|
1
|
Liu X, Li C, Zhao F, Guidoin R, Liu K, Wang F, Wang L. A functional stent with near-infrared light triggered localized photothermal-chemo synergistic therapy for malignant stenosis of esophageal cancer. Colloids Surf B Biointerfaces 2025; 251:114634. [PMID: 40101464 DOI: 10.1016/j.colsurfb.2025.114634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/21/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025]
Abstract
Stent implantation is a widely used palliative treatment for relieving strictures in malignant esophageal cancer. However, conventional fully covered stents play a role in preventing the tumor from ingrowth but increasing the risk of migration. Therefore, there is an urgent need for a multifunctional stent that not only reduces migration but also provides synergistic therapeutic benefits to inhibit tumor growth. This study proposed a braided esophageal stent with synergistic photothermal and chemotherapy functions to achieve precise controllable drug release. The stent was braided of Nitinol fiber and polyethylene terephthalate fiber in one-step, in which Nitinol loaded with high-efficiency photothermal conversion agent gold nanoparticles and polyethylene terephthalate loaded anti-tumor drugs release mediated by a temperature-responsive coating. The stent showed anti-migration ability and orchestrated the localized hyperthermia plus thermal-stimuli drug release during the tumor lesion. Cell experiments confirmed that the stent showed a significantly synergistic tumor cell killing effect (28.29 %). In 3D tumor sphere model, the apoptosis rate of tumor cells reached 31.34 %. In summary, the composite stent design strategy integrates anti-migration features and photoheating-controlled drug release for synergistic cancer therapy, providing a new design idea for the application of nickel-titanium alloy stents in the treatment of malignant esophageal stenosis.
Collapse
Affiliation(s)
- Xiaofeng Liu
- Key Laboratory of Textile Science and Technology of Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China; Key Laboratory of Textile Industry for Biomedical Textile Materials and Technology, Donghua University, Shanghai 201620, China
| | - Chaojing Li
- Key Laboratory of Textile Science and Technology of Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China; Key Laboratory of Textile Industry for Biomedical Textile Materials and Technology, Donghua University, Shanghai 201620, China
| | - Fan Zhao
- Key Laboratory of Textile Science and Technology of Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China; Key Laboratory of Textile Industry for Biomedical Textile Materials and Technology, Donghua University, Shanghai 201620, China
| | - Robert Guidoin
- Department of Surgery, Laval University and Division of Regenerative Medicine, Research Center CHU, Quebec, Canada
| | - Kaitai Liu
- Department of Radiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
| | - Fujun Wang
- Key Laboratory of Textile Science and Technology of Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China; Key Laboratory of Textile Industry for Biomedical Textile Materials and Technology, Donghua University, Shanghai 201620, China.
| | - Lu Wang
- Key Laboratory of Textile Science and Technology of Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China; Key Laboratory of Textile Industry for Biomedical Textile Materials and Technology, Donghua University, Shanghai 201620, China.
| |
Collapse
|
|
2
|
Li Z, Peng T, Yang M, Qiu Y, Ye P, Wang X, Jin H. Dual Functionality of [ 64Cu]Cu-NOTA-San A-Cy7 for Diagnostic Imaging and Surgical Guidance in Hsp90α-Positive Tumors. Mol Pharm 2025. [PMID: 40343454 DOI: 10.1021/acs.molpharmaceut.5c00126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
Intraoperative fluorescence navigation in esophageal cancer enables the clinical translation of fluorescence imaging. Heat shock protein 90 alpha (Hsp90α) plays a vital role in the progression of malignant disease, and elevated Hsp90α expression has been reported in esophageal cancer. The aim of this study was to develop a dual-modality probe, [64Cu]Cu-NOTA-San A-Cy7, for imaging Hsp90α expression in vivo via both positron emission tomography (PET) and fluorescence imaging in esophageal cancer. In this study, the Hsp90α-targeting cyclopeptide Sansalvamide A (San A) was chemically modified with a Cy7 dye and NOTA chelator simultaneously. Experimental assays confirmed that NOTA-San A-Cy7 has a favorable affinity for Hsp90α-positive EC109 cells, with a dissociation constant (Kd) of 1.08 ± 0.19 μM. The probe [64Cu]Cu-NOTA-San A-Cy7 was successfully synthesized with 64CuCl2, achieving a high radiochemical purity of over 95%. Furthermore, the probe demonstrated excellent stability in both saline and serum solutions. The probe was subsequently evaluated in a Hsp90α-positive EC109 tumor-bearing model via PET imaging, which confirmed that Hsp90α-specific uptake was significantly reduced by the co-administration of an excess blocking agent. Biodistribution studies revealed that at 24 hours post-injection, the tumor uptake of the probe was 1.35 ± 0.29%ID/g in the nonblocking group and significantly decreased to 0.73 ± 0.15%ID/g in the blocking group (p < 0.05). Concurrent with the PET experiment, fluorescence imaging was conducted, revealing substantial tumor uptake in the EC109 model. As a proof of concept, imaging-guided surgery utilizing the fluorescent component of this probe was performed. This approach demonstrated the potential for providing surgical guidance in mice positive for Hsp90α, highlighting the dual functionality of the probe for both diagnostic imaging and intraoperative navigation. In summary, our findings unequivocally demonstrate that the dual-modality probe [64Cu]Cu-NOTA-San A-Cy7 holds significant promise as an agent for imaging Hsp90α-positive tumors in vivo, offering a valuable tool for the detection and potential management of such tumors.
Collapse
Affiliation(s)
- Zhijun Li
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Department of Urology, The Second Affiliated Hospital, University of South China, Hengyang, Hunan Province 421001, China
| | - Tukang Peng
- Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
| | - Min Yang
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Yifan Qiu
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Peizhen Ye
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Xiaohui Wang
- Department of Nuclear Medicine, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Hongjun Jin
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| |
Collapse
|
|
3
|
Ding Y, Zhou L, He X, Li L, Wang X. Rhomboid Domain Containing 2 (RHBDD2) is Upregulated and Responds to Cisplatin-Induced DNA Damage in Esophageal Cancer. Biochem Genet 2025:10.1007/s10528-025-11118-y. [PMID: 40295376 DOI: 10.1007/s10528-025-11118-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/22/2025] [Indexed: 04/30/2025]
Abstract
As a pseudoprotease, RHBDD2 regulates tumor survival and progression in several cancers, but its expression and function in most cancers remain unclear. This study aimed to investigate the role of RHBDD2 in esophageal carcinoma (ESCA) via the use of public datasets and performing cytology experiments and RNA-seq analysis in ESCA cells. RHBDD2 was obviously upregulated and contributed to worse relapse-free survival (RFS) in patients with ESCA. Furthermore, chemotherapy increased RHBDD2 expression, and several GEO datasets also demonstrated that RHBDD2 expression was upregulated in both cisplatin-treated and resistant ESCA cells. Additionally, cytology experiments revealed that cisplatin treatment markedly upregulated the expression of RHBDD2 and γH2AX, which is a DNA damage marker, whereas RHBDD2 knockdown or overexpression affected cisplatin-induced γH2AX expression and the cytotoxic effects of cisplatin. The functional enrichment of RNA-seq data from RHBDD2-knockdown EC9706 cells suggested that RHBDD2-induced DEGs were involved in the DNA damage response and repair. Pearson's correlation analysis revealed that RHBDD2 expression was positively correlated with the expression of several genes, such as DMC1, CBX5, RAD1, DDB2, and ERCC1, which are responsible for DNA damage repair. Taken together, our results first revealed that RHBDD2 is upregulated and responds to DNA damage in ESCA, which provides new evidence for the potential role of RHBDD2 in the chemotherapy sensitivity and survival of patients with ESCA.
Collapse
Affiliation(s)
- Youxiang Ding
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China.
| | - Lin Zhou
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Xintao He
- Department of Pathology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Xiaoping Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211100, China.
| |
Collapse
|
|
4
|
Zheng HT, Wang CY, Luo J, Wu YH, Ge QY, Cong ZZ, Shen Y. Endoscopic treatment versus surgical treatment for T1b esophageal cancer: a systematic review and meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:110094. [PMID: 40306193 DOI: 10.1016/j.ejso.2025.110094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/16/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Endoscopic and surgical treatment are the two most common treatment strategies for resectable esophageal cancer (EC), but the optimal treatment for T1b EC remains controversial. This study aims to compare the efficacy and safety of endoscopic treatment versus esophagectomy for T1b EC. METHODS Web of Science, MEDLINE, Scopus, and EMBASE were searched from their inception to December 2023. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, we used the fixed- and random-effect models for this meta-analysis by RevMan. The primary outcomes included overall survival (OS), recurrence, lymph node metastasis, complete resection rate and positive resection margin. The secondary outcomes were 1-year survival, 3-year survival, 5-year survival, overall mortality rate, EC-specific mortality rate and lymphovascular invasion. RESULTS Nine studies with a population of 1637 patients (endoscopic treatment: 715 patients; surgical treatment: 922 patients) were included. The pooled results showed that surgical treatment was associated with a significantly better OS than endoscopic treatment (Hazard Ratio [HR] = 0.78; 95 % confidence interval [CI]: [0.62, 1.00]; P = 0.05). There was also significant difference in positive resection margin (Relative Risk [RR] = 0.13; 95 % CI: [0.09, 0.20]; P < 0.00001) between the two treatment strategies. CONCLUSION The pooled results of this study indicated that surgical treatment had better OS than endoscopic treatment for T1b EC. Furthermore, endoscopic treatment also had significantly higher risk of margin positivity than surgical treatment for T1b EC.
Collapse
Affiliation(s)
- Hao-Tian Zheng
- School of Medicine, Southeast University, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China
| | - Chang-Yong Wang
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China
| | - Jing Luo
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yu-Heng Wu
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qi-Yue Ge
- School of Medicine, Southeast University, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China.
| | - Zhuang-Zhuang Cong
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yi Shen
- School of Medicine, Southeast University, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| |
Collapse
|
|
5
|
Ayala-Aguilera CC, Ge Y, Lorente-Macías Á, Jones BN, Adam C, Carragher NO, Unciti-Broceta A. Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer. RSC Med Chem 2024; 16:d4md00579a. [PMID: 39493221 PMCID: PMC11528321 DOI: 10.1039/d4md00579a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/13/2024] [Indexed: 11/05/2024] Open
Abstract
Oesophageal cancer (OC) is one of the leading causes of cancer-related deaths worldwide. Due in part to its high heterogeneity, OC prognosis remains poor despite the introduction of targeted and immunotherapy drugs. Although numerous kinases play a significant role in the oncogenesis and progression of OC, targeting kinases have shown so far limited therapeutic success. Based on our understanding of the pharmacological properties of the pyrazolo[3,4-d]pyrimidine scaffold and the complex biology of OC, we implemented a ligand-centred strategy combined with phenotypic screening to develop novel antiproliferative inhibitors against OC. This approach is specifically designed to accelerate the discovery of lead compounds in cancers of high molecular heterogeneity such as OC. In an iterative process driven by structure-antiproliferative activity relationships (SAARs), we synthesised and tested 54 novel pyrazolo[3,4-d]pyrimidine derivatives against OC cell lines. The lead compound 2D7 (a.k.a. eCCA352) induces pan-OC activity and cell cycle arrest in the submicromolar range and was determined to inhibit Aurora kinase A, providing a new starting point to develop anticancer targeted agents against OC.
