cells. The functional experiments demonstrated that NDRG1 negatively regulated the cell growth, and reciprocally modulated the osteogenic and adipogenic commitment of marrow stromal progenitor cells, driving the cells to differentiate toward adipocytes at the expense of osteoblast differentiation. Moreover, NDRG1 interacted with low-density lipoprotein receptor-related protein 6 (LRP6) in the stromal progenitor cells and inactivated the canonical Wnt/β-catenin signaling cascade. Furthermore, the impaired differentiation of progenitor cells induced by Ndrg1 siRNA could be attenuated when β-catenin was simultaneously silenced. Finally, in vivo transfection of Ndrg1 siRNA to the marrow of mice prevented the inactivation of canonical Wnt signaling in the BMSCs of ovariectomized mice, and ameliorated the reduction of osteoblasts on the trabeculae and increase of fat accumulation in the marrow observed in the ovariectomized mice. Conclusion This study has provided evidences that NDRG1 plays a role in reciprocally modulating osteogenic and adipogenic commitment of marrow stromal progenitor cells through inactivating canonical Wnt signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02714-5.
Collapse
Affiliation(s)
- Xiaoli Shi
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.,College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yunzhu Cen
- Stomatological Hospital, Tianjin Medical University, Tianjin, 300070, China
| | - Liying Shan
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Lijie Tian
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Endong Zhu
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Hairui Yuan
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Xiaoxia Li
- College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Ying Liu
- Stomatological Hospital, Tianjin Medical University, Tianjin, 300070, China.
| | - Baoli Wang
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
| |
Collapse
|
|
21
|
Zhao N, Zhang Y, Cheng R, Zhang D, Li F, Guo Y, Qiu Z, Dong X, Ban X, Sun B, Zhao X. Spatial maps of hepatocellular carcinoma transcriptomes highlight an unexplored landscape of heterogeneity and a novel gene signature for survival. Cancer Cell Int 2022; 22:57. [PMID: 35109839 PMCID: PMC8812006 DOI: 10.1186/s12935-021-02430-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 12/24/2021] [Indexed: 01/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) often presents with satellite nodules, rendering current curative treatments ineffective in many patients. The heterogeneity of HCC is a major challenge in personalized medicine. The emergence of spatial transcriptomics (ST) provides a powerful strategy for delineating the complex molecular landscapes of tumours. Methods In this study, the heterogeneity of tissue-wide gene expression in tumour and adjacent nonneoplastic tissues using ST technology were investigated. The transcriptomes of nearly 10,820 tissue regions and identified the main gene expression clusters and their specific marker genes (differentially expressed genes, DEGs) in patients were analysed. The DEGs were analysed from two perspectives. First, two distinct gene profiles were identified to be associated with satellite nodules and conducted a more comprehensive analysis of both gene profiles. Their clinical relevance in human HCC was validated with Kaplan–Meier (KM) Plotter. Second, DEGs were screened with The Cancer Genome Atlas (TCGA) database to divide the HCC cohort into high- and low-risk groups according to Cox analysis. HCC patients from the International Cancer Genome Consortium (ICGC) cohort were used for validation. KM analysis was used to compare the overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors for OS. Results Novel markers for the prediction of satellite nodules were identified and a tumour clusters-specific marker gene signature model (6 genes) for HCC prognosis was constructed. Conclusion The establishment of marker gene profiles may be an important step towards an unbiased view of HCC, and the 6-gene signature can be used for prognostic prediction in HCC. This analysis will help us to clarify one of the possible sources of HCC heterogeneity and uncover pathogenic mechanisms and novel antitumour drug targets. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02430-9.
Collapse
Affiliation(s)
- Nan Zhao
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Yanhui Zhang
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China
| | - Runfen Cheng
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China
| | - Danfang Zhang
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Fan Li
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Yuhong Guo
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China
| | - Zhiqiang Qiu
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China
| | - Xueyi Dong
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Xinchao Ban
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Baocun Sun
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China. .,Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China. .,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China.
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China. .,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China.
| |
Collapse
|
|
22
|
Zhang J, Yang Y, Dong Y, Liu C. Microrchidia family CW‑type zinc finger 2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of glioma by regulating PTEN/PI3K/AKT signaling via binding to N‑myc downstream regulated gene 1 promoter. Int J Mol Med 2021; 49:16. [PMID: 34913078 PMCID: PMC8711590 DOI: 10.3892/ijmm.2021.5071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/02/2021] [Indexed: 11/05/2022] Open
Abstract
Glioma is a common malignant tumor of the central nervous system with high incidence and mortality. The present study aimed to investigate the role of Microrchidia family CW‑type zinc finger 2 (MORC2) in the development of glioma. Firstly, MORC2 expression was detected in several glioma cell lines (U251, SHG44, LN229 and T98G). Following MORC2 silencing, cell proliferation was evaluated using the Cell Counting Kit‑8 assay and the expression of proliferation‑related proteins was assessed via immunofluorescence staining or western blotting. Cell invasion and migration were assessed using transwell and wound healing assays, respectively. Western blotting and immunofluorescence staining were employed to determine the expression of epithelial‑mesenchymal transition (EMT)‑associated proteins. The protein expression of N‑myc downstream regulated gene 1 (NDRG1) and PTEN/PI3K/AKT signaling was determined with western blot analysis. Then, the luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to evaluate the binding between MORC2 and NDRG1 promoter. Subsequently, cellular functional experiments were performed to assess the effects of NDRG1 on the progression of glioma after NDRG1 and MORC2 overexpression. In addition, tumor‑bearing experiments were conducted using a U251 tumor‑bearing nude mice model to detect tumor growth. The expression of proliferation (proliferating cell nuclear antigen, cyclin‑dependent kinase 2 and cyclin E1), migration [matrix metalloproteinase (MMP)2 and MMP9], EMT (E‑cadherin, N‑cadherin and Vimentin) and PTEN/PI3K/AKT signaling proteins in tumor tissues was examined with immunohistochemistry assay or western blotting. Results revealed that MORC2 was notably unregulated in glioma cells compared with the normal human astrocyte. Loss‑function of MORC2 inhibited the proliferation, invasion, migration and EMT of glioma cells. Importantly, MORC2 silencing upregulated NDRG1 expression and inactivated PTEN/PI3K/AKT signaling. Additionally, the luciferase reporter‑ and ChIP assays confirmed that MORC2 could bind to the NDRG1 promoter. NDRG1 upregulation suppressed the progression of glioma and these effects were partially reversed by MORC2 overexpression. Results of tumor‑bearing experiments suggested that gain‑function of NDRG1 inhibited tumor growth and downregulated the expression of proliferation, migration and EMT‑related proteins in tumorous tissue in U251 tumor‑bearing mice, which was partially counteracted after MORC2 overexpression. In addition, MORC2 overexpression abrogated the inhibitory effect of NDRG1 on PTEN/PI3K/AKT signaling. In summary, MORC2 promoted the progression of glioma by inactivation of PTEN/PI3K/AKT signaling via binding to NDRG1 promoter, providing a novel and potent target for the treatment of glioma.
Collapse
Affiliation(s)
- Jing Zhang
- Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Yunna Yang
- Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Yipeng Dong
- Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Cang Liu
- Department of Neurosurgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| |
Collapse
|
|
23
|
The Roles of the Colon Cancer Associated Transcript 2 (CCAT2) Long Non-Coding RNA in Cancer: A Comprehensive Characterization of the Tumorigenic and Molecular Functions. Int J Mol Sci 2021; 22:ijms222212491. [PMID: 34830370 PMCID: PMC8620102 DOI: 10.3390/ijms222212491] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/17/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Colon cancer-associated transcript 2 (CCAT2) is an intensively studied lncRNA with important regulatory roles in cancer. As such, cumulative studies indicate that CCAT2 displays a high functional versatility due to its direct interaction with multiple RNA binding proteins, transcription factors, and other species of non-coding RNA, especially microRNA. The definitory mechanisms of CCAT2 are its role as a regulator of the TCF7L2 transcription factor, enhancer of MYC expression, and activator of the WNT/β-catenin pathway, as well as a role in promoting and maintaining chromosome instability through the BOP1–AURKB pathway. Additionally, we highlight how the encompassing rs6983267 SNP has been shown to confer CCAT2 with allele-specific functional and structural particularities, such as the allelic-specific reprogramming of glutamine metabolism. Additionally, we emphasize CCAT2’s role as a competitive endogenous RNA (ceRNA) for multiple tumor suppressor miRNAs, such as miR-4496, miR-493, miR-424, miR-216b, miR-23b, miR-34a, miR-145, miR-200b, and miR-143 and the pro-tumorigenic role of the altered regulatory axis. Additionally, due to its upregulation in tumor tissues, wide distribution across cancer types, and presence in serum samples, we outline CCAT2’s potential as a biomarker and disease indicator and its implications for the development of resistance against current cancer therapy regiments and metastasis.
