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Guo K, Zhou J. Insights into eukaryotic translation initiation factor 5A: Its role and mechanisms in protein synthesis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119849. [PMID: 39303786 DOI: 10.1016/j.bbamcr.2024.119849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 08/29/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024]
Abstract
The protein synthesis within eukaryotic cells is a complex process involving various translation factors. Among these factors, eukaryotic translation initiation factor 5 A (eIF5A) emerges as a crucial translation factor with high evolutionary conservation. eIF5A is unique as it is the only protein in eukaryotic cells containing the hypusine modification. Initially presumed to be a translation initiation factor, eIF5A was subsequently discovered to act mainly during the translation elongation phase. Notably, eIF5A facilitates the translation of peptide sequences containing polyproline stretches and exerts a universal regulatory effect on the elongation and termination phases of protein synthesis. Additionally, eIF5A indirectly affects various physiological processes within the cell by modulating the translation of specific proteins. This review provides a comprehensive overview of the structure, physiological functions, various post-translational modifications of eIF5A, and its association with various human diseases. The comparison between eIF5A and its bacterial homolog, EF-P, extends the discussion to the evolutionary conservation of eIF5A. This highlights its significance across different domains of life.
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Affiliation(s)
- Keying Guo
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Jie Zhou
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
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2
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Fang J, Yu T, Jiang X, Lu Y, Shang X, Shen H, Lu Y, Zheng J, Fu P. Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis. Open Med (Wars) 2024; 19:20240962. [PMID: 38770178 PMCID: PMC11103163 DOI: 10.1515/med-2024-0962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 03/16/2024] [Accepted: 04/05/2024] [Indexed: 05/22/2024] Open
Abstract
Aims In cancer biology, the aberrant overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) has been correlative with an ominous prognosis, thereby underscoring its pivotal role in fostering metastatic progression. Consequently, EIF5A2 has garnered significant attention as a compelling prognostic biomarker for various malignancies. Our research endeavors were thus aimed at elucidating the utility and significance of EIF5A2 as a robust indicator of cancer outcome prediction. Method An exhaustive search of the PubMed, EMBASE, and Web of Science databases found relevant studies. The link between EIF5A2 and survival prognosis was examined using hazard ratios and 95% confidence intervals. Subsequently, The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases were employed to validate EIF5A2 expression across various cancer types. Results Through pooled analysis, we found that increased EIF5A2 expression was significantly associated with decreased overall survival (OS) and disease-free survival/progression-free survival/relapse-free survival (DFS/PFS/RFS). Moreover, TCGA analysis revealed that EIF5A2 was significantly upregulated in 27 types of cancer, with overexpression being linked to shorter OS in three, worse DFS in two, and worse PFS in six types of cancer. GEPIA showed that patients with EIF5A2 overexpression had reduced OS and DFS. Conclusions In solid tumors, EIF5A2 emerges as a reliable prognostic marker. Our meta-analysis comprehensively analyzed the prognostic value of EIF5A2 in solid tumors and assessed its efficacy as a predictive marker.
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Affiliation(s)
- Jianwen Fang
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Tianze Yu
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xiaocong Jiang
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yuexin Lu
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xi Shang
- Department of Breast and Thyroid Surgery, Taizhou Hospital, Zhejiang University, Taizhou, Zhejiang, 318000, China
| | - Haixing Shen
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Department of Breast and Thyroid Surgery, Cixi People’s Hospital, Cixi, Zhejiang, 315300, China
| | - Yue Lu
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang, China
| | - Jingyan Zheng
- Department of Breast and Thyroid Surgery, Lishui People’s Hospital, The Six Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China
| | - Peifen Fu
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
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Novel roles of RNA-binding proteins in drug resistance of breast cancer: from molecular biology to targeting therapeutics. Cell Death Discov 2023; 9:52. [PMID: 36759501 PMCID: PMC9911762 DOI: 10.1038/s41420-023-01352-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Therapy resistance remains a huge challenge for current breast cancer treatments. Exploring molecular mechanisms of therapy resistance might provide therapeutic targets for patients with advanced breast cancer and improve their prognosis. RNA-binding proteins (RBPs) play an important role in regulating therapy resistance. Here we summarize the functions of RBPs, highlight their tremendously important roles in regulating therapy sensitivity and resistance and we also reveal current therapeutic approaches reversing abnormal functions of RBPs in breast cancer.
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Ye S, Wang D, Jin M, Du J, Chen X, Zhang H, Zhou C, Fang S, Liu K. High eukaryotic initiation factor 5A2 expression predicts poor prognosis and may participate in the SNHG16/miR-10b-5p/EIF5A2 regulatory axis in head and neck squamous cell carcinoma. J Clin Lab Anal 2022; 37:e24820. [PMID: 36550070 PMCID: PMC9833988 DOI: 10.1002/jcla.24820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND This study attempted to investigate the significance of eukaryotic initiation factor 5A2 (EIF5A2) in the prognosis and regulatory network of head and neck squamous cell carcinoma (HNSCC). METHODS EIF5A2 expression, prognostic information, and methylation levels of HNSCC were collected from the Cancer Genome Atlas (TCGA) database. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analyses were performed to determine EIF5A2 levels in HNSCC and normal tissue samples. R software was employed for expression analysis and prognosis assessment of EIF5A2 in HNSCC. A competing endogenous RNA (ceRNA) network was generated with the starBase database. Gene set enrichment analysis (GSEA) was used to determine the enriched physiological functions and network related to high expression of EIF5A2 in HNSCC. Immune infiltration-related outcomes were acquired from the CIBERSORT and Tumor Immune Estimation Resource (TIMER) database. RESULTS EIF5A2 overexpression was observed in HNSCC and linked to poor progression-free survival and overall survival time. Cox regression analyses showed that EIF5A2 level was a stand-alone indicator of HNSCC patients' prognosis. A ceRNA network analysis highlighted the SNHG16/miR-10b-5p/EIF5A2 axis in EIF5A2 regulation. The GSEA results indicated that EIF5A2 was involved in complex signaling pathways. The CIBERSORT and TIMER databases revealed significant associations between EIF5A2 expression and immune cell infiltration. CONCLUSION EIF5A2 overexpression may be a risk factor for prognosis in HNSCC and may be regulated by the SNHG16/miR-10b-5p/EIF5A2 axis.
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Affiliation(s)
- Shuang Ye
- Department of Radiation Oncology, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Dan Wang
- Department of Medical Imaging, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Ming Jin
- Department of Radiation Oncology, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Juan Du
- Department of Radiation Oncology, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Xue Chen
- Department of Radiation Oncology, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Hui Zhang
- Department of Radiation Oncology, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Chongchang Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
| | - Shuai Fang
- Department of Thoracic SurgeryThe Affiliated Hospital of Medical School of Ningbo UniversityNingboChina
| | - Kaitai Liu
- Department of Radiation Oncology, The Affiliated Lihuili HospitalNingbo UniversityNingboChina
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Xu G, Chen H, Wu S, Chen J, Zhang S, Shao G, Sun L, Mu Y, Liu K, Pan Q, Li N, An X, Lin S, Chen W. Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance. Cell Death Dis 2022; 13:683. [PMID: 35931669 PMCID: PMC9356061 DOI: 10.1038/s41419-022-05033-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 06/16/2022] [Accepted: 06/17/2022] [Indexed: 01/21/2023]
Abstract
Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development.