Collapse
Affiliation(s)
- Cecilia C Ayala-Aguilera
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| | - Yang Ge
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| | - Álvaro Lorente-Macías
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| | - Benjamin N Jones
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| | - Catherine Adam
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| | - Neil O Carragher
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| | - Asier Unciti-Broceta
- Edinburgh Cancer Research, Institute of Genetics & Cancer, University of Edinburgh Crewe Road South Edinburgh EH4 2XR UK
- Cancer Research UK Scotland Centre UK
| |
Collapse
|
|
6
|
Dave AR, Fating TB. Optimizing Recovery: A Comprehensive Case Report on Physiotherapy Rehabilitation in Esophagectomy Patients. Cureus 2024; 16:e63473. [PMID: 39077274 PMCID: PMC11285731 DOI: 10.7759/cureus.63473] [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: 10/18/2023] [Accepted: 06/29/2024] [Indexed: 07/31/2024] Open
Abstract
Esophageal carcinoma (CA) represents a significant global health risk, attributable to its origin from esophageal epithelium, among many other associated risk factors. Its alarming rise in younger age groups, especially among females, is concerning, even though historically, it has been more common in older populations. This modification emphasizes how complex the interaction of genetic susceptibility, environmental factors, and lifestyle choices is in determining the course of a disease. It is impossible to overstate the importance of an early diagnosis and multidisciplinary care, especially for younger patients where delayed detection is expected. Through the use of evidence-based practices, physical therapy has emerged as a crucial part of the overall care of patients with esophageal cancer. The six-minute walk test (6MWT), a popular physiotherapy evaluation tool, can be used to evaluate functional ability and exercise tolerance. Understanding how well younger people can exercise using the 6MWT is significant since they have more excellent exercise capacity than older people. This test helps physiotherapists evaluate the improvement of a patient's exercise capacity before and after the rehabilitation. In this case study, the 31-year-old woman's incredible recovery from esophageal cancer was made possible by extensive cardio-respiratory physiotherapy rehabilitation, demonstrating the significant influence of this physiotherapeutic intervention on functional status and general well-being. Through this study, we contribute to the advancement of scientific knowledge as well as the caring, patient-centered ideology that guides oncology treatment today.
Collapse
Affiliation(s)
- Anandi R Dave
- Community Health Physiotherapy, Ravi Nair Physiotherapy College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Tejaswini B Fating
- Community Health Physiotherapy, Ravi Nair Physiotherapy College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
7
|
Guo D, Zhou S, Liu R, Yao W, Li S, Zhang X, Shen W, Zhu S. NEK2 contributes to radioresistance in esophageal squamous cell carcinoma by inducing protective autophagy via regulating TRIM21. Cancer Cell Int 2024; 24:179. [PMID: 38783335 PMCID: PMC11112778 DOI: 10.1186/s12935-024-03367-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Radiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms. METHODS Human esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM). RESULTS In the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21. CONCLUSION These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.
Collapse
Affiliation(s)
- Dong Guo
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Shuo Zhou
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Ruixue Liu
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Weinan Yao
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Shuguang Li
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Xueyuan Zhang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Wenbin Shen
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Shuchai Zhu
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
| |
Collapse
|
|
8
|
Yang JY, Lei XY, He KY, Guo JR, Liu MJ, Li JQ, Li QT, Jiang ZH, Zhang L, Wu DH, Li YJ, Sun QH, Jian YP, Xu ZX. HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis. Cell Death Dis 2024; 15:158. [PMID: 38383528 PMCID: PMC10881472 DOI: 10.1038/s41419-024-06467-2] [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: 07/04/2023] [Revised: 01/06/2024] [Accepted: 01/11/2024] [Indexed: 02/23/2024]
Abstract
Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.
Collapse
Affiliation(s)
- Jing-Yu Yang
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Xin-Yuan Lei
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Kai-Yue He
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Jin-Rong Guo
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Meng-Jie Liu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Jun-Qi Li
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Qiu-Tong Li
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Zhi-Hao Jiang
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Lei Zhang
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Dan-Hui Wu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Yu-Jia Li
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Qian-Hui Sun
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China
| | - Yong-Ping Jian
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China.
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, China.
| |
Collapse
|
|
9
|
Oyoshi H, Du J, Sakai SA, Yamashita R, Okumura M, Motegi A, Hojo H, Nakamura M, Hirata H, Sunakawa H, Kotani D, Yano T, Kojima T, Nakamura Y, Kojima M, Suzuki A, Zenkoh J, Tsuchihara K, Akimoto T, Shibata A, Suzuki Y, Kageyama SI. Comprehensive single-cell analysis demonstrates radiotherapy-induced infiltration of macrophages expressing immunosuppressive genes into tumor in esophageal squamous cell carcinoma. SCIENCE ADVANCES 2023; 9:eadh9069. [PMID: 38091397 PMCID: PMC10848745 DOI: 10.1126/sciadv.adh9069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 11/10/2023] [Indexed: 12/18/2023]
Abstract
Radiotherapy (RT) combined with immunotherapy is promising; however, the immune response signature in the clinical setting after RT remains unclear. Here, by integrative spatial and single-cell analyses using multiplex immunostaining (CODEX), spatial transcriptome (VISIUM), and single-cell RNA sequencing, we substantiated the infiltration of immune cells into tumors with dynamic changes in immunostimulatory and immunosuppressive gene expression after RT. In addition, our comprehensive analysis uncovered time- and cell type-dependent alterations in the gene expression profile after RT. Furthermore, myeloid cells showed prominent up-regulation of immune response-associated genes after RT. Notably, a subset of infiltrating tumor-associated myeloid cells showing PD-L1 positivity exhibited significant up-regulation of immunostimulatory (HMGB1 and ISG15), immunosuppressive (SIRPA and IDO1), and protumor genes (CXCL8, CCL3, IL-6, and IL-1AB), which can be targets of immunotherapy in combination with PD-L1. These datasets will provide information on the RT-induced gene signature to seek an appropriate target for personalized immunotherapy combined with RT and guide the timing of combination therapy.
Collapse
Affiliation(s)
- Hidekazu Oyoshi
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Junyan Du
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
- Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8568, Japan
| | - Shunsuke A. Sakai
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
- Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8568, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
- Division of Cancer Immunology, Research Institute/ Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
| | - Masayuki Okumura
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Atsushi Motegi
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Hidehiro Hojo
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Masaki Nakamura
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Hidenari Hirata
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Hironori Sunakawa
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Tomonori Yano
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Yuka Nakamura
- Pathology Division, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Motohiro Kojima
- Pathology Division, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Ayako Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
| | - Junko Zenkoh
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
| | - Katsuya Tsuchihara
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
- Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8568, Japan
| | - Tetsuo Akimoto
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| | - Atsushi Shibata
- Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Shibakouen, Minato-ku, Tokyo, 105-8512, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
| | - Shun-Ichiro Kageyama
- Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
- Division of Cancer Immunology, Research Institute/ Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
- Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan
| |
Collapse
|
|
10
|
Kitagawa Y, Ishihara R, Ishikawa H, Ito Y, Oyama T, Oyama T, Kato K, Kato H, Kawakubo H, Kawachi H, Kuribayashi S, Kono K, Kojima T, Takeuchi H, Tsushima T, Toh Y, Nemoto K, Booka E, Makino T, Matsuda S, Matsubara H, Mano M, Minashi K, Miyazaki T, Muto M, Yamaji T, Yamatsuji T, Yoshida M. Esophageal cancer practice guidelines 2022 edited by the Japan Esophageal Society: part 2. Esophagus 2023:10.1007/s10388-023-00994-1. [PMID: 36995449 DOI: 10.1007/s10388-023-00994-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/27/2023] [Indexed: 03/31/2023]
Affiliation(s)
- Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Ryu Ishihara
- Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Hitoshi Ishikawa
- QST Hospital, National Institutes for Quantum Science and Technology, Chiba, Japan
| | - Yoshinori Ito
- Department of Radiation Oncology, Showa University School of Medicine, Tokyo, Japan
| | - Takashi Oyama
- Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International University of Health and Welfare School of Medicine, Chiba, Japan
| | - Tsuneo Oyama
- Department of Endoscopy, Saku Central Hospital Advanced Care Center, Nagano, Japan
| | - Ken Kato
- Department Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | | | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroshi Kawachi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shiko Kuribayashi
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takahiro Tsushima
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yasushi Toh
- National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Kenji Nemoto
- Department of Radiology, Yamagata University Graduate School of Medicine, Yamagata, Japan
| | - Eisuke Booka
- Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Satoru Matsuda
- Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Mano
- Department of Central Laboratory and Surgical Pathology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Keiko Minashi
- Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan
| | - Tatsuya Miyazaki
- Department of Surgery, Japanese Red Cross Maebashi Hospital, Gunma, Japan
| | - Manabu Muto
- Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Tomoki Yamatsuji
- Department of General Surgery, Kawasaki Medical School, Okayama, Japan
| | - Masahiro Yoshida
- Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, School of Medicine, International University of Health and Welfare Ichikawa Hospital, Chiba, Japan
| |
Collapse
|
|
11
|
Zandieh MA, Farahani MH, Rajabi R, Avval ST, Karimi K, Rahmanian P, Razzazan M, Javanshir S, Mirzaei S, Paskeh MDA, Salimimoghadam S, Hushmandi K, Taheriazam A, Pandey V, Hashemi M. Epigenetic regulation of autophagy by non-coding RNAs in gastrointestinal tumors: Biological functions and therapeutic perspectives. Pharmacol Res 2023; 187:106582. [PMID: 36436707 DOI: 10.1016/j.phrs.2022.106582] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/26/2022]
Abstract
Cancer is the manifestation of changes and mutations in genetic and epigenetic levels. Non-coding RNAs (ncRNAs) are commonly dysregulated in disease pathogenesis, and their role in cancer has been well-documented. The ncRNAs regulate various molecular pathways and mechanisms in cancer that can lead to induction/inhibition of carcinogenesis. Autophagy is a molecular "self-digestion" mechanism its function can be pro-survival or pro-death in tumor cells. The aim of the present review is to evaluate the role of ncRNAs in regulating autophagy in gastrointestinal tumors. The role of the ncRNA/autophagy axis in affecting the progression of gastric, liver, colorectal, pancreatic, esophageal, and gallbladder cancers is investigated. Both ncRNAs and autophagy mechanisms can function as oncogenic or onco-suppressor and this interaction can determine the growth, invasion, and therapy response of gastrointestinal tumors. ncRNA/autophagy axis can reduce/increase the proliferation of gastrointestinal tumors via the glycolysis mechanism. Furthermore, related molecular pathways of metastasis, such as EMT and MMPs, are affected by the ncRNA/autophagy axis. The response of gastrointestinal tumors to chemotherapy and radiotherapy can be suppressed by pro-survival autophagy, and ncRNAs are essential regulators of this mechanism. miRNAs can regulate related genes and proteins of autophagy, such as ATGs and Beclin-1. Furthermore, lncRNAs and circRNAs down-regulate miRNA expression via sponging to modulate the autophagy mechanism. Moreover, anti-cancer agents can affect the expression level of ncRNAs regulating autophagy in gastrointestinal tumors. Therefore, translating these findings into clinics can improve the prognosis of patients.
Collapse
Affiliation(s)
- Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Melika Heydari Farahani
- Faculty of Veterinary Medicine, Islamic Azad University, Shahr-e kord Branch, Chaharmahal and Bakhtiari, Iran
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Kimia Karimi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Vijay Pandey
- Precision Medicine and Healthcare Research Center, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, Guangdong, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| |
Collapse
|
|
12
|
Chen T, Xu B, Chen H, Sun Y, Song J, Sun X, Zhang X, Hua W. Transcription factor NFE2L3 promotes the proliferation of esophageal squamous cell carcinoma cells and causes radiotherapy resistance by regulating IL-6. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2022; 226:107102. [PMID: 36108571 DOI: 10.1016/j.cmpb.2022.107102] [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: 05/16/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To scrutinize the impact of overexpression and interference of NFE2L3 on radiosensitivity of esophageal squamous cell carcinoma cells (ESCC) and its downstream mechanism and to assess whether NFE2L3 expression alters in vivo radiosensitivity of ESCC by developing a subcutaneous tumor model in mice. METHODS Through RNA-Seq, we compared the differentially expressed genes between the ECA-109R cell line and its parent ECA-109 cell line. The differentially expressed genes were selected and verified by qRT-PCR. Transfection of ESCC cell lines with NFE2L3 inhibitor or mimic lentivirus constructs was done to study the activity of NFE2L3. To assess the effect of NFE2L3 on cellular growth and proliferation, clonogenic survival assay, EdU incorporation assay, and CCK-8 assay were done after irradiation. To probe how many irradiated DNA double-strand breaks were produced, the corresponding intensity of γ-H2AX foci were detected by immunofluorescence. Apoptotic cells were assayed by flow cytometry assay after irradiation; To investigate the downstream genes of NFE2L3, we knocked NFE2L3, and RNA-Seq was used to find out the downstream genes. qRT-PCR and western blot ensued to score associated protein profiles. The in vivo ESCC cell radiosensitivity was scrutinized by nude mouse xenograft models. RESULTS The differential genes between ECA-109R cells and its parent ECA-109 cells were compared by qRT-PCR to unveil a significant increase in NFE2L3 expression. Functional analysis indicated that NFE2L3 increased radioresistance in ESCC cells. Then, through high-throughput sequencing and bioinformatics analysis, IL-6 was found to be a hub gene that played a role downstream of NFE2L3 and was verified by qRT-PCR, western blot, and double luciferase reporter gene experiment. NFE2L3 could regulate ESCC cell radiosensitivity via the IL-6-STAT3 signaling pathway, and downregulation of IL-6 expression could reverse the effects of highly expressed NFE2L3. In vivo tumor xenograft experiments confirmed that NFE2L3 affects the sensitivity to radiation therapy. CONCLUSION NFE2L3 can affect the radiosensitivity of ESCC cells through IL-6 transcription and IL-6/STAT3 signaling pathway. This makes NFE2L3 a putative target to regulate ESCC cell radiosensitivity.