Collapse
|
|
24
|
A Cell Cycle Progression-Derived Gene Signature to Predict Prognosis and Therapeutic Response in Hepatocellular Carcinoma. DISEASE MARKERS 2021; 2021:1986159. [PMID: 34721731 PMCID: PMC8553501 DOI: 10.1155/2021/1986159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023]
Abstract
Objective Dysregulation of cell cycle progression (CCP) is one of the hallmarks of cancer. Here, our study is aimed at developing a CCP-derived gene signature for predicting high-risk population of hepatocellular carcinoma (HCC). Methods Our study retrospectively analyzed the transcriptome profiling and clinical information of HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects. Uni- and multivariate cox regression models were conducted for identifying which hallmarks of cancer were risk factors of HCC. CCP-derived gene signature was developed with LASSO method. The predictive efficacy was verified by ROC curves and subgroup analyses. A nomogram was then generated and validated by ROC, calibration, and decisive curves. Immune cell infiltration was estimated with ssGSEA method. Potential small molecular compounds were predicted via CTRP and CMap analyses. The response to chemotherapeutic agents was evaluated based on the GDSC project. Results Among hallmarks of cancer, CCP was identified as a dominant risk factor for HCC prognosis. CCP-derived gene signature displayed the favorable predictive efficacy in HCC prognosis independent of other clinicopathological parameters. A nomogram was generated for optimizing risk stratification and quantifying risk evaluation. CCP-derived signature was in relation to immune cell infiltration, HLA, and immune checkpoint expression. Combining CTRP and CMap analyses, fluvastatin was identified as a promising therapeutic agent against HCC. Furthermore, CCP-derived signature might be applied for predicting the response to doxorubicin and gemcitabine. Conclusion Collectively, CCP-derived gene signature was a promising marker in prediction of survival outcomes and therapeutic responses for HCC patients.
Collapse
|
|
25
|
Ju M, Jiang L, Wei Q, Yu L, Chen L, Wang Y, Hu B, Qian P, Zhang M, Zhou C, Li Z, Wei M, Zhao L, Han J. A Immune-Related Signature Associated with TME Can Serve as a Potential Biomarker for Survival and Sorafenib Resistance in Liver Cancer. Onco Targets Ther 2021; 14:5065-5083. [PMID: 34707365 PMCID: PMC8543032 DOI: 10.2147/ott.s326784] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/06/2021] [Indexed: 12/13/2022] Open
Abstract
Objective Although many curative treatments are being applied in the clinic, a significant number of patients with liver hepatocellular carcinoma (LIHC) suffer from drug resistance. The tumour microenvironment (TME) has been found to be closely associated with resistance, suggesting that identification of predictive biomarkers related to the TME for resistance in LIHC will be very rewarding. However, there has been no study dedicated to identifying a TME-related biomarker that has the potential to predict resistance in LIHC. Methods An integrated analysis was conducted based on data of patients with LIHC suffering from drug resistance from the TCGA database and four GEO datasets. Subsequently, we also validated the expression levels of the identified genes in paraffin-embedded LIHC samples by immunohistochemistry. Results In this study, we developed a robust and acute TME-related signature consisted of five immune-related genes (FABP6, CD4, PRF1, EREG and COLEC10) that could independently predict both the RFS and OS of LIHC patients. Moreover, the TME-related signature was significantly associated with the immune score, immune cytolytic activity (CYT), HLA, interferon (IFN) response and tumour-infiltrating lymphocytes (TILs), and it might influence tumour immunity mainly by affecting B cells, CD8+ T cells and dendritic cells. Furthermore, our analysis also indicated that the TME-related signature was correlated with the immunotherapy response and had an enormous potential to predict sorafenib resistance in LIHC. Conclusion Our findings demonstrated a TME-related signature which can independently predict both the RFS and OS of LIHC patients, highlighting the predictive potential of the signature for immunotherapy response and sorafenib resistance, potentially enabling more precise and personalized sorafenib treatment in LIHC in the future.
Collapse
Affiliation(s)
- Mingyi Ju
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Longyang Jiang
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Qian Wei
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Lifeng Yu
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Lianze Chen
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Yan Wang
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Baohui Hu
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Ping Qian
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Ming Zhang
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Chenyi Zhou
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Zinan Li
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Medical Diagnosis and Treatment Center, Shenyang, Liaoning Province, People's Republic of China
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy; China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Jiali Han
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| |
Collapse
|
|
26
|
Luo Z, Fan Y, Liu X, Liu S, Kong X, Ding Z, Li Y, Wei L. MiR-188-3p and miR-133b Suppress Cell Proliferation in Human Hepatocellular Carcinoma via Post-Transcriptional Suppression of NDRG1. Technol Cancer Res Treat 2021; 20:15330338211033074. [PMID: 34355586 PMCID: PMC8358491 DOI: 10.1177/15330338211033074] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: Previous studies reported that N-myc downstream-regulated gene 1 (NDRG1) was upregulated in various cancer tissues and decreased expression of miR-188-3p and miR-133b could suppress cell proliferation, metastasis, and invasion and induce apoptosis of cancer cells. However, the molecular mechanism of NRDG1 involved in hepatocellular carcinoma (HCC) tumorigenesis is still unknown. Methods: The expressions of miR-188-3p, miR-133b, and NRDG1 in HCC tissues and cells were quantified by qRT-PCR and Western blot. MTT assay and transwell invasion assay were performed to evaluate cell growth and cell migration, respectively. Luciferase reporter assay were performed to determine whether miR-188-3p and miR-133b could directly bind to NRDG1 in HCC cells. Results: The results showed that NRDG1 was upregulated and these 2 microRNAs were downregulated in HCC tissues. NRDG1 was negatively correlated with miR-188-3p and miR-133b in HCC tissues. MiR-188-3p and miR-133b were demonstrated to directly bind to 3′UTR of NRDG1 and inhibit its expression. Upregulation of miR-188-3p and miR-133b reduced NRDG1 expression in hepatocellular carcinoma cell lines, which consequently inhibited cell growth and cell migration. Conclusions: Our finding suggested that miR-188-3p and miR-133b exert a suppressive effect on hepatocellular carcinoma proliferation, invasion, and migration through downregulation of NDRG1.
Collapse
Affiliation(s)
- Zhenzhao Luo
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Yue Fan
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Xianchang Liu
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Shuiyi Liu
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Kong
- Department of General Surgery, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Zhonghuan Ding
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| | - Ying Li
- Physical Examination Center, 117921Renmin Hospital of Wuhan University, Wuhan, China
| | - Liqing Wei
- Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, 12403Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
27
|
Dong L, Dong J, Xiang M, Lei P, Li Z, Zhang F, Sun X, Niu D, Bai L, Lan K. NDRG1 facilitates lytic replication of Kaposi's sarcoma-associated herpesvirus by maintaining the stability of the KSHV helicase. PLoS Pathog 2021; 17:e1009645. [PMID: 34077484 PMCID: PMC8202935 DOI: 10.1371/journal.ppat.1009645] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 06/14/2021] [Accepted: 05/14/2021] [Indexed: 01/10/2023] Open
Abstract
The presumed DNA helicase encoded by ORF44 of Kaposi's sarcoma-associated herpesvirus (KSHV) plays a crucial role in unwinding viral double-stranded DNA and initiating DNA replication during lytic reactivation. However, the regulatory mechanism of KSHV ORF44 has not been fully elucidated. In a previous study, we identified that N-Myc downstream regulated gene 1 (NDRG1), a host scaffold protein, facilitates viral genome replication by interacting with proliferating cell nuclear antigen (PCNA) and the latent viral protein latency-associated nuclear antigen (LANA) during viral latency. In the present study, we further demonstrated that NDRG1 can interact with KSHV ORF44 during viral lytic replication. We also found that the mRNA and protein levels of NDRG1 were significantly increased by KSHV ORF50-encoded replication and transcription activator (RTA). Remarkably, knockdown of NDRG1 greatly decreased the protein level of ORF44 and impaired viral lytic replication. Interestingly, NDRG1 enhanced the stability of ORF44 and inhibited its ubiquitin-proteasome-mediated degradation by reducing the polyubiquitination of the lysine residues at positions 79 and 368 in ORF44. In summary, NDRG1 is a novel binding partner of ORF44 and facilitates viral lytic replication by maintaining the stability of ORF44. This study provides new insight into the mechanisms underlying KSHV lytic replication.
