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Gu C, Wang D, Zhu S, Wang X, Tian X, Liao Y, Gu Z. A Pyroptosis Radiosensitizer Facilitates Hypoxic Tumor Necrosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2409594. [PMID: 39989228 DOI: 10.1002/smll.202409594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/09/2025] [Indexed: 02/25/2025]
Abstract
Hypoxia-related tumor radioresistance markedly impairs the efficacy of radiotherapy. Herein, a targeted radiosensitization strategy is introduced, leveraging the upregulation of gasdermin C (GSDMC) in hypoxic tumor cells, aiming to induce pyroptosis through the application of a cobalt-containing polyoxometalate-based radiosensitizer. This novel radiosensitizer is designed for the precisely controlled release of cobalt ions upon X-ray irradiation, thereby activating caspase-8 and prompting the cleavage of GSDMC. This sequence of events selectively triggers pyroptosis in hypoxic tumor cells, directly addressing radioresistance. The ensuing results highlight the enhanced radiotherapy efficacy and tumor necrosis both in vitro and in vivo models. Overall, the findings confirm the effectiveness of this strategy targeting high GSDMC expression in hypoxic tumors to induce pyroptosis for precise radiotherapy. Such findings encourage further exploration of hypoxia-driven pyroptosis to improve cancer treatment outcomes.
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Affiliation(s)
- Chenglu Gu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dongmei Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shuang Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xue Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinyi Tian
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - You Liao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhanjun Gu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- College of Materials Science and Optoelectronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
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Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy. Cells 2022; 11:cells11182811. [PMID: 36139386 PMCID: PMC9496732 DOI: 10.3390/cells11182811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/27/2022] [Accepted: 09/05/2022] [Indexed: 12/05/2022] Open
Abstract
Previous studies have shown that tumors under a hypoxic environment can induce an important hypoxia-responsive element, hypoxia-induced factor-1α (HIF-1α), which can increase tumor migration, invasion, and metastatic ability by promoting epithelial-to-mesenchymal transition (EMT) in tumor cells. Currently, with the deeper knowledge of long noncoding RNAs (lncRNAs), more and more functions of lncRNAs have been discovered. HIF-1α can regulate hypoxia-responsive lncRNAs under hypoxic conditions, and changes in the expression level of lncRNAs can regulate the production of EMT transcription factors and signaling pathway transduction, thus promoting EMT progress. In conclusion, this review summarizes the regulation of the EMT process by HIF-1α and lncRNAs and discusses their relationship with tumorigenesis. Since HIF-1α plays an important role in tumor progression, we also summarize the current drugs that inhibit tumor progression by modulating HIF-1α.
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Xu H, Zhang F, Gao X, Zhou Q, Zhu L. Fate decisions of breast cancer stem cells in cancer progression. Front Oncol 2022; 12:968306. [PMID: 36046046 PMCID: PMC9420991 DOI: 10.3389/fonc.2022.968306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer has a marked recurrence and metastatic trait and is one of the most prevalent malignancies affecting women’s health worldwide. Tumor initiation and progression begin after the cell goes from a quiescent to an activated state and requires different mechanisms to act in concert to regulate t a specific set of spectral genes for expression. Cancer stem cells (CSCs) have been proven to initiate and drive tumorigenesis due to their capability of self-renew and differentiate. In addition, CSCs are believed to be capable of causing resistance to anti-tumor drugs, recurrence and metastasis. Therefore, exploring the origin, regulatory mechanisms and ultimate fate decision of CSCs in breast cancer outcomes has far-reaching clinical implications for the development of breast cancer stem cell (BCSC)-targeted therapeutic strategies. In this review, we will highlight the contribution of BCSCs to breast cancer and explore the internal and external factors that regulate the fate of BCSCs.
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Blocking C-Raf alleviated high-dose small-volume radiation-induced epithelial mesenchymal transition in mice lung. Sci Rep 2020; 10:11158. [PMID: 32636458 PMCID: PMC7341876 DOI: 10.1038/s41598-020-68175-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 06/12/2020] [Indexed: 11/08/2022] Open
Abstract
The goal of this study was to develop a potential druggable target for lung injury after SABR through the small animal model. Utilising the model, a radiation dose of 70 Gy or 90 Gy was focally (small volume) delivered to the left lung of mice. The highly expressed phosphorylation form of C-Raf was discovered through a protein array experiment, with the protein being extracted from the area of radiated mouse lung tissue, and was confirmed by IHC and western blot. C-Raf activation, along with morphological change and EMT (Epithelial to Mesenchymal Transition) marker expression, was observed after radiation to the mouse type II alveolar cell line MLE-12. C-Raf inhibitor GW5074 was able to reverse the EMT in cells effectively, and was found to be dependent on Twist1 expression. In the animal experiment, pretreatment of GW5074 alleviated EMT and lung injury after 70 Gy radiation was focally delivered to the lung of mice. Conclusively, these results demonstrate that C-Raf inhibitor GW5074 inhibits high-dose small-volume radiation-induced EMT via the C-Raf/Twist1 signalling pathway in mice. Therefore, pharmacological C-Raf inhibitors may be used effectively as inhibitors of SABR-induced lung fibrosis.