Collapse
Affiliation(s)
- Tingting Chen
- Department of Oncology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, PR China
| | - Bing Xu
- Department of Oncology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, PR China
| | - Hui Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Yuanyuan Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Jiahang Song
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Xinchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
| | - Xizhi Zhang
- Department of Oncology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, PR China.
| | - Wei Hua
- Department of Oncology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, PR China.
| |
Collapse
|
|
13
|
Deng W, Fan W, Li P, Yao J, Qi J, Chi H, Ji G, Zhao J. microRNA-497-mediated Smurf2/YY1/HIF2α axis in tumor growth and metastasis of esophageal squamous cell carcinoma. J Biochem Mol Toxicol 2022; 36:e23182. [PMID: 35938691 DOI: 10.1002/jbt.23182] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 06/08/2022] [Accepted: 07/21/2022] [Indexed: 11/12/2022]
Abstract
Aberrant expression of microRNA-497 (miR-497) is associated with tumor progression, but the molecular mechanisms in tumorigenesis remain largely unknown. Here, we report that miR-497 expression is downregulated in esophageal squamous cell carcinoma (ESCC) clinical samples. Consistently, upregulation of miR-497 inhibits ESCC cell malignant properties and tumor growth in vivo. Importantly, we uncovered that miR-497 upregulation suppressed ESCC cell growth and tumor growth by inhibiting Smurf2. Mechanistically, we showed that Smurf2 was a target of miR-497, and mediated YY1 expression to elevate HIF2α expression, thereby enhancing the malignancy of ESCC cells. Together, our study uncovered the role of the miR-497-mediated Smurf2/YY1/HIF2α axis in tumor growth and metastasis, which might provide potential therapeutic targets for human ESCC.
Collapse
Affiliation(s)
- Weijun Deng
- Department of Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Thoracic Surgery, Lianshui County People's Hospital, Huaian, China
| | - Wei Fan
- Department of Clinical Laboratory, Huai'an Tumor Hospital & Huai'an Hospital of Huai'an City, Huaian, China
| | - Peng Li
- Department of Radiotherapy, Huai'an Tumor Hospital & Huai'an Hospital of Huai'an City, Huaian, China
| | - Juan Yao
- Department of Radiotherapy, Huai'an Tumor Hospital & Huai'an Hospital of Huai'an City, Huaian, China
| | - Jinyou Qi
- Department of Clinical Laboratory, Huai'an Tumor Hospital & Huai'an Hospital of Huai'an City, Huaian, China
| | - Hao Chi
- Department of Clinical Laboratory, Huai'an Tumor Hospital & Huai'an Hospital of Huai'an City, Huaian, China
| | - Guoxian Ji
- Department of Radiotherapy, Huai'an Tumor Hospital & Huai'an Hospital of Huai'an City, Huaian, China
| | - Jun Zhao
- Department of Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
14
|
Cabalag CS, Yates M, Corrales MB, Yeh P, Wong SQ, Zhang BZ, Fujihara KM, Chong L, Hii MW, Dawson SJ, Phillips WA, Duong CP, Clemons NJ. Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma. Ann Surg 2022; 276:e120-e126. [PMID: 35737908 PMCID: PMC9259043 DOI: 10.1097/sla.0000000000005177] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To explore the clinical utility of circulating tumor DNA (ctDNA) in esophageal adenocarcinoma (EAC) by developing a cost-effective and rapid technique utilising targeted amplicon sequencing. SUMMARY OF BACKGROUND DATA Emerging evidence suggests that levels of ctDNA in the blood can be used to monitor treatment response and in the detection of disease recurrence in various cancer types. Current staging modalities for EAC such as computerised tomography of the chest/abdomen/pelvis (CT) and positron emission tomography (PET) do not reliably detect occult micro-metastatic disease, the presence of which signifies a poor prognosis. After curative-intent treatment, some patients are still at high risk of recurrent disease, and there is no widely accepted optimal surveillance tool for patients with EAC. METHODS Sixty-two patients with EAC were investigated for the presence of ctDNA using a tumor-informed approach. We designed a custom targeted amplicon sequencing panel of target specific primers covering mutational foci in 9 of the most commonly mutated genes in EAC. Serial blood samples were taken before and after neoadjuvant treatment (NAT), and during surveillance. RESULTS Somatic mutations were detected in pre-treatment biopsy samples of 55 out of 62 (89%) EAC patients. Mutations in TP53 (80%) were the most common. Out of these 55 patients, 20 (36%) had detectable ctDNA at baseline. The majority (90%) of patients with detectable ctDNA had either locally advanced tumors, nodal involvement or metastatic disease. In patients with locally advanced tumors, disease free survival (DFS) was more accurately stratified using pre-treatment ctDNA status [HR 4.34 (95% CI 0.93-20.21); P = 0.05] compared to nodal status on PET-CT. In an exploratory subgroup analysis, patients who are node negative but ctDNA positive have inferior DFS [HR 11.71 (95% CI 1.16-118.80) P = 0.04]. In blood samples taken before and following NAT, clearance of ctDNA after NAT was associated with a favourable response to treatment. Furthermore, patients who are ctDNA positive during post-treatment surveillance are at high risk of relapse. CONCLUSIONS Our study shows that ctDNA has potential to provide additional prognostication over conventional staging investigation such as CT and PET. It may also have clinical utility in the assessment of response to NAT and as a biomarker for the surveillance of recurrent disease.
Collapse
Affiliation(s)
- Carlos S Cabalag
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
| | - Michael Yates
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
| | | | - Paul Yeh
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
| | - Stephen Q Wong
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
| | - Bonnie Z Zhang
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
| | - Kenji M Fujihara
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
| | - Lynn Chong
- Department of Upper GI and Hepatobiliary Surgery, St. Vincent's Hospital, 41 Victoria Parade, Melbourne, Victoria
- University of Melbourne Department of Surgery, St Vincent's Hospital, 41 Victoria Parade, Melbourne, Victoria; and
| | - Michael W Hii
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- University of Melbourne Department of Surgery, St Vincent's Hospital, 41 Victoria Parade, Melbourne, Victoria; and
| | - Sarah-Jane Dawson
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
- The University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Level 10, 305 Grattan Street, Melbourne, Victoria
| | - Wayne A Phillips
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
- University of Melbourne Department of Surgery, St Vincent's Hospital, 41 Victoria Parade, Melbourne, Victoria; and
| | - Cuong P Duong
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
| | - Nicholas J Clemons
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Victoria
| |
Collapse
|
|
15
|
Chen SB, Liu DT, Chen YP. Surgical resection for esophageal adenosquamous carcinoma: an analysis of 56 cases. World J Surg Oncol 2022; 20:143. [PMID: 35509082 PMCID: PMC9066921 DOI: 10.1186/s12957-022-02607-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 04/19/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Esophageal adenosquamous carcinoma (EASC) is a rare disease. The biological behavior and treatment of this malignancy are not well studied. METHODS Data from 56 patients with EASC who underwent esophagectomy were retrospectively analyzed and compared with 5028 patients with esophageal squamous cell carcinoma (ESCC). The impact of clinicopathological factors on the survival of patients with EASC was analyzed. The survival differences between patients with EASC and ESCC were also compared. RESULTS There were 43 males and 13 females with a mean age of 59.7 ± 1.3 years (range, 39-79 years). Only 1 of the 43 patients who received preoperative esophagoscopic biopsy was diagnosed with EASC. The median survival time for patients with EASC was 32.0 months, and the 1-, 3-, and 5-year overall survival rates were 78.3%, 46.1%, and 29.6%, respectively. Resection margin, pN category, and adjuvant chemotherapy were found to be independent predictors. After 1:1 propensity score matching, the 5-year overall survival rate of 29.6% for patients with EASC was similar to that of 42.5% for patients with ESCC (P = 0.179). CONCLUSIONS EASC is a rare disease and is easily misdiagnosed by esophagoscopic biopsy. The prognosis of EASC was similar to that of ESCC. Postoperative adjuvant chemotherapy may improve the survival of patients with EASC after esophagectomy.
Collapse
Affiliation(s)
- Shao-Bin Chen
- Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, 515000, Guangdong Province, China
| | - Di-Tian Liu
- Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, 515000, Guangdong Province, China
| | - Yu-Ping Chen
- Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, 515000, Guangdong Province, China
| |
Collapse
|
|
16
|
Oshikiri T, Goto H, Kato T, Sawada R, Harada H, Urakawa N, Hasegawa H, Kanaji S, Yamashita K, Matsuda T, Fujino Y, Tominaga M, Kakeji Y. Proposed modification of the eighth edition of the AJCC-ypTNM staging system of esophageal squamous cell cancer treated with neoadjuvant chemotherapy: Unification of the AJCC staging system and the Japanese classification. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:1760-1767. [DOI: 10.1016/j.ejso.2022.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/04/2021] [Accepted: 01/14/2022] [Indexed: 10/19/2022]
|
|
17
|
Xiao J, Zhang Y, Fang T, Yuan T, Tian Q, Liu J, Cheng Y, Zhu Y, Cheng L, Cui W. Mineralized manganese dioxide channel as the stent coating for in situ precise tumor navigation. NANO RESEARCH 2021; 14:2145-2153. [DOI: 10.1007/s12274-020-3114-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/06/2020] [Accepted: 09/12/2020] [Indexed: 08/30/2023]
|
|
18
|
Verma R, Sattar RSA, Nimisha, Apurva, Kumar A, Sharma AK, Sumi MP, Ahmad E, Ali A, Mahajan B, Saluja SS. Cross-talk between next generation sequencing methodologies to identify genomic signatures of esophageal cancer. Crit Rev Oncol Hematol 2021; 162:103348. [PMID: 33961993 DOI: 10.1016/j.critrevonc.2021.103348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/22/2021] [Accepted: 05/01/2021] [Indexed: 02/07/2023] Open
Abstract
The asymptomatic behaviour of esophageal cancerous cells at early stages develops advanced clinical presentation of the disease, resulting in poor prognosis and curbed intervention of therapeutic modalities. The endeavours to detect diagnostic and prognostic markers have been proven futile at the clinical platform. While several biomarkers have been investigated, including CYFRA 21-1, carcinoembryonic antigen and squamous cell carcinoma antigen, their sensitivity has not proved consistently satisfactory across the various stages of esophageal cancer. Hence, there is an impending requirement of biomarkers for early diagnosis and better prognosis. In the recent past, next generation sequencing (NGS) tool has emerged as an important tool to highlight the hallmarks of esophageal cancer (EC). This review summarizes the changes/mutations occurred in tumor cells during carcinogenesis and addresses the contribution of NGS techniques, viz. whole genome sequencing (WGS), RNA-Sequencing and Exome sequencing (ES), in EC. Additionally, this review highlights the connection between the findings from these techniques. An effort has been made to emphasize the genes affected and involved signaling pathway in EC. Further, investigations of these mutated genes would not only shed light on the relevant genes to be studied but also help in the better management and cure through personalized therapy.
