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Habeshian TS, Cannavale KL, Slezak JM, Shu YH, Chien GW, Chen X, Shi F, Siegmund KD, Van Den Eeden SK, Huang J, Chao CR. DNA methylation markers for risk of metastasis in a cohort of men with localized prostate cancer. Epigenetics 2024; 19:2308920. [PMID: 38525786 DOI: 10.1080/15592294.2024.2308920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 01/14/2024] [Indexed: 03/26/2024] Open
Abstract
Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997-12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.
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Affiliation(s)
- Talar S Habeshian
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kimberly L Cannavale
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Jeff M Slezak
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Yu-Hsiang Shu
- Biostatistics and Innovations, Biostatistics and Programming, Clinical Affairs, Inari Medical, CA, USA
| | - Gary W Chien
- Department of Urology, Los Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, CA, USA
| | - XuFeng Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Feng Shi
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Kimberly D Siegmund
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Chun R Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J Tyson School of Medicine, Pasadena, CA, USA
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Subramaniyam K, Harihar S. An Overview on the Emerging Role of the Plasma Protease Inhibitor Protein ITIH5 as a Metastasis Suppressor. Cell Biochem Biophys 2024; 82:399-409. [PMID: 38355846 DOI: 10.1007/s12013-024-01227-7] [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: 01/30/2023] [Accepted: 02/02/2024] [Indexed: 02/16/2024]
Abstract
Most cancers are not detected until they have progressed to the point of becoming malignant and life-threatening. Chemotherapy and conventional medicines are often ineffective against cancer. Although we have made significant progress, new conceptual discoveries are still required to investigate new treatments. The role of metastasis suppressor genes as a therapeutic option for limiting tumor progression and metastasis has been on the anvil for some time. In this review, we discuss the role of ITIH5 as a metastasis suppressor gene and catalog its involvement in different cancers. We further shed light on the mode of action of ITIH5 based on the available data. The review will provide a new perspective on ITIH5 as an anti-metastatic protein and hopefully serve as an impetus for future studies towards the application of ITIH5 for clinical intervention in targeting metastatic cancers.
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Affiliation(s)
- Krishnaveni Subramaniyam
- Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Sitaram Harihar
- Department of Biotechnology, GITAM School of Science, GITAM (Deemed to be) University, Visakhapatnam, 530045, Andhra Pradesh, India.
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3
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Wei QY, Jin F, Wang ZY, Li BJ, Cao WB, Sun ZY, Mo SJ. MicroRNAs: A novel signature in the metastasis of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:1497-1523. [PMID: 38617454 PMCID: PMC11008420 DOI: 10.3748/wjg.v30.i11.1497] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/12/2024] [Accepted: 03/01/2024] [Indexed: 03/21/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Affiliation(s)
- Qi-Ying Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Feng Jin
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhong-Yu Wang
- Department of Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bing-Jie Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Wen-Bo Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhi-Yan Sun
- Division of Special Service, Department of Basic Oncology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Sai-Jun Mo
- Department of Basic Science of Oncology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Harihar S, Welch DR. KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers? Cancer Metastasis Rev 2023; 42:183-196. [PMID: 36720764 PMCID: PMC10103016 DOI: 10.1007/s10555-023-10090-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 01/25/2023] [Indexed: 02/02/2023]
Abstract
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells.
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Affiliation(s)
- Sitaram Harihar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu 603203, India
| | - Danny R. Welch
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, USA
- The University of Kansas Comprehensive Cancer Center, 3901 Rainbow Blvd. Kansas City, Kansas City, KS 66160, USA
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Abdel-Azziz IA, Amin NH, El-Saadi MT, Abdel-Rahman HM. Design, synthesis and mechanistic studies of benzophenones hydrazone derivatives as cathepsin inhibitors. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Sun A, Tian X, Yang W, Lin Q. Overexpression of SCYL1 Is Associated with Progression of Breast Cancer. Curr Oncol 2022; 29:6922-6932. [PMID: 36290821 PMCID: PMC9600755 DOI: 10.3390/curroncol29100544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/15/2022] [Accepted: 09/21/2022] [Indexed: 01/13/2023] Open
Abstract
SCYL1 is a pseudokinase and plays roles in cell division and gene transcription, nuclear/cytoplasmic shuttling of tRNA, protein glycosylation, and Golgi morphology. However, the role of SCYL1 in human breast cancer progression remains largely unknown. In this study, we determined expression of SCYL1 in breast cancer by searching the Cancer Genome Atlas (TCGA) and Tumor Immunoassay Resource (TIMER) databases. Meanwhile, we collected breast tumor tissue samples from 247 cases and detected expression of SCYL1 in the tumors using the tissue microarray assay (TMA). Association of SCYL1 with prognosis of breast cancer was determined based on the PrognoScan database. The results have shown that SCYL1 is overexpressed in breast cancer, and the expression of SCYL1 is associated with poor clinical outcomes of breast cancer patients. Furthermore, knockdown of SCYL1 by shRNAs significantly inhibited the proliferation and migration of breast cancer cells. Taken together, our data suggest that SCYL1 is a biomarker for poor prognosis of breast cancer, has a promoting role in breast cancer progression, and is a potential target for breast cancer therapy.
