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Biswas S, Kanodia R, Seervi S, Kaur R, Shukla S, Singh S, Banerjee J, Banerjee S. Portrayal of the complex molecular landscape of multidrug resistance in gastric cancer: Unveiling the potential targets. Exp Cell Res 2025; 449:114580. [PMID: 40306607 DOI: 10.1016/j.yexcr.2025.114580] [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: 11/26/2024] [Revised: 04/27/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Gastric cancer (GC) is an aggressive malignancy among all Gastrointestinal cancer (GIC) types. Worldwide, among all cancer types, gastric cancer incidence and related mortality remain in fifth position. Multidrug resistance (MDR) in GC presents a major challenge to chemotherapy, and it significantly affects patient survival. A better understanding of the dynamic interaction of cellular factors contributing to MDR phenotype, e.g., the presence and expression of variants of MDR-related genes, including various drug-detoxifying and drug-efflux transporters, and expression of regulatory ncRNAs affecting the expression of MDR-related genes, is required to comprehend the molecular mechanisms for MDR development in GCs. This review article provides a holistic discussion of the cellular factors involved in the MDR development in GC cells, i.e., their roles and cross-talk between specific molecules that give rise to drug-sensitive and drug-resistant phenotypes. Moreover, the pharmacological perspective of drug resistance and the underlying biological processes that allow the escape of GC cells from the cytotoxic effects of drugs have also been discussed. Additionally, this review article provides an in-depth discussion on most potential candidates that can serve as MDR biomarkers in GIC cancer and the growing research interest in non-coding RNAs (ncRNAs) in GC. Notably, the miRNAs, circRNAs, and lncRNAs are not only emerging as crucial prognostic biomarkers of MDR in gastric cancers but also as potential targets for personalized medicine to combat the MDR challenge in GC patients.
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Affiliation(s)
- Siddhant Biswas
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Riya Kanodia
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Suman Seervi
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Rajinder Kaur
- Centre of Experimental Medicine & Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
| | - Sakshi Shukla
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Samer Singh
- Centre of Experimental Medicine & Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India.
| | - Juni Banerjee
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India.
| | - Shuvomoy Banerjee
- School of Biotechnology and Bioengineering, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar, Gujarat, 382426, India.
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Wen B, Chen J, Ding T, Mao Z, Jin R, Wang Y, Shi M, Zhao L, Yang A, Qin X, Chen X. Development and experimental validation of hypoxia-related gene signatures for osteosarcoma diagnosis and prognosis based on WGCNA and machine learning. Sci Rep 2024; 14:18734. [PMID: 39134603 PMCID: PMC11319349 DOI: 10.1038/s41598-024-69638-3] [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: 01/21/2024] [Accepted: 08/07/2024] [Indexed: 08/15/2024] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant tumour of the bone with high mortality. Here, we comprehensively analysed the hypoxia signalling in OS and further constructed novel hypoxia-related gene signatures for OS prediction and prognosis. This study employed Gene Set Enrichment Analysis (GSEA), Weighted correlation network analysis (WGCNA) and Least absolute shrinkage and selection operator (LASSO) analyses to identify Stanniocalcin 2 (STC2) and Transmembrane Protein 45A (TMEM45A) as the diagnostic biomarkers, which further assessed by Receiver Operating Characteristic (ROC), decision curve analysis (DCA), and calibration curves in training and test dataset. Univariate and multivariate Cox regression analyses were used to construct the prognostic model. STC2 and metastasis were devised to forge the OS risk model. The nomogram, risk score, Kaplan Meier plot, ROC, DCA, and calibration curves results certified the excellent performance of the prognostic model. The expression level of STC2 and TMEM45A was validated in external datasets and cell lines. In immune cell infiltration analysis, cancer-associated fibroblasts (CAFs) were significantly higher in the low-risk group. And the immune infiltration of CAFs was negatively associated with the expression of STC2 (P < 0.05). Pan-cancer analysis revealed that the expression level of STC2 was significantly higher in Esophageal carcinoma (ESCA), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Lung squamous cell carcinoma (LUSC), and Stomach adenocarcinoma (STAD). Additionally, the higher expression of STC2 was associated with the poor outcome in those cancers. In summary, this study identified STC2 and TMEM45A as novel markers for the diagnosis and prognosis of osteosarcoma, and STC2 was shown to correlate with immune infiltration of CAFs negatively.
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Affiliation(s)
- Bo Wen
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Jian Chen
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China
| | - Tianqi Ding
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China
| | - Zhiyou Mao
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Rong Jin
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Yirui Wang
- Department of Cardiology, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Meiqin Shi
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Lixun Zhao
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Asang Yang
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China
| | - Xianyun Qin
- Department of Orthopedics, No. 945 Hospital of the PLA Joint Logistics Support Force, Yaan, 625000, Sichuan, China.
| | - Xuewei Chen
- Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
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Nam S, Lee Y. HIF1A protein expression is correlated with clinical features in gastric cancer: an updated systematic review and meta-analysis. Sci Rep 2024; 14:13736. [PMID: 38877062 PMCID: PMC11178933 DOI: 10.1038/s41598-024-63019-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/23/2024] [Indexed: 06/16/2024] Open
Abstract
To elucidate the correlation of HIF1A with clinicopathologic characteristics in patients with gastric cancer (GC), we conducted a systematic review and meta-analysis. We searched PubMed, Embase and Web of Science for studies on GC and HIF1A, covering studies published until January 31st, 2022. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for clinical characteristics based on high and low HIF1A protein levels. We used random-effects and fixed-effects meta-analysis methods to determine mean effect sizes of ORs and evaluated publication heterogeneity with τ2, I2, and Q values. Additionally, we generated funnel plots to inspect publication bias. Our meta-analysis included 20 publications with 3416 GC patients to estimate the association between high or low HIF1A expression and clinical characteristics. Positive HIF1A expression was significantly associated with T stage progression (OR: 2.46; 95% CI 1.81-3.36; P < 0.01), TNM stage progression (OR: 2.50; 95% CI 1.61-3.87; P < 0.01), lymph node metastasis (OR: 2.06; 95% CI 1.44-2.94; P < 0.01), undifferentiated status (OR: 1.83; 95% CI 1.45-2.32; P < 0.01), M stage progression (OR: 2.34; 95% CI 1.46-3.77; P < 0.01), Borrmann stage progression (OR: 1.48; 95% CI 1.02-2.15; P = 0.04), larger tumor size (OR: 1.27; 95% CI 1.06-1.52; P < 0.01), vascular invasion (OR: 1.94; 95% CI 1.38-2.72; P < 0.01), and higher vascular endothelial growth factor (VEGF) protein expression (OR: 2.61; 95% CI 1.79-3.80; P < 0.01) in our meta-analysis. GC Patients highly expressing HIF1A protein might be prone to tumor progression, poorly differentiated GC cell types, and a high VEGF expression.
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Affiliation(s)
- Seungyoon Nam
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, 21999, Republic of Korea.
- Department of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, 38-13, 3Beon-gil Dokjeom-ro, Namdong-gu, Incheon, 21565, Republic of Korea.
| | - Yeeun Lee
- Department of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, 38-13, 3Beon-gil Dokjeom-ro, Namdong-gu, Incheon, 21565, Republic of Korea
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Mechanisms of Antitumor Invasion and Metastasis of the Marine Fungal Derivative Epi-Aszonalenin A in HT1080 Cells. Mar Drugs 2023; 21:md21030156. [PMID: 36976205 PMCID: PMC10056024 DOI: 10.3390/md21030156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/03/2023] Open
Abstract
Epi-aszonalenin A (EAA) is an alkaloid that is isolated and purified from the secondary metabolites of coral symbiotic fungi and has been shown to have good atherosclerotic intervention activity and anti-angiogenic activity in our previous studies. In the present study, antiangiogenic activity was used as a basis of an intensive study of its mechanism of action against tumor metastasis and invasion. Invasive metastatic pairs are a hallmark of malignancy, and the dissemination of tumor cells is the most dangerous process in the development of tumors. The results of cell wound healing and the Transwell chamber assay showed that EAA interfered well with PMA-induced migration and invasion of HT1080 cells. Western blot and the ELISA assay showed that EAA decreased MMPs and vascular endothelial growth factor (VEGF) activity and inhibited the expression of N-cadherin and hypoxia-inducible factor-1α (HIF-1α) by regulating the phosphorylation of downstream mitogen-activated protein kinase (MAPK), PI3K/AKT, and NF-κB pathways. Simultaneous molecular docking results revealed that the mimic coupling between the EAA and MMP-2/-9 molecules formed a stable interaction. The results of this study provide a research basis for the inhibition of tumor metastasis by EAA, and together with previous studies, confirm the potential pharmacology and drug potential for this class of compound for application in angiogenesis-related diseases and further improve the availability of coral symbiotic fungi.
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TRPV3 promotes the angiogenesis through HIF-1α-VEGF signaling pathway in A549 cells. Acta Histochem 2022; 124:151955. [DOI: 10.1016/j.acthis.2022.151955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022]
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Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduct Target Ther 2022; 7:218. [PMID: 35798726 PMCID: PMC9261907 DOI: 10.1038/s41392-022-01080-1] [Citation(s) in RCA: 198] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 02/07/2023] Open
Abstract
Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.
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Yu S, Li Q, Wang Y, Cui Y, Yu Y, Li W, Liu F, Liu T. Tumor-derived LIF promotes chemoresistance via activating tumor-associated macrophages in gastric cancers. Exp Cell Res 2021; 406:112734. [PMID: 34265288 DOI: 10.1016/j.yexcr.2021.112734] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/11/2021] [Accepted: 07/06/2021] [Indexed: 12/14/2022]
Abstract
Chemotherapy is the preferred clinical treatment for advanced stage gastric cancer (GC) patients, of which efficacy could be markedly impaired due to the development of chemoresistance. Alternatively activated or M2-type tumor associated macrophages (TAMs) are recruited under chemotherapy and are highly implicated in the chemoresistance development, but underlying molecular mechanism for TAM activation is largely unknown. Here, we present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent manner. Mechanistically, cisplatin-induced HIF1α signaling activation directly drive the transcription of LIF, which promotes the resistance of gastric tumors to chemo drug. Further study revealed that tumor cell-derived LIF stimulates macrophages into tumor-supporting M2-type phenotype via activating STAT3 signaling pathway. Therapeutically, blocking LIF efficiently elevates chemo sensitivity of tumor cells and further represses the growth rates of tumors under chemotherapy. Therefore, our study reveals a novel insight in understanding the cross talking between tumor cells and immune cells and provides new therapeutic targets for gastric cancer.