Collapse
Affiliation(s)
- Renu Verma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Real Sumayya Abdul Sattar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Apurva
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Mamta Parveen Sumi
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ejaj Ahmad
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Department of Biochemistry, All India Institute of Medical Science (AIIMS), Patna, Bihar, India
| | - Bhawna Mahajan
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Sundeep Singh Saluja
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
| |
Collapse
|
|
19
|
Luo Q, Wu X, Zhao P, Nan Y, Chang W, Zhu X, Su D, Liu Z. OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002874. [PMID: 33898171 PMCID: PMC8061361 DOI: 10.1002/advs.202002874] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 12/29/2020] [Indexed: 05/25/2023]
Abstract
Apoptosis-inducing factor (AIF) plays a dual role in regulating cell survival and apoptosis, acting as a prosurvival factor in mitochondria via its NADH oxidoreductase activity and activating the caspase-independent apoptotic pathway (i.e., parthanatos) after nuclear translocation. However, whether one factor conjunctively controls the separated functions of AIF is not clear. Here, it is shown that OTU deubiquitinase 1 (OTUD1) acts as a link between the two functions of AIF via deubiquitination events. Deubiquitination of AIF at K244 disrupts the normal mitochondrial structure and compromises oxidative phosphorylation, and deubiquitination of AIF at K255 enhances its DNA-binding ability to promote parthanatos. Moreover, OTUD1 stabilizes DDB1 and CUL4 associated factor 10 (DCAF10) and recruits the cullin 4A (CUL4A)-damage specific DNA binding protein 1 (DDB1) complex to promote myeloid cell leukemia sequence 1 (MCL1) degradation, thereby activating caspase-dependent apoptotic signaling. Collectively, these results reveal the central role of OTUD1 in activating both caspase-independent and caspase-dependent apoptotic signaling and propose decreased OTUD1 expression as a key event promoting chemoresistance in esophageal squamous cell carcinoma.
Collapse
Affiliation(s)
- Qingyu Luo
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Xiaowei Wu
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Pengfei Zhao
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Yabing Nan
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Wan Chang
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Xiaolin Zhu
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| | - Dan Su
- Department of PathologyZhejiang Cancer HospitalZhejiang310022China
| | - Zhihua Liu
- State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China
| |
Collapse
|
|
20
|
Dai SL, Wei SS, Zhang C, Li XY, Liu YP, Ma M, Lv HL, Zhang Z, Zhao LM, Shan BE. MTA2 promotes the metastasis of esophageal squamous cell carcinoma via EIF4E-Twist feedback loop. Cancer Sci 2021; 112:1060-1074. [PMID: 33340431 PMCID: PMC7935808 DOI: 10.1111/cas.14778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/08/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Metastasis‐associated protein 2 (MTA2) is frequently amplified in many types of cancers; however, the role and underlying molecular mechanism of MTA2 in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we reported that MTA2 is highly expressed in ESCC tissue and cells, and is closely related to the malignant characteristics and poor prognosis of patients with ESCC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promoted ESCC growth, metastasis, and epithelial‐mesenchymal transition (EMT) progression. This integrative analysis combined with expression microarray showed that MTA2 could interact with eukaryotic initiation factor 4E (EIF4E), which positively regulates the expression of Twist, known as a master regulator of EMT. Moreover, the results of chromatin immunoprecipitation revealed that MTA2 was recruited to the E‐cadherin promoter by Twist, which reduced the acetylation level of the promoter region and thus inhibited expression of E‐cadherin, and subsequently promoted the aggressive progression of ESCC. Collectively, our study provided novel evidence that MTA2 plays an aggressive role in ESCC metastasis by a novel EIF4E‐Twist positive feedback loop, which may provide a potential therapeutic target for the management of ESCC.
Collapse
Affiliation(s)
- Su-Li Dai
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Si-Si Wei
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Cong Zhang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiao-Ya Li
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yue-Ping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ming Ma
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hui-Lai Lv
- Department of Fifth Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhenzhen Zhang
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Lian-Mei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bao-En Shan
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
21
|
Schweigert M, Solymosi N, Dubecz A, GonzáLez MP, Stein HJ, Ofner D. One Decade of Experience with Endoscopic Stenting for Intrathoracic Anastomotic Leakage after Esophagectomy: Brilliant Breakthrough or Flash in the Pan? Am Surg 2020. [DOI: 10.1177/000313481408000820] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Management of intrathoracic anastomotic leakage after esophagectomy by means of endoscopic stent insertion has gained wide acceptance as an alternative to surgical reintervention. Between January 2004 and March 2013 all patients who underwent esophagectomy at a German high-volume center for esophageal surgery were included in this retrospective study. The study comprises 356 patients. Anastomotic leakage occurred in 49 cases. There were no significant differences in age, American Society of Anesthesiologists (ASA) score, or frequency of neoadjuvant therapy between cases with and without leak. However, leak patients sustained significantly more often postoperative pneumonia, pleural empyema, sepsis, and acute renal failure. Moreover, leak victims had higher odds for fatal outcome (16 of 49 vs 33 of 307; odds ratio, 5.94; 95% confidence interval, 2.65 to 13.15; P < 0.0001). The leakage was amendable by endoscopic stenting in 29 cases, whereas rethoracotomy was mandatory in 20 patients. Between stent and rethoracotomy cases, we observed no significant differences in age, ASA score, neoadjuvant therapy, occurrence of pneumonia, pleural empyema, or tracheostomy rate. Rethoracotomy patients sustained more often sepsis (16 of 20 vs 14 of 29; P = 0.04) and acute renal failure (nine of 20 vs four of 29; P = 0.02) as expression of more severe septic disease. Nevertheless, there was no significant difference in mortality (seven of 29 vs nine of 20; P = 0.21). Furthermore, we observed three cases of stent-related aortic erosion with peracute death from exsanguination. Despite being the preferred treatment option, endoscopic stenting was only feasible in approximately 60 per cent of all intrathoracic leaks. The results are marred by the occurrence of deadly vascular erosion. Therefore, individualized strategies should be preferred to a general recommendation for endoscopic stenting.
Collapse
Affiliation(s)
- Michael Schweigert
- Department of Surgery, Klinikum Neumarkt, Neumarkt, Germany; the
- Department of General and Thoracic Surgery, Klinikum Nuremberg, Nuremberg, Germany
| | | | - Attila Dubecz
- Department of General and Thoracic Surgery, Klinikum Nuremberg, Nuremberg, Germany
| | | | - Hubert J. Stein
- Department of General and Thoracic Surgery, Klinikum Nuremberg, Nuremberg, Germany
| | - Dietmar Ofner
- Department of Surgery, Paracelsus Medical University, Salzburg, Austria
| |
Collapse
|
|
22
|
Hu J, Li R, Miao H, Wen Z. Identification of key genes for esophageal squamous cell carcinoma via integrated bioinformatics analysis and experimental confirmation. J Thorac Dis 2020; 12:3188-3199. [PMID: 32642240 PMCID: PMC7330802 DOI: 10.21037/jtd.2020.01.33] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Esophageal squamous cell carcinoma (ESCC) as the main subtype of esophageal cancer (EC) is a leading cause of cancer-related death worldwide. Despite advances in early diagnosis and clinical management, the long-term survival of ESCC patients remains disappointing, due to a lack of full understanding of the molecular mechanisms. Methods In order to identify the differentially expressed genes (DEGs) in ESCC, the microarray datasets GSE20347 and GSE26886 from Gene Expression Omnibus (GEO) database were analyzed. The enrichment analyses of gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Set Enrichment Analysis (GSEA) were performed for the DEGs. The protein-protein interaction (PPI) network of these DEGs was constructed using the Cytoscape software based on the STRING database to select as hub genes for weighted co-expression network analysis (WGCNA) with ESCC samples from TCGA database. Results A total of 746 DEGs were commonly shared in the two datasets including 286 upregulated genes and 460 downregulated genes in ESCC. The DEGs were enriched in biological processes such as extracellular matrix organization, proliferation and keratinocyte differentiation, and were enriched in biological pathways such as ECM-receptor interaction and cell cycle. GSEA analysis also indicated the enrichment of upregulated DEGs in cell cycle. The 40 DEGs were selected as hub genes. The MEblack module was found to be enriched in the cell cycle, Spliceosome, DNA replication and Oocyte meiosis. Among the hub genes correlated with MEblack module, GSEA analysis indicated that DEGs of TCGA samples with DLGAP5 upregulation was enriched in cell cycle. Moreover, the highly endogenous expression of DLGAP5 was confirmed in ESCC cells. DLGAP5 knockdown significantly inhibited the proliferation of ESCC cells. Conclusions DEGs and hub genes such as DLGAP5 from independent datasets in the current study will provide clues to elucidate the molecular mechanisms involved in development and progression of ESCC.
Collapse
Affiliation(s)
- Jia Hu
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Rongzhen Li
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Huikai Miao
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Zhesheng Wen
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| |
Collapse
|
|
23
|
Cui Y, Yang D, Wang W, Zhang L, Liu H, Ma S, Guo W, Yao M, Zhang K, Li W, Zhang Y, Guan F. Nicotinamide N-methyltransferase decreases 5-fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect. Mol Carcinog 2020; 59:940-954. [PMID: 32367570 DOI: 10.1002/mc.23209] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 12/28/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with poor prognosis. And different individuals respond to the same drug differently. Increasing evidence has confirmed that metabolism reprogramming was involved in the drug sensitivity of tumor cells. However, the potential molecular mechanism of 5-fluorouracil (5-FU) sensitivity remains to be elucidated in ESCC cells. In this study, we found that the 5-FU sensitivity of TE1 cells was lower than that of EC1 and Eca109 cells. Gas chromatography-mass spectrometry analysis results showed that nicotinate and nicotinamide metabolism and tricarboxylic acid cycle were significantly different in these three cell lines. Nicotinamide N-methyltransferase (NNMT), a key enzyme of nicotinate and nicotinamide metabolism, was significantly higher expressed in TE1 cells than that in EC1 and Eca109 cells. Therefore, the function of NNMT on 5-FU sensitivity was analyzed in vitro and in vivo. NNMT downregulation significantly increased 5-FU sensitivity in TE1 cells. Meanwhile, the glucose consumption and lactate production were decreased, and the expression of glycolysis-related enzymes hexokinase 2, lactate dehydrogenase A, and phosphoglycerate mutase 1 were downregulated in NNMT knockdown TE1 cells. Besides, overexpression of NNMT in EC1 and Eca109 cells caused the opposite effects. Moreover, when glycolysis was inhibited by 2-deoxyglucose, the roles of NNMT on 5-FU sensitivity was weakened. In vivo experiments showed that NNMT knockdown significantly increased the sensitivity of xenografts to 5-FU and suppressed the Warburg effect. Overall, these results demonstrated that NNMT decreases 5-FU sensitivity in human ESCC cells through promoting the Warburg effect, suggesting that NNMT may contribute to predict the treatment effects of the clinical chemotherapy in ESCC.
Collapse
Affiliation(s)
- Yanyan Cui
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Dawei Yang
- Zhongyuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, China
| | - Wenjie Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Luyu Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Hongtao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Wenna Guo
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Minghao Yao
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Kun Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanting Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou.,Clinical Research Guidance Center, Henan Provincial People's Hospital, Zhengzhou, China
| |
Collapse
|
|
24
|
ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness. Cell Death Differ 2019; 27:1981-1997. [PMID: 31831874 DOI: 10.1038/s41418-019-0475-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/03/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022] Open
Abstract
Squamous cell carcinoma (SCC) is defined as a category of aggressive malignancies arising from the squamous epithelium of various organs. Resistance to chemotherapies is a common feature of SCCs, which leads to a poor prognosis among SCC patients. Recently, studies have illustrated the essential tumor suppressive role of ARID1A in several cancer types, but its role in SCCs remains unclear. Cancer stemness has been recognized as a main reason for tumorigenesis and is commonly correlated with chemoresistance, yet the relationship between ARID1A and cancer stemness remains unknown. In this study, we showed that Arid1a conditional knockout mice had a high incidence of SCCs occurring in the tongue and esophagus. ARID1A depletion promoted tumor initiation and cancer stemness in human SCC cells. Mechanistic studies revealed that ARID1A blocked the interaction between cyclin-dependent kinases (CDKs) and retinoblastoma protein (Rb), reducing the phosphorylation of Rb. Dephosphorylated Rb suppressed E2F1 activity and then suppressed cancer stemness by inactivating c-Myc. Furthermore, we showed that ARID1A depletion significantly increased the chemoresistance of SCC and that a CDK inhibitor exhibited a favorable effect on rescuing the chemoresistance caused by ARID1A loss. Collectively, our study showed that ARID1A inhibits the cancer stemness of SCCs by competing with CDKs to bind with Rb to inhibit the E2F1/c-Myc pathway.