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Gold nanoparticles induce apoptosis in HCT-116 colon cancer cell line. Mol Biol Rep 2022; 49:7863-7871. [PMID: 35729479 DOI: 10.1007/s11033-022-07616-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/12/2022] [Accepted: 05/18/2022] [Indexed: 12/08/2022]
Abstract
INTRODUCTION This study aimed to investigate the apoptotic and anti-cancer effect of gold nanoparticles (AuNPs) on apoptosis in HCT-116 colon cancer cells. MATERIALS AND METHODS The level of ROS and apoptosis were determined by fluorimetric method and flow cytometry and Hoechst 33,258 staining, respectively. Furthermore, the mRNA expression of Bax, Bcl-2, CCNB1, P53 genes was evaluated by qRT-PCR method in HCT116 cells. RESULTS The experimental results of this study showed that treatment with nanoparticles led to a significant increase in expression of Bax, P53 genes and a significant decrease in the expression of Bcl-2, CCNB1 genes at concentrations of 25 and 50 µg/ml during 48 h of incubation, compared to control cells (p < 0.05). The flow cytometric results (Annexin-pI) and Hoechst 33,258 staining also showed a significant increase in the level of apoptosis in the treated cells, depending on the concentration and time. CONCLUSIONS The results of this study showed that AuNPs cause apoptosis at the half-maximal inhibitory concentration in the HCT-116 tumor cells during 48 h of incubation.
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Yu CL, Weng MS, Chen WC, Chien KT, Chi CW, Chung CH, Huang CW, Wang PC, Chen CC, Tsai AC, Liu SC, Wang SW. Moscatilin Inhibits Metastatic Behavior of Human Hepatocellular Carcinoma Cells: A Crucial Role of uPA Suppression via Akt/NF-κB-Dependent Pathway. Int J Mol Sci 2021; 22:ijms22062930. [PMID: 33805784 PMCID: PMC8002083 DOI: 10.3390/ijms22062930] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/05/2021] [Accepted: 03/10/2021] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) frequently shows early invasion into blood vessels as well as intrahepatic metastasis. Innovations of novel small-molecule agents to block HCC invasion and subsequent metastasis are urgently needed. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, orchid Dendrobium loddigesii. Although moscatilin has been reported to suppress tumor angiogenesis and growth, the anti-metastatic property of moscatilin has not been elucidated. The present results revealed that moscatilin inhibited metastatic behavior of HCC cells without cytotoxic fashion in highly invasive human HCC cell lines. Furthermore, moscatilin significantly suppressed the activity of urokinase plasminogen activator (uPA), but not matrix metalloproteinase (MMP)-2 and MMP-9. Interestingly, moscatilin-suppressed uPA activity was through down-regulation the protein level of uPA, and did not impair the uPA receptor and uPA inhibitory molecule (PAI-1) expressions. Meanwhile, the mRNA expression of uPA was inhibited via moscatilin in a concentration-dependent manner. In addition, the expression of phosphorylated Akt, rather than ERK1/2, was inhibited by moscatilin treatment. The expression of phosphor-IκBα, and -p65, as well as κB-luciferase activity were also repressed after moscatilin treatment. Transfection of constitutively active Akt (Myr-Akt) obviously restored the moscatilin-inhibited the activation of NF-κB and uPA, and cancer invasion in HCC cells. Taken together, these results suggest that moscatilin impedes HCC invasion and uPA expression through the Akt/NF-κB signaling pathway. Moscatilin might serve as a potential anti-metastatic agent against the disease progression of human HCC.
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Affiliation(s)
- Chen-Lin Yu
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan; (C.-L.Y.); (C.-W.H.)
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan; (W.-C.C.); (C.-H.C.)
| | - Meng-Shih Weng
- Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 252, Taiwan;
| | - Wei-Cheng Chen
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan; (W.-C.C.); (C.-H.C.)
- Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei 104, Taiwan;
| | - Kai-Ting Chien
- Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei 104, Taiwan;
| | - Chih-Wen Chi
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 252, Taiwan;
| | - Ching-Hu Chung
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan; (W.-C.C.); (C.-H.C.)
| | - Chia-Wen Huang
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan; (C.-L.Y.); (C.-W.H.)
| | - Po-Chuan Wang
- Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City 300, Taiwan;
| | - Chien-Chih Chen
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 104, Taiwan;
| | - An-Chi Tsai
- Pharmacological Institutes, College of Medicine, National Taiwan University, Taipei 104, Taiwan;
| | - Shih-Chia Liu
- Department of Orthopedic Surgery, MacKay Memorial Hospital, Taipei 104, Taiwan;
- Correspondence: (S.-C.L.); (S.-W.W.); Tel.: +886-2-25433535 (S.-C.L.); +886-2-26360303 (S.-W.W.)
| | - Shih-Wei Wang
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan; (C.-L.Y.); (C.-W.H.)
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan; (W.-C.C.); (C.-H.C.)
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (S.-C.L.); (S.-W.W.); Tel.: +886-2-25433535 (S.-C.L.); +886-2-26360303 (S.-W.W.)
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Ledet RJ, Ruff SE, Wang Y, Nayak S, Schneider JA, Ueberheide B, Logan SK, Garabedian MJ. Identification of PIM1 substrates reveals a role for NDRG1 phosphorylation in prostate cancer cellular migration and invasion. Commun Biol 2021; 4:36. [PMID: 33398037 PMCID: PMC7782530 DOI: 10.1038/s42003-020-01528-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 11/25/2020] [Indexed: 12/17/2022] Open
Abstract
PIM1 is a serine/threonine kinase that promotes and maintains prostate tumorigenesis. While PIM1 protein levels are elevated in prostate cancer relative to local disease, the mechanisms by which PIM1 contributes to oncogenesis have not been fully elucidated. Here, we performed a direct, unbiased chemical genetic screen to identify PIM1 substrates in prostate cancer cells. The PIM1 substrates we identified were involved in a variety of oncogenic processes, and included N-Myc Downstream-Regulated Gene 1 (NDRG1), which has reported roles in suppressing cancer cell invasion and metastasis. NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated higher grade prostate tumors. We have shown that PIM1 phosphorylation of NDRG1 at S330 reduced its stability, nuclear localization, and interaction with AR, resulting in enhanced cell migration and invasion.