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FOXO3a-dependent up-regulation of Mxi1-0 promotes hypoxia-induced apoptosis in endothelial cells. Cell Signal 2018; 51:233-242. [DOI: 10.1016/j.cellsig.2018.08.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 08/13/2018] [Accepted: 08/13/2018] [Indexed: 02/07/2023]
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Zhang Y, Lin S, Chen Y, Yang F, Liu S. LDH-Apromotes epithelial-mesenchymal transition by upregulating ZEB2 in intestinal-type gastric cancer. Onco Targets Ther 2018; 11:2363-2373. [PMID: 29740212 PMCID: PMC5931238 DOI: 10.2147/ott.s163570] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Introduction Epithelial-mesenchymal transition (EMT) is regarded as a crucial process of invasion and metastasis, which contribute greatly to cancer-related relapse and death. Based on research results that hypoxia can trigger gastric cancer EMT and decreasing lactate production can selectively kill hypoxic cancer cells, we infer that lactate dehydrogenase A (LDH-A) transforming pyruvate into lactate is at least in part responsible for poor prognosis of gastric cancer. Materials and methods We used siRNA to knock down LDH-A in intestinal-type gastric cancer (ITGC) cell lines SGC7901 and BGC823. Western blot and RT-PCR were applied to detect mRNA and protein expression of EMT-related genes, respectively. Transwell invasion assay and migration assay were applied to study invasive and migratory abilities, respectively. Survival analysis was used to evaluate prognostic values. Results and conclusion The results of in vitro experiment demonstrated that LDH-A facilitates ITGC cells’ invasion and migration by upregulating ZEB2. The positive correlation between LDH-A and ZEB2 was verified in 371 ITGC specimens. Survival analysis indicated that co-expression of LDH-A/ZEB2 had synergetic power to predict overall survival. Thus, we conclude that the close relationship between LDH-A and ZEB2 may offer a potential therapeutic strategy for ITGC.
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Affiliation(s)
- Yongjie Zhang
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.,Department of Medical Oncology, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Sen Lin
- Clinical Laboratory, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Yan Chen
- Department of Medical Oncology, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Fei Yang
- Department of Medical Oncology, Huai'an Hospital to Xuzhou Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Shenlin Liu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
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Yeh YH, Hsiao HF, Yeh YC, Chen TW, Li TK. Inflammatory interferon activates HIF-1α-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway. J Exp Clin Cancer Res 2018; 37:70. [PMID: 29587825 PMCID: PMC5870508 DOI: 10.1186/s13046-018-0730-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 03/09/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Tumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development. METHODS IFN was used to induce inflammation response and HIF-1α expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1α in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation. RESULTS We showed for the first time that IFN induced functional HIF-1α expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1α pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1α, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1α is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1α-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay. CONCLUSIONS Our mechanistic study showed an induction of HIF-1α and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1α may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1α programming.
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Affiliation(s)
- Yen-Hsiu Yeh
- Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, Republic of China
| | - Ho-Fu Hsiao
- Department of Emergency Medicine, Sijhih Cathay General Hospital, New Taipei City, Taiwan, Republic of China
| | - Yen-Cheng Yeh
- Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, Republic of China
| | - Tien-Wen Chen
- Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, Republic of China
| | - Tsai-Kun Li
- Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan, Republic of China.
- Center for Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China.
- Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
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Zheng D, Wu W, Dong N, Jiang X, Xu J, Zhan X, Zhang Z, Hu Z. Mxd1 mediates hypoxia-induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene. Mol Carcinog 2017; 56:2234-2244. [PMID: 28543796 DOI: 10.1002/mc.22676] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 05/12/2017] [Accepted: 05/19/2017] [Indexed: 12/18/2022]
Abstract
Hypoxia-induced chemoresistance remains a major obstacle to treating osteosarcoma effectively. Mxd1, a member of the Myc/Max/Mxd family, was shown to be involved in the development of drug resistance under hypoxia. However, the effect of Mxd1 on hypoxia-induced cisplatin (CDDP) resistance and its mechanism in osteosarcoma have not been fully elucidated. In this study, we demonstrated that HIF-1α-induced Mxd1 contributed to CDDP resistance in hypoxic U-2OS and MG-63 cells. The knockdown of Mxd1 expression elevated PTEN expression at both protein and RNA levels in these hypoxic cells. Using Luciferase reporter and ChIP assays, we confirmed that Mxd1 directly bound to the E-box sites within the PTEN promoter region. We further demonstrated that PTEN knockdown decreased CDDP sensitivity in Mxd1 siRNA-transfected U-2OS and MG-63 cells under hypoxia. Our results also showed that Mxd1 deficiency in hypoxic U-2OS and MG-63 cells lead to inactivation of PI3K/AKT signaling, which is the downstream of PTEN. Furthermore, blockade of PI3K/AKT signal re-sensitized hypoxic U-2OS and MG-63 cells to CDDP. Taken together, these findings suggest that HIF-1α-induced Mxd1 up-regulation suppresses the expression of PTEN under hypoxia, which leads to the activation of PI3K/AKT antiapoptotic and survival pathway. As a result CDDP resistance in osteosarcoma cells is induced.