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Affiliation(s)
- Shan Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Qian Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yan Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Wei Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Center of Evidence-based Medicine, Fudan University, Shanghai, China.
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Yin J, Yi J, Yang C, Xu B, Lin J, Hu H, Wu X, Shi H, Fei X. Chronic atrophic gastritis and intestinal metaplasia induced by high-salt and N-methyl-N'-nitro-N-nitrosoguanidine intake in rats. Exp Ther Med 2021; 21:315. [PMID: 33717258 PMCID: PMC7885066 DOI: 10.3892/etm.2021.9746] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to induce chronic atrophic gastritis (CAG) with intestinal metaplasia (IM) in rats by administering saturated salt and methyl-N'-nitro-N-nitrosoguanidine (MNNG) via oral gavage. Changes in gastric mucosal blood microcirculation and activation of the cyclo-oxygenase-2 (COX-2)/hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway during CAG and IM development were investigated. After administering saturated salt and MNNG for 25 weeks, mild atrophy was detected in the stomach of model rats using hematoxylin and eosin staining. CAG with IM was successfully induced in the gastric mucosa of the model rats after 35 weeks. Gastric mucosal blood flow was decreased in comparison with controls as early as 15 weeks after treatment to induce CAG and the mRNA expression levels of COX-2, HIF-1α, vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 were increased in comparison with untreated rats as early as 25 weeks after treatment. HIF-1α, COX-2 and VEGFR2 expression levels were increased as early as 25 weeks after CAG induction treatment when compared to controls and HIF-1α, COX-2, VEGFR1 and VEGFR2 expression levels were significantly increased after 35 weeks. These findings indicated that administering saturated salt and MNNG by gavage for 35 weeks successfully induced CAG and IM in rats. Furthermore, the microcirculation was disturbed before activation of the COX-2/HIF-1α/VEGF signaling pathway.
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Affiliation(s)
- Jing Yin
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Jinyu Yi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Chun Yang
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Bo Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Jiang Lin
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Hongyi Hu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Xiaojun Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Xiaoyan Fei
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
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Yu S, Li Q, Yu Y, Cui Y, Li W, Liu T, Liu F. Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer. Cancer Immunol Immunother 2020; 69:1973-1987. [PMID: 32388677 DOI: 10.1007/s00262-020-02598-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 04/27/2020] [Indexed: 12/15/2022]
Abstract
Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients, and developing chemoresistance is a tremendous challenge to efficacy of GC treatment. The treatments of anti-tumor chemo-agents recruit more tumor-associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that hypoxia-inducible factor 1α (HIF1α) in GC cells is activated upon 5-fluorouracil (5-FU) treatment and results in much more accumulation of M2-type TAMs which protect tumor cells from chemo-agents. Mechanistically, in the GC cells under the 5-FU treatment, reactive oxygen species is accumulated and then induces the activation of HIF1α signaling to drive the expression of high-mobility group box 1, which leads to more macrophage's infiltration into GC tumor. In turn, the recruited TAMs exhibit tumor-protected M2-type phenotype and promote the chemoresistance of GC cells via producing growth differentiation factor 15 (GDF15) to exacerbate the fatty acid β-oxidation in tumor cells. Blocking GDF15 using antibody or inhibiting FAO of tumor cells by etomoxir efficiently gave rise to the tumor cell sensitivity to 5-FU. Therefore, our study demonstrates a novel insight in understanding the cross talking between tumor cells and immune microenvironment and provides new therapeutic targets for clinic treatments of gastric cancer.
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Affiliation(s)
- Shan Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Qian Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Wei Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
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10
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Effects of Environmental pH on the Growth of Gastric Cancer Cells. Gastroenterol Res Pract 2020; 2020:3245359. [PMID: 32211041 PMCID: PMC7085403 DOI: 10.1155/2020/3245359] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/04/2019] [Accepted: 02/27/2020] [Indexed: 12/14/2022] Open
Abstract
Background Proton pump inhibitor (PPI) and other acid-suppressing drugs are widely used in the treatment of gastrointestinal ulcer, upper gastrointestinal bleeding, gastritis, and gastric cancer (GC). About 80% of GC patients receive acid suppression treatment. PPI suppresses the production of gastric acid by inhibiting the function of H+/K+-ATPase in gastric parietal cells and raises the pH value to achieve therapeutic purposes. Some studies have found that PPI had a certain antitumor effect in the proliferation and apoptosis of tumor cells. But the effects of environmental pH on the growth of GC cells and its mechanism are unknown. Therefore, we hoped to find the effects of culture medium pH on the biological behavior of GC cells by in vitro experiments and provide guidance for the use of acid-suppressing drugs in GC patients. Aims We aimed to observe the effects of pH changes in GC cell culture medium on the cell biological behavior of cancer cells and to analyze the potential mechanisms. We hoped to find out the effect of acid suppression on the growth of GC cells. Methods The GC cell lines (SGC-7901 and MKN45) were used as the research object. We adjusted the pH value in the cell culture medium to observe the changes in cell viability (MTT), apoptosis (flow cytometry), and invasion (Transwell) at pH 6, pH 7, and pH 8. qRT-PCR and western blot (WB) assays were used to determine the expression changes of genes and proteins (mTOR, AKT, Wnt, Glut, and HIF-1α) at pH 6, pH 7, and pH 8. Results The results of MTT showed that the viability of SGC-7901 and MKN45 in the pH 8.0 group was significantly weaker than that in the pH 6.0 or pH 7.0 group (P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (α) at pH 6, pH 7, and pH 8. P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group ( Conclusions Compared with the microacid environment, the microalkaline environment inhibited the viability, invasion, and expression of genes and proteins (mTOR, AKT, Wnt, Glut, and HIF-1α) but promoted the apoptosis of GC cells and thus inhibited the growth of GC.α) at pH 6, pH 7, and pH 8.
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11
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Ruan T, Liu W, Tao K, Wu C. A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer. Onco Targets Ther 2020; 13:1797-1807. [PMID: 32184615 PMCID: PMC7053652 DOI: 10.2147/ott.s239336] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/15/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is one of the most common malignant tumors, and it is also one of the leading causes of cancer death worldwide. Because of its insidious symptoms and lack of early dictation screening, many cases of gastric cancer are at late stages which make it more complicated to cure. For these advanced-stage gastric cancers, combination therapy of surgery, chemotherapy, radiotherapy and target therapy would bring more benefit to the patients. However, the drug-resistance to the chemotherapy restricts its effect and might lead to treatment failure. In this review article, we discuss the mechanisms which have been found in recent years of drug resistance in gastric cancer. And we also want to find new approaches to counteract chemotherapy resistance and bring more benefits to the patients.
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Affiliation(s)
- Tuo Ruan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuanqing Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Hu X, Mu Y, Liu J, Mu X, Gao F, Chen L, Wu H, Wu H, Liu W, Zhao Y. Exosomes Derived from Hypoxic Colorectal Cancer Cells Transfer miR-410-3p to Regulate Tumor Progression. J Cancer 2020; 11:4724-4735. [PMID: 32626519 PMCID: PMC7330706 DOI: 10.7150/jca.33232] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 05/12/2020] [Indexed: 12/11/2022] Open
Abstract
Hypoxia is a common characteristic of solid tumors and is associated with cancer progression and poor outcomes. However, the roles and specific mechanisms of exosomes and hypoxia during cancer progression still remain unclear. Herein, we found that exosomes secreted from hypoxic colorectal cancer (CRC) cells promoted the proliferation, migration, invasion, and metastasis of normoxic CRC cells, and these hypoxic exosomes exerted their biological effects depending on miR-410-3p. We discovered that miR-410-3p was highly enriched in hypoxic CRC-derived exosomes in a HIF1α or HIF2α-dependent manner, and miR-410-3p levels positively associated with poor prognosis of CRC. Moreover, decreased PTEN levels caused by hypoxic CRC cells-derived exosomal miR-410-3p increased activation of PI3K/Akt as well as tumor progression. Conversely, inhibition of miR-410-3p or PI3K/Akt signaling pathway effectively decreased hypoxic CRC cells-derived exosomes-mediated tumor progression. In conclusion, our findings indicate that the hypoxic microenvironment in CRC may promote tumor cells to release miR-410-3p-rich exosomes that are transferred to normoxic cells to enhance tumor progression, revealing a new investigation into the therapeutic targets of exosome for CRC treatment.
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Affiliation(s)
- Xiufeng Hu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yu Mu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jie Liu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaoqian Mu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Fangfang Gao
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Lijuan Chen
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huijuan Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Hongbo Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Wenjing Liu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yanqiu Zhao
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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Chen X, Yu X, Shen E. Overexpression of CDKN2B is involved in poor gastric cancer prognosis. J Cell Biochem 2019; 120:19825-19831. [PMID: 31297846 DOI: 10.1002/jcb.29287] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 02/28/2019] [Indexed: 12/13/2022]
Abstract
The objective of this investigation is to elucidate the clinical significance of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression regarding gastric cancer (GC), as well as to detect the involvement of CDKN2B expression in the clinicopathological indexes and prognosis of GC. Immunohistochemical analysis was used for identification of CDKN2B expression in GC specimens. Chi-square (χ2 ) test was applied to detect the association of CDKN2B expression and clinicopathological parameters of GC. The involvement of CDKN2B expression in the prognosis was analyzed via univariate and multivariate analysis. It was indicated that relative to the corresponding para-carcinoma tissues, CDKN2B expression was notably upregulated in GC specimens. Moreover, the expression of CDKN2B was strongly correlated with the differentiation (r = -0.182; P = .015), invasion (r = -0.157; P = .038), distant metastases (r = -0.196; P = .004), and TNM stage (r = -0.204; P = .005). Nevertheless, no remarkable variance was related to age, tumor loci, or sex. Kaplan-Meier survival curve and univariate analysis showed that CDKN2B overexpression predicted poorer disease-free survival (P = .007) and overall survival (P = .005) in those with GC. In addition, Cox proportional hazards regression model revealed that CDKN2B was an isolated biomarker of disease-free survival and overall survival in patients with GC. Taken together, our data demonstrated that the overexpression of CDKN2B could be an isolated factor for GC prognostic in patients. CDKN2B gene may be a useful target and new treatment for improving the prognosis of GC.