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Affiliation(s)
- Russell J Ledet
- Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Urology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA
| | - Sophie E Ruff
- Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Urology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA
| | - Yu Wang
- Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Urology, New York University School of Medicine, New York, NY, 10016, USA
| | - Shruti Nayak
- Proteomics Laboratory, New York University School of Medicine, New York, NY, 10016, USA
| | - Jeffrey A Schneider
- Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Urology, New York University School of Medicine, New York, NY, 10016, USA
- Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA
| | - Beatrix Ueberheide
- Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA
- Proteomics Laboratory, New York University School of Medicine, New York, NY, 10016, USA
| | - Susan K Logan
- Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
- Department of Urology, New York University School of Medicine, New York, NY, 10016, USA.
| | - Michael J Garabedian
- Department of Urology, New York University School of Medicine, New York, NY, 10016, USA.
- Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
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Liang H, Xiong Z, Li R, Hu K, Cao M, Yang J, Zhong Z, Jia C, Yao Z, Deng M. BDH2 is downregulated in hepatocellular carcinoma and acts as a tumor suppressor regulating cell apoptosis and autophagy. J Cancer 2019; 10:3735-3745. [PMID: 31333791 PMCID: PMC6636298 DOI: 10.7150/jca.32022] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 05/05/2019] [Indexed: 02/06/2023] Open
Abstract
BDH2 is a short-chain dehydrogenase/reductase family member involved in several biological and pathological processes, including the utilization of cytosolic ketone bodies, immunocyte regulation and tumor progression. In this study, we first revealed that BDH2 was downregulated in HCC tissues by qRT-PCR and immunohistochemistry analysis and that low BHD2 expression was significantly associated with poor overall survival, poor tumor differentiation, increased tumor size, venous invasion and an advanced BCLC stage. Moreover, the results of a univariate analysis and multivariate analysis revealed that BDH2 may be regarded as an independent prognostic marker. As a member of a gene family involved in ketone metabolism, BDH2 upregulated the level of β-HB in liver cells as well as the level of H3 histone acetylation. Functional analysis showed that BDH2 expression inhibited tumor cell growth, proliferation and migration. The results of the mechanistic analysis revealed that BDH2 induced mitochondrial apoptosis and inhibited autophagy through the unfolded protein response. Therefore, BDH2 may be a new HCC prognostic marker and a useful treatment target.
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Affiliation(s)
- Hao Liang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China.,Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Zhiyong Xiong
- Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Ruixi Li
- Department of Hepatobiliary Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518000, China
| | - Kunpeng Hu
- Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Mingbo Cao
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Jiarui Yang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Zhaozhong Zhong
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Changchang Jia
- Department of Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Zhicheng Yao
- Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
| | - Meihai Deng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China
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Tsai CW, Wang JH, Young TH. Core/shell multicellular spheroids on chitosan as in vitro 3D coculture tumor models. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:S651-S660. [PMID: 30311795 DOI: 10.1080/21691401.2018.1505744] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
An ideal in vitro drug screening model is important for the drug development. In addition to monoculture systems, 3 dimensional (3D) coculture systems are extensively used to simulate the in vivo tumor microenvironment as cell-cell and cell-extracellular matrix interactions within the tumor tissues can be mimicked. In this study, in vitro 3D suspension coculture multicellular spheroids with core/shell cell distribution were developed on chitosan-coated surfaces. Based on the characteristic of chitosan inhibiting cell adhesion, SW620 (colon cancer cell line), 3A6 (mesenchymal stem-like cell line) and Hs68 (foreskin fibroblast line) cells could aggregate to form 3D coculture spheroids with intimate cell contacts. When cells were cocultured on chitosan, 3A6 and Hs68 cells always located in the core of spheroids and were completely enveloped by SW620 cells due to their N-cadherin protein expression following the differential adhesion hypothesis. The core cells could be the feeder layers to stimulate the shell SW620 cells to enhance their mitochondria activity. Moreover, 3D coculture core/shell multicellular spheroids could enhance the resistance of SW620 cells against the cytotoxicity effect of chemotherapy drugs. To sum up, based on the specificity of the core/shell coculture multicellular spheroids, a novel in vitro tumor model was proposed in this study.