Collapse
|
|
25
|
Xiao J, Cheng L, Fang T, Zhang Y, Zhou J, Cheng R, Tang W, Zhong X, Lu Y, Deng L, Cheng Y, Zhu Y, Liu Z, Cui W. Nanoparticle-Embedded Electrospun Fiber-Covered Stent to Assist Intraluminal Photodynamic Treatment of Oesophageal Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1904979. [PMID: 31659867 DOI: 10.1002/smll.201904979] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/03/2019] [Indexed: 06/10/2023]
Abstract
Drug-eluting stents (DESs) are promising candidates for treating human oesophageal cancer. However, the use of DESs to assist photodynamic therapy (PDT) of orthotopic oesophageal tumors is not yet demonstrated to the best of current knowledge. Herein, through an electrospinning technology it is shown that oxygen-producing manganese dioxide nanoparticles are embedded into elelctrospun fibers, which are subsequently covered onto stents. Upon implantation, the nanoparticles are gradually released from the fibers and then diffuse into the nearby tumor tissue. Then, the hypoxic microenvironment can be effectively alleviated by reaction of MnO2 with the endogenous H2 O2 within the tumor. After demonstrating the excellent PDT efficacy of the stents in a conventional subcutaneous mouse tumor model, such stents are further used for PDT treatment in a rabbit orthotopic oesophageal cancer model by inserting an optical fiber into the tumor site. Greatly prolonged survival of rabbits is observed after such intraluminal PDT treatment. Taken together, this work shows that the fiber-covered stent as a nanoparticle delivery platform can enable effective PDT as a noninvasive treatment method for patients with advanced-stage oesophageal cancer.
Collapse
Affiliation(s)
- Junyuan Xiao
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, China
- Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Liang Cheng
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Tonglei Fang
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, China
| | - Yiran Zhang
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, China
| | - Jia Zhou
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, China
| | - Ruoyu Cheng
- Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wantao Tang
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Xiaoyan Zhong
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Yong Lu
- Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lianfu Deng
- Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yingsheng Cheng
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, China
| | - Yueqi Zhu
- Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai, 200233, China
| | - Zhuang Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory of Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Wenguo Cui
- Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| |
Collapse
|
|
26
|
CBX8 promotes tumorigenesis and confers radioresistance in esophageal squamous cell carcinoma cells through targeting APAF1. Gene 2019; 711:143949. [DOI: 10.1016/j.gene.2019.143949] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/24/2019] [Accepted: 06/26/2019] [Indexed: 11/22/2022]
|
|
27
|
Laursen L, Schønau MN, Bergenholtz HM, Siemsen M, Christensen M, Missel M. Table in the corner: a qualitative study of life situation and perspectives of the everyday lives of oesophageal cancer patients in palliative care. BMC Palliat Care 2019; 18:60. [PMID: 31331302 PMCID: PMC6647132 DOI: 10.1186/s12904-019-0445-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 07/09/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Incurable oesophageal cancer patients are often affected by existential distress and deterioration of quality of life. Knowledge about the life situation of this patient group is important to provide relevant palliative care and support. The purpose of this study is to illuminate the ways in which incurable oesophageal cancer disrupts the patients' lives and how the patients experience and adapt to life with the disease. METHODS Seventeen patients receiving palliative care for oesophageal cancer were interviewed 1-23 months after diagnosis. The epistemological approach was inspired by phenomenology and hermeneutics, and the method of data collection, analysis and interpretation consisted of individual qualitative interviews and meaning condensation, inspired by Kvale and Brinkmann. RESULTS The study reveals how patients with incurable oesophageal cancer experience metaphorically to end up at a "table in the corner". The patients experience loss of dignity, identity and community. The study illuminated how illness and symptoms impact and control daily life and social relations, described under these subheadings: "sense of isolation"; "being in a zombie-like state"; "one day at a time"; and "at sea". Patients feel alone with the threat to their lives and everyday existence; they feel isolated due to the inhibiting symptoms of their illness, anxiety, worry and daily losses and challenges. CONCLUSIONS The patients' lives are turned upside down, and they experience loss of health, function and familiar, daily habits. The prominent issues for the patients are loneliness and lack of continuity. As far as their normal everyday lives, social networks and the health system are concerned, patients feel they have been banished to a "table in the corner". These patients have a particular need for healthcare professionals who are dedicated to identifying what can be done to support the patients in their everyday lives, preserve dignity and provide additional palliative care.
Collapse
Affiliation(s)
- Louise Laursen
- Department of Palliative Care, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mai Nanna Schønau
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.,Roskilde University, Roskilde, Denmark
| | - Heidi Maria Bergenholtz
- Medical and Surgical Department, Holbaek Sygehus, Denmark & The Danish Knowledge Centre for Rehabilitation and Palliative Care, University of Southern Denmark, Odense, Denmark
| | - Mette Siemsen
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Merete Christensen
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - Malene Missel
- Department of Cardiothoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
| |
Collapse
|
|
28
|
Shi Y, Xu J, Wang Y, Tang J, Zhang C, Lv W, Hu J. Prognostic significance of preoperative lymph node assessment for patients with stage pN0 esophageal squamous cell carcinoma after esophagectomy. J Thorac Dis 2019; 11:732-743. [PMID: 31019761 DOI: 10.21037/jtd.2019.02.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Background Accurate preoperative lymph node (LN) staging is important for surgical treatments of esophageal squamous cell carcinoma (ESCC). The aim of the study was to investigate the role of preoperative lymph nodes assessment by computed tomography (CT) scans in prognostic estimates and lymph nodes dissection strategy. Methods A total of 233 stage pN0 ESCC patients who underwent radical esophagectomy from 2009 to 2016 were included, with the last follow-up time in 2018. Survival analysis was conducted to assess the relationship between preoperative clinical LN metastasis and the prognosis of patients with pN0 ESCC. Results Ninety-nine patients were classified as clinical positive LN metastasis by CT scans, but were confirmed as stage N0 by postoperative pathological examination, and survival analysis suggested that these patients had relatively poorer prognosis (P=0.027). Cox regression analysis indicated that the clinical LN metastasis on CT scans was an independent negative prognostic factor for patients with pN0 ESCC (P=0.031). The number of LNs dissected affected the prognosis of pN0 patients. Patients with positive LN metastasis on CT would have better prognosis when the number of dissected LNs was equal to or more than 15 LNs (P=0.036). Especially for patients with higher T stage, they were would obtain prognostic benefit with at least 17 LNs dissected (P=0.037). On the other hand, for those with negative LN metastasis on CT, at least 12 LNs dissected indicated better prognosis (P=0.019). Conclusions Preoperative LN assessment for ESCC patients is critically important, the optimal LN dissection number should refer to the preoperative CT performance.
Collapse
Affiliation(s)
- Yan Shi
- Department of Thoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jinming Xu
- Department of Thoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Ying Wang
- Operating Room, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jie Tang
- Department of Thoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chong Zhang
- Department of Thoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Wang Lv
- Department of Thoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jian Hu
- Department of Thoracic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| |
Collapse
|
|
29
|
Wang JN, Che Y, Yuan ZY, Lu ZL, Li Y, Zhang ZR, Li N, Li RD, Wan J, Sun HD, Sun N, Puno PT, He J. Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762. Toxicol Appl Pharmacol 2019; 365:71-83. [PMID: 30633885 DOI: 10.1016/j.taap.2019.01.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/04/2019] [Accepted: 01/04/2019] [Indexed: 11/17/2022]
Abstract
Natural products derived from herbal medicines have become a major focus of anti-cancer drug discovery studies. Acetyl-macrocalin B (A-macB) is an ent-diterpenoid isolated from Isodon silvatica. This study aimed to examine the effect and molecular action of A-macB in esophageal squamous cell carcinoma (ESCC) and explore possible drug synergistic modalities. A-macB induced cellular reactive oxygen species (ROS) generation, initiated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and triggered the caspase-9-dependent apoptosis cascade in ESCC cells. The ROS scavenger N-acetylcysteine (NAC) and the specific p38 inhibitor SB203580 reversed the effects of A-macB on the p38 network and thus rescued ESCC cells from apoptosis. The cellular ROS increase was at least partially due to the suppression of glutathione-S-transferase P1 (GSTP1) by A-macB. A-macB also upregulated the Chk1/Chk2-Cdc25C/Cdc2/Cyclin B1 axis to induce G2/M phase arrest. The cell growth inhibition induced by A-macB was further enhanced by AZD7762, a specific Chk1/Chk2 inhibitor, with a combination index (CI) of <1. Moreover, A-macB efficiently suppressed xenograft growth without inducing significant toxicity, and AZD7762 potentiated the effects of A-macB in the suppression of tumor growth in vivo. Taken together, A-macB is a promising lead compound for ESCC and exerts synergistic anti-cancer effects with AZD7762.
Collapse
Affiliation(s)
- Jing-Nan Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yun Che
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zu-Yang Yuan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhi-Liang Lu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuan Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhi-Rong Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ning Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ren-Da Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jun Wan
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China
| | - Han-Dong Sun
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China
| | - Nan Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Pema-Tenzin Puno
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| |
Collapse
|
|
30
|
Nariman-Saleh-Fam Z, Saadatian Z, Nariman-Saleh-Fam L, Ouladsahebmadarek E, Tavakkoly-Bazzaz J, Bastami M. An Association and Meta-Analysis of Esophageal Squamous Cell Carcinoma Risk Associated with PLCE1 rs2274223, C20orf54 rs13042395 and RUNX1 rs2014300 Polymorphisms. Pathol Oncol Res 2019; 26:681-692. [PMID: 30666517 DOI: 10.1007/s12253-019-00579-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 01/04/2019] [Indexed: 02/06/2023]
Abstract
One of the highest risk of esophageal squamous cell carcinoma (ESCC) in the world has been reported in Iran, which is located in the Asian esophageal cancer belt. ESCC constitutes 90% of the esophageal cancer cases in Iran. Genome wide association studies (GWASs) in Chinese have identified a number of candidate variants, of which PLCE1rs2274223, C20orf54rs13042395 and RUNX1rs2014300 are studied in high risk populations including Chinese, Caucasians and Africans. However, results are inconsistent and it is unknown whether similar associations exist in Iranian population. We evaluated association of three GWAS identified variants with risk of ESCC in an Iranian cohort consisted of 200 ESCC patients and 300 healthy controls and conducted meta-analysis of ESCC risk associated with rs2274223 (involving 9810 cases and 13,128 controls) and rs13042395 (involving 2363 cases and 5329 controls). Logistic regression analysis showed that rs2274223 was associated with ESCC under codominant [GG/AA, 2.47(1.17-5.23), P:0.021], dominant [AG + GG/AA, 1.57(1.09-2.27), P:0.016], recessive [GG/AA+AG, 2.18(1.04-4.56), P:0.036] and log-additive models [1.51(1.12-2.02), P:0.006]. C20orf54 rs13042395 was not associated with ESCC under any genetic model. RUNX1 rs2014300 was associated with risk of ESCC assuming codominant [AG/GG, 0.63(0.41-0.97), P:0.018], dominant [AG + AA/GG, 0.59 (0.39-0.89), P:0.010] and log-additive models [0.61 (0.42-0.87), P: 0.005]. Meta-analysis found significant associations between rs2274223 and ESCC under all analyzed genetic models. However, meta-analysis stratified by ethnicity showed a significant association in Asians but not non-Asian populations. No significant association was found for rs13042395 in meta-analysis. This study provided first evidence for association of GWAS-identified variants with risk of ESCC in an Iranian cohort.