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Affiliation(s)
- Datong Zheng
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Weiling Wu
- The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Na Dong
- The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Xiuqin Jiang
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Jinjin Xu
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Xi Zhan
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland
| | - Zhengdong Zhang
- School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Zhenzhen Hu
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
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Shang Y, Chen H, Ye J, Wei X, Liu S, Wang R. HIF-1α/Ascl2/miR-200b regulatory feedback circuit modulated the epithelial-mesenchymal transition (EMT) in colorectal cancer cells. Exp Cell Res 2017; 360:243-256. [PMID: 28899657 DOI: 10.1016/j.yexcr.2017.09.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/06/2017] [Accepted: 09/08/2017] [Indexed: 12/17/2022]
Abstract
We have reported that Achaete scute-like 2 (Ascl2) transcriptionally repressed miR-200 family members and affected the epithelial-mesenchymal transition (EMT)-mesenchymal-epithelial transition (MET) plasticity in colorectal cancer (CRC) cells. However, little is known about the regulation of the Ascl2/miR-200 axis. Here, we found that hypoxia inducible factor-1α (HIF-1α) mRNA levels were positively correlated with Ascl2 mRNA levels and inversely correlated with miR-200b in CRC samples. Mechanistically, we showed that Ascl2 was a downstream target of HIF-1α and had a critical role in the EMT phenotype induced by hypoxia or HIF-1α over-expression. Hypoxia or HIF-1α over-expression activated Ascl2 expression in CRC cells in a direct transcriptional mechanism via binding with the hypoxia-response element (HRE) at the proximal Ascl2 promoter. HIF-1α-induced Ascl2 expression repressed miR-200b expression to induce EMT occurrence. Furthermore, we found HIF-1α was a direct target of miR-200b. MiR-200b bound with the 3'-UTR of HIF-1α in CRC cells. HIF-1α/Ascl2/miR-200b regulatory feedback circuit modulated the EMT-MET plasticity of CRC cells. Our results confirmed a novel HIF-1α/Ascl2/miR-200b regulatory feedback circuit in modulating EMT-MET plasticity of CRC cells, which could serve as a possible therapeutic target.
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Affiliation(s)
- Yangyang Shang
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Haoyuan Chen
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Jun Ye
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Xiaolong Wei
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Shanxi Liu
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China
| | - Rongquan Wang
- Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
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Zhang K, Xu P, Sowers JL, Machuca DF, Mirfattah B, Herring J, Tang H, Chen Y, Tian B, Brasier AR, Sowers LC. Proteome Analysis of Hypoxic Glioblastoma Cells Reveals Sequential Metabolic Adaptation of One-Carbon Metabolic Pathways. Mol Cell Proteomics 2017; 16:1906-1921. [PMID: 28874504 DOI: 10.1074/mcp.ra117.000154] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Indexed: 02/04/2023] Open
Abstract
Rapidly proliferating tumors are exposed to a hypoxic microenvironment because of their density, high metabolic consumption, and interruptions in blood flow because of immature angiogenesis. Cellular responses to hypoxia promote highly malignant and metastatic behavior, as well as a chemotherapy-resistant state. To better understand the complex relationships between hypoxic adaptations and cancer progression, we studied the dynamic proteome responses of glioblastoma cells exposed to hypoxia via an innovative approach: quantification of newly synthesized proteins using heavy stable-isotope arginine labeling combined with accurate assessment of cell replication by quantification of the light/heavy arginine ratio of peptides in histone H4. We found that hypoxia affects cancer cells in multiple intertwined ways: inflammation, typically with over-expressed glucose transporter (GLUT1), DUSP4/MKP2, and RelA proteins; a metabolic adaptation with overexpression of all glycolytic pathway enzymes for pyruvate/lactate synthesis; and the EMT (epithelial-mesenchymal transition) and cancer stem cell (CSC) renewal with characteristic morphological changes and mesenchymal/CSC protein expression profiles. For the first time, we identified the vitamin B12 transporter protein TCN2, which is essential for one-carbon metabolism, as being significantly downregulated. Further, we found, by knockdown and overexpression experiments, that TCN2 plays an important role in controlling cancer cell transformation toward the highly aggressive mesenchymal/CSC stage; low expression of TCN2 has an effect similar to hypoxia, whereas high expression of TCN2 can reverse it. We conclude that hypoxia induces sequential metabolic responses of one-carbon metabolism in tumor cells. Our mass spectrometry data are available via ProteomeXchange with identifiers PXD005487 (TMT-labeling) and PXD007280 (label-free).
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Affiliation(s)
- Kangling Zhang
- From the ‡Department of Pharmacology, University of Texas Medical Branch, Galveston (UTMB), Texas, 77555; .,¶Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, 77555
| | - Pei Xu
- ‖Department of Neuroscience and Cell Biology, UTMB, Galveston, Texas, 77555
| | - James L Sowers
- ‖Department of Neuroscience and Cell Biology, UTMB, Galveston, Texas, 77555
| | - Daniel F Machuca
- From the ‡Department of Pharmacology, University of Texas Medical Branch, Galveston (UTMB), Texas, 77555
| | - Barsam Mirfattah
- From the ‡Department of Pharmacology, University of Texas Medical Branch, Galveston (UTMB), Texas, 77555
| | - Jason Herring
- From the ‡Department of Pharmacology, University of Texas Medical Branch, Galveston (UTMB), Texas, 77555
| | - Hui Tang
- From the ‡Department of Pharmacology, University of Texas Medical Branch, Galveston (UTMB), Texas, 77555
| | - Yan Chen
- ‖Department of Neuroscience and Cell Biology, UTMB, Galveston, Texas, 77555
| | - Bing Tian
- §Institute for Translational Sciences, UTMB, Galveston, Texas, 77555.,¶Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, 77555
| | - Allan R Brasier
- §Institute for Translational Sciences, UTMB, Galveston, Texas, 77555.,¶Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, 77555
| | - Lawrence C Sowers
- From the ‡Department of Pharmacology, University of Texas Medical Branch, Galveston (UTMB), Texas, 77555.,§Institute for Translational Sciences, UTMB, Galveston, Texas, 77555
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Kim JH, Shim JW, Eum DY, Kim SD, Choi SH, Yang K, Heo K, Park MT. Downregulation of UHRF1 increases tumor malignancy by activating the CXCR4/AKT-JNK/IL-6/Snail signaling axis in hepatocellular carcinoma cells. Sci Rep 2017; 7:2798. [PMID: 28584306 PMCID: PMC5459852 DOI: 10.1038/s41598-017-02935-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 04/20/2017] [Indexed: 12/19/2022] Open
Abstract
UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells.