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Affiliation(s)
- Xi Chen
- Department of Pathology, Taizhou Municipal Hospital, Taizhou, Zhejiang, China
| | - Xingtong Yu
- Department of Pathology, Taizhou Municipal Hospital, Taizhou, Zhejiang, China
| | - Enjian Shen
- Department of Pathology, Taizhou Municipal Hospital, Taizhou, Zhejiang, China
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Weiqi Decoction Attenuated Chronic Atrophic Gastritis with Precancerous Lesion through Regulating Microcirculation Disturbance and HIF-1 α Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:2651037. [PMID: 31320912 PMCID: PMC6610735 DOI: 10.1155/2019/2651037] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 06/04/2019] [Indexed: 02/06/2023]
Abstract
Aim Chronic atrophic gastritis (CAG), the precancerous lesions of gastric cancer, plays an important role in the stepwise process of gastric cancer. The ancient Chinese medicine believes in that Qi deficiency and blood stasis are involved in the pathogenesis of CAG. Weiqi decoction, a classical formula from Longhua Hospital, could supplement Qi and activate blood circulation of human beings and has been used for treating CAG in clinic over twenty years. The study aims to clarify the effect and underlying molecular mechanism of Weiqi decoction on CAG rats. Methods Forty-eight male Wistar rats were divided randomly into six groups: control group, model group, folic acid group, and WQD-treated groups at doses of 4 g/kg, 2 g/kg, and 1 g/kg, with eight rats in each group. MNNG and saturated NaCl were used to induce CAG rat with precancerous lesion (intestinal metaplasia and dysplasia). After 40 weeks, gastric mucosal blood flow was measured using Laser Doppler Flowmetry. The pathological changes of the gastric mucosa were identified by H&E staining and AB-PAS staining. The protein expression of COX-2, HIF-1α, VEGFR1, VEGFR2, Ki67, and cleaved caspase 3 in the gastric tissues was measured by western blotting approach. Gene expression of COX-2, HIF-1α, VEGF, VEGFR1, VEGFR2, Ang-1, and Ang-2 was detected by using Quantitative PCR method. The PGE2 concentrations in serum were detected by ELISA method. The protein expression of Ki67 in gastric mucosa was also detected by immunohistochemistry. Results Compared with control rats, atrophy and intestinal metaplasia as well as the microcirculation disturbance of gastric mucosa were induced in the stomach of CAG rats identified by the H&E and AB-PAS staining as well as microcirculation measurement, which could be significantly attenuated by WQD treatment. Moreover, compared with the control group, the protein and gene expression of COX-2, HIF-1α, VEGFR1, and VEGFR2 in gastric tissues of pylorus was obviously increased and the serum PGE2 level was significantly deceased in CAG rats, which could be significantly counteracted by WQD administration. However, the gene expression of Ang-1 and Ang-2 was not significant difference between control rats and CAG rats, and WQD also had no significant effect on the gene expression of Ang-1 and Ang-2. Furthermore, the increased cell proliferation marked by upregulated protein expression of Ki67 and decreased cell apoptosis marked by downregulated protein expression of cleaved caspase 3 in stomach of pylorus in CAG rats were obviously reversed by WQD treatment. Conclusion WQD attenuated CAG with precancerous lesion through regulating gastric mucosal blood flow disturbance and HIF-1α signaling pathway.
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15
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Hao LS, Liu Q, Tian C, Zhang DX, Wang B, Zhou DX, Li ZP, Yuan ZX. Correlation and expression analysis of hypoxia-inducible factor 1α, glucose transporter 1 and lactate dehydrogenase 5 in human gastric cancer. Oncol Lett 2019; 18:1431-1441. [PMID: 31423208 DOI: 10.3892/ol.2019.10457] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 04/15/2019] [Indexed: 01/01/2023] Open
Abstract
The development and identification of novel potential targeting sites for intervention therapy are essential in the search for improved treatment methods for gastric cancer (GC). Previously, it has been reported that hypoxia inducible factor-1α (HIF-1α) is a potential target gene involved in the endogenous hypoxic response and bioenergetic metabolism of GC cells. In the present study, with the assumption of a close interplay among HIF-1α, glucose transporter 1 (GLUT1) and lactate dehydrogenase-5 (LDH-5), 85 patients with GC were recruited and the protein and gene expression levels of HIF-1α, GLUT1 and LDH-5 in tumor tissues were evaluated in order to assess clinical correlations and co-expression patterns, using Immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction. The results demonstrated that the protein and gene expression levels of HIF-1α were significantly associated with the depth of invasion, nodal metastasis, clinical stage, differentiation and distant metastasis. Consistent with the protein expression results, the mRNA expression levels of the genes coding for GLUT1 and LDH-5 were clearly associated with tumor size, depth of invasion, distant metastasis, clinical stage and differentiation. Correlation analysis of HIF-1α with GLUT1 and LDH-5 at the protein and mRNA expression levels in gastric carcinoma indicated that HIF-1α expression was positively correlated with the expression of GLUT1 (P<0.01, r=0.765 for mRNA expression; P<0.01, r=0.697 for protein expression) and LDH-5 (P<0.01, r=0.892 for mRNA expression; P<0.01, r=0.783 for protein expression) at the mRNA and protein levels. Therefore, it may be concluded that HIF-1α, GLUT1 and LDH-5 are potential target genes involved in the endogenous tumor response to hypoxia and the inhibition of tumor energy metabolism, highlighting a novel therapeutic target for GC.
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Affiliation(s)
- Lang-Song Hao
- Department of General Surgery, Guizhou Provincial People's Hospital, Guiyang Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Qi Liu
- Graduate School of Surgery, Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Chuan Tian
- Graduate School of Surgery, Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Dong-Xing Zhang
- Department of General Surgery, Guizhou Provincial People's Hospital, Guiyang Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Bo Wang
- Department of General Surgery, Guizhou Provincial People's Hospital, Guiyang Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Dong-Xu Zhou
- Department of General Surgery, Guizhou Provincial People's Hospital, Guiyang Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Zhao-Peng Li
- Department of General Surgery, Guizhou Provincial People's Hospital, Guiyang Medical University, Guiyang, Guizhou 550002, P.R. China
| | - Zhi-Xiang Yuan
- Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
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Rizzieri D, Paul B, Kang Y. Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma. ACTA ACUST UNITED AC 2019; 5. [PMID: 31020046 PMCID: PMC6476731 DOI: 10.20517/2394-4722.2019.05] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids; the generation of energy (ATP); and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.
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Affiliation(s)
- Dustin Rizzieri
- Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA
| | - Barry Paul
- Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA
| | - Yubin Kang
- Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA
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Jiang X, Zhang S, Yin Z, Sheng Y, Yan Q, Sun R, Lu M, Zhang Z, Li Y. The correlation between NEDD4L and HIF-1α levels as a gastric cancer prognostic marker. Int J Med Sci 2019; 16:1517-1524. [PMID: 31673244 PMCID: PMC6818201 DOI: 10.7150/ijms.34646] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 09/09/2019] [Indexed: 12/26/2022] Open
Abstract
NEDD4L (neural precursor cell expressed developmentally down-regulated 4-like) protein is a member of ubiquitin ligases Nedd4 family. Although studies have shown that Nedd4L may act as a tumor suppressor in various cancers, including gastric cancer (GC), its clinical significance and the diagnostic value in GC is not well defined. HIF-1α (hypoxia inducible factor family of transcription factors) is actively involved in the metabolism of many tumors, although the relationship between its expression levels and clinical significance in GC still need to be established. In this study, the level of HIF-1α and NEDD4L mRNA and protein in 25 freshly frozen GC- and matched normal-tissues were determined by western blot and quantitative PCR (qPCR). Additionally, immunohistochemistry assay was performed to measure the protein level of NEDD4L and HIF-1α in 124 GC and 25 normal control tissues. We observed that the NEDD4L mRNA and protein levels decreased significantly (P < 0.001) in GC tissues, while that of HIF-1α increased (P < 0.001), and they both were associated with a poor prognosis, as was the case in patients with lower NEDD4L and higher HIF-1α expression (P < 0.001). On correlation analysis, a significantly negative relationship (r = 0.288, P < 0.01) was revealed between NEDD4L and HIF-1α expressions. Multivariate analysis revealed that co-expression of NEDD4L (P < 0.05) and HIF-1α (P < 0.001) were independent predictors of GC prognosis. Thus, the correlation of NEDD4L and HIF-1α levels may act as a prognostic marker of GC.
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Affiliation(s)
- Xingwang Jiang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Shangxin Zhang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Zihuan Yin
- Department of Thoracic Surgery, Anhui chest hospital, Hefei 230022, People's Republic of China
| | - Yi Sheng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Qiang Yan
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Ruochuan Sun
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Mingdian Lu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Zhen Zhang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
| | - Yongxiang Li
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, People's Republic of China
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18
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Zhang X, Li Z, Xuan Z, Xu P, Wang W, Chen Z, Wang S, Sun G, Xu J, Xu Z. Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis. J Exp Clin Cancer Res 2018; 37:320. [PMID: 30572959 PMCID: PMC6302516 DOI: 10.1186/s13046-018-0993-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/04/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Autophagy plays a crucial role in sustaining the homeostasis in various malignant diseases. It has also been reported to promote tumor development in multiple cancers. Glutaminolysis instead of Warburg Effect produce adequate ATP and provide nitrogen and carbon to replenish the TCA cycle which has been discovered to be a new energy source for tumor cells recently. By means of degrading intracellular particles including amino acids, nucleotides, fatty acids, sugars and aged organisms, autophagy can recycle the aforementioned particles into bioenergetics and biosynthesis pathways, finally favoring tumor cells. MicroRNA is a kind of noncoding RNA that regulates the targeting gene expression mostly at post-transcription level. Among these miRNAs, microRNA-133a-3p is reported to be a tumor suppressor in numerous cancers. METHODS We characterized the down-regulated expression level of microRNA-133a-3p in gastric cancer via TCGA database. Subsequently, we verified the tumor suppressor role of microRNA-133a-3p in gastric cancer cells through a series biological function assay. We used immunofluorescence and transmission electron microscope to observe the negative effect of microRNA-133a-3p on autophagy and used dual-luciferase report assay to identify the candidate gene GABARAPL1 of microRNA-133A-3p.Then we used high performance liquid phase mass spectrometry and seahorse analysis to detect whether miR-133a-3p could block the glutaminolysis metabolism through autophagy. At last, we confirmed the tumor suppressor role of microRNA-133a-3p in vivo on PDX mice model. RESULTS We demonstrated that microRNA-133a-3p overexpression could block the activation of autophagy to ruin the abnormal glutaminolysis and further inhibit the growth and metastasis of gastric cancer cells. We successfully proved gastric cancer cells can replenish glutaminolysis via autophagy and microRNA-133a-3p could block aforementioned pathway by targeting core autophagy participants GABARAPL1 and ATG13.We then verified the negative function of microRNA-133a-3p on autophagy-mediated glutaminolysis both in PDX model and human gastric cancer organoid model. CONCLUSIONS MicroRNA-133a-3p targets GABARAPL1 to block autophagy-mediated glutaminolysis, further repressing gastric cancer growth and metastasis.