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Affiliation(s)
- Guodong Xu
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Hang Chen
- grid.203507.30000 0000 8950 5267Medical School, Ningbo University, Ningbo, PR China
| | - Shibo Wu
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Jiabin Chen
- grid.417168.d0000 0004 4666 9789Department of Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
| | - Shufen Zhang
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
| | - Guofeng Shao
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Lebo Sun
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Yinyu Mu
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Kaitai Liu
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Qiaoling Pan
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Ni Li
- grid.203507.30000 0000 8950 5267Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, PR China
| | - Xiaoxia An
- grid.452661.20000 0004 1803 6319Department of Anesthesiology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang China
| | - Shuang Lin
- grid.452661.20000 0004 1803 6319Department of Thoracic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
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Shen X, Li L, He Y, Lv X, Ma J. EIF5A2 Is Involved in the Biological Process of Cervical Cancer Cells through AGR2. Pharmacology 2022; 107:376-385. [PMID: 35640539 DOI: 10.1159/000524017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/08/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Cervical cancer is a severe malignant tumor that endangers the health of women worldwide. Eukaryotic initiation factor-5A2 (EIF5A2) expression has been reported to be increased in cervical cancer and correlates with prognosis. An attempt was made in this paper to explore the impact and potential mechanisms of EIF5A2 in the cell biology of cervical cancer. METHODS We first knocked down EIF5A2 in cervical cancer cells. Then, we examined the proliferation, migration, invasion, and apoptosis of these cells by cell counting kit 8, wound healing, Transwell, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays. Cells were processed with different concentrations of cisplatin to observe their sensitivity to cisplatin. Next, the relationship between EIF5A2 and anterior gradient 2 (AGR2) was verified by co-immunoprecipitation. Following AGR2 overexpression, the biological processes of these cells were examined. RESULTS EIF5A2 knockdown inhibited cell proliferation, migration, and invasion, and it promoted apoptosis and enhanced the sensitivity to cisplatin in cervical cancer cells. Additionally, AGR2 expression was positively correlated with EIF5A2, and its overexpression alleviated the reduction in proliferation, migration, and invasion of cervical cancer cells induced by EIF5A2 knockdown. Overexpression of AGR2 also reduced apoptosis and their sensitivity to cisplatin in EIF5A2-knockdwon cervical cancer cells. CONCLUSION EIF5A2 knockdown inhibited the biological process of cervical cancer cells through modulation of AGR2. The in-depth investigation of the molecular mechanism of EIF5A2 in cervical cancer cells provides new strategies for the prevention and treatment of clinical malignancies.
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Affiliation(s)
- Xin Shen
- Department of Gastrointestinal Surgery, Xi'an Daxing Hospital, Xi'an, China
| | - Lingxia Li
- Department of Obstetrics & Gynecology, Fourth Military Medical University, Xi'an, China
| | - Yuanyuan He
- Department of Obstetrics & Gynecology, Fourth Military Medical University, Xi'an, China
| | - Xiaohui Lv
- Department of Obstetrics & Gynecology, Fourth Military Medical University, Xi'an, China
| | - Jiajia Ma
- Department of Obstetrics & Gynecology, Fourth Military Medical University, Xi'an, China
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Miglioli C, Bakalli G, Orso S, Karemera M, Molinari R, Guerrier S, Mili N. Evidence of antagonistic predictive effects of miRNAs in breast cancer cohorts through data-driven networks. Sci Rep 2022; 12:5166. [PMID: 35338170 PMCID: PMC8956684 DOI: 10.1038/s41598-022-08737-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 03/07/2022] [Indexed: 12/03/2022] Open
Abstract
Non-coding micro RNAs (miRNAs) dysregulation seems to play an important role in the pathways involved in breast cancer occurrence and progression. In different studies, opposite functions may be assigned to the same miRNA, either promoting the disease or protecting from it. Our research tackles the following issues: (i) why aren’t there any concordant findings in many research studies regarding the role of miRNAs in the progression of breast cancer? (ii) could a miRNA have either an activating effect or an inhibiting one in cancer progression according to the other miRNAs with which it interacts? For this purpose, we analyse the AHUS dataset made available on the ArrayExpress platform by Haakensen et al. The breast tissue specimens were collected over 7 years between 2003 and 2009. miRNA-expression profiling was obtained for 55 invasive carcinomas and 70 normal breast tissue samples. Our statistical analysis is based on a recently developed model and feature selection technique which, instead of selecting a single model (i.e. a unique combination of miRNAs), delivers a set of models with equivalent predictive capabilities that allows to interpret and visualize the interaction of these features. As a result, we discover a set of 112 indistinguishable models (in a predictive sense) each with 4 or 5 miRNAs. Within this set, by comparing the model coefficients, we are able to identify three classes of miRNA: (i) oncogenic miRNAs; (ii) protective miRNAs; (iii) undefined miRNAs which can play both an oncogenic and a protective role according to the network with which they interact. These results shed new light on the biological action of miRNAs in breast cancer and may contribute to explain why, in some cases, different studies attribute opposite functions to the same miRNA.
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Affiliation(s)
- Cesare Miglioli
- University of Geneva, Geneva School of Economics and Management, Geneva, 1205, Switzerland.
| | - Gaetan Bakalli
- Auburn University, Department of Mathematics and Statistics, Auburn, AL, 36849, USA
| | - Samuel Orso
- University of Geneva, Geneva School of Economics and Management, Geneva, 1205, Switzerland
| | - Mucyo Karemera
- Auburn University, Department of Mathematics and Statistics, Auburn, AL, 36849, USA
| | - Roberto Molinari
- Auburn University, Department of Mathematics and Statistics, Auburn, AL, 36849, USA
| | - Stéphane Guerrier
- University of Geneva, Geneva School of Economics and Management, Geneva, 1205, Switzerland.,University of Geneva, Faculty of Science, Geneva, 1211, Switzerland
| | - Nabil Mili
- University of Lausanne, Lausanne, 1015, Switzerland.
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Zheng Y, Li P, Huang H, Ye X, Chen W, Xu G, Zhang F. Androgen receptor regulates eIF5A2 expression and promotes prostate cancer metastasis via EMT. Cell Death Discov 2021; 7:373. [PMID: 34864817 PMCID: PMC8643356 DOI: 10.1038/s41420-021-00764-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/24/2022] Open
Abstract
Androgen receptor (AR) is an androgen-activated transcription factor of the nuclear receptor superfamily. AR plays a role in the development and progression of prostate cancer (PCa). However, the exact role of AR in PCa metastasis remains unclear. In the present study, we aimed to elucidate the function of AR in PCa. We found that eukaryotic translation initiation factor (EIF) 5A2, an elongation factor that induces epithelial-to-mesenchymal transition (EMT) in PCa cells, was significantly upregulated after 5α-dihydrotestosterone (DHT) stimulation and downregulated after anti‐androgen bicalutamide treatment in PCa cells with high AR expression, but not in cells with low AR expression. Moreover, eIF5A2 knockdown could eliminate DHT-induced invasion and migration of AR-positive PCa cells. DHT treatment decreased epithelial expression of E‐cadherin and β-catenin but increased the expression of the mesenchymal marker proteins Vimentin and N-cadherin. DHT therefore induced EMT, and knockdown of eIF5A2 inhibited DHT-induced EMT. Moreover, in vivo study, Luciferase signals from the lungs of the eIF5A2 plasmid group indicated higher metastasis ability, and the eIF5A2 siRNA group had lower metastasis ability. Our results suggest that AR positively regulates eIF5A2 expression in androgen-dependent cells, and stimulation of AR expression and signaling in prostate tumors promotes PCa metastasis by EMT induction and upregulation of eIF5A2.