Collapse
Affiliation(s)
- Lianghui Dong
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jiazhen Dong
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Min Xiang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Ping Lei
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Zixian Li
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Fang Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiaoyi Sun
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Danping Niu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Lei Bai
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
- * E-mail: (LB); (KL)
| | - Ke Lan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
- * E-mail: (LB); (KL)
| |
Collapse
|
|
28
|
Intrahepatic recurrence of hepatocellular carcinoma after resection: an update. Clin J Gastroenterol 2021; 14:699-713. [PMID: 33774785 DOI: 10.1007/s12328-021-01394-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma recurrence occurs in 40-70% of patients after hepatic resection. Despite the high frequency of hepatocellular cancer relapse, there is no established guidance for the management of such cases. The evaluation of prognostic factors that indicate a high risk of recurrence after surgery such as the tumor number and size and the presence of microvascular invasion may guide the therapeutic strategy and point out which patients should be strictly monitored. Additionally, the administration of adjuvant treatment or ab initio liver transplantation in selected patients with high-risk characteristics could have a significant impact on the prevention of relapse and overall survival. Once the recurrence has occurred in the liver remnant, the available therapeutic options include re-resection, salvage liver transplantation and locoregional treatments, although the therapeutic choice is often challenging and should be based on the characteristics of the recurrent tumor, the patient profile and most importantly the timing of relapse. Aggressive combination treatments are often required in challenging cases of early relapse. The results of the above treatment strategies are reviewed and compared to determine the optimal management of patients with recurrent hepatocellular cancer following liver resection.
Collapse
|
|
29
|
Chen H, Li Y, Xiao SY, Guo J. Identification of a five-immune gene model as an independent prognostic factor in hepatocellular carcinoma. BMC Cancer 2021; 21:278. [PMID: 33726698 PMCID: PMC7962305 DOI: 10.1186/s12885-021-08012-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 03/04/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor with a poor prognosis. We aimed to identify a new prognostic model of HCC based on differentially expressed (DE) immune genes. METHODS The DE immune genes were identified based on an analysis of 374 cases of HCC and 50 adjacent non-tumor specimens from the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, Lasso regression, and multivariate Cox analysis were used to construct the model based on the training group. Survival analysis and the receiver operating characteristic (ROC) curves were used to evaluate model performance. The testing group and the entire group were subsequently used for validation of the model. RESULTS A five-immune gene model consisted of HSPA4, ISG20L2, NDRG1, EGF, and IL17D was identified. Based on the model, the overall survival was significantly different between the high-risk and low-risk groups (P = 7.953e-06). The AUCs for the model at 1- and 3-year were 0.849 and 0.74, respectively. The reliability of the model was confirmed using the validation groups. The risk score was identified as an independent prognostic parameter and closely related to the content of immune cells from human HCC specimens. CONCLUSION We identified a five-immune gene model that can be used as an independent prognostic marker for HCC.
Collapse
Affiliation(s)
- Haitao Chen
- Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
| | - Yueying Li
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
- Wuhan University Center for Pathology and Molecular Diagnostics, Wuhan, 430071 China
| | - Shu-Yuan Xiao
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
- Wuhan University Center for Pathology and Molecular Diagnostics, Wuhan, 430071 China
- Department of Pathology, University of Chicago Medicine, Chicago, IL USA
| | - Jianchun Guo
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
- Wuhan University Center for Pathology and Molecular Diagnostics, Wuhan, 430071 China
| |
Collapse
|
|
30
|
Grimes MM, Kenney SR, Dominguez DR, Brayer KJ, Guo Y, Wandinger-Ness A, Hudson LG. The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo. BMC Cancer 2021; 21:40. [PMID: 33413202 PMCID: PMC7791840 DOI: 10.1186/s12885-020-07716-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Rho-family GTPases, including Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), are important modulators of cancer-relevant cell functions and are viewed as promising therapeutic targets. Based on high-throughput screening and cheminformatics we identified the R-enantiomer of an FDA-approved drug (ketorolac) as an inhibitor of Rac1 and Cdc42. The corresponding S-enantiomer is a non-steroidal anti-inflammatory drug (NSAID) with selective activity against cyclooxygenases. We reported previously that R-ketorolac, but not the S-enantiomer, inhibited Rac1 and Cdc42-dependent downstream signaling, growth factor stimulated actin cytoskeleton rearrangements, cell adhesion, migration and invasion in ovarian cancer cell lines and patient-derived tumor cells. METHODS In this study we treated mice with R-ketorolac and measured engraftment of tumor cells to the omentum, tumor burden, and target GTPase activity. In order to gain insights into the actions of R-ketorolac, we also performed global RNA-sequencing (RNA-seq) analysis on tumor samples. RESULTS Treatment of mice with R-ketorolac decreased omental engraftment of ovarian tumor cells at 18 h post tumor cell injection and tumor burden after 2 weeks of tumor growth. R-ketorolac treatment inhibited tumor Rac1 and Cdc42 activity with little impact on mRNA or protein expression of these GTPase targets. RNA-seq analysis revealed that R-ketorolac decreased expression of genes in the HIF-1 signaling pathway. R-ketorolac treatment also reduced expression of additional genes associated with poor prognosis in ovarian cancer. CONCLUSION These findings suggest that R-ketorolac may represent a novel therapeutic approach for ovarian cancer based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor. R-ketorolac modulates relevant pathways and genes associated with disease progression and worse outcome.
Collapse
Affiliation(s)
- Martha M. Grimes
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico USA
| | - S. Ray Kenney
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico USA
- Division of Molecular Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico USA
| | - Dayna R. Dominguez
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico USA
| | - Kathryn J. Brayer
- Analytical and Translational Genomics Shared Resource, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico USA
- Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico USA
| | - Yuna Guo
- Department of Pathology, School of Medicine, University of New Mexico, Albuquerque, New Mexico USA
| | - Angela Wandinger-Ness
- Department of Pathology, School of Medicine, University of New Mexico, Albuquerque, New Mexico USA
| | - Laurie G. Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico USA
| |
Collapse
|
|
31
|
Guenzle J, Akasaka H, Joechle K, Reichardt W, Venkatasamy A, Hoeppner J, Hellerbrand C, Fichtner-Feigl S, Lang SA. Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma. Int J Mol Sci 2020; 22:ijms22010030. [PMID: 33375117 PMCID: PMC7792954 DOI: 10.3390/ijms22010030] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/16/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.
Collapse
Affiliation(s)
- Jessica Guenzle
- Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; (J.G.); (H.A.); (K.J.); (J.H.); (S.F.-F.)
| | - Harue Akasaka
- Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; (J.G.); (H.A.); (K.J.); (J.H.); (S.F.-F.)
| | - Katharina Joechle
- Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; (J.G.); (H.A.); (K.J.); (J.H.); (S.F.-F.)
| | - Wilfried Reichardt
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany;
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Radiology Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Killianstrasse 5a, 79106 Freiburg, Germany;
| | - Aina Venkatasamy
- Department of Radiology Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Killianstrasse 5a, 79106 Freiburg, Germany;
- Service de Radiologie 1, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, 67098 Strasbourg, France
- Laboratory Stress Response and Innovative Therapies “Streinth”, Inserm IRFAC UMR_S1113, Université de Strasbourg, 67098 Strasbourg, France
| | - Jens Hoeppner
- Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; (J.G.); (H.A.); (K.J.); (J.H.); (S.F.-F.)
| | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich–Alexander University Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany;
| | - Stefan Fichtner-Feigl
- Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; (J.G.); (H.A.); (K.J.); (J.H.); (S.F.-F.)