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Affiliation(s)
- Xing Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Zhe Xuan
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Penghui Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Zheng Chen
- Department of Surgical Oncology, University of Miami, Miami, USA
| | - Sen Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Guangli Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Jianghao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province China
- Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029 Jiangsu Province China
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Liu K, Zhang J, Wang H. Small ubiquitin-like modifier/sentrin-specific peptidase 1 associates with chemotherapy and is a risk factor for poor prognosis of non-small cell lung cancer. J Clin Lab Anal 2018; 32:e22611. [PMID: 30043429 DOI: 10.1002/jcla.22611] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 05/31/2018] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND SUMO/sentrin-specific peptidase 1 (SENP1) was associated with radioresistance of cancer cells and was upregulated in non-small cell lung cancer (NSCLC). This study was to investigate the association of SENP1 with resistance of NSCLC tumor to chemoradiotherapy. METHODS Sentrin-specific peptidase 1 expression profile was detected using the immunohistochemistry and quantitative real-time PCR (qRT-PCR) analyses. The relative expression level of SENP1 mRNA was detected using qRT-PCR. The response to chemoradiotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors. RESULTS AND CONCLUSION When compared with adjacent non-tumor tissues, the overexpression of SENP1 mRNA and protein in NSCLC tumor tissues was determined using qRT-PCR and immunochemistry. Based on the chemoradiotherapy response rate, we found that NSCLC patients with higher SENP1 expression showed lower rates of complete response and higher partial and non-response rate to chemoradiotherapy. In the overall survival analysis, we found patients with high SENP1 expression showed significant shorter survival time compared with those with low SENP1 expression. In the multivariate Cox regression model, we found SENP1 overexpression, TNM stage, and lymph metastasis were independent risk factors for poor prognosis of NSCLC. SENP1 overexpression contributed to chemoradiotherapy resistance of NSCLC. The overexpression of SENP1 could be used as a risk factor for the poor prognosis of NSCLC.
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Affiliation(s)
- Keyuan Liu
- Department of Thoracic Surgery, The Affiliated Hospital of Hangzhou Normal University, Hangzhou City, Zhejiang Province, China
| | - Jing Zhang
- Department of Thoracic Surgery, The Affiliated Hospital of Hangzhou Normal University, Hangzhou City, Zhejiang Province, China
| | - Hao Wang
- Department of Thoracic Surgery, The Affiliated Hospital of Hangzhou Normal University, Hangzhou City, Zhejiang Province, China
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Li J, Song P, Jiang T, Dai D, Wang H, Sun J, Zhu L, Xu W, Feng L, Shin VY, Morrison H, Wang X, Jin H. Heat Shock Factor 1 Epigenetically Stimulates Glutaminase-1-Dependent mTOR Activation to Promote Colorectal Carcinogenesis. Mol Ther 2018; 26:1828-1839. [PMID: 29730197 DOI: 10.1016/j.ymthe.2018.04.014] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 04/01/2018] [Accepted: 04/10/2018] [Indexed: 01/05/2023] Open
Abstract
Heat shock factor 1 (HSF1) generally exhibits its properties under stress conditions. In tumors, HSF1 has a pleiotropic feature in regulating growth, survival, and aggressiveness of cancer cells. In this study, we found HSF1 was increased in colorectal cancer (CRC) and had a positive correlation with shorter disease-free survival (DFS). Knockdown of HSF1 in CRC cells attenuated their growth while inhibiting mTOR activation and glutamine metabolism. HSF1 inhibited the expression of microRNA137 (MIR137), which targeted GLS1 (glutaminase 1), thus stimulating GLS1 protein expression to promote glutaminolysis and mTOR activation. HSF1 bound DNA methyltransferase DNMT3a and recruited it to the promoter of lncRNA MIR137 host gene (MIR137HG), suppressing the generation of primary MIR137. The chemical inhibitor of HSF1 also reduced cell growth, increased apoptosis, and impaired glutamine metabolism in vitro. Moreover, both chemical inhibition and genetic knockout of HSF1 succeeded in increasing MIR137 expression, reducing GLS1 expression, and alleviating colorectal tumorigenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice. In conclusion, HSF1 expression was increased and associated with poor prognosis in CRC. By recruiting DNMT3a to suppress the expression of MIR137 that targets GLS1 mRNA, HSF1 stimulated GLS1-dependent mTOR activation to promote colorectal carcinogenesis. Therefore, targeting HSF1 to attenuate glutaminolysis and mTOR activation could be a promising approach for CRC treatment.
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Affiliation(s)
- Jiaqiu Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Ping Song
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Tingting Jiang
- Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Dongjun Dai
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Hanying Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Jie Sun
- Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Liyuan Zhu
- Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Wenxia Xu
- Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Lifeng Feng
- Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Vivian Y Shin
- Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Helen Morrison
- Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany
| | - Xian Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
| | - Hongchuan Jin
- Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
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Cai FF, Xu C, Pan X, Cai L, Lin XY, Chen S, Biskup E. Prognostic value of plasma levels of HIF-1a and PGC-1a in breast cancer. Oncotarget 2018; 7:77793-77806. [PMID: 27780920 PMCID: PMC5363621 DOI: 10.18632/oncotarget.12796] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 10/10/2016] [Indexed: 01/01/2023] Open
Abstract
Cellular adaptive mechanisms are crucial for tumorigenesis and a common feature in solid tumor progression. Hypoxia-inducible factor-1α (HIF-1α) facilitates the biological response to hypoxia, advancing angiogenesis and metastatic potential of the tumor. The peroxisome proliferator–activated receptor γ coactivators 1α (PGC-1α) enhances mitochondrial biogenesis, favored by migratory/invasive cancer cells. We conducted a prospective, long-term follow up study to determine whether HIF-1α and PGC-1α can be implemented as predictive biomarker in breast cancer. HIF-1α and PGC-1α plasma concentrations were measured in patients and in healthy controls by enzyme linked immune sorbent assay. Breast cancer patients had significantly higher HIF-1α and PGC-1α levels, which correlated with clinicopathological features, overall with more aggressive cancer characteristics. Disease free and overall survival of breast cancer patients with high HIF-1α and PGC-1α were significantly poorer than in patients with low plasma levels. In multivariate analysis, high amount of PGC-1α showed independent prognostic value. Our data suggests that HIF-1α and PGC-1α may be promising, noninvasive, biomarkers with a high potential for future clinical implication to identify subgroups of patients with poorer prognosis and to indicate early, subclinical metastasis.
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Affiliation(s)
- Feng-Feng Cai
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Cheng Xu
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Xin Pan
- Department of Central Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Lu Cai
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Xiao-Yan Lin
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Su Chen
- Department of Molecular and Cellular Biology, School of Forensic Sciences, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, PR China
| | - Ewelina Biskup
- Department of Oncology, Department of Internal Medicine, University Hospital of Basel, Basel, Switzerland
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Hong WG, Ko YS, Pyo JS. Clinicopathological significance and prognostic role of microvessel density in gastric cancer: A meta-analysis. Pathol Res Pract 2017; 213:1459-1463. [PMID: 29129495 DOI: 10.1016/j.prp.2017.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/21/2017] [Accepted: 11/03/2017] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The aim of this study was to elucidate the clinicopathological significance and prognostic role of microvessel density (MVD) in gastric cancer (GC) through a meta-analysis. METHODS This meta-analysis included 4094 patients from 26 eligible studies. We investigated the correlation between MVD and clinicopathological characteristics, including survival rate. In addition, subgroup analysis based on microscopic magnification among evaluation criteria of MVD was performed. RESULTS High MVD was significantly correlated with worse overall and disease-free survival rates [hazard ratio (HR), 3.028, 95% confidence interval (CI) 2.105-4.357 and HR 2.045, 95% CI 1.530-2.732, respectively]. MVD was significantly increased in GC with diffuse type of Lauren's classification [mean difference (MD) 3.091, 95% CI 0.615-5.567], lymphatic invasion (MD 8.262, 95% CI 3.310-13.214), lymph node metastasis (MD 5.730, 95% CI 2.444-9.016), higher pT stage (pT3-4) (MD 7.093, 95% CI 0.060-14.126) and higher pTNM stage (III-IV) (MD 3.023, 95% CI 0.181-5.865). However, MD of MVD was not significantly different in regard to vascular invasion (MD 7.430, 95% CI 1.015-15.875), tumor differentiation (MD 5.501, 95% CI 1.353-12.355) and tumor size (MD 4.731, 95% CI 2.003-11.465). CONCLUSION Taken together, higher MVD was significantly correlated with worse prognosis. In addition, MVD was significantly higher in GC with aggressive tumor behavior than in GC without aggressive features.
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Affiliation(s)
- Won Gi Hong
- Eulji University School of Medicine, Daejeon 34824, Republic of Korea
| | - Young San Ko
- Department of Forensic Medicine, National Forensic Service Busan Institute, Yangsan 50612, Republic of Korea
| | - Jung-Soo Pyo
- Department of Pathology, Eulji University Hospital, Eulji University School of Medicine, 95 Dunsanseo-ro, Seo-gu, Daejeon 35233, Republic of Korea.
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Zhang WJ, Chen C, Zhou ZH, Gao ST, Tee TJ, Yang LQ, Xu YY, Pang TH, Xu XY, Sun Q, Feng M, Wang H, Lu CL, Wu GZ, Wu S, Guan WX, Xu GF. Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients. J Cancer 2017; 8:1818-1825. [PMID: 28819379 PMCID: PMC5556645 DOI: 10.7150/jca.19057] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 05/10/2017] [Indexed: 12/12/2022] Open
Abstract
Background: Hypoxia was a common feature for accelerating tumor metastasis by both inducting epithelial-mesenchymal transition (EMT) of tumor cells and polarization of tumor-associated macrophages (TAMs). The association and roles between hypoxia, EMT and TAMs in the biological behavior of gastric cancer (GC) for the time being recurrence is unclear. Material and methods: hypoixa by expression of hypoxia-inducible factor-1 alpha (HIF-1α), polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68 and CD163, and the expression of E-cadherin as EMT property had been evaluated in 236 patients consecutive with histologically confirmed GC. Clinical significance was assessed for all these patients. Results: High expression of HIF-1α was found in patients with aggressive features, especially for recurrent patients. High infiltration of TAMs and abnormal expression of EMT-marker were also related to aggressive characteristics and predicted poor prognosis in GC. Meanwwhile, there existed a significant correlation among expression of HIF-1α, infiltration of TAMs and EMT marker in GC tissues. Multivariate Cox analysis revealed that high expression of HIF-1α combined TAMs infiltration were independent prognostic factors for disease-specific survival rate. Conclusion: HIF-1α is an unfavorable indicator for prognosis, may promote tumor progression through the induction of EMT and establishment of a pro-tumor immunosuppressive microenvironment. Further investigation into the therapeutic effects of blocking hypoxia is possible a potential strategy for GC treatment.