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Affiliation(s)
- Ching-Wen Tsai
- a Institute of Biomedical Engineering , National Taiwan University , Taipei , Taiwan
| | - Jyh-Horng Wang
- b Department of Orthopedic Surgery , National Taiwan University Hospital , Taipei , Taiwan
| | - Tai-Horng Young
- a Institute of Biomedical Engineering , National Taiwan University , Taipei , Taiwan
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12
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Jana S, Jana J, Patra K, Mondal S, Bhat J, Sarkar A, Sengupta P, Biswas A, Mukherjee M, Tripathi SP, Gangwal R, Hazra J, Sangamwar AT, Mukherjee G, Bhattacharjee S, Mandal DP, Chatterjee S. LINCRNA00273 promotes cancer metastasis and its G-Quadruplex promoter can serve as a novel target to inhibit cancer invasiveness. Oncotarget 2017; 8:110234-110256. [PMID: 29299144 PMCID: PMC5746379 DOI: 10.18632/oncotarget.22622] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 09/13/2017] [Indexed: 01/16/2023] Open
Abstract
Discovery of anti-metastatic drugs is of immense clinical significance as metastasis is responsible for 90% of all cancer deaths. Here we report the inhibitory effect of a bis schiff base (M2) on cancer cell migration and invasion in vitro and in vivo. M2 has shown good solubility and permeability across the intestinal cell wall and hence can be classified as BCS (Biopharmaceutical classification system) class I. Microarray studies identified a long non coding intergenic RNA, LINC00273 as a novel molecular target of M2. We report that LINC00273 harbors a unique (4n-1) parallel G-Quadruplex structure in its promoter as validated by DMS footprint. M2 is proposed to stabilize this G-quadruplex structure resulting in the down-regulation of LINC00273 expression. Dual Luciferase reporter assay also suggests inhibition of LINC00273 promoter activity by M2. Involvement of this linc in metastasis is proven by siRNA and shRNA mediated knock down of LINC00273 in vitro and in vivo in nude mice which significantly decelerates cancer cell migration and invasion and also makes the cells unresponsive to TGF-β's pro-metastatic effects. Furthermore, the real time expression of LINC00273 in thirty seven human clinical samples is found to be positively correlated with the histopathological staging of metastasis.
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Affiliation(s)
- Samarjit Jana
- Department of Zoology, West Bengal State University, Malikapur, Kolkata 700126, India
| | - Jagannath Jana
- Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
| | - Kartick Patra
- Department of Zoology, West Bengal State University, Malikapur, Kolkata 700126, India
| | - Soma Mondal
- Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
| | - Jyotsna Bhat
- Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
| | - Arnab Sarkar
- Department of Zoology, West Bengal State University, Malikapur, Kolkata 700126, India
| | - Pallabi Sengupta
- Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
| | - Anindya Biswas
- Department of Biochemistry, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
| | - Meghomukta Mukherjee
- Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
| | - Satya Prakash Tripathi
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, Punjab 160062, India
| | - Rahul Gangwal
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, Punjab 160062, India
| | - Joyita Hazra
- Department of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi Kolkata 700054, India
| | - Abhay T Sangamwar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, Punjab 160062, India
| | - Gopeswar Mukherjee
- Barasat Cancer Research and Welfare Centre, Barasat, Kolkata 700124, India
| | - Shamee Bhattacharjee
- Department of Zoology, West Bengal State University, Malikapur, Kolkata 700126, India
| | - Deba Prasad Mandal
- Department of Zoology, West Bengal State University, Malikapur, Kolkata 700126, India
| | - Subhrangsu Chatterjee
- Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India
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13
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Baharara J, Amini E, Musavi M. Anti-Vasculogenic Activity of a Polysaccharide Derived from Brittle Star via Inhibition of VEGF, Paxillin and MMP-9. IRANIAN JOURNAL OF BIOTECHNOLOGY 2017; 15:179-185. [PMID: 29845067 DOI: 10.15171/ijb.1208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 05/28/2017] [Accepted: 08/23/2017] [Indexed: 12/31/2022]
Abstract
Background: Bioactive compounds such as terpenoids, chondroitin sulfate, and polysaccharides with added value can be found in prestine marine creatures. These compounds often do have highly valuable therapeutic applications such as being antioxidant, antitumorogenic, anti-inflammatory and anti-angiogenic. For the latter, varieties of angiogenesis factors can suppress this issue within the bodily tissues. Objectives: The anti-angiogenic and anti-metastatic capacity of a polysaccharide derived from brittle star was investigated. Material and Methods: The anti-proliferative effect of derived polysaccharide on umbilical vein endothelial cells (HUVEC) was measured using MTT (dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. The anti-angiogenic effect of the isolated polysaccharide was examined by Chorioallantoic membrane (CAM) assay. The transcriptional expression of VEGF (Vascular Endothelial Growth Factor) was evaluated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). The anti-metastatic activity was investigated via scratch-wound healing assay. The levels of Paxillin and Matrix Metalloproteinase-9 (MMP-9) expression were analyzed by RT-PCR. Statistical analysis and mean comparisons (p< 0.05) were carried out by SPSS 16. Results: Our results elucidated that the brittle star isolated polysaccharide exerted a dose dependent cytotoxic effect on the HUVEC endothelial cells. The CAM assay exhibited potent anti-angiogenic activity in vivo. The RT-PCR analysis showed that the extracted polysaccharide (40, 60 µg.mL-1) down-regulated the VEGF expression. Further, the diminished attachment of endothelial cells demonstrated that the anti-invasiveness of the derived polysaccharide (25, 50 µg.mL-1) was administrated via down-regulation of paxillin and MMP-9 mRNA expression. Conclusions: Taken together, these results indicated that the polysaccharide extracted from brittle star was able to decrease the viability of the HUVEC cells, to suppress angiogenesis, and possibly act as a natural anti-angiogenic and anti-metastatic marine organic compound against angiogenesis related pathologies.