Collapse
Affiliation(s)
- Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Saadatian
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lida Nariman-Saleh-Fam
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elaheh Ouladsahebmadarek
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Tavakkoly-Bazzaz
- Medical Genetics Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Milad Bastami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
31
|
Kitagawa Y, Uno T, Oyama T, Kato K, Kato H, Kawakubo H, Kawamura O, Kusano M, Kuwano H, Takeuchi H, Toh Y, Doki Y, Naomoto Y, Nemoto K, Booka E, Matsubara H, Miyazaki T, Muto M, Yanagisawa A, Yoshida M. Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2. Esophagus 2019; 16:25-43. [PMID: 30171414 PMCID: PMC6510875 DOI: 10.1007/s10388-018-0642-8] [Citation(s) in RCA: 316] [Impact Index Per Article: 52.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 08/22/2018] [Indexed: 02/03/2023]
Affiliation(s)
- Yuko Kitagawa
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan
| | - Takashi Uno
- grid.136304.30000 0004 0370 1101Department of Radiology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tsuneo Oyama
- grid.416751.00000 0000 8962 7491Department of Gastroenterology, Saku Central Hospital, Nagano, Japan
| | - Ken Kato
- grid.272242.30000 0001 2168 5385Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroyuki Kato
- grid.411582.b0000 0001 1017 9540Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hirofumi Kawakubo
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan
| | - Osamu Kawamura
- grid.411887.30000 0004 0595 7039Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Maebashi, Gunma Japan
| | - Motoyasu Kusano
- grid.411887.30000 0004 0595 7039Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Maebashi, Gunma Japan
| | - Hiroyuki Kuwano
- grid.256642.10000 0000 9269 4097Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma Japan
| | - Hiroya Takeuchi
- grid.505613.40000 0000 8937 6696Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka Japan
| | - Yasushi Toh
- Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka, Japan
| | - Yuichiro Doki
- grid.136593.b0000 0004 0373 3971Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka Japan
| | - Yoshio Naomoto
- grid.415086.e0000 0001 1014 2000Department of General Surgery, Kawasaki Medical School, Okayama, Japan
| | - Kenji Nemoto
- grid.268394.20000 0001 0674 7277Department of Radiation Oncology, Yamagata University School of Medicine, Yonezawa, Japan
| | - Eisuke Booka
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan
| | - Hisahiro Matsubara
- grid.136304.30000 0004 0370 1101Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuya Miyazaki
- grid.256642.10000 0000 9269 4097Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma Japan
| | - Manabu Muto
- grid.411217.00000 0004 0531 2775Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan
| | - Akio Yanagisawa
- grid.272458.e0000 0001 0667 4960Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Yoshida
- grid.411731.10000 0004 0531 3030Department of Hemodialysis and Surgery, Chemotherapy Research Institute, International University of Health and Welfare, Ichikawa, Japan
| |
Collapse
|
|
32
|
Sugimoto K, Ito T, Woo J, Tully E, Sato K, Orita H, Brock MV, Gabrielson E. Prognostic Impact of Phosphorylated Discoidin Domain Receptor-1 in Esophageal Cancer. J Surg Res 2018; 235:479-486. [PMID: 30691832 DOI: 10.1016/j.jss.2018.10.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/17/2018] [Accepted: 10/18/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is common in East Asia and also is often deadly. We sought to determine whether measuring the discoidin domain receptor-1 (DDR1)-both total and phosphorylated proteins-could improve our ability to predict recurrence in ESCC. MATERIALS AND METHODS Total DDR1 and phosphorylated DDR1 (pDDR1) were measured using semiquantitative immunohistochemistry in a cohort of 60 patients with ESCC. Association between these immunohistochemical measurements and standard clinical-pathological variables such as patient recurrence-free survival was examined using univariate and multivariate analyses. RESULTS Six patients (10.0%) had regional recurrence and eight patients (13.3%) had distant recurrence. In univariate analysis, early disease recurrence correlated with intense staining of total DDR1 (P = 0.03) as well as intense staining of pDDR1 (P < 0.001). On multivariate analysis, only regional lymph node metastasis (P = 0.04, HR = 4.20) and intensity of pDDR1 immunohistochemistry (P = 0.03, HR = 4.27) emerged as significant independent prognostic factors for recurrence. CONCLUSIONS This study suggests that immunohistochemical measurements of both the DDR1 protein and pDDR1 can provide prognostic value in ESCC, even when other clinical and pathological factors are also being considered.
Collapse
Affiliation(s)
- Kiichi Sugimoto
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Coloproctological Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Tomoaki Ito
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Juntendo University Shizuoka Hospital, Izunokuni-shi, Shizuoka, Japan
| | - Juhyung Woo
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ellen Tully
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Koichi Sato
- Department of Surgery, Juntendo University Shizuoka Hospital, Izunokuni-shi, Shizuoka, Japan
| | - Hajime Orita
- Department of Surgery, Juntendo University Shizuoka Hospital, Izunokuni-shi, Shizuoka, Japan
| | - Malcolm V Brock
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Edward Gabrielson
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| |
Collapse
|
|
33
|
Involving the microRNA Targetome in Esophageal-Cancer Development and Behavior. Cancers (Basel) 2018; 10:cancers10100381. [PMID: 30322005 PMCID: PMC6210990 DOI: 10.3390/cancers10100381] [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: 08/30/2018] [Revised: 10/09/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer (EC) is the eighth most common and sixth leading cause of cancer-related mortality in the world. Despite breakthroughs in EC diagnosis and treatment, patients with complete pathologic response after being submitted to chemoradiotherapy are still submitted to surgery, despite its high morbidity. Single-nucleotide polymorphisms (SNPs) in miRNA, miRNA-binding sites, and in its biogenesis pathway genes can alter miRNA expression patterns, thereby influencing cancer risk and prognosis. In this review, we systematized the information available regarding the impact of these miR-SNPs in EC development and prognosis. We found 34 miR-SNPs that were associated with EC risk. Despite the promising applicability of these miR-SNPs as disease biomarkers, they still lack validation in non-Asian populations. Moreover, there should be more pathway-based approaches to evaluate the cumulative effect of multiple unfavorable genotypes and, consequently, identify miR-SNPs signatures capable of predicting EC therapy response and prognosis.
Collapse
|
|
34
|
Tong Q, Wang XL, Li SB, Yang GL, Jin S, Gao ZY, Liu XB. Combined detection of IL-6 and IL-8 is beneficial to the diagnosis of early stage esophageal squamous cell cancer: a preliminary study based on the screening of serum markers using protein chips. Onco Targets Ther 2018; 11:5777-5787. [PMID: 30254470 PMCID: PMC6140751 DOI: 10.2147/ott.s171242] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background The diagnosis rate of early stage esophageal squamous cell carcinoma (ESCC) is low due to the lack of specific tumor markers. Seeking for these markers is beneficial to improve the early diagnosis rate and the prognosis of patients. This study profiles the differentially expressed proteins of early stage ESCC patients via the AAH-BLG-507 protein chip, which further consolidates the clinical evidence of ESCC diagnosis. Materials and methods In this study, 20 serum samples were collected from Taihe Hospital between August 2016 and June 2017. Ten of them carried ESCC, while the rest were healthy controls. To profile the proteins’ expression level, the AAH-BLG-507 protein chip was used, and both highly expressed and lowly expressed proteins were fished out. Meanwhile, their biological roles were examined by using Gene Ontology (GO) database and String database, and they were further verified by ELISA. Results Results showed that the expression levels of AXL, ARTN, Ang2, BDNF, BMP7, cripto-1, CCL28, E-selectin, IL-6, IL-8 and SHH in the serum of early ESCC were significantly upregulated (P<0.05), particularly IL-6 and IL-8. The expression levels of TSP1 and MMP-8 were markedly downregulated (P<0.05). Analysis showed that these proteins were mainly involved in angiogenesis, signal transduction, cell proliferation and migration, indicating the close relationship with the development of ESCC. Conclusion It suggested that IL-6 and IL-8 proteins could be considered as the markers for ESCC diagnosis.
Collapse
Affiliation(s)
- Qiang Tong
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Xiao-Long Wang
- Department of Gastroenterology, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China
| | - Sheng-Bao Li
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Gong-Li Yang
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Shu Jin
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Zi-Ye Gao
- Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China
| | - Xiao-Bo Liu
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| |
Collapse
|
|
35
|
Missel M, Hansen M, Jackson R, Siemsen M, Schønau MN. Re-embodying eating after surgery for oesophageal cancer: Patients' lived experiences of participating in an education and counselling nutritional intervention. J Clin Nurs 2018; 27:1420-1430. [PMID: 29399901 DOI: 10.1111/jocn.14297] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2018] [Indexed: 12/20/2022]
Abstract
AIMS AND OBJECTIVES To provide in-depth insight into patients' lived experiences of participating in an education and counselling nutritional intervention after curative surgery for oesophageal cancer. BACKGROUND Surgery for oesophageal cancer carries a risk of malnutrition. The consequences of nutritional problems may lead to increased morbidity and mortality postoperatively and have consequences for convalescence, rehabilitation and quality of life. DESIGN Qualitative study based on a phenomenological approach. The theoretical framework was grounded in the philosophy of Merleau-Ponty. METHODS Qualitative interviews were conducted with 10 patients who participated in an education and counselling nutritional intervention after surgery for oesophageal squamous-cell carcinoma. Data were analysed according to the principles of Kvale and Brinkmann, and their three levels of interpretation were applied. FINDINGS The essence of experiencing the education and counselling nutritional intervention can be divided into three themes: embodied disorientation, living with increased attention to bodily functions and re-embodying eating. CONCLUSIONS Patients were living with increased attention to bodily functions and tried to find a balance between the task of eating and nutritional needs. Despite the embodied perceptions of alterations after oesophageal cancer surgery, the patients developed high levels of bodily awareness and skills in self-management. This process was characterised by reconnecting to the body and re-embodying eating. The intervention empowered the patients to regain some control of their own bodies in an effort to regain agency in their own lives. RELEVANCE TO CLINICAL PRACTICE There is a need for systematic long-term follow-up after surgery for oesophageal cancer regarding nutrition. The findings of this study can inform future supportive nutrition care service development aimed at supporting patients to learn to eat sufficiently after oesophageal resection.
Collapse
Affiliation(s)
- Malene Missel
- Department of Cardiothoracic Surgery, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Rie Jackson
- Department of Anaesthesiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Mette Siemsen
- Department of Cardiothoracic Surgery, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Mai Nanna Schønau
- Department of Cardiothoracic Surgery, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
36
|
Mo R, Chen C, Pan L, Yu A, Wang D, Wang T. Is the new distribution of early esophageal adenocarcinoma stages improving the prognostic prediction of the 8 th edition of the TNM staging system for esophageal cancer? J Thorac Dis 2018; 10:5192-5198. [PMID: 30416766 DOI: 10.21037/jtd.2018.08.98] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background The 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system released in 2017 reclassified the pTNM stage of early esophageal adenocarcinoma from stage IA in the 7th edition to stage IA and IB and from stage IB in the 7th edition to stage IC. In this study, we analyzed the reliability of the new staging system through clinical data analysis. Methods We selected patient data from the Surveillance, Epidemiology, and End Results (SEER) database. From 2004 to 2014, data for a total of 714 patients were included in the study and were divided into groups representing stage IA (n=84), IB (n=386) and IC (n=244) according to the 8th edition. Results In the 8th edition, there was no significant difference between groups IA and IB in overall survival (OS) (P=0.331) or esophageal cancer-specific survival (ECSS) (P=0.341). However, the long-term survival rates of groups IA and IB were significantly higher than those of group IC. Cox regression analysis indicated that the use of new staging system does not affect prognosis. We also attempted to stratify the tumors by T stage and histological grade but found no significant difference. Conclusions We used the SEER database to compare the staging of early esophageal adenocarcinomas between the 8th and 7th editions of the AJCC/UICC TNM staging system. Based on our data, the 8th edition is not superior to the 7th edition.