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Affiliation(s)
- Wei-Jie Zhang
- Department of General surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.,Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Cheng Chen
- Department of Radiotherapy, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zhi-Hua Zhou
- Department of Pathology, 101th Hospital of PLA, Wuxi, Jiangsu Providence, China
| | - Shan-Ting Gao
- Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Teong Jin Tee
- Department of Medical, Gastroenterology unit, Nilai Medical Center, Nilai, Negeri Sembilan, Malaysia
| | - Liu-Qing Yang
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Yuan-Yuan Xu
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Tao-Hong Pang
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Xin-Yun Xu
- Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Qi Sun
- Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Min Feng
- Department of General surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.,Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Hao Wang
- Department of General surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.,Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Chun-Lei Lu
- Department of General surgery, 101th Hospital of PLA, Wuxi, Jiangsu Providence, China
| | - Guo-Zhong Wu
- Department of General surgery, 101th Hospital of PLA, Wuxi, Jiangsu Providence, China
| | - Sheng Wu
- Department of General surgery, 101th Hospital of PLA, Wuxi, Jiangsu Providence, China
| | - Wen-Xian Guan
- Department of General surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.,Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
| | - Gui-Fang Xu
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China
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24
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Zhou J, Huang S, Wang L, Yuan X, Dong Q, Zhang D, Wang X. Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis. World J Surg Oncol 2017; 15:104. [PMID: 28521842 PMCID: PMC5437521 DOI: 10.1186/s12957-017-1163-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 04/23/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Recent studies have indicated an association between hypoxia inducible factor-1 alpha (HIF-1α) expression and poor prognosis in patients with oral squamous cell carcinoma (OSCC); however, definitive evidence of this association is yet to be obtained. We performed a meta-analysis to evaluate the association of HIF-1α expression with clinicopathological characteristics and overall survival (OS) of patients with OSCC. METHODS A literature search for relevant studies published in English language as of February 05, 2016, was performed on PubMed, Web of Science, and EMBASE databases. Eighteen studies with a combined study population of 1474 patients with OSCC are included in the meta-analysis. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was calculated using random-effects model or fixed-effects model. RESULTS HIF-1α overexpression was significantly associated with larger tumor size (OR = 2.28, 95% CI = 1.49-3.50, P = 0.017), advanced TNM stage (OR = 2.29, 95% CI = 1.50-3.49, P = 0.158), and lymph node metastasis (OR = 2.05, 95% CI = 1.19-3.53, P < 0.001), but not with poor differentiation (OR = 1.21, 95% CI = 0.55-2.64, P = 0.024). These results demonstrated an association between HIF-1α expression and biological behavior of OSCC. On pooled analyses, high expression of HIF-1α was associated with worse OS (HR = 1.70, 95% CI = 1.10-2.61, P < 0.001). On subgroup analyses, overexpression of HIF-1α was significantly associated with poor prognosis in Asian population (HR = 2.33, 95% CI = 1.72-3.15, P = 0.862). CONCLUSIONS Our findings demonstrate an association of HIF-1α overexpression with tumor size, tumor stage, lymph node metastasis, and overall survival. HIF-1α could be an independent prognostic marker in patients with OSCC.
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Affiliation(s)
- Jianhua Zhou
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, Shandong, 250012, China
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, Shandong, 250012, China
- Department of Stomatology, Qingdao Municipal Hospital, Qingdao, Shandong, 266071, China
| | - Shengyun Huang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, Shandong, 250012, China
| | - Lili Wang
- Central laboratories, Qingdao Municipal Hospital, Qingdao, Shandong, 266071, China
| | - Xiao Yuan
- Department of Stomatology, Qingdao Municipal Hospital, Qingdao, Shandong, 266071, China
| | - Quanjiang Dong
- Central laboratories, Qingdao Municipal Hospital, Qingdao, Shandong, 266071, China
| | - Dongsheng Zhang
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, Shandong, 250012, China.
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, Shandong, 250012, China.
| | - Xuxia Wang
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, Shandong, 250012, China.
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Shi WJ, Gao JB. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016; 8:673-681. [PMID: 27672425 PMCID: PMC5027022 DOI: 10.4251/wjgo.v8.i9.673] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 06/07/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance.
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26
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Kim JI, Lee HJ, Goo JM, Kim MA, Chung DH. Correlation of volumetric perfusion CT parameters with hypoxia inducible factor-1 alpha expression in a rabbit VX2 tumor model. Acta Radiol 2016; 57:708-15. [PMID: 26339038 DOI: 10.1177/0284185115603243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 08/01/2015] [Indexed: 11/17/2022]
Abstract
BACKGROUND Hypoxia inducible factor-1 alpha (HIF-1α) plays a critical role in tumoral angiogenesis and HIF-1α overexpression is associated with an increased risk of patient mortality in many cancers. A number of studies have introduced perfusion computed tomography (CT) as a monitoring modality for antiangiogenic therapy. PURPOSE To investigate significance of volumetric perfusion CT parameters in relationship to HIF-1α expression in VX2 tumor rabbit models. MATERIAL AND METHODS Twenty VX2 carcinoma tumors of bilateral back muscles of 10 rabbits were evaluated with serial volumetric perfusion CT in 7, 10, and 14 days after tumor implantation. CT perfusion data were analyzed to calculate blood flow (BF), blood volume (BV), and permeability surface area product (PS) of whole tumor and non-necrotic peripheral area (periphery). Immunohistochemical analysis of HIF-1α expression and microvessel density (MVD) was performed. RESULTS HIF-1α was expressed in 12 tumors; two, three, and seven tumors classified as scores 1, 2 and 3, respectively. Mean MVD was 24.85 ± 13.7. PS of both the whole tumor and periphery showed positive correlations with HIF-1α score (r = 0.41, P = 0.046; r = 0.43, P = 0.002, respectively). BV of periphery showed a negative correlation with HIF-1α (r = -0.48, P = 0.040). There was strong positive correlation between HIF-1α expression and MVD (r = 0.82, P < 0.001). CONCLUSION In VX2 tumors, volumetric perfusion CT parameters were of limited value for the prediction of HIF-1α activity although HIF-1α expression was found to be weakly positively correlated with PS and negatively correlated with BV.
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Affiliation(s)
- Jung Im Kim
- Department of Radiology, Seoul National University College of Medicine, and Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
- Department of Radiology, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Hyun-Ju Lee
- Department of Radiology, Seoul National University College of Medicine, and Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Jin Mo Goo
- Department of Radiology, Seoul National University College of Medicine, and Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Min A Kim
- Department of Pathology, Seoul National University College of Medicine, and Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University College of Medicine, and Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Republic of Korea
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27
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Liu K, Min XL, Peng J, Yang K, Yang L, Zhang XM. The Changes of HIF-1α and VEGF Expression After TACE in Patients With Hepatocellular Carcinoma. J Clin Med Res 2016; 8:297-302. [PMID: 26985249 PMCID: PMC4780492 DOI: 10.14740/jocmr2496w] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2016] [Indexed: 02/05/2023] Open
Abstract
As a common malignant tumor, hepatocellular carcinoma (HCC) has a high prevalence and is a serious threat to human health. The surgical resection rate of HCC is low, and the prognosis is poor. Although transarterial chemoembolization (TACE) is the main treatment for HCC patients who are not candidates for surgical resection, it is not considered a curative procedure. For HCC, poor TACE efficacy or TACE failure may be related to tumor angiogenesis of the residual disease. Among the many regulatory factors in tumor angiogenesis, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) play vital roles in this process. In this paper, we conducted a review of the dynamic change and relevance of HIF-1α and VEGF levels after TACE of HCC patients.
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Affiliation(s)
- Kang Liu
- Department of Pain Management, Xianyang Hospital, Yan’an University, Xianyang, Shanxi 712000, China
- Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Xu-Li Min
- Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Juan Peng
- Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Ke Yang
- Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Lin Yang
- Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
| | - Xiao-Ming Zhang
- Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China
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Senchukova MA, Ryabov АB. Modern concepts of factors for gastric cancer progression. ONKOLOGIYA. ZHURNAL IMENI P.A.GERTSENA 2016; 5:82. [DOI: 10.17116/onkolog20165182-87] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
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29
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Associations of hypoxia inducible factor-1α gene polymorphisms with susceptibility to digestive tract cancers: a case–control study and meta-analysis. Genes Genomics 2015. [DOI: 10.1007/s13258-015-0322-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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30
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Naruke A, Azuma M, Takeuchi A, Ishido K, Katada C, Sasaki T, Higuchi K, Tanabe S, Saegusa M, Koizumi W. Comparison of site-specific gene expression levels in primary tumors and synchronous lymph node metastases in advanced gastric cancer. Gastric Cancer 2015; 18:262-70. [PMID: 24651981 DOI: 10.1007/s10120-014-0357-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 02/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Many malignant tumors consist of heterogeneous subpopulations of cells. This heterogeneity is associated with genetic characteristics. However, it remains unclear whether gene expression levels differ among specific sites of tumors in gastric cancer. METHODS We studied differences in gene expression levels among specific sites of primary tumors and synchronous lymph node metastases, using formalin-fixed, paraffin-embedded specimens resected surgically from 48 patients with previously untreated advanced gastric cancer. Specimens were obtained by laser-captured microdissection from five regions: (1) nonneoplastic mucosa, (2) surface layer (mucosa) of the primary tumor (surface sections), (3) middle layer (submucosa) of the primary tumor (middle sections), (4) the deepest layer of the primary tumor (muscularis propria or deeper) at the site of deepest invasion (deep sections), and (5) level 1 synchronous lymph node metastasis (lymph node metastases). Expression levels of the following target genes were determined by quantitative real-time polymerase chain reaction: thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF1α). RESULTS TP, DPD, EGFR, and HIF1α gene expression levels were significantly higher in deep sections than in surface sections. TP, EGFR, VEGF, and HIF1α gene expression levels were significantly higher in lymph node metastases than in surface sections. TP, DPD, EGFR, VEGF, and HIF1α gene expression levels were positively correlated with the specific samples harvested from the tumors. CONCLUSIONS Our results show that the expression levels of some genes in tumor cells can change in specific sites of tumors and can become higher in association with tumor progression.