- Comprehensive Cancer Center Freiburg-CCCF, Medical Center-University of Freiburg, 79106 Freiburg, Germany
| | - Sven A. Lang
- Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany; (J.G.); (H.A.); (K.J.); (J.H.); (S.F.-F.)
- Department of Surgery and Transplantation, University Hospital RWTH, 52074 Aachen, Germany
- Correspondence:
| |
Collapse
|
|
32
|
Lin Y, Wang L, Luo W, Zhou X, Chen Y, Yang K, Liao J, Wu D, Cai L. CYLD Promotes Apoptosis of Nasopharyngeal Carcinoma Cells by Regulating NDRG1. Cancer Manag Res 2020; 12:10639-10649. [PMID: 33149672 PMCID: PMC7604974 DOI: 10.2147/cmar.s268216] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/02/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose Nasopharyngeal carcinoma (NPC) is among the most common malignancies derived from the epithelium of the nasopharynx. To date, the regulatory networks involved in NPC have not been fully identified. Previous studies revealed multiple loss-of-function mutations in NPC and specifically in cylindromatosis lysine 63 deubiquitinase (CYLD); however, the exact role of CYLD in NPC progression and its potential mechanism remains unclear. Methods We performed immunohistochemical (IHC) staining and real-time quantitative polymerase chain reaction (qPCR) to measure CYLD expression in NPC tissues, and Western blot was conducted to determine CYLD levels in NPC cell lines. Cell proliferation was detected by CCK8 assay and colony formation analysis, and apoptosis was determined by Annexin V/propidium iodide staining. Potential targets of CYLD were verified by co-immunoprecipitation and mass spectrometry. Xenograft assay was conducted to confirm the role of CYLD in vivo. Results We found that CYLD levels were significantly decreased in both NPC tissues and cell lines, and that CYLD overexpression inhibited NPC cell proliferation and promoted apoptosis. Additionally, we revealed that CYLD bound and upregulated N-Myc downstream regulated 1 (NDRG1), and that silencing NDRG1 abolished the tumor-suppressor effect of CYLD on NPC cells. Furthermore, CYLD suppressed tumor growth in xenograft mice models. Conclusion These results suggest CYLD as a tumor suppressor, potential biomarker for diagnosing NPC, and therapeutic target.
Collapse
Affiliation(s)
- Yanling Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Lingzhi Wang
- First Clinical Medical College, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Wenxiao Luo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiaohan Zhou
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuting Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Kaifan Yang
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jinrong Liao
- Second Clinical Medical College, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Dehua Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Longmei Cai
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| |
Collapse
|
|
33
|
Dai Y, Qiang W, Lin K, Gui Y, Lan X, Wang D. An immune-related gene signature for predicting survival and immunotherapy efficacy in hepatocellular carcinoma. Cancer Immunol Immunother 2020; 70:967-979. [PMID: 33089373 DOI: 10.1007/s00262-020-02743-0] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/12/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks the fourth in terms of cancer-related mortality globally. Herein, in this research, we attempted to develop a novel immune-related gene signature that could predict survival and efficacy of immunotherapy for HCC patients. METHODS The transcriptomic and clinical data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) and GSE14520 datasets, followed by acquiring immune-related genes from the ImmPort database. Afterwards, an immune-related gene-based prognostic index (IRGPI) was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. Kaplan-Meier survival curves as well as time-dependent receiver operating characteristic (ROC) curve were performed to evaluate its predictive capability. Besides, both univariate and multivariate analyses on overall survival for the IRGPI and multiple clinicopathologic factors were carried out, followed by the construction of a nomogram. Finally, we explored the possible correlation of IRGPI with immune cell infiltration or immunotherapy efficacy. RESULTS Analysis of 365 HCC samples identified 11 differentially expressed immune-related genes, which were selected to establish the IRGPI. Notably, it can predict the survival of HCC patients more accurately than published biomarkers. Furthermore, IRGPI can predict the infiltration of immune cells in the tumor microenvironment of HCC, as well as the response of immunotherapy. CONCLUSION Collectively, the currently established IRGPI can accurately predict survival, reflect the immune microenvironment, and predict the efficacy of immunotherapy among HCC patients.
Collapse
Affiliation(s)
- Yifei Dai
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Weijie Qiang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China
| | - Kequan Lin
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yu Gui
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xun Lan
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China.
| | - Dong Wang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| |
Collapse
|
|
34
|
Park KC, Paluncic J, Kovacevic Z, Richardson DR. Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer. Free Radic Biol Med 2020; 157:154-175. [PMID: 31132412 DOI: 10.1016/j.freeradbiomed.2019.05.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/24/2019] [Accepted: 05/16/2019] [Indexed: 12/18/2022]
Abstract
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO.), and various stress stimuli. This intriguing molecule exhibits diverse functions in cancer, inhibiting epithelial-mesenchymal transition (EMT), cell migration and angiogenesis by modulation of a plethora of oncogenes via cellular signaling. Thus, pharmacological targeting of NDRG1 signaling in cancer is a promising therapeutic strategy. Of note, novel anti-tumor agents of the di-2-pyridylketone thiosemicarbazone series, which exert the "double punch" mechanism by binding metal ions to form redox-active complexes, have been demonstrated to markedly up-regulate NDRG1 expression in cancer cells. This review describes the mechanisms underlying NDRG1 modulation by the thiosemicarbazones and the diverse effects NDRG1 exerts in cancer. As a major induction mechanism, iron depletion appears critical, with NO. also inducing NDRG1 through its ability to bind iron and generate dinitrosyl-dithiol iron complexes, which are then effluxed from cells. Apart from its potent anti-metastatic role, several studies have reported a pro-oncogenic role of NDRG1 in a number of cancer-types. Hence, it has been suggested that NDRG1 plays pleiotropic roles depending on the cancer-type. The molecular mechanism(s) underlying NDRG1 pleiotropy remain elusive, but are linked to differential regulation of WNT signaling and potentially differential interaction with the tumor suppressor, PTEN. This review discusses NDRG1 induction mechanisms by metal ions and NO. and both the anti- and possible pro-oncogenic functions of NDRG1 in multiple cancer-types and compares the opposite effects this protein exerts on cancer progression.
Collapse
Affiliation(s)
- Kyung Chan Park
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Jasmina Paluncic
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia.
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia.
| |
Collapse
|
|
35
|
Zolfaghari Emameh R, Nosrati H, Eftekhari M, Falak R, Khoshmirsafa M. Expansion of Single Cell Transcriptomics Data of SARS-CoV Infection in Human Bronchial Epithelial Cells to COVID-19. Biol Proced Online 2020; 22:16. [PMID: 32754004 PMCID: PMC7377208 DOI: 10.1186/s12575-020-00127-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/21/2020] [Indexed: 02/07/2023] Open
Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19) that was emerged as a new member of coronaviruses since December 2019 in Wuhan, China and then after was spread in all continentals. Since SARS-CoV-2 has shown about 77.5% similarity to SARS-CoV, the transcriptome and immunological regulations of SARS-CoV-2 was expected to have high percentage of overlap with SARS-CoV. Results In this study, we applied the single cell transcriptomics data of human bronchial epithelial cells (2B4 cell line) infected with SARS-CoV, which was annotated in the Expression Atlas database to expand this data to COVID-19. In addition, we employed system biology methods including gene ontology (GO) and Reactome pathway analyses to define functional genes and pathways in the infected cells with SARS-CoV. The transcriptomics analysis on the Expression Atlas database revealed that most genes from infected 2B4 cell line with SARS-CoV were downregulated leading to immune system hyperactivation, induction of signaling pathways, and consequently a cytokine storm. In addition, GO:0016192 (vesicle-mediated transport), GO:0006886 (intracellular protein transport), and GO:0006888 (ER to Golgi vesicle-mediated transport) were shown as top three GOs in the ontology network of infected cells with SARS-CoV. Meanwhile, R-HAS-6807070 (phosphatase and tensin homolog or PTEN regulation) showed the highest association with other Reactome pathways in the network of infected cells with SARS-CoV. PTEN plays a critical role in the activation of dendritic cells, B- and T-cells, and secretion of proinflammatory cytokines, which cooperates with downregulated genes in the promotion of cytokine storm in the COVID-19 patients. Conclusions Based on the high similarity percentage of the transcriptome of SARS-CoV with SARS-CoV-2, the data of immunological regulations, signaling pathways, and proinflammatory cytokines in SARS-CoV infection can be expanded to COVID-19 to have a valid platform for future pharmaceutical and vaccine studies.