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Affiliation(s)
- Javad Baharara
- Department of Biology, Research Center For Applied Biology, Mashhad Branch, Islamic Azad University, Mashhad, 9183897194, Iran
| | - Elaheh Amini
- Department of Cellular & Molecular Biology, Faculty of Biology, Kharazmi University, Tehran, 14911-15719, Iran
| | - Marziyeh Musavi
- Department Faculty of Biological Science, Mashhad Branch, Islamic Azad University, Mashhad, 9183897194, Iran
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14
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Joshi V, Upadhyay A, Kumar A, Mishra A. Gp78 E3 Ubiquitin Ligase: Essential Functions and Contributions in Proteostasis. Front Cell Neurosci 2017; 11:259. [PMID: 28890687 PMCID: PMC5575403 DOI: 10.3389/fncel.2017.00259] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/09/2017] [Indexed: 11/26/2022] Open
Abstract
As per the requirement of metabolism and fitness, normal cellular functions are controlled by several proteins, and their interactive molecular and signaling events at multiple levels. Protein quality control (PQC) mechanisms ensure the correct folding and proper utilization of these proteins to avoid their misfolding and aggregation. To maintain the optimum environment of complex proteome PQC system employs various E3 ubiquitin ligases for the selective degradation of aberrant proteins. Glycoprotein 78 (Gp78) is an E3 ubiquitin ligase that prevents multifactorial deleterious accumulation of different misfolded proteins via endoplasmic reticulum-associated degradation (ERAD). However, the precise role of Gp78 under stress conditions to avoid bulk misfolded aggregation is unclear, which can act as a crucial resource to establish the dynamic nature of the proteome. Present article systematically explains the detailed molecular characterization of Gp78 and also addresses its various cellular physiological functions, which could be crucial to achieving protein homeostasis. Here, we comprehensively represent the current findings of Gp78, which shows its PQC roles in different physiological functions and diseases; and thereby propose novel opportunities to better understand the unsolved questions for therapeutic interventions linked with different protein misfolding disorders.
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Affiliation(s)
- Vibhuti Joshi
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology JodhpurJodhpur, India
| | - Arun Upadhyay
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology JodhpurJodhpur, India
| | - Amit Kumar
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology IndoreIndore, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology JodhpurJodhpur, India
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15
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Intaraphairot T, Chinpaisal C, Apirakaramwong A. Effect of Curcumin on SMCT-1 Expression and Dichloroacetate Toxicity in HCT116 Colon Cancer Cells. PHARMACEUTICAL SCIENCES 2017. [DOI: 10.15171/ps.2017.17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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16
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Connacher MK, Tay JW, Ahn NG. Rear-polarized Wnt5a-receptor-actin-myosin-polarity (WRAMP) structures promote the speed and persistence of directional cell migration. Mol Biol Cell 2017; 28:1924-1936. [PMID: 28592632 PMCID: PMC5541843 DOI: 10.1091/mbc.e16-12-0875] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 05/19/2017] [Accepted: 05/30/2017] [Indexed: 12/31/2022] Open
Abstract
The WRAMP structure is a Wnt5-induced association of a cell adhesion molecule with F-actin and myosin IIB at the rear of migrating cells. WRAMP structures control the speed and persistence of directional cell movement in melanoma and nonmelanoma cells. In contrast to events at the cell leading edge, rear-polarized mechanisms that control directional cell migration are poorly defined. Previous work described a new intracellular complex, the Wnt5a-receptor-actomyosin polarity (WRAMP) structure, which coordinates the polarized localization of MCAM, actin, and myosin IIB in a Wnt5a-induced manner. However, the polarity and function for the WRAMP structure during cell movement were not determined. Here we characterize WRAMP structures during extended cell migration using live-cell imaging. The results demonstrate that cells undergoing prolonged migration show WRAMP structures stably polarized at the rear, where they are strongly associated with enhanced speed and persistence of directional movement. Strikingly, WRAMP structures form transiently, with cells displaying directional persistence during periods when they are present and cells changing directions randomly when they are absent. Cells appear to pause locomotion when WRAMP structures disassemble and then migrate in new directions after reassembly at a different location, which forms the new rear. We conclude that WRAMP structures represent a rear-directed cellular mechanism to control directional migration and that their ability to form dynamically within cells may control changes in direction during extended migration.
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Affiliation(s)
| | - Jian Wei Tay
- BioFrontiers Institute Advanced Light Microscopy Core, University of Colorado, Boulder, CO 80309
| | - Natalie G Ahn
- Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309
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17
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Synthetic Isoliquiritigenin Inhibits Human Tongue Squamous Carcinoma Cells through Its Antioxidant Mechanism. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1379430. [PMID: 28203317 PMCID: PMC5292127 DOI: 10.1155/2017/1379430] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 12/09/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023]
Abstract
Isoliquiritigenin (ISL), a natural antioxidant, has antitumor activity in different types of cancer cells. However the antitumor effect of ISL on human tongue squamous carcinoma cells (TSCC) is not clear. Here we aimed to investigate the effects of synthetic isoliquiritigenin (S-ISL) on TSCC and elucidate the underlying mechanisms. S-ISL was synthesized and elucidated from its nuclear magnetic resonance spectrum and examined using high performance liquid chromatography. The effects of S-ISL on TSCC cells (Tca8113) were evaluated in relation to cell proliferation, apoptosis and adhesion, migration, and invasion using sulforhodamine B assay, fluorescence microscopy technique, flow cytometry (FCM) analysis, and Boyden chamber assay. The associated regulatory mechanisms were examined using FCM and fluorescence microscopy for intracellular reactive oxygen species (ROS) generation, Gelatin zymography assay for matrix metalloproteinase (MMP) activities, and Western blot for apoptosis regulatory proteins (Bcl-2 and Bax). Our data indicated that S-ISL inhibited Tca8113 cell proliferation, adhesion, migration, and invasion while promoting the cell apoptosis. Such effects were accompanied by downregulation of Bcl-2 and upregulation of Bax, reduction of MMP-2 and MMP-9 activities, and decreased ROS production. We conclude that S-ISL is a promising agent targeting TSCC through multiple anticancer effects, regulated by its antioxidant mechanism.