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Affiliation(s)
- Akira Naruke
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan,
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Chen S, Zhang M, Xing L, Wang Y, Xiao Y, Wu Y. HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling. PLoS One 2015; 10:e0121115. [PMID: 25811359 PMCID: PMC4374675 DOI: 10.1371/journal.pone.0121115] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 02/10/2015] [Indexed: 12/31/2022] Open
Abstract
The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on the proliferation, migration and invasion of neuroblastoma (NB) cells and the mechanisms involved. We here initially used the real-time polymerase chain reaction (real-time PCR), Western blotting and immunohistochemistry (IHC) to detect the expression of HIF-1α and components of the sonic hedgehog (SHH) signaling pathway in NB cells and human specimens. Subsequently, cell proliferation, migration and invasion were analyzed using the cell counting assay, wound healing assay and Transwell system in two types of human NB cell lines, SH-SY5Y and IMR32. In addition, the role of HIF-1α in NB cells growth was determined in a xenograft nude mouse model. We found that the level of HIF-1α was significantly upregulated during NB progression and was associated with the expression of two components of SHH signaling, SHH and GLI1. We next indicated that the proliferation, migration and invasiveness of SH-SY5Y and IMR32 cells were significantly inhibited by HIF-1α knockdown, which was mediated by small interfering RNAs (siRNAs) targeting against its mRNA. Furthermore, the growth of NB cells in vivo was also suppressed by HIF-1α inhibition. Finally, the pro-migration and proliferative effects of HIF-1α could be reversed by disrupting SHH signaling. In conclusion, our results demonstrated that upregulation of HIF-1α in NB promotes proliferation, migration and invasiveness via SHH signaling.
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Affiliation(s)
- Sheng Chen
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Min Zhang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Lili Xing
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yue Wang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yongtao Xiao
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Yeming Wu
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- * E-mail:
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Zhang SQ, Sun KK, Wu XY, Zhong N, Zhao H, Li DC. Clinicopathological significance of cytoplasmic transducer of ErbB2. 1 expression in gastric cancer. Mol Med Rep 2015; 12:1177-82. [PMID: 25760308 DOI: 10.3892/mmr.2015.3470] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 02/17/2015] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the expression of transducer of ErbB2. 1 (TOB1) in gastric carcinoma and to clarify the association between TOB1 expression and the clinical significance of this expression in patients with gastric carcinoma. Western blot analysis was performed to confirm the expression of TOB1 in gastric cancer. Immunohistochemistry (IHC) was performed on a tissue microarray containing 90 pairs of primary gastric cancer and adjacent normal tissue samples. TOB1 expression was evaluated separately with cytoplasmic and nuclear staining. Western blot analysis revealed significantly lower expression levels of TOB1 in gastric cancer tissues than those in adjacent normal tissues in 91.7% of cases. This was confirmed by IHC, which revealed decreased cytoplasmic TOB1 expression in cancer tissues compared with those of normal tissue samples in 84.4% of cases. The IHC data also revealed low cytoplasmic expression of TOB1 in 67.8% of human gastric cancer samples. Nuclear TOB1 expression exhibited no significant association with specific pathological features. However, a significant association was identified between cytoplasmic expression levels of TOB1 and clinicopathological characteristics, including the depth of invasion (P=0.017), differentiation grade (P=0.034) and tumor-node-metastasis stage (P<0.000). In conclusion, cytoplasmic TOB1 expression was suggested to be significant in angiogenesis and cell differentiation in gastric cancer tissues and may be used as a potential prognostic marker.
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Affiliation(s)
- Su-Qing Zhang
- Department of General Surgery, First Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ke-Kang Sun
- Department of Gastrointestinal Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Xiao-Yang Wu
- Department of Gastrointestinal Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Ning Zhong
- Department of Gastrointestinal Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Hua Zhao
- Department of General Surgery, First Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - De-Chun Li
- Department of General Surgery, First Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Guan G, Zhang Y, Lu Y, Liu L, Shi D, Wen Y, Yang L, Ma Q, Liu T, Zhu X, Qiu X, Zhou Y. The HIF-1α/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells. Cancer Lett 2014; 357:254-264. [PMID: 25444927 DOI: 10.1016/j.canlet.2014.11.034] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 11/13/2014] [Accepted: 11/14/2014] [Indexed: 12/11/2022]
Abstract
HIF-1α mediates hypoxia-induced expression of the chemokine receptor CXCR4 and contributes to metastasis in many different cancers. We have previously shown that hypoxia promotes migration of human osteosarcoma cells by activating the HIF-1α/CXCR4 pathway. Here, immunohistochemical analysis showed that unlike control osteochondroma samples, osteosarcoma specimens were characterized by elevated expression levels of HIF-1α and CXCR4. Moreover, we found that hypoxia-induced invasiveness was more pronounced in high metastatic potential F5M2 osteosarcoma cells than in low metastatic potential F4 cells, and that this induction was sensitive to treatment with the CXCR4 antagonist AMD3100 and the HIF-1α inhibitor KC7F2. Interestingly, hypoxia-induced CXCR4 expression persisted after cultured osteosarcoma cells were returned to normoxic conditions. These observations were confirmed by experiments in a mouse model of osteosarcoma lung metastasis showing that hypoxia stimulation of pulmonary metastasis was greater in F5M2 than in F4 cells, and was sensitive to treatment with AMD3100. Our study provides further evidence of the contributions of hypoxia and the HIF-1α/CXCR4 pathway to the progression of osteosarcoma, and suggests that this axis might be efficiently leveraged in the development of novel osteosarcoma therapeutics.
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Affiliation(s)
- Guofeng Guan
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Yinglong Zhang
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Yao Lu
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Lijuan Liu
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Doufei Shi
- Department of Geriatrics, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, China
| | - Yanhua Wen
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Lianjia Yang
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Qiong Ma
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Tao Liu
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
| | - Xiaodong Zhu
- Department of Microsurgery, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, China.
| | - Xiuchun Qiu
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
| | - Yong Zhou
- Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
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Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1α and β-catenin via a p-21 activated kinase 1-dependent pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1853:157-65. [PMID: 25409929 DOI: 10.1016/j.bbamcr.2014.10.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 09/17/2014] [Accepted: 10/15/2014] [Indexed: 01/22/2023]
Abstract
p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/β-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1α (HIF-1α), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [(3)H]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1α and β-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1α and β-catenin via a PAK1-dependent pathway.
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Sawayama H, Ishimoto T, Sugihara H, Miyanari N, Miyamoto Y, Baba Y, Yoshida N, Baba H. Clinical impact of the Warburg effect in gastrointestinal cancer (review). Int J Oncol 2014; 45:1345-54. [PMID: 25070157 DOI: 10.3892/ijo.2014.2563] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 07/09/2014] [Indexed: 12/11/2022] Open
Abstract
Cancer cells exhibit altered glucose metabolism, termed the Warburg effect, which is described by the increased uptake of glucose and the conversion of glucose to lactate in cancer cells under adequate oxygen tension. Recent genetic and metabolic analyses have provided insights into the molecular mechanisms of genes that are involved in the Warburg effect and tumorigenesis. The aim of this review was to discuss significant molecular insights into clinical impacts of the Warburg effect such as oncogenic alterations and overexpression of transcriptional factors (c-Myc and hypoxia-inducible factor), metabolite transporters (glucose transporters) and glycolytic enzymes (hexokinases 2, pyruvate kinase M2, pyruvate dehydrogenase kinase, isozyme 1, lactate dehydrogenase A). Overexpression of transcriptional factors, metabolite transporters and glycolytic enzymes was associated with poor prognosis and may be associated with chemoradiotherapy resistance in multiple gastrointestinal cancer cell types. Novel small molecules targeting these enzymes or transporters exert anti-proliferative effects. Glycolytic enzymes and metabolite transporters may be significant biomarkers for predicting cancer prognosis and may be therapeutic targets in gastrointestinal cancer.
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Affiliation(s)
- Hiroshi Sawayama
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hidetaka Sugihara
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Nobutomo Miyanari
- Department of Surgery, National Hospital Organization Kumamoto Medical Center, Kumamoto 860-0008, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Zhang ZG, Zhang QN, Wang XH, Tian JH. Hypoxia-inducible factor 1 alpha (HIF-1α) as a prognostic indicator in patients with gastric tumors: a meta-analysis. Asian Pac J Cancer Prev 2014; 14:4195-8. [PMID: 23991975 DOI: 10.7314/apjcp.2013.14.7.4195] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND AND OBJECTIVE Though researched for years, the prognostic role of hypoxia-inducible factor 1 alpha (HIF-1α) in gastric cancer is still controversial. We thus undertook a systematic review to assess the relationship. METHOD A systematically literature search of Pubmed, Embase, Web of Science, China Biological Medicine Disc and Cochrane Library was undertaken in February 2013, and the reference lists of articles were retrieved. RESULTS 12 trials (1,555 participants) were included to assess the association between HIF-1α expression and survival. Summary hazard ratios (HRs) were calculated. HIF-1α expression was significantly correlated with poor overall survival of gastric cancer patients (HR=1.34, 95%CI: 1.13-1.58; P=0.0009), but not with poor disease free survival of gastric cancer patients (HR=1.67, 95%CI: 0.99-2.82; P=0.06). CONCLUSION HIF-1α was associated with poor OS, but not DFS, especially for Asian patients. But studies evaluating relationships of HIF- 1α with OS and DFS in non-Asian gastric cancer patients appear needed.