Collapse
Affiliation(s)
- Ran Mo
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University, Nanjing 210008, China
| | - Chen Chen
- Department of Nutrition, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University, Nanjing 210008, China
| | - Liang Pan
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University, Nanjing 210008, China
| | - Ao Yu
- Medical School of Southeast University, Nanjing 210018, China
| | - Dongjin Wang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University, Nanjing 210008, China
| | - Tao Wang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University, Nanjing 210008, China
| |
Collapse
|
|
37
|
Kröll D, Noser L, Erdem S, Storni F, Arnold D, Dislich B, Zlobec I, Candinas D, Seiler CA, Langer R. Application of the 8th edition of the AJCC yTNM staging system shows improved prognostication in a single center cohort of esophageal carcinomas. Surg Oncol 2018; 27:100-105. [DOI: 10.1016/j.suronc.2017.12.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/22/2017] [Accepted: 12/29/2017] [Indexed: 01/08/2023]
|
|
38
|
Liu DS, Hoefnagel SJM, Fisher OM, Krishnadath KK, Montgomery KG, Busuttil RA, Colebatch AJ, Read M, Duong CP, Phillips WA, Clemons NJ. Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis. Oncotarget 2018; 7:83342-83358. [PMID: 27863424 PMCID: PMC5347774 DOI: 10.18632/oncotarget.13391] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 10/19/2016] [Indexed: 12/21/2022] Open
Abstract
There is currently a paucity of preclinical models available to study the metastatic process in esophageal cancer. Here we report FLO-1, and its isogenic derivative FLO-1LM, as two spontaneously metastatic cell line models of human esophageal adenocarcinoma. We show that FLO-1 has undergone epithelial-mesenchymal transition and metastasizes following subcutaneous injection in mice. FLO-1LM, derived from a FLO-1 liver metastasis, has markedly enhanced proliferative, clonogenic, anti-apoptotic, invasive, immune-tolerant and metastatic potential. Genome-wide RNAseq profiling revealed a significant enrichment of metastasis-related pathways in FLO-1LM cells. Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1. Consistent with this, repression of E-cadherin expression in FLO-1 cells resulted in increased metastatic activity. Importantly, reduced E-cadherin expression is commonly reported in esophageal adenocarcinoma and independently predicts poor patient survival. Collectively, these findings highlight the biological importance of E-cadherin activity in the pathogenesis of metastatic esophageal adenocarcinoma and validate the utility of FLO-1 parental and FLO-1LM cells as preclinical models of metastasis in this disease.
Collapse
Affiliation(s)
- David S Liu
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Sanne J M Hoefnagel
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands
| | - Oliver M Fisher
- Gastroesophageal Cancer Program, St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, 2010, Australia
| | - Kausilia K Krishnadath
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.,Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands
| | - Karen G Montgomery
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
| | - Rita A Busuttil
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.,The University of Melbourne Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, 3010, Australia
| | - Andrew J Colebatch
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
| | - Matthew Read
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Cuong P Duong
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia
| | - Wayne A Phillips
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.,University of Melbourne Department of Surgery, St Vincent's Hospital, Fitzroy, Victoria, 3065, Australia
| | - Nicholas J Clemons
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia
| |
Collapse
|
|
39
|
Qiao Y, Zhang C, Li A, Wang D, Luo Z, Ping Y, Zhou B, Liu S, Li H, Yue D, Zhang Z, Chen X, Shen Z, Lian J, Li Y, Wang S, Li F, Huang L, Wang L, Zhang B, Yu J, Qin Z, Zhang Y. IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene 2018; 37:873-883. [PMID: 29059160 DOI: 10.1038/onc.2017.387] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 08/28/2017] [Accepted: 09/12/2017] [Indexed: 12/18/2022]
Abstract
Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers. Here, we analyzed the factors and molecular mechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC). We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway. CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance. In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial-mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay. In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation. These results suggest that the IL6-CXCR7 axis may provide a promising target for the treatment of ESCC.
Collapse
MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Apoptosis
- Biomarkers, Tumor
- Cancer-Associated Fibroblasts/drug effects
- Cancer-Associated Fibroblasts/metabolism
- Cancer-Associated Fibroblasts/pathology
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/secondary
- Cell Proliferation
- Drug Resistance, Neoplasm
- Epithelial-Mesenchymal Transition
- Esophageal Neoplasms/drug therapy
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Interleukin-6/genetics
- Interleukin-6/metabolism
- Lymphatic Metastasis
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Neoplasm Invasiveness
- Neoplasm Recurrence, Local
- Prognosis
- Receptors, CXCR/genetics
- Receptors, CXCR/metabolism
- Signal Transduction
- Survival Rate
- Tumor Cells, Cultured
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
Collapse
Affiliation(s)
- Y Qiao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - C Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - A Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - D Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Z Luo
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Y Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - B Zhou
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - S Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - H Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - D Yue
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Z Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - X Chen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Z Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - J Lian
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Y Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - S Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - F Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - L Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - L Wang
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - B Zhang
- Department of Hematology/Oncology, School of Medicine, Northwestern University, Chicago, IL, USA
| | - J Yu
- Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Z Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Y Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
- Key Laboratory for Tumor Immunology and Biotherapy of Henan Province, Zhengzhou, China
| |
Collapse
|
|
40
|
Novel circulating peptide biomarkers for esophageal squamous cell carcinoma revealed by a magnetic bead-based MALDI-TOFMS assay. Oncotarget 2018; 7:23569-80. [PMID: 26993605 PMCID: PMC5029648 DOI: 10.18632/oncotarget.8123] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 02/28/2016] [Indexed: 12/31/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant neoplasms worldwide. Patients are often diagnosed at advanced stages with poor prognosis due to the absence of obvious early symptoms. Here, we applied a high-throughput serum peptidome analysis to identify circulating peptide markers of ESCC. Weak cationic exchange magnetic beads coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used for two-stage proteotypic peptide profiling in complex serum samples collected from 477 cancer patients and healthy controls. We established a genetic algorithm model containing three significantly differentially expressed peptides at 1,925.5, 2,950.6 and 5,900.0 Da with a sensitivity and specificity of 97.00% and 95.92% in the training set and 97.03% and 100.00% in the validation set, respectively. The model's diagnostic capability was significantly better than SCC-Ag and Cyfra 21-1, especially for early stage ESCC, with an achieved sensitivity of 96.94%. Subsequently, these peptides were identified as fragments of AHSG, TSP1 and FGA by linear ion trap-orbitrap hybrid tandem mass spectrometry. Notably, increased tissue and serum levels of TSP1 in ESCC were verified and correlated with disease progression. In addition, tissue TSP1 was an independent poor prognostic factor in ESCC. In conclusion, the newly established circulating peptide panel and identified proteins could serve as potential biomarkers for the early detection and diagnosis of ESCC. Nevertheless, a larger cohort will be required for further unequivocal validation of their clinical application.
Collapse
|
|
41
|
Yang Q, Lin W, Liu Z, Zhu J, Huang N, Cui Z, Han Z, Pan Q, Goel A, Sun F. RAP80 is an independent prognosis biomarker for the outcome of patients with esophageal squamous cell carcinoma. Cell Death Dis 2018; 9:146. [PMID: 29396516 PMCID: PMC5833679 DOI: 10.1038/s41419-017-0177-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 11/21/2017] [Accepted: 11/22/2017] [Indexed: 12/14/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most popular pathology of esophageal cancer (EC) in China, especially in Henan province, mid-east of China. Presently, targeting DNA damage repair (DDR) factors is a promising approach for cancer therapy. Our group has been focusing on exploring the DDR factors overexpressed in ESCC tissues to provide potential targets for therapies for many years. RAP80/UIMC1 (ubiquitin interaction motif containing 1), one of those DDR factors we tested, was highly overexpressed in ESCC tissues compared with adjacent normal tissues. Moreover, the RAP80 mRNA level was validated to be an independent prognosis biomarker for the overall survival time of ESCC patients. The following biological assays revealed that it promoted cell proliferation both in vitro and in vivo, inhibited cell apoptosis at both early and late stages, and participated in G2/M checkpoint regulation. Even though studies have reported that ATM phosphorylates RAP80 at different serine sites upon DNA damage, the reversal regulation of RAP80 on the activity of ATM has never been investigated. In the study, mechanism explorations revealed that RAP80 positively regulated the ATM activity via proteasome–ubiquitination pathway to promote the transition of G2/M phase in cell cycle. By examining a number of E3 ubiquitination ligases (Ub) and deubiquitination (DUb) enzymes, we found that RAP80 positively regulated the stability of USP13 to promote cell proliferation of EC cells. Moreover, inhibition of RAP80 greatly sensitized EC cells to ATM inhibitor KU-55933, triggering a potential combination of RAP80 inhibitors and ATM inhibitors to enhance the therapeutic efficiency of ESCC patients for the clinicians.
Collapse
Affiliation(s)
- Qingyuan Yang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Wanrun Lin
- Center for Gastrointestinal Research, Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Zhiwei Liu
- Department of Laboratory, Central Hospital of Panyu, Guangzhou, Guangdong, China
| | - Jiabei Zhu
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Nan Huang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Zhongqi Cui
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Zeping Han
- Department of Laboratory, Central Hospital of Panyu, Guangzhou, Guangdong, China
| | - Qiuhui Pan
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| | - Fenyong Sun
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
| |
Collapse
|
|
42
|
Zhang GJ, Zhao J, Jiang ML, Zhang LC. ING5 inhibits cell proliferation and invasion in esophageal squamous cell carcinoma through regulation of the Akt/NF-κB/MMP-9 signaling pathway. Biochem Biophys Res Commun 2018; 496:387-393. [DOI: 10.1016/j.bbrc.2018.01.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 01/07/2018] [Indexed: 12/20/2022]
|
|
43
|
Zou S, Shang ZF, Liu B, Zhang S, Wu J, Huang M, Ding WQ, Zhou J. DNA polymerase iota (Pol ι) promotes invasion and metastasis of esophageal squamous cell carcinoma. Oncotarget 2017; 7:32274-85. [PMID: 27057634 PMCID: PMC5078012 DOI: 10.18632/oncotarget.8580] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 03/28/2016] [Indexed: 01/17/2023] Open
Abstract
DNA polymerase iota (Pol ι) is an error-prone DNA polymerase involved in translesion DNA synthesis (TLS) that contributes to the accumulation of DNA mutations. We recently showed that Pol ι is overexpressed in human esophageal squamous cell cancer (ESCC) tissues which promotes ESCC' progression. The present study was aimed at investigating the molecular mechanisms by which Pol ι enhances the invasiveness and metastasis of ESCC cells. We found that the expression of Pol ι is significantly higher in ESCCs with lymph node metastasis compared to those without lymph node metastasis. Kaplan-Meier analysis revealed an inverse correlation between Pol ι expression and patient prognosis. The expression levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two essential regulators of cells' invasiveness, were positively associated with Pol ι expression in ESCC tissues. Ectopic expression of Pol ι enhanced the motility and invasiveness of ESCC cells as evaluated by wound-healing and transwell assays, respectively. A xenograft nude mouse model showed that Pol ι promotes the colonization of ESCC cells in the liver, lung and kidney. Signaling pathway analysis identified the JNK-AP-1 cascade as a mediator of the Pol ι-induced increase in the expression of MMP-2/9 and enhancement of ESCC progression. These data demonstrate the underlying mechanism by which Pol ι promotes ESCC progression, suggesting that Pol ι is a potential novel prognostic biomarker and therapeutic target for ESCC.
Collapse
Affiliation(s)
- Shitao Zou
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, 215001, P.R. China
| | - Zeng-Fu Shang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu, 215123, P.R. China
| | - Biao Liu
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, 215001, P.R. China
| | - Shuyu Zhang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu, 215123, P.R. China
| | - Jinchang Wu
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, 215001, P.R. China
| | - Min Huang
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, 215001, P.R. China
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
| | - Jundong Zhou
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, 215001, P.R. China
| |
Collapse
|
|
44
|
Pritchett NR, Burgert SL, Murphy GA, Brockman JD, White RE, Lando J, Chepkwony R, Topazian MD, Abnet CC, Dawsey SM, Mwachiro MM. Cross sectional study of serum selenium concentration and esophageal squamous dysplasia in western Kenya. BMC Cancer 2017; 17:835. [PMID: 29216866 PMCID: PMC5721656 DOI: 10.1186/s12885-017-3837-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 11/23/2017] [Indexed: 12/13/2022] Open
Abstract
Background Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya. Methods 294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol’s iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression. Results The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05–8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06–14.19). Conclusion This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.