Collapse
Affiliation(s)
- Reza Zolfaghari Emameh
- Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), 14965/161, Tehran, Iran
| | - Hassan Nosrati
- Department of Materials Engineering, Tarbiat Modares University, Tehran, Iran
| | - Mahyar Eftekhari
- Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), 14965/161, Tehran, Iran
| | - Reza Falak
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Immunology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Khoshmirsafa
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.,Immunology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
36
|
Dang H, Chen L, Tang P, Cai X, Zhang W, Zhang R, Huang A, Tang H. LINC01419 promotes cell proliferation and metastasis in hepatocellular carcinoma by enhancing NDRG1 promoter activity. Cell Oncol (Dordr) 2020; 43:931-947. [PMID: 32557341 DOI: 10.1007/s13402-020-00540-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2020] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Emerging evidence indicates that dysfunction of long non-coding RNAs (lncRNAs) plays an essential role in the initiation and progression of hepatocellular carcinoma (HCC). In this study we investigated the potential roles and molecular mechanisms involving LINC01419 in HCC. METHODS The expression of LINC01419 in 40 pairs of HCC/normal tissues and 6 HCC cell lines was detected by qRT-PCR. MTS, EdU, colony formation, scratch wound-healing and transwell assays were performed to assess the role of LINC01419 in HCC cell (SMMC7721 and SK-Hep1) proliferation, migration and invasion in vitro. Artificial modulation of LINC01419 (up- and downregulation) was performed to explore the role of LINC01419 in tumor growth and metastasis in vivo. Interaction of LINC01419 with NDRG1 was assessed using qRT-PCR, RNA sequencing, Western blotting and immunohistochemistry. Physical interaction of LINC01419 with the NDRG1 promoter was assessed using a dual-luciferase reporter assay. RESULTS We observed LINC01419 overexpression in primary HCC tissues and HCC cell lines and that this overexpression positively correlated with large tumor size, increased vascular invasion and advanced TNM stage in 40 HCC patients. Exogenous LINC01419 expression significantly promoted HCC cell proliferation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, we found that LINC01419 expression knockdown elicited opposite effects. Mechanistic investigations revealed that LINC01419 exerted its biological effects by regulating NDRG1. A dual-luciferase reporter assay revealed that LINC01419 interacts with a specific region within the NDRG1 promoter, resulting in its activation. CONCLUSIONS From our data we conclude that LINC01419 acts clinically, functionally and mechanistically oncogenic in HCC. LINC01419 may, therefore, serve as a promising prognostic indicator and therapeutic target for HCC.
Collapse
Affiliation(s)
- Hao Dang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China.,Department of Clinical Laboratory, The Third Hospital of Mianyang (Sichuan mental health center), Mianyang, Sichuan, China
| | - Ling Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Ping Tang
- Department of Head and Neck Surgery, The Third Hospital of Mianyang (Sichuan mental health center), Mianyang, Sichuan, China
| | - Xuefei Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Wenlu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Renfei Zhang
- Department of Clinical Laboratory, The Third Hospital of Mianyang (Sichuan mental health center), Mianyang, Sichuan, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China
| | - Hua Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Yi Xue Yuan Road, Chongqing, 400016, China.
| |
Collapse
|
|
37
|
Emma MR, Augello G, Cusimano A, Azzolina A, Montalto G, McCubrey JA, Cervello M. GSK-3 in liver diseases: Friend or foe? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118743. [PMID: 32417256 DOI: 10.1016/j.bbamcr.2020.118743] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/09/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023]
Abstract
Liver diseases, including hepatitis due to hepatitis B or C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma pose major challenges for overall health due to limited curative treatment options. Thus, there is an urgent need to develop new therapeutic strategies for the treatment of these diseases. A better understanding of the signaling pathways involved in the pathogenesis of liver diseases can help to improve the efficacy of emerging therapies, mainly based on pharmacological approaches, which influence one or more specific molecules involved in key signal transduction pathways. These emerging therapies are very promising for the prevention and treatment of liver diseases. One promising druggable molecular target is the multifunctional serine/threonine kinase, glycogen synthase kinase 3 (GSK-3). In this review, we discuss conditions in which GSK-3 is implicated in liver diseases. In addition, we explore newly emerging drugs that target GSK-3β, as well as their potential use in and impact on the management of liver diseases.
Collapse
Affiliation(s)
- Maria R Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonina Azzolina
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy; Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy.
| |
Collapse
|
|
38
|
Qian Z, Hu W, Lv Z, Liu H, Chen D, Wang Y, Wu J, Zheng S. PKM2 upregulation promotes malignancy and indicates poor prognosis for intrahepatic cholangiocarcinoma. Clin Res Hepatol Gastroenterol 2020; 44:162-173. [PMID: 31303531 DOI: 10.1016/j.clinre.2019.06.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 05/19/2019] [Accepted: 06/07/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Although pyruvate kinase M2 (PKM2) has been shown to be among the crucial enzymes that regulate aerobic glycolysis in multiple tumour cells, its role in the treatment and prognosis of intrahepatic cholangiocarcinoma (ICC) remains unclear. This study primarily aimed to determine whether the expression status of PKM2 is potentially associated with the clinical outcomes of ICC. METHODS PKM2 expression was evaluated in ICC cell lines and tissues via real-time quantitative reverse-transcription polymerase chain reaction, immunofluorescence assays, and Western blot, and its prognostic value was determined according to its impact on the overall survival of patients. RESULTS We found that PKM2 is highly expressed in ICC, and this was correlated with patient survival. Moreover, we found that PKM2 knockdown could considerably inhibit ICC cell proliferation, invasion, and migration in vitro. CONCLUSIONS PKM2 was overexpressed in ICC, and it may regulate proliferation, invasion, and migration and lead to poor prognosis. Thus, PKM2 might be a potential independent prognostic factor for ICC.
Collapse
Affiliation(s)
- Ze Qian
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Wendi Hu
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Zhen Lv
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Hua Liu
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Diyu Chen
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China
| | - Yacong Wang
- Department of Gerontology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Wu
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
| | - Shusen Zheng
- Division of Hepatobiliary, Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
| |
Collapse
|
|
39
|
Wang Z, Zhu J, Liu Y, Liu C, Wang W, Chen F, Ma L. Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma. J Transl Med 2020; 18:67. [PMID: 32046766 PMCID: PMC7011553 DOI: 10.1186/s12967-020-02255-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background Growing evidence has suggested that immune-related genes play crucial roles in the development and progression of hepatocellular carcinoma (HCC). Nevertheless, the utility of immune-related genes for evaluating the prognosis of HCC patients are still lacking. The study aimed to explore gene signatures and prognostic values of immune-related genes in HCC. Methods We comprehensively integrated gene expression data acquired from 374 HCC and 50 normal tissues in The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) analysis and univariate Cox regression analysis were performed to identify DEGs that related to overall survival. An immune prognostic model was constructed using the Lasso and multivariate Cox regression analyses. Furthermore, Cox regression analysis was applied to identify independent prognostic factors in HCC. The correlation analysis between immune-related signature and immune cells infiltration were also investigated. Finally, the signature was validated in an external independent dataset. Results A total of 329 differentially expressed immune‐related genes were detected. 64 immune‐related genes were identified to be markedly related to overall survival in HCC patients using univariate Cox regression analysis. Then we established a TF-mediated network for exploring the regulatory mechanisms of these genes. Lasso and multivariate Cox regression analyses were applied to construct the immune-based prognostic model, which consisted of nine immune‐related genes. Further analysis indicated that this immune-related prognostic model could be an independent prognostic indicator after adjusting to other clinical factors. The relationships between the risk score model and immune cell infiltration suggested that the nine-gene signature could reflect the status of tumor immune microenvironment. The prognostic value of this nine-gene prognostic model was further successfully validated in an independent database. Conclusions Together, our study screened potential prognostic immune-related genes and established a novel immune-based prognostic model of HCC, which not only provides new potential prognostic biomarkers and therapeutic targets, but also deepens our understanding of tumor immune microenvironment status and lays a theoretical foundation for immunotherapy.