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Affiliation(s)
- Ji-Hyun Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea
| | - Jae-Woong Shim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea
| | - Da-Young Eum
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea
| | - Sung Dae Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea
| | - Si Ho Choi
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea
| | - Kwangmo Yang
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea
| | - Kyu Heo
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea.
| | - Moon-Taek Park
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, Republic of Korea.
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Palumbo-Zerr K, Soare A, Zerr P, Liebl A, Mancuso R, Tomcik M, Sumova B, Dees C, Chen CW, Wohlfahrt T, Mallano T, Distler A, Ramming A, Gelse K, Mihai C, Distler O, Schett G, Distler JHW. Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis. Ann Rheum Dis 2017; 76:244-251. [PMID: 27113414 DOI: 10.1136/annrheumdis-2015-208470] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 02/26/2016] [Accepted: 03/31/2016] [Indexed: 01/23/2023]
Abstract
OBJECTIVES TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc). METHODS The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)β receptor I. RESULT The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGFβ/SMAD3-dependent manner. TWIST1 in turn enhanced TGFβ-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGFβ promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1. CONCLUSIONS Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGFβ signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGFβ signalling in SSc.
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Affiliation(s)
- Katrin Palumbo-Zerr
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Alina Soare
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
- Department of Internal Medicine and Rheumatology, Dr. I. Cantacuzino Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Pawel Zerr
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Andrea Liebl
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Rossella Mancuso
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Michal Tomcik
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
- Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Barbora Sumova
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
- Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Clara Dees
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Chih-Wei Chen
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Thomas Wohlfahrt
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Tatjana Mallano
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Alfiya Distler
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Andreas Ramming
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Kolja Gelse
- Department of Trauma Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Carina Mihai
- Department of Internal Medicine and Rheumatology, Dr. I. Cantacuzino Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Oliver Distler
- Research of Systemic Autoimmune Diseases, Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland
| | - Georg Schett
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jörg H W Distler
- Department of Internal Medicine III, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
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13
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Velaei K, Samadi N, Barazvan B, Soleimani Rad J. Tumor microenvironment-mediated chemoresistance in breast cancer. Breast 2016; 30:92-100. [PMID: 27668856 DOI: 10.1016/j.breast.2016.09.002] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 09/02/2016] [Accepted: 09/02/2016] [Indexed: 12/20/2022] Open
Abstract
Therapy resistance or tumor relapse in cancer is common. Tumors develop resistance to chemotherapeutic through a variety of mechanisms, with tumor microenvironment (TM) serving pivotal roles. Using breast cancer as a paradigm, we propose that responses of cancer cells to drugs are not exclusively determined by their intrinsic characteristics but are also controlled by deriving signals from TM. Affected microenvironment by chemotherapy is an avenue to promote phenotype which tends to resist on to be ruined. Therefore, exclusively targeting cancer cells does not demolish tumor recurrence after chemotherapy. Regardless of tumor-microenvironment pathways and their profound influence on the responsiveness of treatment, diversity of molecular properties of breast cancer also behave differently in terms of response to chemotherapy. And also it is assumed that there is cross-talk between phenotypic diversity and TM. Collectively, raising complex signal from TM in chemotherapy condition often encourages cancer cells are not killed but strengthen. Here, we summarized how TM modifies responses to chemotherapy in breast cancer. We also discussed successful treatment strategies have been considered TM in breast cancer treatment.
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Affiliation(s)
- Kobra Velaei
- Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Balal Barazvan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Soleimani Rad
- Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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14
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Lee HG, Kim H, Son T, Jeong Y, Kim SU, Dong SM, Park YN, Lee JD, Lee JM, Park JH. Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma. Oncotarget 2016; 7:41798-41810. [PMID: 27260001 PMCID: PMC5173097 DOI: 10.18632/oncotarget.9723] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/23/2016] [Indexed: 02/07/2023] Open
Abstract
Hexokinase 2 (HK2) is a rate-determining enzyme in aerobic glycolysis, a process upregulated in tumor cells. HK2 expression is controlled by various transcription factors and epigenetic alterations and is heterogeneous in hepatocellular carcinomas (HCCs), though the cause of this heterogeneity is not known. DNA methylation in the HK2 promoter CpG island (HK2-CGI) and its surrounding regions (shore and shelf) has not previously been evaluated, but may provide clues about the regulation of HK2 expression. Here, we compared HK2 promoter methylation in HCCs and adjacent non-cancerous liver tissues using a HumanMethylation450 BeadChip array. We found that, while the HK2-CGI N-shore was hypomethylated, thereby enhancing HK2 expression, the HK2-CGI was itself hypermethylated in some HCCs. This hypermethylation suppressed HK2 expression by inhibiting interactions between HIF-1α and a hypoxia response element (HRE) located at -234/-230. HCCs that were HK2negative and had distinct promoter CGI methylation were denoted as having a HK2-CGI methylation phenotype (HK2-CIMP), which was associated with poor clinical outcome. These findings indicate that HK2-CGI N-shore hypomethylation and HK2-CGI hypermethylation affect HK2 expression by influencing the interaction between HIF 1α and HRE. HK2-CGI hypermethylation induces HK2-CIMP and could represent a prognostic biomarker for HCC.