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Affiliation(s)
- Yuancai Zheng
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ping Li
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Hang Huang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xueting Ye
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Wei Chen
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Guodong Xu
- Department of Cardiothoracic Surgery, The Affiliated Hospital, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315041, China
| | - Fangyi Zhang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Wang S, Cheng M, Zheng X, Zheng L, Liu H, Lu J, Liu Y, Chen W. Interactions Between lncRNA TUG1 and miR-9-5p Modulate the Resistance of Breast Cancer Cells to Doxorubicin by Regulating eIF5A2. Onco Targets Ther 2020; 13:13159-13170. [PMID: 33380806 PMCID: PMC7767720 DOI: 10.2147/ott.s255113] [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: 07/09/2020] [Accepted: 12/01/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Breast cancer (BC) is one of the leading causes of cancer-related deaths. Chemoresistance of BC remains a major unmet clinical obstacle. TUG1 (taurine-upregulated gene 1), a long noncoding RNA (lncRNA), and microRNAs (miRNA) are implicated in therapeutic resistance. However, the interactions between TUG1 and miRNAs that regulate doxorubicin (Dox) resistance in BC remain elusive. Materials and Methods Expression of TUG1 and miR-9 was measured by real-time PCR. EIF5A2 (eukaryotic translation initiation factor 5A-2) was detected by Western blot. Transfection of siRNAs or miRNA inhibitors was applied to silence lncRNA TUG1, eIF5A2 or miR-9. Cell viability, proliferation, and apoptosis were determined by CCK-8 (cell counting kit-8), flow cytometry, and EdU (5-ethynyl-2ʹ-deoxyuridine) assays, respectively. The regulatory relationship between TUG1 and miR-9 was determined by a luciferase assay. Results LncRNA TUG1 was highly expressed in BC tissues and positively associated with Dox resistance in BC cell lines. SiRNA knockdown of TUG1 reversed Dox resistance in MCF-7/ADR cells. Mechanistically, TUG1 acted as a “sponge” for miR-9 and downregulated miR-9. Treatment with a miR-9 inhibitor blocked the effect of TUG1 siRNA, and knockdown of TUG1 inhibited the effects of miR-9. Furthermore, TUG1 inhibition of apoptosis induced by Dox involved miR-9 targeting of eIF5A2. Conclusion TUG1 modulates the susceptibility of BC cells to Dox by regulating the expression of eIF5A2 via interacting with miR-9. These results indicate that the lncRNA TUG1 may be a novel therapeutic target in breast cancer.
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Affiliation(s)
- Shuqian Wang
- Department of Breast Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Mengjing Cheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People's Republic of China
| | - Xiaoxiao Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People's Republic of China
| | - Li Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People's Republic of China
| | - Hao Liu
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People's Republic of China
| | - Jianju Lu
- Department of Breast Surgery, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing College, Jiaxing 314000, People's Republic of China
| | - Yu Liu
- Department of Breast Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People's Republic of China
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Tang Y, Chen K, Luan X, Zhang J, Liu R, Zheng X, Xie S, Ke H, Zhang X, Chen W. Knockdown of eukaryotic translation initiation factor 5A2 enhances the therapeutic efficiency of doxorubicin in hepatocellular carcinoma cells by triggering lethal autophagy. Int J Oncol 2020; 57:1368-1380. [PMID: 33174013 PMCID: PMC7646588 DOI: 10.3892/ijo.2020.5143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/13/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an invasive malignant neoplasm with a poor prognosis. The development of chemoresistance severely obstructs the chemotherapeutic efficiency of HCC treatment. Therefore, understanding the mechanisms of chemoresistance is important for improving the outcomes of patients with HCC. Eukaryotic translation initiation factor 5A2 (eIF5A2), which is considered to be an oncogene, has been reported to mediate chemoresistance in various types of cancer; however, its precise role in HCC remains unclear. Accumulating evidence has suggested that autophagy serves a dual role in cancer chemotherapy. The present study aimed to investigate the role of autophagy in eIF5A2‑mediated doxorubicin resistance in HCC. High expression levels of eIF5A2 in human HCC tissues were observed by immunohistochemistry using a tissue microarray, which was consistent with the results of reverse transcription‑quantitative PCR analysis in paired HCC and adjacent healthy tissues. HCC patient‑derived tumor xenograft mouse model was used for the in vivo study, and knockdown of eIF5A2 effectively enhanced the efficacy of doxorubicin chemotherapy compared with that in the control group. Notably, eIF5A2 served as a repressor in regulating autophagy under chemotherapy. Silencing of eIF5A2 induced doxorubicin sensitivity in HCC cells by triggering lethal autophagy. In addition, 5‑ethynyl‑2'‑deoxyuridine, lactate dehydrogenase release assay and calcein‑AM/PI staining were used to determine the enhanced autophagic cell death induced by the silencing of eIF5A2 under doxorubicin treatment. Suppression of autophagy attenuated the sensitivity of HCC cells to doxorubicin induced by eIF5A2 silencing. The results also demonstrated that knockdown of the Beclin 1 gene, which is an autophagy regulator, reversed the enhanced autophagic cell death and doxorubicin sensitivity induced by eIF5A2 silencing. Taken together, these results suggested eIF5A2 may mediate the chemoresistance of HCC cells by suppressing autophagic cell death under chemotherapy through a Beclin 1‑dependent pathway, and that eIF5A2 may be a novel potential therapeutic target for HCC treatment.
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Affiliation(s)
- Yuexiao Tang
- Department of Genetics, Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012
| | - Ke Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016
| | - Xiaorui Luan
- Department of Genetics, Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012
| | - Jinyan Zhang
- Department of Genetics, Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012
| | - Rongrong Liu
- Division of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003
| | - Xiaoxiao Zheng
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012
| | - Shangzhi Xie
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012
| | - Haiping Ke
- Department of Biology, Ningbo College of Health Sciences, Ningbo, Zhejiang 315100, P.R. China
| | - Xianning Zhang
- Department of Genetics, Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012
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11
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Yang X, Amgad M, Cooper LAD, Du Y, Fu H, Ivanov AA. High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients. J Transl Med 2020; 18:334. [PMID: 32873298 PMCID: PMC7465409 DOI: 10.1186/s12967-020-02502-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 08/25/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND African American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort. METHODS The systematic differential analysis of mRNA expression integrated with the analysis of clinical outcomes was performed for 1055 samples from the breast invasive carcinoma TCGA PanCancer cohorts. A deep learning fully-convolutional model was used to determine the association between gene expression and tumor features based on breast cancer patient histopathological images. RESULTS We found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. We have determined a set of 32 genes whose overexpression in African American patients strongly correlates with decreased survival of African American but not White breast cancer patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific negative impacts on the survival of African American patients, specifically with triple-negative breast cancer. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating of the epithelial-to-mesenchymal transition induced by master regulator MYC. CONCLUSIONS The poor clinical outcomes in African American women with breast cancer can be associated with the abnormal elevation of individual gene expression. Such genes, including those identified and prioritized in this study, could represent new targets for therapeutic intervention. A strong correlation between MKK3 overexpression, activation of its binding partner and major oncogene MYC, and worsened clinical outcomes suggests the MKK3-MYC protein-protein interaction as a new promising target to reduce racial disparity in breast cancer survival.