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18
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Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L. Bioorg Med Chem Lett 2016; 27:1304-1310. [PMID: 28117205 DOI: 10.1016/j.bmcl.2016.12.039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 11/22/2022]
Abstract
The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.
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19
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Çelik H, Bulut G, Han J, Graham GT, Minas TZ, Conn EJ, Hong SH, Pauly GT, Hayran M, Li X, Özdemirli M, Ayhan A, Rudek MA, Toretsky JA, Üren A. Ezrin Inhibition Up-regulates Stress Response Gene Expression. J Biol Chem 2016; 291:13257-70. [PMID: 27137931 DOI: 10.1074/jbc.m116.718189] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Indexed: 12/21/2022] Open
Abstract
Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes.
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Affiliation(s)
| | - Gülay Bulut
- From the Departments of Oncology and the Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Bahçeşehir University, 34349 Istanbul, Turkey
| | - Jenny Han
- From the Departments of Oncology and
| | | | | | | | | | - Gary T Pauly
- the Chemical Biology Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702
| | - Mutlu Hayran
- the Department of Preventive Oncology, Cancer Institute, Hacettepe University, 06800 Ankara, Turkey
| | - Xin Li
- the Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, D. C. 20057
| | - Metin Özdemirli
- Pathology, Georgetown University Medical Center, Washington, D. C. 20007
| | - Ayşe Ayhan
- the Department of Pathology, Seirei Mikatahara Hospital and Hamamatsu University School of Medicine, Hamamatsu, Japan, and the Department of Pathology and
| | - Michelle A Rudek
- the Departments of Oncology and Medicine, Division of Clinical Pharmacology, School of Medicine, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21218
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20
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Garnett DJ. Caveolae as a target to quench autoinduction of the metastatic phenotype in lung cancer. J Cancer Res Clin Oncol 2015; 142:611-8. [PMID: 26573510 PMCID: PMC4751176 DOI: 10.1007/s00432-015-2074-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 10/14/2015] [Indexed: 12/17/2022]
Abstract
Purpose Mevalonate pathway inhibitors are potentially useful chemotherapeutic agents showing growth inhibition and pro-apoptotic effects in cancer cells. The effects of statins and bisphosphonates on cancer growth are attributed to a reduction in protein isoprenylation. Post-translational modification and activation of GTPase binding Ras superfamily permit the recruitment of these signal proteins to membranes where they mediate the cancer phenotype. Here, the effects of three inhibitors of the mevalonate pathway and one specific inhibitor of sterol regulatory element-binding proteins were studied in both an ER-negative, Ras-inactive breast (MDA-MB-231) and lung adenocarcinoma (CaLu-1) cells in vitro. Methods Treated cells were subject to genome-wide gene expression profiling. A gene subset was established so that the epithelial to mesenchymal transition (EMT) could be observed and compared with signalling protein shifts. Results Within the subset, some genes normally up-regulated during EMT were asymmetrically reduced by a Δ-24 DHCR inhibitor in the lung cells. Signalling proteins associated with caveolae were down-regulated by this oxidoreductase inhibitor, while those associated with membrane rafts were up-regulated. Conclusions This study decouples isoprenylation effects from cholesterol events per se. The data support a hypothesis that caveolae are abolished by Δ-24 DHCR intervention and it is revealed that these microdomains are vital EMT signalling structures for lung cells but not ER- and Ras-negative breast cells. When signalling by extracellular signals is quenched by removal of the hydrophilic conduit provided by caveolae, the transcriptome responds by moving the cellular identity towards quiescence. Electronic supplementary material The online version of this article (doi:10.1007/s00432-015-2074-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- David John Garnett
- Institute of Science Technology in Medicine, Keele University, Keele, Staffordshire, ST5 5BG, UK.
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21
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Çelik H, Hong SH, Colón-López DD, Han J, Kont YS, Minas TZ, Swift M, Paige M, Glasgow E, Toretsky JA, Bosch J, Üren A. Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box. Mol Cancer Ther 2015; 14:2497-507. [PMID: 26358752 DOI: 10.1158/1535-7163.mct-15-0511] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/31/2015] [Indexed: 11/16/2022]
Abstract
Ezrin is a member of the ERM (ezrin, radixin, moesin) family of proteins and functions as a linker between the plasma membrane and the actin cytoskeleton. Ezrin is a key driver of tumor progression and metastatic spread of osteosarcoma. We discovered a quinoline-based small molecule, NSC305787, that directly binds to ezrin and inhibits its functions in promoting invasive phenotype. NSC305787 possesses a very close structural similarity to commonly used quinoline-containing antimalarial drugs. On the basis of this similarity and of recent findings that ezrin has a likely role in the pathogenesis of malaria infection, we screened antimalarial compounds in an attempt to identify novel ezrin inhibitors with better efficacy and drug properties. Screening of Medicines for Malaria Venture (MMV) Malaria Box compounds for their ability to bind to recombinant ezrin protein yielded 12 primary hits with high selective binding activity. The specificity of the hits on ezrin function was confirmed by inhibition of the ezrin-mediated cell motility of osteosarcoma cells. Compounds were further tested for phenocopying the morphologic defects associated with ezrin suppression in zebrafish embryos as well as for inhibiting the lung metastasis of high ezrin-expressing osteosarcoma cells. The compound MMV667492 exhibited potent anti-ezrin activity in all biologic assays and had better physicochemical properties for drug-likeness than NSC305787. The drug-like compounds MMV020549 and MMV666069 also showed promising activities in functional assays. Thus, our study suggests further evaluation of antimalarial compounds as a novel class of antimetastatic agents for the treatment of metastatic osteosarcoma.