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Affiliation(s)
- Hyun Gyu Lee
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyemi Kim
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Taekwon Son
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Youngtae Jeong
- Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Seung Up Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Myung Dong
- Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea
| | - Young Nyun Park
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jong Doo Lee
- Department of Nuclear Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Republic of Korea
| | - Jae Myun Lee
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeon Han Park
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea
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15
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Cui Y, Li YY, Li J, Zhang HY, Wang F, Bai X, Li SS. STAT3 regulates hypoxia-induced epithelial mesenchymal transition in oesophageal squamous cell cancer. Oncol Rep 2016; 36:108-16. [PMID: 27220595 PMCID: PMC4899013 DOI: 10.3892/or.2016.4822] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 03/29/2016] [Indexed: 12/22/2022] Open
Abstract
Hypoxia plays a key role in tumour initiation and metastasis; one of the mechanisms is to induce epithelial-mesenchymal transition (EMT). Signal transducer and activator of transcription 3 (STAT3) is involved in EMT by regulating the transcriptional regulators of E-cadherin, the biomarker of EMT. Until now, however, few studies have focused on the effects of STAT3 in hypoxia-induced EMT in tumour cells. The goal of this study was to investigate the roles of STAT3 in hypoxia-induced EMT in oesophageal squamous cell carcinoma (ESCC). The ESCC cells, TE-1 and EC-1, were incubated in normoxia, or in CoCl2, which was used to mimic hypoxia. With CoCl2, the ESCC cells showed increased migration and invasion abilities, accompanied with upregulation of HIF-1α, STAT3, and vimentin, and downregulation of E-cadherin. Knockdown of STAT3 inhibited EMT of ESCC cells and downregulated HIF-1α in vitro and in vivo. In ChIP assays, STAT3 bound to the promoter of HIF-1α, suggesting that STAT3 regulates transcription of HIF-1α. In conclusion, hypoxia induces EMT of ESCC, and STAT3 regulates this process by promoting HIF-1α expression.
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Affiliation(s)
- Yao Cui
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University and Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yun-Yun Li
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jian Li
- Department of General Surgery, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Hong-Yan Zhang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University and Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Feng Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University and Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xue Bai
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University and Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shan-Shan Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University and Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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16
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Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m⁶A-demethylation of NANOG mRNA. Proc Natl Acad Sci U S A 2016; 113:E2047-56. [PMID: 27001847 DOI: 10.1073/pnas.1602883113] [Citation(s) in RCA: 769] [Impact Index Per Article: 85.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
N(6)-methyladenosine (m(6)A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m(6)A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxia-inducible factor (HIF)-1α- and HIF-2α-dependent expression of AlkB homolog 5 (ALKBH5), an m(6)A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m(6)A residue in the 3'-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF- and ALKBH5-dependent manner. Insertion of the NANOG 3'-UTR into a luciferase reporter gene led to regulation of luciferase activity by O2, HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.
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17
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Qiu Y, Zheng H, Sun LH, Peng K, Xiao WD, Yang H. Hypoxia-inducible factor-1 modulates upregulation of mutT homolog-1 in colorectal cancer. World J Gastroenterol 2015; 21:13447-13456. [PMID: 26730155 PMCID: PMC4690173 DOI: 10.3748/wjg.v21.i48.13447] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 09/12/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the roles and interactions of mutT homolog (MTH)-1 and hypoxia-inducible factor (HIF)-1α in human colorectal cancer (CRC).
METHODS: The expression and distribution of HIF-1α and MTH-1 proteins were detected in human CRC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). SW480 and HT-29 cells were exposed to normoxia or hypoxia. Protein and mRNA levels of HIF-1α and MTH-1 were analyzed by western blotting and qRT-PCR, respectively. In order to determine the effect of HIF-1α on the expression of MTH-1 and the amount of 8-oxo-deoxyguanosine triphosphate (dGTP) in SW480 and HT-29 cells, HIF-1α was silenced with small interfering RNA (siRNA). Growth studies were conducted on cells with HIF-1α inhibition using a xenograft tumor model. Finally, MTH-1 protein was detected by western blotting in vivo.
RESULTS: High MTH-1 mRNA expression was detected in 64.2% of cases (54/84), and this was significantly correlated with tumor stage (P = 0.023) and size (P = 0.043). HIF-1α protein expression was correlated significantly with MTH-1 expression (R = 0.640; P < 0.01) in human CRC tissues. Hypoxic stress induced mRNA and protein expression of MTH-1 in SW480 and HT-29 cells. Inhibition of HIF-1α by siRNA decreased the expression of MTH-1 and led to the accumulation of 8-oxo-dGTP in SW480 and HT-29 cells. In the in vivo xenograft tumor model, expression of MTH-1 was decreased in the HIF-1α siRNA group, and the tumor volume was much smaller than that in the mock siRNA group.
CONCLUSION: MTH-1 expression in CRC cells was upregulated via HIF-1α in response to hypoxic stress, emphasizing the crucial role of HIF-1α-induced MTH-1 in tumor growth.
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18
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Haga CL, Velagapudi SP, Strivelli JR, Yang WY, Disney MD, Phinney DG. Small Molecule Inhibition of miR-544 Biogenesis Disrupts Adaptive Responses to Hypoxia by Modulating ATM-mTOR Signaling. ACS Chem Biol 2015; 10:2267-76. [PMID: 26181590 DOI: 10.1021/acschembio.5b00265] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hypoxia induces a complex circuit of gene expression that drives tumor progression and increases drug resistance. Defining these changes allows for an understanding of how hypoxia alters tumor biology and informs design of lead therapeutics. We probed the role of microRNA-544 (miR-544), which silences mammalian target of rapamycin (mTOR), in a hypoxic breast cancer model by using a small molecule (1) that selectively impedes the microRNA's biogenesis. Application of 1 to hypoxic tumor cells selectively inhibited production of the mature microRNA, sensitized cells to 5-fluorouracil, and derepressed mRNAs affected by miR-544 in cellulo and in vivo, including boosting mTOR expression. Thus, small molecule inhibition of miR-544 reverses a tumor cell's physiological response to hypoxia. Importantly, 1 sensitized tumor cells to hypoxia-associated apoptosis at a 25-fold lower concentration than a 2'-O-methyl RNA antagomir and was as selective. Further, the apoptotic effect of 1 was suppressed by treatment of cell with rapamycin, a well-known inhibitor of the mTOR signaling pathway, illustrating the selectivity of the compound. Thus, RNA-directed chemical probes, which could also serve as lead therapeutics, enable interrogation of complex cellular networks in cells and animals.