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Affiliation(s)
- Xuan Yang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, 1510 Clifton Road, Atlanta, GA, 30322, USA
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Mohamed Amgad
- Department of Biomedical Informatics, Emory University School of Medicine, Emory University, Atlanta, GA, USA
| | - Lee A D Cooper
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yuhong Du
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, 1510 Clifton Road, Atlanta, GA, 30322, USA
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA
- Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Haian Fu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, 1510 Clifton Road, Atlanta, GA, 30322, USA.
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
- Winship Cancer Institute, Emory University, Atlanta, GA, USA.
- Department of Hematology & Medical Oncology, Emory University, Atlanta, GA, USA.
| | - Andrey A Ivanov
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Emory University, 1510 Clifton Road, Atlanta, GA, 30322, USA.
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
- Winship Cancer Institute, Emory University, Atlanta, GA, USA.
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12
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Ning L, Wang L, Zhang H, Jiao X, Chen D. Eukaryotic translation initiation factor 5A in the pathogenesis of cancers. Oncol Lett 2020; 20:81. [PMID: 32863914 PMCID: PMC7436936 DOI: 10.3892/ol.2020.11942] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/10/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer is the leading cause of death worldwide. The absence of obvious symptoms and insufficiently sensitive biomarkers in early stages of carcinoma limits early diagnosis. Cancer therapy agents and targeted therapy have been used extensively against tissues or organs of specific cancers. However, the intrinsic and/or acquired resistance to the agents or targeted drugs as well as the serious toxic side effects of the drugs would limit their use. Therefore, identifying biomarkers involved in tumorigenesis and progression represents a challenge for cancer diagnosis and therapeutic strategy development. The eukaryotic translation factor 5A (eIF5A), originally identified as an initiation factor, was later shown to promote translation elongation of iterated proline sequences. There are two eIF5A isoforms (eIF5A1 and eIF5A2). eIF5A2 protein consists of 153 residues, and shares 84% amino acid identity with eIF5A1. However, the biological functions of these two isoforms may be significantly different. Recently, it was demonstrated that eIF5Ais widely involved in the pathogenesis of a number of diseases, including cancers. In particular, eIF5A plays an important role in regulating tumor growth, invasion, metastasis and tumor microenvironment. It was also shown to serve as a potential biomarker and target for the diagnosis and treatment of cancers. The present review briefly discusses the latest findings of eIF5A in the pathogenesis of certain malignant cancers and evolving clinical applications.
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Affiliation(s)
- Liang Ning
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Lei Wang
- Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Honglai Zhang
- Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xuelong Jiao
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Dong Chen
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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13
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Lin YM, Chen ML, Chen CL, Yeh CM, Sung WW. Overexpression of EIF5A2 Predicts Poor Prognosis in Patients with Oral Squamous Cell Carcinoma. Diagnostics (Basel) 2020; 10:diagnostics10070436. [PMID: 32605067 PMCID: PMC7400414 DOI: 10.3390/diagnostics10070436] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/17/2020] [Accepted: 06/25/2020] [Indexed: 12/20/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the most common epithelial malignancy affecting the oral cavity, and it is especially significant in Asian countries. Patients diagnosed with OSCC have an unfavorable prognosis and additional prognostic markers would help improve therapeutic strategies. We sought to investigate the association between eukaryotic translation initiation factor 5A2 (EIF5A2) and epithelial–mesenchymal transition (EMT) markers as well as the prognostic significance of EIF5A2 in OSCC. The expression of EIF5A2 and EMT markers was measured through the immunohistochemical staining of specimens from 272 patients with OSCC. In addition, the correlation between different clinicopathological factors and EIF5A2 expression was analyzed. The prognostic role of EIF5A2 was then analyzed via Kaplan–Meier analysis and Cox proportional hazard models. Among the 272 patients, high EIF5A2 expression was significantly associated with an advanced N value (p = 0.008). High tumor expression of EIF5A2 was prone to the expression of low E-cadherin and high beta-catenin (p = 0.046 and p = 0.020, respectively). Patients with high EIF5A2 expression had unfavorable five-year survival rates as compared with those with low expression (49.7% and 67.3%, respectively). The prognostic role of EIF5A2 was further confirmed through multivariate analysis (hazard ratio = 1.714, 95% confidence interval: 1.134–2.590, p = 0.011). High EIF5A2 expression is associated with an advanced N value and EMT markers and may serve as a marker for an unfavorable prognosis in patients with OSCC.
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Affiliation(s)
- Yueh-Min Lin
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-M.L.); (M.-L.C.); (C.-L.C.)
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua 50006, Taiwan;
| | - Mei-Ling Chen
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-M.L.); (M.-L.C.); (C.-L.C.)
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua 50006, Taiwan;
| | - Chia-Lo Chen
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-M.L.); (M.-L.C.); (C.-L.C.)
| | - Chung-Min Yeh
- Department of Surgical Pathology, Changhua Christian Hospital, Changhua 50006, Taiwan;
- Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 35664, Taiwan
| | - Wen-Wei Sung
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-M.L.); (M.-L.C.); (C.-L.C.)
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Correspondence: ; Tel.: +886-4-24739595 (ext.*10646)
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14
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Ai J, Sun J, Zhou G, Zhu T, Jing L. Long non-coding RNA GAS6-AS1 acts as a ceRNA for microRNA-585, thereby increasing EIF5A2 expression and facilitating hepatocellular carcinoma oncogenicity. Cell Cycle 2020; 19:742-757. [PMID: 32089066 PMCID: PMC7145326 DOI: 10.1080/15384101.2020.1729323] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 12/22/2019] [Accepted: 12/29/2019] [Indexed: 12/23/2022] Open
Abstract
Long non-coding RNA termed GAS6 antisense RNA 1 (GAS6-AS1) plays an essential role in gastric and non-small cell lung cancers. Nonetheless, the function of GAS6-AS1 in hepatocellular carcinoma (HCC) has not been so far studied in detail. In this study, reverse-transcription quantitative PCR was performed to measure GAS6-AS1 expression in HCC samples. A series of functional experiments, including MTT assay, colony formation assay, flow-cytometric analysis, and transwell migration and invasion assays, was performed to determine the influence of GAS6-AS1 knockdown on the malignant phenotype of HCC. The results showed that GAS6-AS1 was significantly upregulated in HCC tissue samples and cell lines. Increased GAS6-AS1 expression was associated with tumor size, Edmondson grade, and Tumor-Node-Metastasis (TNM) stage among patients with HCC. The overall survival of patients with HCC characterized with high expression of GAS6-AS1 was significantly shorter in comparison to that of patients with low level of GAS6-AS1. Functional experiments indicated that knockdown of GAS6-AS1 suppressed HCC cell proliferation, colony formation, migration, and invasion in vitro; promoted apoptosis in vitro; and decreased tumor growth in vivo. Of note, GAS6-AS1 was validated as a competing endogenous RNA (ceRNA) for microRNA-585 (miR-585) and consequently increased the expression of eukaryotic translation initiation factor 5A2 (EIF5A2). Finally, rescue experiments confirmed the association among GAS6-AS1, miR-585, and EIF5A2 in HCC cells. Our study provides substantial evidence that the GAS6-AS1/miR-585/EIF5A2 pathway plays an important role in HCC progression and that might be considered as a potential target for therapeutic approaches in HCC.