Collapse
Affiliation(s)
- Zheng Wang
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Wenhua Xi Road 107, Jinan, 250012, Shandong, China
| | - Jie Zhu
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Wenhua Xi Road 107, Jinan, 250012, Shandong, China
| | - Yongjuan Liu
- Shandong Center for Disease Control and Prevention, Health Education Institute, Jinan, 250000, Shandong, China
| | - Changhong Liu
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated With Shandong First Medical University, Jingshi Road 16766, Jinan, 250014, Shandong, China
| | - Wenqi Wang
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated With Shandong First Medical University, Jingshi Road 16766, Jinan, 250014, Shandong, China
| | - Fengzhe Chen
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Wenhua Xi Road 107, Jinan, 250012, Shandong, China.
| | - Lixian Ma
- Department of Infectious Diseases, Qilu Hospital, Shandong University, Wenhua Xi Road 107, Jinan, 250012, Shandong, China.
| |
Collapse
|
|
40
|
Zhou W, Huang K, Zhang Q, Ye S, Zhong Z, Zeng C, Peng G, Li L, Ye Q. LINC00844 promotes proliferation and migration of hepatocellular carcinoma by regulating NDRG1 expression. PeerJ 2020; 8:e8394. [PMID: 32025371 PMCID: PMC6993750 DOI: 10.7717/peerj.8394] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/13/2019] [Indexed: 12/14/2022] Open
Abstract
Background Aberrant expression of long noncoding RNAs are implicated in the pathogenesis of human malignancies. LINC00844 expression is dramatically downregulated in prostate cancer, and functional studies have revealed the association between the aberrant expression of LINC00844 and prostate cancer cell invasion and metastasis. However, the function and mechanism of action of LINC00844 in the pathogenesis of hepatocellular carcinoma (HCC) are poorly understood. Methods LINC00844 and N-Myc downstream-regulated 1 (NDRG1) expression in HCC tissues and cell lines was detected with real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Correlations between LINC00844 expression level and clinicopathological features were investigated using the original data from The Cancer Genome Atlas (TCGA) database. HepG2 and HCCLM9 cell lines were transfected with Lv-LIN00844 virus to obtain LINC00844-overexpressing cell lines. Cell proliferation and cell invasion and migration were examined with the cell counting kit-8 (CCK-8) and transwell assay, respectively. Furthermore, the correlation between LINC00844 and NDRG1 expression was analysed using Pearson’s correlation analysis. Results LINC00844 expression was significantly downregulatedin HCC tissues and cell lines, and a statistical correlation was detected between low LINC00844 expression and sex (Female), advanced American Joint Committee on Cancer (AJCC) stage (III + IV), histological grade (G3 + G4), and vascular invasion (Micro and Macro). In vitro experiments showed that LINC00844 overexpression significantly repressed the proliferation, migration, and invasion of HCC cells. NDRG1 expression was higher in HCC tissues and LINC00844 could partly inhibit the expression of NDRG1.
Collapse
Affiliation(s)
- Wei Zhou
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Kang Huang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Qiuyan Zhang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Shaojun Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Zibiao Zhong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Cheng Zeng
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Guizhu Peng
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Ling Li
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China.,The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
| |
Collapse
|
|
41
|
Zhang S, Yu C, Yang X, Hong H, Lu J, Hu W, Hao X, Li S, Aikemu B, Yang G, He Z, Zhang L, Xue P, Cai Z, Ma J, Zang L, Feng B, Yuan F, Sun J, Zheng M. N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:490. [PMID: 31831018 PMCID: PMC6909641 DOI: 10.1186/s13046-019-1476-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/11/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND N-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure. METHODS Immunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay. RESULTS NDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation. CONCLUSION Our study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.
Collapse
Affiliation(s)
- Sen Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaoran Yu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hiju Hong
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaoyang Lu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenjun Hu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohui Hao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuchun Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Batuer Aikemu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zirui He
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Luyang Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pei Xue
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenghao Cai
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junjun Ma
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Zang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Feng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
42
|
Zeng L, Deng X, Zhong J, Yuan L, Tao X, Zhang S, Zeng Y, He G, Tan P, Tao Y. Prognostic value of biomarkers EpCAM and αB-crystallin associated with lymphatic metastasis in breast cancer by iTRAQ analysis. BMC Cancer 2019; 19:831. [PMID: 31443698 PMCID: PMC6708189 DOI: 10.1186/s12885-019-6016-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 08/05/2019] [Indexed: 02/08/2023] Open
Abstract
Background Metastasis is responsible for the majority of deaths in a variety of cancer types, including breast cancer. Although several factors or biomarkers have been identified to predict the outcome of patients with breast cancer, few studies have been conducted to identify metastasis-associated biomarkers. Methods Quantitative iTRAQ proteomics analysis was used to detect differentially expressed proteins between lymph node metastases and their paired primary tumor tissues from 23 patients with metastatic breast cancer. Immunohistochemistry was performed to validate the expression of two upregulated (EpCAM, FADD) and two downregulated (NDRG1, αB-crystallin) proteins in 190 paraffin-embedded tissue samples. These four proteins were further analyzed for their correlation with clinicopathological features in 190 breast cancer patients. Results We identified 637 differentially regulated proteins (397 upregulated and 240 downregulated) in lymph node metastases compared with their paired primary tumor tissues. Data are available via ProteomeXchange with identifier PXD013931. Furthermore, bioinformatics analysis using GEO profiling confirmed the difference in the expression of EpCAM between metastases and primary tumors tissues. Two upregulated (EpCAM, FADD) and two downregulated (NDRG1, αB-crystallin) proteins were associated with the progression of breast cancer. Obviously, EpCAM plays a role in the metastasis of breast cancer cells to the lymph node. We further identified αB-crystallin as an independent biomarker to predict lymph node metastasis and the outcome of breast cancer patients. Conclusion We have identified that EpCAM plays a role in the metastasis of breast cancer cells to the lymph node. αB-crystallin, a stress-related protein that has recently been shown to be important for cell invasion and survival, was identified as a potential prognostic biomarker to predict the outcome of breast cancer patients. Electronic supplementary material The online version of this article (10.1186/s12885-019-6016-3) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Liang Zeng
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiyun Deng
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China.
| | - Jingmin Zhong
- Department of Pathology, Union Hospital, Tongji Medical College, HuaZhong University of Science and Technology, WuHan, China
| | - Li Yuan
- Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiaojun Tao
- Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, Hunan, China
| | - Sai Zhang
- Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yong Zeng
- College of Life Science, Hunan Normal University, Changsha, Hunan, China
| | - Guangchun He
- Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China
| | - Pingping Tan
- Department of Pathology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, Cancer Research Institute, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| |
Collapse
|
|
43
|
Dong X, Hong Y, Sun H, Chen C, Zhao X, Sun B. NDRG1 suppresses vasculogenic mimicry and tumor aggressiveness in gastric carcinoma. Oncol Lett 2019; 18:3003-3016. [PMID: 31452779 PMCID: PMC6704281 DOI: 10.3892/ol.2019.10642] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 06/24/2019] [Indexed: 01/28/2023] Open
Abstract
N-myc downstream regulated gene 1 (NDRG1) has been well characterized as a suppressor of metastasis in numerous types of carcinoma. NDRG1 inhibits the metastatic progression of cancer cells via its inhibitory effects on a wide variety of cellular signaling pathways. Vasculogenic mimicry (VM) refers to the unique ability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks, and is the main reason for the poor prognosis and failure of antivascular therapy in gastric carcinoma (GC). Tumor cells can mimic the function of endothelial cells to exhibit VM through epithelial-mesenchymal transition (EMT). However, the potential function of NDRG1 in metastatic GC progression in patients has not yet been fully elucidated. To date, data regarding the function of NDRG1 in VM formation in GC have not been reported. The aim of the present study was to elucidate these unknown areas. To this end, 228 samples of human GC were used to identify the protein expression levels of NDRG1, VM-associated proteins and EMT-associated proteins via immunohistochemistry, and their clinical significance was assessed. In addition, the data of 415 patients with GC were collected from The Cancer Genome Atlas database. A functional enrichment analysis concerning NDRG1 was performed using Metascape and the Gene Set Enrichment Analysis (GSEA). In conclusion, the results of the present study indicate that NDRG1 is negatively correlated with poor prognosis through suppression of VM formation in GC. The results of the present study demonstrated that NDRG1 decreases EMT-associated protein expression and that HER2 expression may serve a significant role in this process. The Metascape and GSEA results also indirectly support this conclusion. The present study discusses the status NDRG1 as a prognostic and selective biomarker in GC, as well as current and future NDRG1-targeted therapies.