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Affiliation(s)
- Zhi-Gang Zhang
- Evidence Based Medicine Center of Lanzhou University, Lanzhou, China
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Guo M, Cai C, Zhao G, Qiu X, Zhao H, Ma Q, Tian L, Li X, Hu Y, Liao B, Ma B, Fan Q. Hypoxia promotes migration and induces CXCR4 expression via HIF-1α activation in human osteosarcoma. PLoS One 2014; 9:e90518. [PMID: 24618817 PMCID: PMC3949690 DOI: 10.1371/journal.pone.0090518] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 02/03/2014] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Cellular adaptation to a hypoxic microenvironment is essential for tumor progression and is largely mediated by HIF-1α through coordinated regulation of hypoxia-responsive genes. The chemokine SDF-1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers. In this study, we investigated the response of osteosarcoma cells to hypoxia and the expression of CXCR4 and HIF-1α in human osteosarcoma specimens and explored the roles of CXCR4 and HIF-1α in the cell migration process. METHODOLOGY/PRINCIPAL FINDINGS We performed immunohistochemistry, immunocytochemistry, quantitative real-time PCR, Western blots and fluorescent reporter assays to evaluate the correlation between CXCR4 and HIF-1α expression in human osteosarcoma specimens or SOSP-9607 cells under normoxic and hypoxic conditions. Transwell assays were used to assess cell migration under different conditions. Exposure of SOSP-9607 cells to hypoxic conditions resulted in significantly increased migration. When SOSP-9607 cells were subjected to hypoxic conditions, the mRNA and protein levels of CXCR4 were significantly increased in a time-dependent manner. Moreover, siHIF-1α significantly decreased the mRNA and protein levels of CXCR4 under hypoxia, whereas pcDNA-HIF-1α significantly increased the mRNA and protein levels of CXCR4 under normoxia. A luciferase reporter gene study showed that siHIF-1α reduced pGL3-CXCR4 luciferase activity. Furthermore, coexpression of HIF-1α and CXCR4 was significantly higher in patients with distant metastasis compared with those without metastasis. CONCLUSIONS/SIGNIFICANCE The hypoxia-HIF-1α-CXCR4 pathway plays a crucial role during the migration of human osteosarcoma cells, and targeting this pathway might represent a novel therapeutic strategy for patients suffering from osteosarcoma.
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Affiliation(s)
- Mingjun Guo
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Chengkui Cai
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Guangyi Zhao
- Department of Orthopaedics, Bethune International Peace Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Xiuchun Qiu
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Haien Zhao
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Qiong Ma
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Liying Tian
- Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Xuelian Li
- Department of Surgery, Xi'an Hospital of TCM, Shaanxi, People's Republic of China
| | - Yunsheng Hu
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Bo Liao
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Baoan Ma
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- * E-mail: (BM); (QF)
| | - Qingyu Fan
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
- * E-mail: (BM); (QF)
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Zhang J, Guo H, Zhu JS, Yang YC, Chen WX, Chen NW. Inhibition of phosphoinositide 3-kinase/Akt pathway decreases hypoxia inducible factor-1α expression and increases therapeutic efficacy of paclitaxel in human hypoxic gastric cancer cells. Oncol Lett 2014; 7:1401-1408. [PMID: 24765145 PMCID: PMC3997665 DOI: 10.3892/ol.2014.1963] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 02/20/2014] [Indexed: 12/22/2022] Open
Abstract
The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, transformation, apoptosis, tumor growth and angiogenesis. Paclitaxel is commonly used to treat multiple human malignancies; however, the underlying mechanisms of paclitaxel in gastric cancer (GC) have not been fully investigated. In the present study, specimens from 45 GC and 36 chronic gastritis patients were collected, and the correlations of PI3K, phosphorylated-Akt (p-Akt) and hypoxia-inducible factor-1α (HIF-1α) expression with the clinicopathological characteristics of GC were analyzed by immunohistochemistry. The human SGC-7901 GC cells under hypoxic conditions were pretreated with the PI3K inhibitor, LY294002 (40 μM), and paclitaxel (0.1 μM). The expression levels of PI3K, p-Akt and HIF-1α were detected by quantitative polymerase chain reaction and western blotting. Cell proliferative activity and apoptosis were evaluated by the Cell Counting Kit-8 assay and flow cytometry. As a result, the rates of positive expression of PI3K, p-Akt and HIF-1α were significantly higher in GC compared with chronic gastritis patients (each P<0.01), and were positively associated with the tumor-node-metastasis (TNM) staging, lymph node metastases, lymphatic infiltration and vascular infiltration (each P<0.01), but inversely correlated with tumor differentiation (P<0.01) in patients with GC. Under hypoxic conditions, the combined inhibition of the PI3K/Akt pathway with paclitaxel markedly reduced the proliferative activity and induced cell apoptosis in GC cells compared with the single treatment of PI3K inhibitor or paclitaxel (each P<0.01), and was accompanied by a decreased expression of HIF-1α. Overall, our findings indicate that the increased expression of the PI3K/Akt/HIF-1α pathway was closely correlated with tumor differentiation, TNM staging, lymph node metastases and lymphatic and vascular infiltration. The inhibition of the PI3K/Akt pathway enhanced the therapeutic efficacy of paclitaxel in GC cells under hypoxic conditions, suggesting that the PI3K/Akt/HIF-1α pathway may act as an important therapeutic target for paclitaxel treatment of GC.
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Affiliation(s)
- Jing Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Hua Guo
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Jin-Shui Zhu
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Yu-Chen Yang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Wei-Xiong Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Ni-Wei Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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Lin S, Ma R, Zheng XY, Yu H, Liang X, Lin H, Cai XJ. Meta-analysis of immunohistochemical expression of hypoxia inducible factor-1α as a prognostic role in gastric cancer. World J Gastroenterol 2014; 20:1107-1113. [PMID: 24574785 PMCID: PMC3921536 DOI: 10.3748/wjg.v20.i4.1107] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 10/26/2013] [Accepted: 11/13/2013] [Indexed: 02/07/2023] Open
Abstract
AIM: To conduct a meta-analysis to evaluate the prognostic role of hypoxia inducible factor-1α (HIF-1α) expression in gastric cancer.
METHODS: The PubMed, EMBASE, and Web of Science databases were searched systematically for all articles published in English before August, 2013. Pooled effect was calculated from the available data to evaluate the association between HIF-1α expression and 5-year overall survival and tumor clinicopathological features in gastric cancer patients. Pooled odds ratios (ORs) with 95%CIs were calculated using either a fixed-effects or a random-effects model.
RESULTS: Nine studies matched the selection criteria, which reported on 1103 subjects, 548 of whom had HIF-1α positive expression (50%). This meta-analysis indicated that HIF-1α positive expression in gastric cancer correlated with lower 5-year overall survival (OR = 0.36; 95%CI: 0.21-0.64), worse tumor differentiation (OR = 0.38; 95%CI: 0.23-0.64), deeper invasion (OR = 0.42; 95%CI: 0.32-0.57), higher rates of lymph node metastasis (OR = 2.23; 95%CI: 1.46-3.40), lymphatic invasion (OR = 2.50; 95%CI: 1.46-4.28), and vascular invasion (OR = 1.80; 95%CI: 1.29-2.51), and higher TNM stage (III + IV) (OR = 0.31; 95%CI: 0.15-0.60).
CONCLUSION: HIF-1α positive expression indicates a poor prognosis for patients with gastric cancer. Further studies are required to confirm these results.
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Hashimoto K, Aoyagi K, Isobe T, Kouhuji K, Shirouzu K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 2014; 17:97-106. [PMID: 23558457 PMCID: PMC3889295 DOI: 10.1007/s10120-013-0255-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 03/15/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND CD133 is one of the most important stem cell markers in solid cancers. Some recent reports have described a possible relationship between CD133 and hypoxia-inducing factor-1-alpha (HIF-1α). The aim of this study was to clarify the clinical role of CD133 expression in gastric cancer and to investigate the correlation between CD133 expression and HIF-1α expression. METHODS We studied 189 gastric cancer patients who underwent gastrectomy at Kurume University Hospital. CD133 and HIF-1α expression was examined using immunohistochemical staining. Fifty-six cases were CD133 positive, and they were divided into two expression types: luminal expression of the gland and cytoplasmic expression. We investigated the relationship among CD133 expression types, clinicopathological variables, prognosis, and HIF-1α expression. RESULTS When comparing clinicopathological variables, expression of CD133 in the cytoplasm was related to metastasis and tumor progression. However, this relationship was not observed with luminal expression of the gland type. The survival rate in patients with cytoplasmic CD133 expression was significantly worse than that in the CD133-negative group. This relationship was observed in the survival rate of the adjuvant chemotherapy group and the curative resection group. Multivariate analysis revealed that the expression of CD133 in the cytoplasm was an independent prognostic factor in gastric cancer. Regarding the correlation between CD133 expression and HIF-1α expression, the HIF-1α positive rate was lower in patients with CD133 luminal expression of the gland type and higher in patients with cytoplasmic expression of CD133. CONCLUSION Gastric cancer cells with CD133 expression in the cytoplasm were cells with high potential for malignancy, and this phenotype was associated with cancer progression, chemotherapy resistance, recurrence, and poor prognosis. Cytoplasmic expression of CD133 may be a useful prognostic marker in gastric cancer. Significant correlation was observed between HIF-1α expression and the immunohistochemical staining pattern of CD133.
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Affiliation(s)
- Kousuke Hashimoto
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Keishiro Aoyagi
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Taro Isobe
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Kikuo Kouhuji
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
| | - Kazuo Shirouzu
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011 Japan
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Prognostic value of HIF-1α expression in patients with gastric cancer. Mol Biol Rep 2013; 40:6055-62. [PMID: 24057269 DOI: 10.1007/s11033-013-2715-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 09/14/2013] [Indexed: 12/20/2022]
Abstract
The role of hypoxia-inducible factors-1 alpha (HIF-1α) expression in gastric cancer remains controversial. We performed a systematic review of the literature with meta-analysis. Electronic databases were used to identify published studies before December 1, 2012. Pooled hazard ratio (HR) or odds ratio (OR) with 95 % confidence interval (95 % CI) was used to estimate the strength of the association between HIF-1α expression and survival of gastric cancer patients. Heterogeneity and publication bias were also assessed. Final analysis of 1,268 patients from 9 eligible studies was performed. High HIF-1α expression was significantly correlated with poor overall survival (OS) of gastric cancer patients (HR = 2.14, 95 % CI = 1.32-3.48). Subgroup analysis indicated that HIF-1α over-expression had an unfavorable impact on OS in Asian patients (HR = 2.35, 95 % CI = 1.41-3.92). Moreover, up-regulation of HIF-1α was significantly associated with the depth of invasion (OR = 2.49, 95 % CI = 1.28-4.83), lymph node metastasis (OR = 2.15, 95 % CI = 1.27-3.66), and vascular invasion (OR = 2.23, 95 % CI = 1.20-4.14). HIF-1α expression might be a predicative factor of poor prognosis for gastric cancer particularly in Asia.