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Affiliation(s)
- Jing Ai
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Junhui Sun
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Guanhui Zhou
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Tongyin Zhu
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
| | - Li Jing
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China
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15
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Tu C, Chen W, Wang S, Tan W, Guo J, Shao C, Wang W. MicroRNA-383 inhibits doxorubicin resistance in hepatocellular carcinoma by targeting eukaryotic translation initiation factor 5A2. J Cell Mol Med 2019; 23:7190-7199. [PMID: 30801960 PMCID: PMC6815770 DOI: 10.1111/jcmm.14197] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 12/19/2022] Open
Abstract
Drug resistance occurs commonly in cancers, especially in hepatocellular carcinoma (HCC). Accumulating evidence has demonstrated that microRNAs (miRNAs) play a vital role in tumour chemoresistance. However, little is known about the role of miR-383 in HCC chemoresistance. In the present study, RT-PCR and western blotting were used to identify the expression profile of miR-383 and eukaryotic translation initiation factor 5A2 (EIF5A2). The bioinformatics website Targetscan was used to predict the target genes of miR-383. In vitro and in vivo loss- and gain-of-function studies were performed to reveal the effects and potential mechanism of the miR-383/EIF5A2 axis in chemoresistance of HCC cells. The expression level of miR-383 correlated negatively with doxorubicin (Dox) sensitivity. Overexpression of miR-383 promoted HCC cells to undergo Dox-induced cytotoxicity and apoptosis, whereas miR-383 knockdown had the opposite effects. EIF5A2 was predicted as a target gene of miR-383. EIF5A2 knockdown sensitized HCC cells to Dox. Moreover, miR-383 inhibition-mediated HCC Dox resistance could be reversed by silencing EIF5A2. Finally, we demonstrated that miR-383 inhibition could enhance Dox sensitivity by targeting EIF5A2 in vivo. The results indicated that miR-383 inhibited Dox resistance in HCC cells by targeting EIF5A2. Targeting the miR-383/EIF5A2 axis might help to alleviate the chemoresistance of HCC cells.
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MESH Headings
- Animals
- Antibiotics, Antineoplastic/pharmacology
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation
- Doxorubicin/pharmacology
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- Peptide Initiation Factors/genetics
- Peptide Initiation Factors/metabolism
- Prognosis
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
- Eukaryotic Translation Initiation Factor 5A
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Affiliation(s)
- Chaoyong Tu
- Department of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiangP.R. China
- Department of Hepatobiliary and Pancreatic Surgery, Lishui HospitalZhejiang University School of Medicine, The Fifth Affiliated Hospital of Wenzhou Medical UniversityLishuiZhejiangP.R. China
| | - Wei Chen
- Tongde Hospital of Zhejiang ProvinceCancer Institute of Integrated traditional Chinese and Western MedicineZhejiang Academy of Traditional Chinese MedicineHangzhouZhejiangChina
| | - Shuqian Wang
- Division of Breast Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangP.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangP.R. China
| | - Wei Tan
- Department of Hepatobiliary and Pancreatic Surgery, Lishui HospitalZhejiang University School of Medicine, The Fifth Affiliated Hospital of Wenzhou Medical UniversityLishuiZhejiangP.R. China
| | - Jingqiang Guo
- Department of Hepatobiliary and Pancreatic Surgery, Lishui HospitalZhejiang University School of Medicine, The Fifth Affiliated Hospital of Wenzhou Medical UniversityLishuiZhejiangP.R. China
| | - Chuxiao Shao
- Department of Hepatobiliary and Pancreatic Surgery, Lishui HospitalZhejiang University School of Medicine, The Fifth Affiliated Hospital of Wenzhou Medical UniversityLishuiZhejiangP.R. China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiangP.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangP.R. China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, School of MedicineThe First Affiliated Hospital, Zhejiang UniversityHangzhouZhejiangP.R. China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseaseZhejiang UniversityHangzhouZhejiangP.R. China
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16
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Guan X, Gu S, Yuan M, Zheng X, Wu J. MicroRNA-33a-5p overexpression sensitizes triple-negative breast cancer to doxorubicin by inhibiting eIF5A2 and epithelial-mesenchymal transition. Oncol Lett 2019; 18:5986-5994. [PMID: 31788073 PMCID: PMC6865640 DOI: 10.3892/ol.2019.10984] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 08/06/2019] [Indexed: 12/13/2022] Open
Abstract
Drug resistance is a significant obstacle when treating triple-negative breast cancer (TNBC). Several studies have demonstrated that microRNAs (miRNAs) have essential roles in regulating drug resistance in different types of cancer. miR-33a-5p has previously been reported to be a tumor suppressor in several types of cancer. However, its role in breast cancer remains unknown. The present study aimed to investigate the role of miR-33a-5p in the chemoresistance of TNBC and uncover its potential molecular mechanisms. Cell Counting Kit-8 assay was used to examine cell proliferation, reverse transcription-quantitative PCR analysis was used to examine miR-33a levels, and western blotting and immunofluorescence assays were used to examine the expression of epithelial-mesenchymal transition (EMT)-associated proteins and of eukaryotic translation initiation factor 5A2 (eIF5A2). The results indicated that miR-33a-5p expression was lower in TNBC cells compared with non-TNBC cells. miR-33a-5p overexpression significantly improved the doxorubicin (Dox) sensitivity of TNBC cells, but not that of non-TNBC cells. It was then observed that Dox treatment inhibited miR-33a-5p expression and induced EMT in TNBC cells, by increasing the expression levels of vimentin, while decreasing the expression levels of E-cadherin. Furthermore, it was revealed that forced expression of miR-33a-5p attenuated Dox-induced EMT. eIF5A2 was identified as a potential target of miR-33a-5p, and miR-33a-5p overexpression inhibited the expression of eIF5A2. eIF5A2 inhibition, via its inhibitor GC7, sensitized TNBC cells to Dox and reversed Dox-induced EMT. Overall, the present study demonstrated that miR-33a-5p enhanced the sensitivity of TNBC cells to Dox, by suppressing eIF5A2 expression and reversing Dox-induced EMT, providing a potential therapeutic target for treating drug-resistant TNBC.