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Affiliation(s)
- Haydar Çelik
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Sung-Hyeok Hong
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Daisy D Colón-López
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Jenny Han
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Yasemin Saygideger Kont
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Tsion Z Minas
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Matthew Swift
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Mikell Paige
- Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia
| | - Eric Glasgow
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Jeffrey A Toretsky
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia
| | - Jürgen Bosch
- Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Aykut Üren
- Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia.
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22
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Signorelli P, Fabiani C, Brizzolari A, Paroni R, Casas J, Fabriàs G, Rossi D, Ghidoni R, Caretti A. Natural Grape Extracts Regulate Colon Cancer Cells Malignancy. Nutr Cancer 2015; 67:494-503. [DOI: 10.1080/01635581.2015.1004591] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Paola Signorelli
- Department of Health Sciences, University of Milan, Milan, Italy, and San Paolo Hospital, Milan, Italy
| | - Carlotta Fabiani
- Department of Health Sciences, University of Milan, Milan, Italy, and San Paolo Hospital, Milan, Italy
| | - Andrea Brizzolari
- Department of Health Sciences, University of Milan, Milan, Italy, and San Paolo Hospital, Milan, Italy
| | - Rita Paroni
- Department of Health Sciences, University of Milan, Milan, Italy, and San Paolo Hospital, Milan, Italy
| | - Josefina Casas
- Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Catalan Institute of Advanced Chemistry, Barcelona, Spain
| | - Gemma Fabriàs
- Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Catalan Institute of Advanced Chemistry, Barcelona, Spain
| | - Dario Rossi
- Immobiliare Ca’ Novella srl, Alessandria, Italy
| | - Riccardo Ghidoni
- Department of Health Sciences, University of Milan, Milan, Italy, and San Paolo Hospital, Milan, Italy
| | - Anna Caretti
- Department of Health Sciences, University of Milan, Milan, Italy, and San Paolo Hospital, Milan, Italy
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23
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TGFβ signaling in myeloid cells regulates mammary carcinoma cell invasion through fibroblast interactions. PLoS One 2015; 10:e0117908. [PMID: 25629162 PMCID: PMC4309578 DOI: 10.1371/journal.pone.0117908] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 01/05/2015] [Indexed: 11/19/2022] Open
Abstract
Metastasis is the most devastating aspect of cancer, however we know very little about the mechanisms of local invasion, the earliest step of metastasis. During tumor growth CD11b+ Gr1+ cells, known also as MDSCs, have been shown to promote tumor progression by a wide spectrum of effects that suppress the anti-tumor immune response. In addition to immunosuppression, CD11b+ Gr1+ cells promote metastasis by mechanisms that are currently unknown. CD11b+ Gr1+ cells localize near fibroblasts, which remodel the ECM and leave tracks for collective cell migration of carcinoma cells. In this study we discovered that CD11b+ Gr1+ cells promote invasion of mammary carcinoma cells by increasing fibroblast migration. This effect was directed by secreted factors derived from CD11b+ Gr1+ cells. We have identified several CD11b+ Gr1+ cell secreted proteins that activate fibroblast migration, including CXCL11, CXCL15, FGF2, IGF-I, IL1Ra, Resistin, and Shh. The combination of CXCL11 and FGF2 had the strongest effect on fibroblast migration that is associated with Akt1 and ERK1/2 phosphorylation. Analysis of subsets of CD11b+ Gr1+ cells identified that CD11b+ Ly6Chigh Ly6Glow cells increase fibroblast migration more than other myeloid cell populations. Additionally, tumor-derived CD11b+ Gr1+ cells promote fibroblast migration more than splenic CD11b+ Gr1+ cells of tumor-bearing mice. While TGFβ signaling in fibroblasts does not regulate their migration toward CD11b+ Gr1+ cells, however deletion of TGFβ receptor II on CD11b+ Gr1+ cells downregulates CXCL11, Shh, IGF1 and FGF2 resulting in reduced fibroblast migration. These studies show that TGFβ signaling in CD11b+ Gr1+ cells promotes fibroblast directed carcinoma invasion and suggests that perivascular CD11b+ Ly6Chigh Ly6Glow cells may be the stimulus for localized invasion leading to metastasis.
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24
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Tsai MF, Wang CC, Chen JJW. Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer. World J Clin Oncol 2014; 5:865-873. [PMID: 25493224 PMCID: PMC4259948 DOI: 10.5306/wjco.v5.i5.865] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/10/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins (HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmental or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1’s role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC.
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25
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Khanna C, Fan TM, Gorlick R, Helman LJ, Kleinerman ES, Adamson PC, Houghton PJ, Tap WD, Welch DR, Steeg PS, Merlino G, Sorensen PHB, Meltzer P, Kirsch DG, Janeway KA, Weigel B, Randall L, Withrow SJ, Paoloni M, Kaplan R, Teicher BA, Seibel NL, Smith M, Uren A, Patel SR, Trent J, Savage SA, Mirabello L, Reinke D, Barkaukas DA, Krailo M, Bernstein M. Toward a drug development path that targets metastatic progression in osteosarcoma. Clin Cancer Res 2014; 20:4200-9. [PMID: 24803583 DOI: 10.1158/1078-0432.ccr-13-2574] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting.