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Affiliation(s)
- Christopher L. Haga
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
| | - Sai Pradeep Velagapudi
- Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
| | - Jacqueline R. Strivelli
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
| | - Wang-Yong Yang
- Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
| | - Matthew D. Disney
- Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
| | - Donald G. Phinney
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
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19
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Huang B, Xiao E, Huang M. MEK/ERK pathway is positively involved in hypoxia-induced vasculogenic mimicry formation in hepatocellular carcinoma which is regulated negatively by protein kinase A. Med Oncol 2014; 32:408. [PMID: 25487444 DOI: 10.1007/s12032-014-0408-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 11/24/2014] [Indexed: 11/24/2022]
Abstract
The aim of present investigation is to explore the molecular mechanisms of vasculogenic mimicry (VM) induced by hypoxia. Hepatocellular carcinoma cell lines were treated with CoCl2, and the VM-related parameters were assayed by real-time qPCR, Western blotting and immunofluorescence. Matrigel tube structure was also detected. We demonstrated that the expression of pMEK, MEK, pERK1/2 and ERK1/2 had a positive correlation with VM induced by hypoxia in MHCC97H while HepG2 signified VM under normoxia condition. PD98059 was negatively while epidermal growth factor positively participated in the increased tubes and area of VM. At the meaning time, the increased VM-related genes VE-cadherin, MMP2, MMP9, EphA2 and LAMC2 in hypoxia group were down-regulated by PD98059 in a dose-dependent manner. Furthermore, we elucidated that PKA, but not PKC, mediated the MEK/ERK pathway in a negative manner in VM. In conclusion, MEK/ERK pathway is positively involved in VM in hepatocellular carcinoma cell line, which was mediated by PKA negatively.
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Affiliation(s)
- Bin Huang
- Radiology Department, The Second Xiangya Hospital of Central South University, No. 139, Renmin Road, Changsha, 410008, China
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20
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Guan Z, Ding C, Du Y, Zhang K, Zhu JN, Zhang T, He D, Xu S, Wang X, Fan J. HAF drives the switch of HIF-1α to HIF-2α by activating the NF-κB pathway, leading to malignant behavior of T24 bladder cancer cells. Int J Oncol 2013; 44:393-402. [PMID: 24316875 PMCID: PMC3898811 DOI: 10.3892/ijo.2013.2210] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 11/19/2013] [Indexed: 12/14/2022] Open
Abstract
Hypoxia is a characteristic feature of solid tumors, leading to malignant behavior. During this process, HIF family members (HIFs) and the NF-κB pathway are activated. In addition, the hypoxia-associated factor (HAF) is reported to participate in the regulation of HIFs. However, the precise relationship among HIFs, HAF and the NF-κB pathway in bladder cancer (BC) remains unknown. In the current investigation, T24 BC cells were exposed to hypoxia, or by plasmid transfection to overexpress HAF or RelA (P65) to demonstrate their roles. The results indicate that hypoxia leads to the elevation of HAF plus activation of the NF-κB pathway, accompanied by the switch of HIF-1α to HIF-2α, resulting in the enhanced ability of malignancy in T24 cells. In order to further demonstrate the significance of this switch, HIF-1α and HIF-2α were co-transfected into T24 cells with HIF-β, respectively. The following results indicate that the T24hif-2α/β cells show enhanced ability of malignancy, accompanied by the maintenance of stem-cell markers, but the T24hif-1α/β cells show higher expression of metabolism-related genes. Boyden assays and wound-healing assays indicate the enhanced ability of malignancy for T24hif-2α/β. Thus, we conclude that on the hypoxic microenvironment, the switching of HIF-1α to HIF-2α, which is driven by HAF through activating the NF-κB pathway, contributes to the malignancy of T24 cells, accompanied by the maintenance of stem-cell markers. This provides us an avenue for understanding the progression of bladder cancer.