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Lee SJ, No YR, Dang DT, Dang LH, Yang VW, Shim H, Yun CC. Regulation of hypoxia-inducible factor 1α (HIF-1α) by lysophosphatidic acid is dependent on interplay between p53 and Krüppel-like factor 5. J Biol Chem 2013; 288:25244-25253. [PMID: 23880760 DOI: 10.1074/jbc.m113.489708] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hypoxia-inducible factor 1α (HIF-1α) and p53 are pivotal regulators of tumor growth. Lysophosphatidic acid (LPA) is a lipid mediator that functions as a mitogen by acting through LPA receptors. We have shown previously that LPA stimulates HIF-1α expression in colon cancer cells. To determine the mechanism of HIF-1α induction by LPA, we compared the effect of LPA on HIF-1α in several colon cancer cell lines. LPA transcriptionally induced HIF-1α in colon cancer cells. HIF-1α induction was observed in cells expressing WT p53, where LPA decreased p53 expression. However, LPA failed to induce HIF-1α when the p53 gene was mutated. A decrease in p53 expression was dependent on induction of p53-specific E3 ubiquitin ligase Mdm2 by LPA. Krüppel-like factor 5 (KLF5) is an effector of LPA-induced proliferation of colon cancer cells. Because HIF-1α was necessary for LPA-induced growth of colon cancer cells, we determined the relationship between KLF5 and HIF-1α by a loss-of-function approach. Silencing of KLF5 inhibited LPA-induced HIF-1α induction, suggesting that KLF5 is an upstream regulator of HIF-1α. KLF5 and p53 binding to the Hif1α promoter was assessed by ChIP assay. LPA increased the occupancy of the Hif1α promoter by KLF5, while decreasing p53 binding. Transfection of HCT116 cells with KLF5 or p53 attenuated the binding of the other transcription factor. These results identify KLF5 as a transactivator of HIF-1α and show that LPA regulates HIF-1α by dynamically modulating its interaction with KLF5 and p53.
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Affiliation(s)
- Sei-Jung Lee
- From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322
| | - Yi Ran No
- From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322
| | - Duyen T Dang
- the Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109
| | - Long H Dang
- the Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida 32610
| | - Vincent W Yang
- the Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York 11794
| | - Hyunsuk Shim
- the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, and; the Department of Radiology, Emory University, Atlanta, Georgia 30322
| | - C Chris Yun
- From the Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322,; the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, and.
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Hu X, Lin S, Zheng J, Guo R, Li H, You C. Clinicopathological significance of hypoxia-inducible factor-1 alpha polymorphisms in cancers: evidence from a meta-analysis. Tumour Biol 2013; 34:2477-87. [PMID: 23857282 DOI: 10.1007/s13277-013-0971-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Accepted: 06/24/2013] [Indexed: 02/05/2023] Open
Abstract
The associations between hypoxia-inducible factor-1 alpha (HIF-1α) and clinicopathological characteristics of cancers have been evaluated in various studies, with the conflicting results. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure (CNKI) were searched until February 2013 to identify eligible studies. A total of 25 studies were included, with all studies investigating the role of HIF-1α C1772T polymorphism in clinicopathological parameters in cancers while 17 of them investigating HIF-1α G1790A polymorphism only. Results suggested that HIF-1α C1772T polymorphism was associated with histological grade of cancer (T/T + C/T vs. C/C, grade 3 vs. grade 2: OR = 1.51, 95% CI = 1.08-2.13; grade 2 vs. grade 1: OR = 0.67, 95% CI = 0.46-0.97) and increased risk of lymph node metastasis (T/T + C/T vs. C/C: OR = 1.38, 95% CI = 1.13-1.68). HIF-1α G1790A polymorphism was found to be associated with increased risk of larger tumor size (G/G + G/A vs. A/A: OR = 1.64, 95% CI = 1.04-2.58) and borderline significant risk of lymph node metastasis (G/G + G/A vs. A/A: OR = 1.33, 95% CI = 1.00-1.78). Therefore, HIF-1α polymorphisms could be a potential prognostic factor for cancer. Further studies with larger data set and well-designed models are required to validate our findings.
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Affiliation(s)
- Xin Hu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
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Deng B, Zhu JM, Wang Y, Liu TT, Ding YB, Xiao WM, Lu GT, Bo P, Shen XZ. Intratumor hypoxia promotes immune tolerance by inducing regulatory T cells via TGF-β1 in gastric cancer. PLoS One 2013; 8:e63777. [PMID: 23723999 PMCID: PMC3664556 DOI: 10.1371/journal.pone.0063777] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 04/06/2013] [Indexed: 02/05/2023] Open
Abstract
Regulatory T cell (Treg)-mediated immunosuppression represents one of the crucial tumor immune evasion mechanisms and is a main obstacle for successful tumor immunotherapy. Hypoxia, a common feature of solid tumors, has been associated with potentiated immunosuppression, decreased therapeutic response, malignant progression and local invasion. Unfortunately, the link between hypoxia and Treg-mediated immune tolerance in gastric cancer remains poorly understood. In our study, Tregs and hypoxia inducible factor-1α were found to be positively correlated with each other and were increased with the tumor progression. A subsequent in vitro study indicated that supernatants derived from gastric cancer cells under hypoxic condition, could induce the expression of Foxp3 via TGF-β1. These findings confirmed the crucial role of Tregs as a therapeutic target in gastric cancer therapy and provided helpful thoughts for the design of immunotherapy for gastric cancer in the future.
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Affiliation(s)
- Bin Deng
- Department of Gastroenterology, Second Clinical School of Yangzhou University, Yangzhou, Jiangsu, China
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yi Wang
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yan-Bing Ding
- Department of Gastroenterology, Second Clinical School of Yangzhou University, Yangzhou, Jiangsu, China
| | - Wei-Ming Xiao
- Department of Gastroenterology, Second Clinical School of Yangzhou University, Yangzhou, Jiangsu, China
| | - Guo-Tao Lu
- Department of Gastroenterology, Second Clinical School of Yangzhou University, Yangzhou, Jiangsu, China
| | - Ping Bo
- Institute of Integrated Chinese Traditional and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu, China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
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Hashimoto K, Aoyagi K, Isobe T, Kouhuji K, Shirouzu K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 2013. [PMID: 23558457 DOI: 10.1007/s10120-] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND CD133 is one of the most important stem cell markers in solid cancers. Some recent reports have described a possible relationship between CD133 and hypoxia-inducing factor-1-alpha (HIF-1α). The aim of this study was to clarify the clinical role of CD133 expression in gastric cancer and to investigate the correlation between CD133 expression and HIF-1α expression. METHODS We studied 189 gastric cancer patients who underwent gastrectomy at Kurume University Hospital. CD133 and HIF-1α expression was examined using immunohistochemical staining. Fifty-six cases were CD133 positive, and they were divided into two expression types: luminal expression of the gland and cytoplasmic expression. We investigated the relationship among CD133 expression types, clinicopathological variables, prognosis, and HIF-1α expression. RESULTS When comparing clinicopathological variables, expression of CD133 in the cytoplasm was related to metastasis and tumor progression. However, this relationship was not observed with luminal expression of the gland type. The survival rate in patients with cytoplasmic CD133 expression was significantly worse than that in the CD133-negative group. This relationship was observed in the survival rate of the adjuvant chemotherapy group and the curative resection group. Multivariate analysis revealed that the expression of CD133 in the cytoplasm was an independent prognostic factor in gastric cancer. Regarding the correlation between CD133 expression and HIF-1α expression, the HIF-1α positive rate was lower in patients with CD133 luminal expression of the gland type and higher in patients with cytoplasmic expression of CD133. CONCLUSION Gastric cancer cells with CD133 expression in the cytoplasm were cells with high potential for malignancy, and this phenotype was associated with cancer progression, chemotherapy resistance, recurrence, and poor prognosis. Cytoplasmic expression of CD133 may be a useful prognostic marker in gastric cancer. Significant correlation was observed between HIF-1α expression and the immunohistochemical staining pattern of CD133.
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Affiliation(s)
- Kousuke Hashimoto
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
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RUNX3 inhibits hypoxia-inducible factor-1α protein stability by interacting with prolyl hydroxylases in gastric cancer cells. Oncogene 2013; 33:1458-67. [DOI: 10.1038/onc.2013.76] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 01/29/2013] [Accepted: 02/01/2013] [Indexed: 12/12/2022]
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Saponaro C, Malfettone A, Ranieri G, Danza K, Simone G, Paradiso A, Mangia A. VEGF, HIF-1α expression and MVD as an angiogenic network in familial breast cancer. PLoS One 2013; 8:e53070. [PMID: 23326384 PMCID: PMC3543407 DOI: 10.1371/journal.pone.0053070] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 11/28/2012] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis, which plays an important role in tumor growth and progression of breast cancer, is regulated by a balance between pro- and anti-angiogenic factors. Expression of vascular endothelial growth factor (VEGF) is up-regulated during hypoxia by hypoxia-inducible factor-1α (HIF-1α). It is known that there is an interaction between HIF-1α and BRCA1 carrier cancers, but little has been reported about angiogenesis in BRCA1-2 carrier and BRCAX breast cancers. In this study, we investigated the expression of VEGF and HIF-1α and microvessel density (MVD) in 26 BRCA1-2 carriers and 58 BRCAX compared to 77 sporadic breast cancers, by immunohistochemistry. VEGF expression in BRCA1-2 carriers was higher than in BRCAX cancer tissues (p = 0.0001). Furthermore, VEGF expression was higher in both BRCA1-2 carriers and BRCAX than the sporadic group (p<0.0001). VEGF immunoreactivity was correlated with poor tumor grade (p = 0.0074), hormone receptors negativity (p = 0.0206, p = 0.0002 respectively), and MIB-1-labeling index (p = 0.0044) in familial cancers (BRCA1-2 and BRCAX). The percentage of nuclear HIF-1α expression was higher in the BRCA1-2 carriers than in BRCAX cancers (p<0.05), and in all familial than in sporadic tumor tissues (p = 0.0045). A higher MVD was observed in BRCA1-2 carrier than in BRCAX and sporadic cancer tissues (p = 0.002, p = 0.0001 respectively), and in all familial tumors than in sporadic tumors (p = 0.01). MVD was positively related to HIF-1α expression in BRCA1-2 carriers (r = 0.521, p = 0.006), and, in particular, we observed a highly significant correlation in the familial group (r = 0.421, p<0.0001). Our findings suggest that angiogenesis plays a crucial role in BRCA1-2 carrier breast cancers. Prospective studies in larger BRCA1-2 carrier series are needed to improve the best therapeutic strategies for this subgroup of breast cancer patients.
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Affiliation(s)
- Concetta Saponaro
- Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Andrea Malfettone
- Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Girolamo Ranieri
- Unit of Interventional Radiology, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Katia Danza
- Molecular Genetics Laboratory, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Giovanni Simone
- Pathology Department, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Angelo Paradiso
- Scientific Direction, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Anita Mangia
- Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori “Giovanni Paolo II”, Bari, Italy
- * E-mail:
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