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Affiliation(s)
- Xiaoqing Guan
- Department of Breast Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu 223800, P.R. China
| | - Shucheng Gu
- Department of Breast Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu 223800, P.R. China
| | - Mu Yuan
- Department of Breast Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu 223800, P.R. China
| | - Xiangxin Zheng
- Department of Breast Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu 223800, P.R. China
| | - Ji Wu
- Department of Breast Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, Jiangsu 223800, P.R. China
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17
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Bernier C, Soliman A, Gravel M, Dankner M, Savage P, Petrecca K, Park M, Siegel PM, Shore GC, Roulston A. DZ-2384 has a superior preclinical profile to taxanes for the treatment of triple-negative breast cancer and is synergistic with anti-CTLA-4 immunotherapy. Anticancer Drugs 2019; 29:774-785. [PMID: 29878901 PMCID: PMC6133219 DOI: 10.1097/cad.0000000000000653] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Triple-negative breast cancer (TNBC) is typically aggressive, difficult to treat, and commonly metastasizes to the visceral organs and soft tissues, including the lungs and the brain. Taxanes represent the most effective and widely used therapeutic class in metastatic TNBC but possess limiting adverse effects that often result in a delay, reduction, or cessation of their use. DZ-2384 is a candidate microtubule-targeting agent with a distinct mechanism of action and strong activity in several preclinical cancer models, with reduced toxicities. DZ-2384 is highly effective in patient-derived taxane-sensitive and taxane-resistant xenograft models of TNBC at lower doses and over a wider range relative to paclitaxel. When comparing compound exposure at minimum effective doses relative to safe exposure levels, the therapeutic window for DZ-2384 is 14-32 compared with 2.0 and less than 2.8 for paclitaxel and docetaxel, respectively. DZ-2384 is effective at reducing brain metastatic lesions when used at maximum tolerated doses and is equivalent to paclitaxel. Drug distribution experiments indicate that DZ-2384 is taken up more efficiently by tumor tissue but at equivalent levels in the brain compared with paclitaxel. Selective DZ-2384 uptake by tumor tissue may in part account for its wider therapeutic window compared with taxanes. In view of the current clinical efforts to combine chemotherapy with immune checkpoint inhibitors, we demonstrate that DZ-2384 acts synergistically with anti-CTLA-4 immunotherapy in a syngeneic murine model. These results demonstrate that DZ-2384 has a superior pharmacologic profile over currently used taxanes and is a promising therapeutic agent for the treatment of metastatic TNBC.
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Affiliation(s)
- Cynthia Bernier
- Laboratory for Therapeutic Development.,Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Ahmed Soliman
- Laboratory for Therapeutic Development.,Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Michel Gravel
- Laboratory for Therapeutic Development.,Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Matthew Dankner
- Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Paul Savage
- Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Kevin Petrecca
- Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada
| | - Morag Park
- Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Peter M Siegel
- Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Gordon C Shore
- Laboratory for Therapeutic Development.,Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
| | - Anne Roulston
- Laboratory for Therapeutic Development.,Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre
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18
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Meng QB, Peng JJ, Qu ZW, Zhu XM, Wen Z, Kang WM. Eukaryotic initiation factor 5A2 and human digestive system neoplasms. World J Gastrointest Oncol 2019; 11:449-458. [PMID: 31236196 PMCID: PMC6580320 DOI: 10.4251/wjgo.v11.i6.449] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 04/17/2019] [Accepted: 05/04/2019] [Indexed: 02/05/2023] Open
Abstract
Eukaryotic initiation factor 5A2 (eIF5A2), as one of the two isoforms in the family, is reported to be a novel oncogenic protein that is involved in multiple aspects of many types of human cancer. Overexpression or gene amplification of EIF5A2 has been demonstrated in many cancers. Accumulated evidence shows that eIF5A2 initiates tumor formation, enhances cancer cell growth, increases cancer cell metastasis, and promotes treatment resistance through multiple means, including inducing epithelial–mesenchymal transition, cytoskeletal rearrangement, angiogenesis, and metabolic reprogramming. Expression of eIF5A2 in cancer correlates with poor survival, advanced disease stage, as well as metastasis, suggesting that eIF5A2 function is crucial for tumor development and maintenance but not for normal tissue homeostasis. All these studies suggest that eIF5A2 is a useful biomarker in the prediction of cancer prognosis and serves as an anticancer molecular target. This review focuses on the expression, subcellular localization, post-translational modifications, and regulatory networks of eIF5A2, as well as its biochemical functions and evolving clinical applications in cancer, especially in human digestive system neoplasms.
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Affiliation(s)
- Qing-Bin Meng
- Department of Gastrointestinal Surgery, the First Hospital of Wuhan City, Wuhan 430022, Hubei Province, China
| | - Jing-Jing Peng
- Department of Gastroenterology, General Hospital of the Yangtze River Shipping, Wuhan 430015, Hubei Province, China
| | - Zi-Wei Qu
- Department of Gastrointestinal Surgery, the First Hospital of Wuhan City, Wuhan 430022, Hubei Province, China
| | | | - Zhang Wen
- Department of Hepato-Biliary-Pancreatic Surgery and Liver Transplantation, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Wei-Ming Kang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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19
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Post AEM, Bussink J, Sweep FCGJ, Span PN. Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer. Oncol Res 2019; 28:33-40. [PMID: 31046897 PMCID: PMC7851527 DOI: 10.3727/096504019x15555794826018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.
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Affiliation(s)
- Annemarie E M Post
- Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands
| | - Johan Bussink
- Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands
| | - Fred C G J Sweep
- Radboud University Medical Center, Department of Laboratory MedicineNijmegenThe Netherlands
| | - Paul N Span
- Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands
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20
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Fang L, Gao L, Xie L, Xiao G. Eukaryotic translation initiation factor 5A-2 involves in doxorubicin-induced epithelial-mesenchymal transition in oral squamous cell carcinoma cells. J Cancer 2018; 9:3479-3488. [PMID: 30310504 PMCID: PMC6171023 DOI: 10.7150/jca.26136] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 07/18/2018] [Indexed: 12/16/2022] Open
Abstract
Background: Epithelial-mesenchymal transition (EMT) is considered to be vital during chemotherapy resistance in oral squamous cell carcinoma (OSCC). Recently, eukaryotic initiation factor 5A-2 (eIF5A-2), a potential oncogene, has been reported to be involved in chemotherapy resistance in human cancers. Materials and Methods: N1-guanyl-1,7-diaminoheptane (GC7, a novel eIF5A-2 inhibitor) or siRNA on responses to doxorubicin were examined in OSCC cells. Cytotoxicity and protein expression were evaluated by CCK-8 and EdU incorporation assay and western blotting. Tca8113 cells were used for establishment and treatment of tumor xenografts in vivo. Results: Low concentration of GC7 (5μΜ) significantly enhanced doxorubicin cytotoxicity in both epithelial phenotype OSCC cells (Cal27) and mesenchymal phenotype OSCC cells (HN30 and Tca8113). EMT process promoted by doxorubicin in Cal27 cells could be reversed by GC7. Additionally, GC7 induced mesenchymal-epithelial transition (MET) in HN30 and Tca8113 cells. Silencing of eIF5A-2 by specific siRNA exhibited the similar effects. The synergistic cytotoxicity of doxorubicin/GC7 combination was not induced in Twist-1, an EMT driving factor, silenced Cal27, HN30, and Tca8113 cells. GC7 also synergized doxorubicin to inhibit tumor growth in vivo treatment. Conclusions: Our study strongly proved that combined treatment with GC7 may boost the therapeutic effect of doxorubicin in OSCC by inhibiting the EMT.