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Affiliation(s)
- Zhenfeng Guan
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Chen Ding
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Yiqing Du
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Kai Zhang
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Jian Ning Zhu
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Tingting Zhang
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Dalin He
- Department of Urology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Shan Xu
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Xinyang Wang
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, P.R. China
| | - Jinhai Fan
- Department of Urology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, P.R. China
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21
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Yang Z, Deng R, Sun G, Huang X, Tang E. Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: A retrospective study of 10 years. Head Neck 2013; 36:969-75. [PMID: 23733304 DOI: 10.1002/hed.23398] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 01/05/2013] [Accepted: 05/23/2013] [Indexed: 12/27/2022] Open
Affiliation(s)
- Zinan Yang
- Department of Oral and Maxillofacial Surgery; Stomatological Hospital Affiliated Medical School; Nanjing University; Nanjing Jiangsu province People's Republic of China
- Department of Oral and Maxillofacial Surgery; Hospital of Stomatology, Guangzhou Medical University; Guangzhou Guangdong province People's Republic of China
| | - Runzhi Deng
- Department of Oral and Maxillofacial Surgery; Stomatological Hospital Affiliated Medical School; Nanjing University; Nanjing Jiangsu province People's Republic of China
| | - Guowen Sun
- Department of Oral and Maxillofacial Surgery; Stomatological Hospital Affiliated Medical School; Nanjing University; Nanjing Jiangsu province People's Republic of China
| | - Xiaofeng Huang
- Department of Oral and Maxillofacial Surgery; Stomatological Hospital Affiliated Medical School; Nanjing University; Nanjing Jiangsu province People's Republic of China
| | - Enyi Tang
- Department of Oral and Maxillofacial Surgery; Stomatological Hospital Affiliated Medical School; Nanjing University; Nanjing Jiangsu province People's Republic of China
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22
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Philip B, Ito K, Moreno-Sánchez R, Ralph SJ. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 2013; 34:1699-707. [PMID: 23740838 DOI: 10.1093/carcin/bgt209] [Citation(s) in RCA: 128] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hypoxic microenvironments frequently exist in many solid tumours with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors (HIFs), a family of transcription factors which orchestrate signalling events leading to angiogenesis and tumorigenesis. Several events conspire together to lead to the stabilization of HIF-α, commonly expressed in many cancer cell types. These events can result from low oxygen tensions occurring within the expanding tumour mass to produce hypoxic microenvironments or from mutations whereby the HIFs cause changes in expression of genes involved in several cellular functions. Hypoxia-mediated HIF-α regulation has gained significant prominence in tumour biology over recent years, and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary to drive the progression of tumours to malignancy. More recently, it has been realized that the hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. In addition, the hypoxic microenvironment promotes many other oncogenic events, such as the metabolic reconfiguration of tumour cells, neovascularization, epithelial to mesenchymal transition (EMT), and cancer stem cell renewal and accumulation. This article reviews the molecular mechanisms underlying tumour hypoxia and their pro-tumour contributions, such as immune suppression, development of nascent and more permeable tumour vasculature, selective cancer stem cell renewal, accumulation, mobilization and promotion of EMT leading to tumour cell metastasis.
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Affiliation(s)
- Beatrice Philip
- School of Medical Sciences, Griffith University, Gold Coast Campus, Parklands, Queensland 4222, Australia
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23
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Kutluk Cenik B, Ostapoff KT, Gerber DE, Brekken RA. BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 2013; 12:992-1001. [PMID: 23729403 DOI: 10.1158/1535-7163.mct-12-0995] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Signaling from other angiokinases may underlie resistance to VEGF-directed therapy. We evaluated the antitumor and biologic effects of BIBF 1120 (nintedanib), a tyrosine kinase inhibitor that targets VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor in preclinical models of lung and pancreatic cancer, including models resistant to VEGF-targeted treatments. In vitro, BIBF 1120 did not show antiproliferative effects, nor did it sensitize tumor cells to chemotherapy. However, in vivo BIBF 1120 inhibited primary tumor growth in all models as a single agent and in combination with standard chemotherapy. Analysis of tumor tissue posttreatment revealed that BIBF 1120 reduced proliferation (phospho-histone 3) and elevated apoptosis (cleaved caspase-3) to a greater extent than chemotherapy alone. Furthermore, BIBF 1120 showed potent antiangiogenic effects, including decreases in microvessel density (CD31), pericyte coverage (NG2), vessel permeability, and perfusion, while increasing hypoxia. Despite the induction of hypoxia, markers of epithelial-to-mesenchymal transition (EMT) were not elevated in BIBF 1120-treated tumors. In summary, BIBF 1120 showed potent antitumor and antiangiogenic activity in preclinical models of lung and pancreatic cancer where it induced hypoxia but not EMT. The absence of EMT induction, which has been implicated in resistance to antiangiogenic therapies, is noteworthy. Together, these results warrant further clinical studies of BIBF 1120.
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Affiliation(s)
- Bercin Kutluk Cenik
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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24
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Mao Y, Xu J, Song G, Zhang N, Yin H. Twist2 promotes ovarian cancer cell survival through activation of Akt. Oncol Lett 2013; 6:169-174. [PMID: 23946798 PMCID: PMC3742652 DOI: 10.3892/ol.2013.1316] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 04/11/2013] [Indexed: 12/26/2022] Open
Abstract
Hypoxia-inducible factor-1 α (HIF-1α) is an important prognostic factor in ovarian carcinoma. Hypoxia contributes to tumor progression and is involved in the epithelial-mesenchymal transition (EMT). Twist2 is an EMT regulator, however, it remains poorly understood in ovarian carcinoma. The present study evaluated the expression of HIF-1α and Twist2 and further investigated whether Twist2 is involved in hypoxia-induced apoptosis in ovarian cancer. A series of matched paraffin-embedded tissue sections from human primary ovarian cancer and normal ovarian tissues were examined through immunohistochemical analysis, a Twist2-overexpressing stable ovarian cancer cell line was established and deferoxamine (DFO) was introduced to simulate hypoxic conditions. DFO-induced apoptosis was examined by fluorescence microscopy, MTT assays and flow cytometry. In addition, a western blot analysis was performed to examine the molecular mechanism(s) of action. Twist2 increased in epithelial ovarian cancers associated with HIF-1α expression. The acquired expression of Twist2 was able to promote the survival of ovarian cancer cells through Akt phosphorylation under DFO-induced hypoxic stress. The results suggest that Twist2 activates the PI-3K-Akt pathway to protect cells from apoptosis in a hypoxic environment. Moreover, Twist2 may be involved in the HIF-1α signaling pathway in ovarian cancer.