Collapse
Affiliation(s)
| | | | | | - John D Brockman
- University of Missouri Research Reactor Center, Columbia, MO, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Zhang X, Sun L. Anaphylatoxin C3a: A potential biomarker for esophageal cancer diagnosis. Mol Clin Oncol 2017; 8:315-319. [PMID: 29435296 DOI: 10.3892/mco.2017.1524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 11/28/2017] [Indexed: 12/30/2022] Open
Abstract
Esophageal carcinoma is a common malignancy worldwide, with a low 5-year survival rate. As the majority of cases are diagnosed at an advanced stage, there is an urgent need for an effective biomarker for early diagnosis of esophageal cancer patients. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was applied to detect the serum protein expression in esophageal cancer patients using ProteinChip software, and the results were analyzed and screened using Biomarker Patterns and SPSS16.0 software. The ELISA method was conducted to determine the concentration of anaphylatoxin C3a, which is one of the complement proteins, in the serum of esophageal cancer patients and non-esophageal cancer participants. A total of 144 effective differential expression protein peaks in the window of 1-10 kDa were obtained (P<0.05). M/Z 8,926.478 (P<10-6) protein peak was employed as the diagnostic biomarker for esophageal carcinoma. This established diagnostic biomarker has a sensitivity of 95% (19/20) and an accuracy of 100% (19/19) for positive prediction. The results suggested that anaphylatoxin C3a may be a promising biomarker in the diagnosis of esophageal carcinoma, and may play a key role in promoting esophageal carcinogenesis.
Collapse
Affiliation(s)
- Xu Zhang
- School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu 224002, P.R. China
| | - Lingzhi Sun
- School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu 224002, P.R. China
| |
Collapse
|
|
46
|
Chen P, Song Q, Han J, Xu H, Chen T, Xu J, Cheng Y. Sitting time and occupational and recreational physical activity in relation to the risk of esophageal squamous cell carcinoma. Onco Targets Ther 2017; 10:4787-4794. [PMID: 29033590 PMCID: PMC5628682 DOI: 10.2147/ott.s147711] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Backgrounds Sitting time and physical activity are associated with cancer risk; however, their roles in the development of esophageal squamous cell carcinoma (ESCC) are inconclusive. This study aimed to investigate the effects of total sitting time, occupational activity time (OAT), and recreational activity time (RAT) on ESCC risk. Methods Five hundred fifty-seven ESCC patients and 543 healthy controls matched by sex and age were recruited for this study. Conditional logistic regression was performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Results Longer total sitting time (adjusted OR [AOR] 2.54, 95% CI 1.58–4.09) and longer OAT (AOR 2.90, 95% CI 2.11–3.99) were associated with higher ESCC risk, while longer RAT (AOR 0.27, 95% CI 0.19–0.38) could reduce ESCC risk. When the body mass index was incorporated into the multivariable models, the results changed slightly. In risk estimation according to sex, the same trends were observed in both men and women. Furthermore, longer RAT could completely or partially diminish the impacts of longer sitting time and OAT on increasing ESCC risk. Conclusion Long sitting time and long OAT can increase the risk of ESCC, while long RAT is significantly associated with decreased ESCC risk.
Collapse
Affiliation(s)
- Pengxiang Chen
- Department of Radiation Oncology, Qilu Hospital of Shandong University
| | - Qingxu Song
- Department of Radiation Oncology, Qilu Hospital of Shandong University
| | - Jie Han
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan
| | - Huapu Xu
- Department of Oncology, Pingyi Hospital of Traditional Chinese Medicine, Pingyi
| | - Tong Chen
- Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Jiaqi Xu
- Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University
| |
Collapse
|
|
47
|
Ma W, Su H, Cheetham AG, Zhang W, Wang Y, Kan Q, Cui H. Synergistic antitumor activity of a self-assembling camptothecin and capecitabine hybrid prodrug for improved efficacy. J Control Release 2017; 263:102-111. [PMID: 28082170 DOI: 10.1016/j.jconrel.2017.01.015] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 12/31/2016] [Accepted: 01/08/2017] [Indexed: 11/29/2022]
Abstract
The direct use of anticancer drugs to create their own nanostructures is an emerging concept in the field of drug delivery to obtain nanomedicines of high drug loading and high reproducibility, and the combination use of two or more drugs has been a proven clinical strategy to enhance therapeutic outcomes. We report here the synthesis, assembly and cytotoxicity evaluation of self-assembling hybrid prodrugs containing both camptothecin (CPT) and a capecitabine (Cap) analogue. CPT and Cap molecules were conjugated onto a short β-sheet-forming peptide (Sup35) to yield three different self-assembling prodrugs (dCPT-Sup35, CPT-Cap-Sup35 and dCap-Sup35). We found that the chemical structure of conjugated drugs could strongly influence their assembled morphology as well as their structural stability in aqueous solution. With a decrease in number of CPT units, the resulting nanostructures exhibited a morphological transformation from nanofibers (dCPT-Sup35) to filaments (CPT-Cap-Sup35) then to spherical particles (dCap-Sup35). Notably, the hybrid CPT-Cap prodrug showed a synergistic effect and significantly enhanced potency against three esophageal adenocarcinoma cell lines compared with the two homo-prodrugs (dCPT-Sup35 and dCap-Sup35) as well as free parent drugs (CPT, 5-Fu and CPT/5-FU mixture (1:1)). We believe this work represents a conceptual advancement in integrating two structurally distinct drugs of different action mechanisms into a single self-assembling hybrid prodrug to construct self-deliverable nanomedicines for more effective combination chemotherapy.
Collapse
Affiliation(s)
- Wang Ma
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China
| | - Hao Su
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - Andrew G Cheetham
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - Weifang Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China
| | - Yuzhu Wang
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA
| | - QuanCheng Kan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China.
| | - Honggang Cui
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA.
| |
Collapse
|
|
48
|
Taioli E, Schwartz RM, Lieberman-Cribbin W, Moskowitz G, van Gerwen M, Flores R. Quality of Life after Open or Minimally Invasive Esophagectomy in Patients With Esophageal Cancer-A Systematic Review. Semin Thorac Cardiovasc Surg 2017; 29:377-390. [PMID: 28939239 DOI: 10.1053/j.semtcvs.2017.08.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2017] [Indexed: 02/08/2023]
Abstract
Although esophageal cancer is rare in the United States, 5-year survival and quality of life (QoL) are poor following esophageal cancer surgery. Although esophageal cancer has been surgically treated with esophagectomy through thoracotomy, an open procedure, minimally invasive surgical procedures have been recently introduced to decrease the risk of complications and improve QoL after surgery. The current study is a systematic review of the published literature to assess differences in QoL after traditional (open) or minimally invasive esophagectomy. We hypothesized that QoL is consistently better in patients treated with minimally invasive surgery than in those treated with a more traditional and invasive approach. Although global health, social function, and emotional function improved more commonly after minimally invasive surgery compared with open surgery, physical function and role function, as well as symptoms including choking, dysphagia, eating problems, and trouble swallowing saliva, declined for both surgery types. Cognitive function was equivocal across both groups. The potential small benefits in global and mental health status among those who experience minimally invasive surgery should be considered with caution given the possibility of publication and selection bias.
Collapse
Affiliation(s)
- Emanuela Taioli
- Department of Population Health Science and Policy, Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Rebecca M Schwartz
- Department of Population Health Science and Policy, Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Occupational Medicine, Epidemiology and Prevention, Northwell Health Hofstra Northwell School of Medicine, Great Neck, New York
| | - Wil Lieberman-Cribbin
- Department of Population Health Science and Policy, Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gil Moskowitz
- Department of Population Health Science and Policy, Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Maaike van Gerwen
- Department of Population Health Science and Policy, Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Raja Flores
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, New York
| |
Collapse
|
|
49
|
Gong T, Zheng S, Huang S, Fu S, Zhang X, Pan S, Yang T, Sun Y, Wang Y, Hui B, Guo J, Zhang X. PTENP1 inhibits the growth of esophageal squamous cell carcinoma by regulating SOCS6 expression and correlates with disease prognosis. Mol Carcinog 2017; 56:2610-2619. [PMID: 28731203 PMCID: PMC6084318 DOI: 10.1002/mc.22705] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 07/03/2017] [Accepted: 07/19/2017] [Indexed: 12/31/2022]
Abstract
PTEN pseudogene (PTENP1) has a tumor suppressive role in multiple cancers. However, its involvement in esophageal squamous cell carcinoma (ESCC) remains largely unknown. In this study, we set out to identify the role of PTENP1 in the development of ESCC. Gene Expression Omnibus database was employed to investigate the expression of PTENP1 in ESCC. sRNA target Database (StarBase v2.0) was used to query the downstream of PTENP1. Next, both in vitro and in vivo experiments were employed to explore the function. Cell proliferation was evaluated by CCK‐8, soft agar, and colony formation assays. Expression of relative genes was assessed by quantitative real‐time PCR (qRT‐PCR) and Western blotting. 3′UTR luciferase assay was used to confirm the miRNA binding. The clinical significance of PTENP1 was further validated by immunohistochemistry (IHC) and correlation with clinicopathological indicators in additional samples (n = 93). We found expression of PTENP1 in ESCC was lower than that in the corresponding adjacent normal tissues (n = 17). Overexpression of PTENP1 in Eca109 and TE‐1 cells resulted in inhibited proliferation and altered expression of SOCS6‐p‐STAT3‐HIF‐1α pathway both in vitro and in vivo. Subsequent IHC reported a similar trend in human ESCC samples. 3′UTR luciferase assay demonstrated that PTENP1 3′UTR decoyed miR‐17‐5p from binding to SOCS6. Moreover, PTENP1 expression was correlated with clinicopathological indicators to varying degrees, including histological grade, TNM stage, infiltration depth, lymph node metastasis, and overall survival. Taken together, these results suggested an anti‐oncogenic role of PTENP1. Meanwhile, PTENP1 may also serve as a candidate of prognostic indicator for ESCC patients.
Collapse
Affiliation(s)
- Tuotuo Gong
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Shuyu Zheng
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Shan Huang
- Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Shenbo Fu
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Xuanwei Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Shupei Pan
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Tian Yang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Yuchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Ya Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Beina Hui
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Jia Guo
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| | - Xiaozhi Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi Province, China
| |
Collapse
|
|
50
|
Xie ZH, Yu J, Shang L, Zhu YQ, Hao JJ, Cai Y, Xu X, Zhang Y, Wang MR. KIAA1522 overexpression promotes tumorigenicity and metastasis of esophageal cancer cells through potentiating the ERK activity. Onco Targets Ther 2017; 10:3743-3754. [PMID: 28794639 PMCID: PMC5538704 DOI: 10.2147/ott.s142610] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly malignant tumor associated with a poor prognosis, and the molecular mechanisms underlying its formation and progression remain poorly understood. KIAA1522 is upregulated in various tumor tissues, but its function is unknown. Alterations in KIAA1522 expression and its implication in ESCC are currently unclear. In this study, an immunohistochemical analysis of ESCC tissues showed that KIAA1522 was highly expressed in 46% (157/342) of ESCC specimens and that its expression was inversely correlated with the degree of differentiation (P=0.03). Furthermore, small interfering RNA-mediated silencing of KIAA1522 revealed that overexpression of this protein reinforced malignant cell proliferation and anoikis resistance of ESCC cells in vitro. More importantly, KIAA1522 depletion significantly suppressed the growth of ESCC xenograft tumors and lung metastasis of ESCC cells in nude mice. At the molecular level, inhibition of KIAA1522 expression markedly reduced the phosphorylated extracellular signal-regulated kinase (ERK) levels in both suspended and adherent ESCC cells, suggesting that KIAA1522 might promote cell proliferation and survival via the ERK cascade. Taken together, these data suggest that upregulation of KIAA1522 might enhance tumorigenicity and metastasis of ESCC cells through potentiating the ERK activity. Thus, aberrant expression of KIAA1522 plays oncogenic roles in ESCC and might serve as a novel molecular target in ESCC treatment.
Collapse
Affiliation(s)
- Zhi-Hui Xie
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jing Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Li Shang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yi-Qing Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jia-Jie Hao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yan Cai
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xin Xu
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yu Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Ming-Rong Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| |
Collapse
|