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Affiliation(s)
- Liang Fang
- Department of head and neck surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, P.R. China
| | - Li Gao
- Department of head and neck surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, P.R. China
| | - Lei Xie
- Department of head and neck surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, P.R. China
| | - Guizhou Xiao
- Department of head and neck surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, P.R. China
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21
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Liu Y, Xue F, Zhang Y, Lei P, Wang Z, Zhu Z, Sun K. N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of acute lymphoblastic leukemia cells to vincristine through inhibition of eif5a-2 activation. Anticancer Drugs 2017; 28:1097-1105. [PMID: 28885268 DOI: 10.1097/cad.0000000000000550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
N1-guanyl-1,7-diaminoheptane (GC7), a deoxyhypusine synthase inhibitor, has been shown to exert antiproliferation effects in many solid tumors by regulating eukaryotic translation initiation factor 5a2 (eif5a-2). However, little is known about the role of GC7 and eif5a-2 in drug resistance in acute lymphoblastic leukemia (ALL). In the present study, we investigated the effect of GC7 on drug-resistant ALL and its potential mechanism. We found that using the CCK-8 assay that combined treatment with GC7 and vincristine (VCR) significantly inhibited the cell viability of two ALL cell lines. Using EdU incorporation assays and flow cytometry, we also showed that GC7 could markedly enhance the VCR sensitivity of ALL cells by suppressing cell proliferation and promoting apoptosis. Furthermore, we showed that GC7 could downregulate eif5a-2 and myeloid cell leukemia-1 (Mcl-1) expression. Knockdown of eif5a-2 inhibited the expression of Mcl-1 and significantly enhanced the VCR sensitivity. Moreover, eif5a-2 knockdown decreased the regulatory role of GC7 in increasing VCR sensitivity. Thus, our findings indicate that combined treatment with GC7 could enhance VCR sensitivity of ALL cells by regulating the eif5a-2/Mcl-1 axis. Together, our results highlight the potential clinical application of GC7 in VCR-based chemotherapy for the treatment of ALL.
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Affiliation(s)
- Yanhui Liu
- Departments of aHemotology bHepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, People's Republic of China
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22
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Bhosale PG, Cristea S, Ambatipudi S, Desai RS, Kumar R, Patil A, Kane S, Borges AM, Schäffer AA, Beerenwinkel N, Mahimkar MB. Chromosomal Alterations and Gene Expression Changes Associated with the Progression of Leukoplakia to Advanced Gingivobuccal Cancer. Transl Oncol 2017; 10:396-409. [PMID: 28433800 PMCID: PMC5403767 DOI: 10.1016/j.tranon.2017.03.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/21/2017] [Accepted: 03/21/2017] [Indexed: 12/11/2022] Open
Abstract
We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associated with this progression, including amplification of 8q24.3, deletion of 8p23.2, and dysregulation of DERL3, EIF5A2, ECT2, HOXC9, HOXC13, MAL, MFAP5 and NELL2. Comparing copy number profiles of primary tumors with and without lymph-node metastasis, we identify alterations associated with metastasis, including amplifications of 3p26.3, 8q24.21, 11q22.1, 11q22.3 and deletion of 8p23.2. Integrative analysis reveals several biomarkers that have never or rarely been reported in previous OSCC studies, including amplifications of 1p36.33 (attributable to MXRA8), 3q26.31 (EIF5A2), 9p24.1 (CD274), and 12q13.2 (HOXC9 and HOXC13). Additionally, we find that amplifications of 1p36.33 and 11q22.1 are strongly correlated with poor clinical outcome. Overall, our findings delineate genomic changes that can be used in treatment management for patients with potentially malignant leukoplakia and OSCC patients with higher risk of lymph-node metastasis.
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Affiliation(s)
- Priyanka G Bhosale
- Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Navi Mumbai, 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400085, India
| | - Simona Cristea
- Department of Biosystems Science and Engineering, ETH Zurich, 4058, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, 4058, Basel, Switzerland
| | - Srikant Ambatipudi
- Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Navi Mumbai, 410210, India; MRC Integrative Epidemiology Unit, University of Bristol, BS8 1TH, UK
| | - Rajiv S Desai
- Department of Oral Pathology & Microbiology, Nair Hospital Dental College, Mumbai, 400 008, India
| | - Rajiv Kumar
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre (TMC), Parel, Mumbai, 400012, India
| | - Asawari Patil
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre (TMC), Parel, Mumbai, 400012, India
| | - Shubhada Kane
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre (TMC), Parel, Mumbai, 400012, India
| | - Anita M Borges
- Department of Pathology & Laboratory Medicine, S. L. Raheja Hospital, Mumbai, 400016, India
| | - Alejandro A Schäffer
- Computational Biology Branch, National Center for Biotechnology Information, National Institute of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD, 20894, USA
| | - Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Zurich, 4058, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, 4058, Basel, Switzerland
| | - Manoj B Mahimkar
- Cancer Research Institute (CRI), Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Navi Mumbai, 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400085, India.
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23
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Huang PY, Zeng TT, Ban X, Li MQ, Zhang BZ, Zhu YH, Hua WF, Mai HQ, Zhang L, Guan XY, Li Y. Expression of EIF5A2 associates with poor survival of nasopharyngeal carcinoma patients treated with induction chemotherapy. BMC Cancer 2016; 16:669. [PMID: 27549330 PMCID: PMC4994420 DOI: 10.1186/s12885-016-2714-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 08/03/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a type of head-neck cancer with a distinguishable geographic and racial distribution worldwide. Increasing evidence supports that the accumulation of additional genetic and epigenetic abnormalities is important in driving the NPC tumorigenic process. In this study, we aim to investigate the association between EIF5A2 (Eukaryotic translation initiation factor 5A2) expression status and NPC clinical outcomes. METHODS The expression status of EIF5A2 was investigated in the NPC tissue microarray. Tissues were from 166 NPC patients staging II-IV, collected between 1999 and 2005. All patients were administered 2-3 cycles of DDP (cisplatin) + 5-Fu (5-fluorouracil) induction therapy and then treated with a uniform conventional two-dimensional radiotherapy. Cell motility assay, tumor growth assay and cytotoxicity assay were performed on the EIF5A2 overexpressed cells and control cells. siRNA was also used in the in vitro studies. RESULTS Positive staining of EIF5A2 was observed in 85.4 % (105/123) informative tumor cases. Multivariate analyses demonstrated that EIF5A2 was an independent prognostic marker of poor overall survival (OS) (P = 0.041), failure-free survival (FFS) (P = 0.029), and distant failure-free survival (D-FFS) (P = 0.043) in patients with locoregionally advanced NPC patients treated with cisplatin + 5-Fu chemoradiotherapy. The forced expression of EIF5A2 in NPC cells enhanced the cells' motility and growth ability. Knock-down of EIF5A2 in NPC cells decreased the cell's motility and growth ability. Our results also demonstrated that EIF5A2 overexpression induced chemoresistance of NPC cells to 5-Fu. CONCLUSIONS Our findings suggested that EIF5A2 expression, as examined by immunohistochemistry, could function as an independent prognostic factor of outcomes in NPC patients with cisplatin + 5-Fu chemoradiotherapy. EIF5A2 might be a novel therapeutic target for the inhibition of NPC progress.