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Affiliation(s)
- Yubin Mao
- Department of Pathophysiology in Basic Science, Medical College of Xiamen University, Xiamen, Fujian 361102, P.R. China
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Clark DW, Phang T, Edwards MG, Geraci MW, Gillespie MN. Promoter G-quadruplex sequences are targets for base oxidation and strand cleavage during hypoxia-induced transcription. Free Radic Biol Med 2012; 53:51-9. [PMID: 22583700 PMCID: PMC3377816 DOI: 10.1016/j.freeradbiomed.2012.04.024] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 03/29/2012] [Accepted: 04/18/2012] [Indexed: 01/17/2023]
Abstract
The G-quadruplex, a non-B DNA motif that forms in certain G-rich sequences, is often located near transcription start sites in growth regulatory genes. Multiple lines of evidence show that reactive oxygen species generated as second messengers during physiologic signaling target specific DNA sequences for oxidative base modifications. Because guanine repeats are uniquely sensitive to oxidative damage, and G4 sequences are known "hot spots" for genetic mutation and DNA translocation, we hypothesized that G4 sequences are targeted for oxidative base modifications in hypoxic signaling. Approximately 25% of hypoxia-regulated genes in pulmonary artery endothelial cells harbored G4 sequences within their promoters. Chromatin immunoprecipitation showed that common base oxidation product 8-oxoguanine was selectively introduced into G4s, in promoters of hypoxia up-, down-, and nonregulated genes. Additionally, base excision DNA repair (BER) enzymes were recruited, and transient strand breaks formed in these sequences. Transcription factor Sp1, constitutively bound to G4 sequences in normoxia, was evicted as 8-oxoguanine accumulated during hypoxic exposure. Blocking hypoxia-induced oxidant production prevented both base modifications and decreased Sp1 binding. These findings suggest that oxidant stress in hypoxia causes oxidative base modifications, recruitment of BER enzymes, and transient strand breaks in G4 promoter sequences potentially altering G4 integrity and function.
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Affiliation(s)
- David W. Clark
- Department of Pharmacology and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA
| | - Tzu Phang
- Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado Denver, CO, 80045, USA
| | - Michael G. Edwards
- Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado Denver, CO, 80045, USA
| | - Mark W. Geraci
- Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado Denver, CO, 80045, USA
| | - Mark N. Gillespie
- Department of Pharmacology and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA
- To whom correspondence should be addressed. Tel: (251) 460-6497; Fax: (251) 460-6798;
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Wang N, Eckert KA, Zomorrodi AR, Xin P, Pan W, Shearer DA, Weisz J, Maranus CD, Clawson GA. Down-regulation of HtrA1 activates the epithelial-mesenchymal transition and ATM DNA damage response pathways. PLoS One 2012; 7:e39446. [PMID: 22761798 PMCID: PMC3383700 DOI: 10.1371/journal.pone.0039446] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 05/21/2012] [Indexed: 12/18/2022] Open
Abstract
Expression of the serine protease HtrA1 is decreased or abrogated in a variety of human primary cancers, and higher levels of HtrA1 expression are directly related to better response to chemotherapeutics. However, the precise mechanisms leading to HtrA1 down regulation during malignant transformation are unclear. To investigate HtrA1 gene regulation in breast cancer, we characterized expression in primary breast tissues and seven human breast epithelial cell lines, including two non-tumorigenic cell lines. In human breast tissues, HtrA1 expression was prominent in normal ductal glands. In DCIS and in invasive cancers, HtrA1 expression was greatly reduced or lost entirely. HtrA1 staining was also reduced in all of the human breast cancer cell lines, compared with the normal tissue and non-tumorigenic cell line controls. Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines. To mechanistically examine the functional consequences of HtrA1 loss, we stably reduced and/or overexpressed HtrA1 in the non-tumorigenic MCF10A cell line. Reduction of HtrA1 levels resulted in the epithelial-to-mesenchymal transition with acquisition of mesenchymal phenotypic characteristics, including increased growth rate, migration, and invasion, as well as expression of mesenchymal biomarkers. A concomitant decrease in expression of epithelial biomarkers and all microRNA 200 family members was also observed. Moreover, reduction of HtrA1 expression resulted in activation of the ATM and DNA damage response, whereas overexpression of HtrA1 prevented this activation. Collectively, these results suggest that HtrA1 may function as a tumor suppressor by controlling the epithelial-to-mesenchymal transition, and may function in chemotherapeutic responsiveness by mediating DNA damage response pathways.
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Affiliation(s)
- Ning Wang
- Gittlen Cancer Research Institute & Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Kristin A. Eckert
- Gittlen Cancer Research Institute & Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Ali R. Zomorrodi
- Department of Chemical Engineering, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Ping Xin
- Gittlen Cancer Research Institute & Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Weihua Pan
- Gittlen Cancer Research Institute & Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Debra A. Shearer
- Department of Obstetrics & Gynecology, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Judith Weisz
- Department of Obstetrics & Gynecology, Pennsylvania State University, Hershey, Pennsylvania, United States of America
| | - Costas D. Maranus
- Department of Chemical Engineering, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Gary A. Clawson
- Gittlen Cancer Research Institute & Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, United States of America
- Materials Research Institute, Pennsylvania State University, University Park, Pennsylvania, United States of America
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Hashimoto Y, Tazawa H, Teraishi F, Kojima T, Watanabe Y, Uno F, Yano S, Urata Y, Kagawa S, Fujiwara T. The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment. PLoS One 2012; 7:e39292. [PMID: 22720091 PMCID: PMC3376103 DOI: 10.1371/journal.pone.0039292] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 05/18/2012] [Indexed: 12/11/2022] Open
Abstract
Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.
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Affiliation(s)
- Yuuri Hashimoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
- Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, Japan
| | - Fuminori Teraishi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toru Kojima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuichi Watanabe
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Futoshi Uno
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Shuya Yano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | | | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
- * E-mail:
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