Collapse
Affiliation(s)
- Xueyi Dong
- Department of Pathology, Tianjin Medical University, Tianjin 300070, P.R. China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Yuheng Hong
- School of Medical Imaging, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Huizhi Sun
- Department of Pathology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Chen Chen
- Department of Pathology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin 300070, P.R. China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Baocun Sun
- Department of Pathology, Tianjin Medical University, Tianjin 300070, P.R. China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China.,Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| |
Collapse
|
|
44
|
Yu C, Hao X, Zhang S, Hu W, Li J, Sun J, Zheng M. Characterization of the prognostic values of the NDRG family in gastric cancer. Therap Adv Gastroenterol 2019; 12:1756284819858507. [PMID: 31384305 PMCID: PMC6647212 DOI: 10.1177/1756284819858507] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 05/07/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The N-myc downstream-regulated gene (NDRG) family, NDRG1-4, has been involved in a wide spectrum of biological functions in multiple cancers. However, their prognostic values remain sparse in gastric cancer (GC). Therefore, it is crucial to systematically investigate the prognostic values of the NDRG family in GC. METHODS The prognostic values of the NDRG family were evaluated by Kaplan-Meier Plotter and SurvExpress. The mRNA of the NDRG family was investigated in The Cancer Genome Atlas (TCGA). Transcription factors (TFs) and miRNAs associated with the NDRG family were predicted by NetworkAnalysis. The prognostic values of DNA methylation levels were analyzed by MethSurv. The correlation between immune cells and the NDRG family was evaluated by the Tumor Immune Estimation Resource (TIMER) database. RESULTS High levels of mRNA expression of NDRG2 and NDRG3 were associated with a favorable prognosis in all GCs. In HER2 - GC, NDRG1 was significantly associated with a poor prognosis of GC [hazard ratio (HR) = 1.65, 95% confidence interval (CI) = 1.16-2.33, p = 0.0046]. In HER2 + GC, NDRG4 showed a poor prognosis (HR = 1.4, 95% CI: 1.06-1.85, p = 0.017). NDRG4 was an independent prognostic factor in recurrence-free survival by TCGA cohort. The low-risk NDRG-signature group displayed a significantly favorable survival outcome than the high-risk group (HR = 1.76, 95% CI: 1.2-2.59, p = 0.00385). The phosphorylated protein NDRG1 (NDRG1_pT346) displayed a favorable overall survival and was significantly associated with HER2 and phosphorylated HER2. Epidermis development was the top biological process (BP) for coexpressed genes associated with NDRG1 and NDRG4, while mitotic nuclear division and mitotic cell processes were the top BPs for NDRG2 and NDRG3, respectively. Overall, 6 CpGs of NDRG1, 4 CpGs of NDRG2, 3 CpGs of NDRG3 and 24 CpGs of NDRG4 were associated with significant prognosis. CD4+ T-cells showed the highest correlation with NDRG4 (correlation = 0.341, p = 2.14e-11). Furthermore, BCL6 in follicular helper T-cells (Tfh) cells showed the highest association with NDRG4 (correlation = 0.438, p = 00e+00). CONCLUSIONS This study analyzed the multilevel prognostic values and biological roles of the NDRG family in GC.
Collapse
Affiliation(s)
- Chaoran Yu
- Department of Gastrointestinal Surgery, Ruijin
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai,
China
- Shanghai Minimally Invasive Surgery Center,
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai, China
| | - Xiaohui Hao
- Department of Gastrointestinal Surgery, Ruijin
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai,
China
- Shanghai Minimally Invasive Surgery Center,
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai, China
| | - Sen Zhang
- Department of Gastrointestinal Surgery, Ruijin
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai,
China
- Shanghai Minimally Invasive Surgery Center,
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai, China
| | - Wenjun Hu
- Department of Gastrointestinal Surgery, Ruijin
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai,
China
- Shanghai Minimally Invasive Surgery Center,
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai, China
| | - Jianwen Li
- Department of Gastrointestinal Surgery, Ruijin
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai,
China
- Shanghai Minimally Invasive Surgery Center,
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai, China
| | - Jing Sun
- Department of Gastrointestinal Surgery, Ruijin
Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai,
China
- Shanghai Minimally Invasive Surgery Center,
Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai, China
| | | |
Collapse
|
|
45
|
Weng X, Wu J, Lv Z, Peng C, Chen J, Zhang C, He B, Tong R, Hu W, Ding C, Cao L, Chen D, Wu J, Zheng S. Targeting Mybbp1a suppresses HCC progression via inhibiting IGF1/AKT pathway by CpG islands hypo-methylation dependent promotion of IGFBP5. EBioMedicine 2019; 44:225-236. [PMID: 31109829 PMCID: PMC6606930 DOI: 10.1016/j.ebiom.2019.05.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/10/2019] [Accepted: 05/10/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Myb-binding protein 1A (Mybbp1a) is a nucleolar protein that can regulate rRNA metabolism, the stress response and carcinogenesis. However, the function of Mybbp1a in the progression of hepatocellular carcinoma (HCC) is unclear. We aimed to determine the role of Mybbp1a in HCC and the underlying mechanism. METHODS We investigated the function of Mybbp1a in HCC cell models and the xenograft mouse model. The relationship between Mybbp1a and IGFBP5 was found through expression profile chip. The molecular mechanism of Mybbp1a regulating IGFBP5 was proved through CO-IP, CHIP, Bisulfite Sequencing and Pyrosequencing. FINDINGS In this study, we observed that Mybbp1a was overexpressed in HCC tissues and associated with the poor prognosis of HCC patients. Suppression of Mybbp1a led to a reduction in the proliferation and migration ability of HCC cells through inhibiting the IGF1/AKT signaling pathway. Further study found that Mybbp1a could form a complex with DNMT1 and induce aberrant hyper-methylation of CpG islands of IGFBP5, which inhibits secretion of IGFBP5 and then activates IGF1/AKT signaling pathway. INTERPRETATION These findings extend our understanding of the function of Mybbp1a in the progression of HCC. The newly identified Mybbp1a may provide a novel biomarker for developing potential therapeutic targets of HCC. FUND: Science Technology Department of Zhejiang Province (No. 2015C03034), National Health and Family Planning Commission of China (No. 2016138643), Innovative Research Groups of National Natural Science Foundation of China (No. 81721091), Major program of National Natural Science Foundation of China (No. 91542205).