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Affiliation(s)
- Pei-Yu Huang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ting-Ting Zeng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Xiaojiao Ban
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Meng-Qing Li
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Bao-Zhu Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Ying-Hui Zhu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Wen-Feng Hua
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Hai-Qiang Mai
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Li Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
- Room 706, Building 2, No.651 East Dongfeng Road, Guangzhou, 510060 Guangdong China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- Room 706, Building 2, No.651 East Dongfeng Road, Guangzhou, 510060 Guangdong China
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24
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Yang SS, Gao Y, Wang DY, Xia BR, Liu YD, Qin Y, Ning XM, Li GY, Hao LX, Xiao M, Zhang YY. Overexpression of eukaryotic initiation factor 5A2 (EIF5A2) is associated with cancer progression and poor prognosis in patients with early-stage cervical cancer. Histopathology 2016; 69:276-87. [PMID: 26799253 DOI: 10.1111/his.12933] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 01/16/2016] [Indexed: 02/06/2023]
Abstract
AIMS As one of the only two isoforms of the eukaryotic initiation factor (EIF)5A family, EIF5A2 plays an important role in tumour progression and prognosis evaluation. The aim of this study was to investigate EIF5A2 expression in International Federation of Gynecology and Obstetrics (FIGO) stage I-II cervical cancer and to evaluate its clinical significance. METHODS AND RESULTS The mRNA and protein expression levels of EIF5A2 were analysed in 20 tissue samples of FIGO stage I-II cervical cancer and paired surrounding non-tumour cervical tissues by real-time polymerase chain reaction and western blot analysis. Immunohistochemistry was performed to examine EIF5A2 protein expression in paraffin-embedded tissues from 314 patients with cervical cancer. The mRNA and protein expression levels of EIF5A2 were significantly elevated in tumour tissues. The increased EIF5A2 expression was correlated with higher FIGO stage (P < 0.001), deep cervical stromal invasion (P = 0.026), lymphovascular space involvement (P = 0.002), pelvic lymph node metastasis (P < 0.001) and postoperative recurrence (P < 0.001) in patients with cervical cancer. Patients with tumours showing high EIF5A2 expression had a poorer survival time than those with normal EIF5A2 expression, especially the patients with negative pelvic lymph nodes and FIGO stage II. In addition, multivariate Cox analysis showed that high EIF5A2 expression was an independent prognostic factor for overall survival [hazard ratio 1.949; 95% confidence interval (CI) 1.116-3.404; P = 0.019] and disease-free survival (hazard ratio 1.980; 95% CI 1.189-3.297; P = 0.009). CONCLUSIONS EIF5A2 overexpression may contribute to cancer progression and poor prognosis. Therefore, EIF5A2 could be a novel potential prognostic marker for FIGO stage I-II cervical cancer.
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Affiliation(s)
- Shan-Shan Yang
- Department of Gynaecological Radiotherapy, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Ying Gao
- Department of Gynaecology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - De-Ying Wang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bai-Rong Xia
- Department of Gynaecology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Yun-Duo Liu
- Department of Gynaecology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Yu Qin
- Department of Pathology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Xiao-Ming Ning
- Department of Pathology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Gen-Ying Li
- Department of Gynaecological Radiotherapy, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Li-Xiao Hao
- Department of Gynaecological Radiotherapy, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Min Xiao
- Department of Breast Surgery, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
| | - Yun-Yan Zhang
- Department of Gynaecology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China
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25
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Chu J, Cargnello M, Topisirovic I, Pelletier J. Translation Initiation Factors: Reprogramming Protein Synthesis in Cancer. Trends Cell Biol 2016; 26:918-933. [PMID: 27426745 DOI: 10.1016/j.tcb.2016.06.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 06/03/2016] [Accepted: 06/13/2016] [Indexed: 12/11/2022]
Abstract
Control of mRNA translation plays a crucial role in the regulation of gene expression and is critical for cellular homeostasis. Dysregulation of translation initiation factors has been documented in several pathologies including cancer. Aberrant function of translation initiation factors leads to translation reprogramming that promotes proliferation, survival, angiogenesis, and metastasis. In such context, understanding how altered levels (and presumably activity) of initiation factors can contribute to tumor initiation and/or maintenance is of major interest for the development of novel therapeutic strategies. In this review we provide an overview of translation initiation mechanisms and focus on recent findings describing the role of individual initiation factors and their aberrant activity in cancer.
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Affiliation(s)
- Jennifer Chu
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Marie Cargnello
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada; Gerald Bronfman Department of Oncology, McGill University, Quebec, Canada
| | - Ivan Topisirovic
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Lady Davis Institute, SMBD JGH, McGill University, Montreal, Quebec, Canada; Gerald Bronfman Department of Oncology, McGill University, Quebec, Canada.
| | - Jerry Pelletier
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Gerald Bronfman Department of Oncology, McGill University, Quebec, Canada; The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
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26
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Yang H, Li XD, Zhou Y, Ban X, Zeng TT, Li L, Zhang BZ, Yun J, Xie D, Guan XY, Li Y. Stemness and chemotherapeutic drug resistance induced by EIF5A2 overexpression in esophageal squamous cell carcinoma. Oncotarget 2015; 6:26079-89. [PMID: 26317793 PMCID: PMC4694887 DOI: 10.18632/oncotarget.4581] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 07/08/2015] [Indexed: 01/25/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies of the digestive tract in East Asian countries. Multimodal therapies, including adjuvant chemotherapy and neo-adjuvant chemotherapy, have become more often used for patients with advanced ESCC. However, the chemotherapy effect is often limited by patients' drug resistance. This study demonstrated that EIF5A2 (eukaryotic translation initiation factor 5A2) overexpression induced stemness and chemoresistance in ESCC cells. We showed that EIF5A2 overexpression in ESCC cells resulted in increased chemoresistance to 5-fluorouracil (5-FU), docetaxel and taxol. In contrast, shRNAs suppressing eIF5A2 increased tumor sensitivity to these chemotherapeutic drugs. In addition, EIF5A2 overexpression was correlated with a poorer overall survival in patients with ESCC who underwent taxane-based chemotherapy after esophagectomy (P < 0.05). Based on these results, we suggest that EIF5A2 could be a predictive biomarker for selecting appropriate chemo-treatment for ESCC patients and EIF5A2 inhibitors might be considered as combination therapy to enhance chemosensitivity in patients with ESCC.
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Affiliation(s)
- Hong Yang
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Xiao-dong Li
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Ying Zhou
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiaojiao Ban
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ting-ting Zeng
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lei Li
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Bao-zhu Zhang
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jingping Yun
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dan Xie
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xin-Yuan Guan
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Yan Li
- Sun Yat-sen University Cancer Center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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27
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Wang FW, Cai MY, Mai SJ, Chen JW, Bai HY, Li Y, Liao YJ, Li CP, Tian XP, Kung HF, Guan XY, Xie D. Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression. Oncotarget 2014; 5:6716-33. [PMID: 25071013 PMCID: PMC4196158 DOI: 10.18632/oncotarget.2236] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 07/15/2014] [Indexed: 12/21/2022] Open
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways. CONCLUSION This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Down-Regulation
- Female
- Humans
- Liver Neoplasms/blood supply
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- MAP Kinase Signaling System
- Male
- Matrix Metalloproteinase 2/biosynthesis
- Mice
- Mice, Nude
- Middle Aged
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/therapy
- Peptide Initiation Factors/genetics
- Peptide Initiation Factors/metabolism
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Xenograft Model Antitumor Assays
- p38 Mitogen-Activated Protein Kinases/metabolism
- Eukaryotic Translation Initiation Factor 5A
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Affiliation(s)
- Feng-Wei Wang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mu-Yan Cai
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jie-Wei Chen
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hai-Yan Bai
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yi-Ji Liao
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chang-Peng Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao-Peng Tian
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hsiang-Fu Kung
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, the Chinese University of Hong Kong, Hong Kong, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
| | - Dan Xie
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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