Collapse
Affiliation(s)
- Xiaoyu Weng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Jingbang Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Zhen Lv
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chuanhui Peng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Junru Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Cheng Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Bin He
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Rongliang Tong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Wendi Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Chaofeng Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Linping Cao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Diyu Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
- The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
- The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China
| |
Collapse
|
|
46
|
Upregulation of NDRG1 predicts poor outcome and facilitates disease progression by influencing the EMT process in bladder cancer. Sci Rep 2019; 9:5166. [PMID: 30914736 PMCID: PMC6435802 DOI: 10.1038/s41598-019-41660-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 03/14/2019] [Indexed: 12/12/2022] Open
Abstract
N-myc downstream regulated gene 1 (NDRG1) is an intracellular protein involved in cell differentiation and was recently reported to exert various effects in several cancers. However, its expression and role in bladder cancer remain unclear. Our study enrolled 100 bladder cancer patients to detect NDRG1 expression in tumour tissues by immunohistochemistry. Correlations between NDRG1 expression and clinical factors were analysed. An NDRG1 overexpression plasmid and NDRG1 siRNAs were transfected into bladder cancer cell lines. Cell biological behaviours were assessed by CCK-8, flow cytometry, wound healing and Transwell assays. Additionally, the influence of NDRG1 on epithelial-mesenchymal transition (EMT) was investigated by western blotting and real-time PCR. NDRG1 expression in urine from bladder cancer patients was examined by ELISA. NDRG1 protein levels were significantly increased in bladder cancer patients and correlated with tumour stage (p = 0.025), lymph node metastasis (p = 0.034) and overall survival (p = 0.016). Patients with high NDRG1 expression had poorer outcomes than those with low NDRG1 expression. NDRG1 overexpression was associated with increased cell proliferation, migration, and invasion and decreased apoptotic cell numbers; NDRG1 knockdown resulted in the inverse effects. Moreover, upregulated NDRG1 expression was associated with downregulated Cytokeratin 7 and Claudin-1 expression and upregulated N-cad, β-catenin and slug expression. Downregulated NDRG1 expression was associated with the inverse effects. Urine protein levels could distinguish bladder cancer patients from healthy controls, with an area under the curve of 0.909. NDRG1 promoted EMT in bladder cancer and could be an effective diagnostic and prognostic biomarker in bladder cancer patients.
Collapse
|
|
47
|
Liu Y, Wang D, Li Y, Yan S, Dang H, Yue H, Ling J, Chen F, Zhao Y, Gou L, Tang P, Huang A, Tang H. Long noncoding RNA CCAT2 promotes hepatocellular carcinoma proliferation and metastasis through up-regulation of NDRG1. Exp Cell Res 2019; 379:19-29. [PMID: 30922920 DOI: 10.1016/j.yexcr.2019.03.029] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 03/11/2019] [Accepted: 03/22/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Emerging studies demonstrate that long noncoding RNAs (lncRNAs) play crucial roles in hepatocarcinogenesis through various mechanisms. LncRNA CCAT2 was a newly discovered lncRNA and amplified in several cancers. However, the mechanisms involved in function of CCAT2 in hepatocellular carcinoma (HCC) remain to be explored. METHODS CCAT2 expressions in HCC tissues and cell lines were measured by RT-qPCR. MTS assay, colony formation assay, wound-healing assay and transwell assay were used to explore the biological functions of CCAT2 on HCC cells proliferation and metastasis. Experiments in vivo were carried out to confirm these effects. The underlying mechanisms were analyzed by western blot and dual-luciferase reporter assay. RESULTS In this study, we found that CCAT2 were significantly elevated in HCC tissues and cell lines, and it promoted HCC cells proliferation and metastasis both in vitro and in vivo. Additionally, we identified that NDRG1 was a downstream target of CCAT2. Meanwhile, depletion of CCAT2 inhibited cellular proliferation and metastasis behaviors induced by NDRG1- overexpression. Analysis of mechanism underlying these effects revealed that CCAT2 increased the expression of NDRG1 by enhancing its promoter activity. Furthermore, the active region between CCAT2 and NDRG1 promoter was confirmed by dual-luciferase reporter assay. CONCLUSIONS All these observations demonstrate that CCAT2 acts as an oncogene by up-regulating NDRG1, which may have the potential to be used as a promising prognostic biomarker and therapeutic target for HCC.
Collapse
Affiliation(s)
- Yuyang Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Department of Clinical Laboratory, The Sixth People's Hospital of Chengdu, Chengdu, Sichuan, China.
| | - Dan Wang
- Department of Clinical Laboratory, The People's Hospital of Rongchang, Chongqing, China.
| | - Yongguo Li
- Department of Forensic Medicine, Chongqing Medical University, Chongqing, China.
| | - Shaoying Yan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Hao Dang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Huan Yue
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Jiaji Ling
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Fengjiao Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Yannan Zhao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Luxia Gou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Ping Tang
- Department of Otorhinolaryngology Head and Neck Surgery, The Third Hospital of Mianyang, SiChuan Mental Health Center, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Hua Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
48
|
Chen K, Liu XH, Wang FR, Liu HP, Huang ZP, Chen X. The prognostic value of decreased NDRG1 expression in patients with digestive system cancers: A meta-analysis. Medicine (Baltimore) 2018; 97:e12455. [PMID: 30313035 PMCID: PMC6203522 DOI: 10.1097/md.0000000000012455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers. METHODS We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included. RESULTS The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22-2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1-3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32-0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23-1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45-1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26-2.24, P = .62). CONCLUSION The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms.
Collapse
Affiliation(s)
- Kang Chen
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Xiao-Hong Liu
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Fu-Rong Wang
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
- Department of pathology, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Hai-Peng Liu
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Ze-Ping Huang
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| | - Xiao Chen
- Department of General Surgery
- Gansu Provincial Key Laboratory of Digestive System Tumors
| |
Collapse
|
|
49
|
Ocker M. Biomarkers for hepatocellular carcinoma: What's new on the horizon? World J Gastroenterol 2018; 24:3974-3979. [PMID: 30254402 PMCID: PMC6148424 DOI: 10.3748/wjg.v24.i35.3974] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 07/29/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Treatment of advanced hepatocellular carcinoma remains unsatisfying and so far only prognostic biomarkers like α-fetoprotein have been established. No clear predictive biomarker is currently available for standard of care therapies, including targeted therapies like sorafenib. Novel therapeutic options like immune checkpoint inhibitors may pose new challenges to identification and validation of such markers. Currently, PD-L1 expression via immunohistochemistry and tumor mutational burden via next-generation sequencing are explored as predictive biomarkers for these novel treatments. Limited tissue availability due to lack of biopsies still restricts the use of tissue based approaches. Novel methods exploring circulating or cell free nucleic acids (DNA, RNA or miRNA-containing exosomes) could provide a new opportunity to establish predictive biomarkers. Epigenetic profiling and next-generation sequencing approaches from liquid biopsies are under development. Sample size, etiologic and geographical background need to be carefully addressed in such studies to achieve meaningful results that could be translated into clinical practice. Proteomics, metabolomics and molecular imaging are further emerging technologies.
Collapse
Affiliation(s)
- Matthias Ocker
- Department of Translational Medicine Oncology, Bayer AG, Berlin 13353, Germany
- Charité University Medicine Berlin, Berlin 10117, Germany
| |
Collapse
|
|
50
|
Zhao K, Zhao Y, Zhu JY, Dong H, Cong WM, Yu Y, Wang H, Zhu ZZ, Xu Q. A Panel of Genes Identified as Targets for 8q24.13-24.3 Gain Contributing to Unfavorable Overall Survival in Patients with Hepatocellular Carcinoma. Curr Med Sci 2018; 38:590-596. [PMID: 30128866 DOI: 10.1007/s11596-018-1918-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/17/2018] [Indexed: 12/12/2022]
Abstract
Copy number aberrations (CNAs) in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma (HCC). This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months (range, 2.6-108.6 months). One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 (33.3%) of the 66 HCC cases. The most recurrent gains (with frequencies >20%) were 8q13.3-21.3,8q21.3-23.3,8q23.3-24.13,8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival (jP=0.010). Multivariate Cox analysis identified 8q24.13-24.3 gain as an independent prognostic factor for poor overall survival (HR=2.47; 95% CI=1.16-5.26; Р=0.019). Apanel of 17 genes within the 8q24.13-24.3 region, including ATAD2,SQLE,PVT1,ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2,SQLE, PVT1, ASAP1,and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.
Collapse
Affiliation(s)
- Kun Zhao
- Department of Oncology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072, China.,Shanghai Clinical College of Anhui Medical University, Shanghai, 200072, China
| | - Yu Zhao
- Department of Oncology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jia-Yi Zhu
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hui Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Yi Yu
- Department of Oncology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Hui Wang
- Department of Oncology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhong-Zheng Zhu
- Department of Oncology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Qing Xu
- Department of Oncology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| |
Collapse
|