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Affiliation(s)
- Chand Khanna
- Molecular Oncology Section, Metastasis Biology; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Timothy M Fan
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois;
| | - Richard Gorlick
- Department of Pediatrics and Molecular Pharmacology, The Albert Einstein College of Medicine of Yeshiva University; Division of Hematology/Oncology, Department of Pediatrics, The Children's Hospital at Montefiore, Bronx
| | - Lee J Helman
- Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | | | - Peter C Adamson
- Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Peter J Houghton
- Center for Childhood Cancer, The Research Institute, Nationwide Children's Hospital, Columbus, Ohio
| | - William D Tap
- Sarcoma Oncology, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York; Departments of
| | - Danny R Welch
- Kansas University Medical Center, Kansas City, Kansas
| | - Patricia S Steeg
- Laboratory of Molecular Pharmacology; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Glenn Merlino
- Laboratory of Cancer Biology and Genetics; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Poul H B Sorensen
- Department of Pathology, University of British Columbia; BC Cancer Research Centre, Vancouver, British Columbia; and
| | - Paul Meltzer
- Genetics Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - David G Kirsch
- Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina
| | - Katherine A Janeway
- Department of Pediatrics, Harvard Medical School; Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
| | - Brenda Weigel
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Lor Randall
- Huntsman Cancer Institute & Primary Children's Medical Center, University of Utah, Salt Lake City, Utah
| | - Stephen J Withrow
- Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado; Departments of
| | - Melissa Paoloni
- Comparative Oncology Program; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Rosandra Kaplan
- Tumor Microenvironment Section, Pediatric Oncology Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Beverly A Teicher
- Molecular Pharmacology Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Nita L Seibel
- Cancer Therapy Evaluations Program; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | | | - Aykut Uren
- Oncology and Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Shreyaskumar R Patel
- Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey Trent
- Translational Genomics Research Institute (TGen), Phoenix, Arizona
| | - Sharon A Savage
- Clinical Genetics Branch; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Lisa Mirabello
- Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics; Center for Cancer Research; National Cancer Institute, NIH, Bethesda, Maryland
| | - Denise Reinke
- University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
| | - Donald A Barkaukas
- Children's Oncology Group, QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office, Monrovia
| | - Mark Krailo
- Department of Preventive Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California
| | - Mark Bernstein
- Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada
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The roles of miR-200c in colon cancer and associated molecular mechanisms. Tumour Biol 2014; 35:6475-83. [PMID: 24682933 DOI: 10.1007/s13277-014-1860-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 03/18/2014] [Indexed: 02/07/2023] Open
Abstract
The expression of miR-200c has been widely reported to be elevated in tumor tissues and sera of patients with colorectal cancer (CRC) and has been found to correlate with poor prognosis. However, how miR-200c regulates the apoptosis, survival, invasion, metastasis, and tumor growth in colon cancer cells remains to be fully elucidated. This study seeks to further investigate the role of miR-200c in colon cancer development. The expression of miR-200c in tumor and peritumoral tissues of 101 colon cancer patients was measured by real-time PCR. miR-200c expression in HCT-116 and HT-29 colon cancer cells was silenced by adenovirus-carried expression of antisense mRNA against miR-200c. The protein levels of PTEN, p53 Ser(15), PP1, and activated caspase-3 in HCT-116 and HT-29 cells were measured by Western blot. This study demonstrated that the expression of miR-200c was significantly higher in tumor tissues than in peritumoral tissues of colon cancer patients. The elevated miR-200c expression significantly correlated with the TNM stage, lymph node metastasis, and invasion of colon cancer. Silencing miR-200c expression significantly induced cell apoptosis, inhibited long-term survival, invasion, and metastasis, and delayed xenograft tumor growth. Importantly, silencing miR-200c expression sensitized the therapeutic effect of Ara-C (Cytarabine). The effects of silencing miR-200c expression were associated with upregulation of PTEN protein and p53 Ser(15) phosphorylation levels in HCT-116 cells and PTEN protein expression in HT-29 cells. In conclusion, miR-200c functions as an oncogene in colon cancer cells through regulating tumor cell apoptosis, survival, invasion, and metastasis as well as xenograft tumor growth through inhibition of PTEN expression and p53 phosphorylation.
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27
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Barras D, Lorusso G, Lhermitte B, Viertl D, Rüegg C, Widmann C. Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression. Int J Cancer 2014; 135:242-7. [PMID: 24347041 DOI: 10.1002/ijc.28674] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 12/02/2013] [Indexed: 12/23/2022]
Abstract
The p120 RasGAP protein negatively regulates Ras via its GAP domain. RasGAP carries several other domains that modulate several signaling molecules such as Rho. RasGAP is also a caspase-3 substrate. One of the caspase-3-generated RasGAP fragments, corresponding to amino acids 158-455 and called fragment N2, was previously reported to specifically sensitize cancer cells to death induced by various anticancer agents. Here, we show that fragment N2 inhibits migration in vitro and that it impairs metastatic progression of breast cancer to the lung. Hence, stress-activated caspase-3 might contribute to the suppression of metastasis through the generation of fragment N2. These results indicate that the activity borne by fragment N2 has a potential therapeutic relevance to counteract the metastatic process.
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Affiliation(s)
- David Barras
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
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Song Y, Cao L. N-myc downstream-regulated gene 1: Diverse and complicated functions in human hepatocellular carcinoma (Review). Oncol Lett 2013; 6:1539-1542. [PMID: 24260043 PMCID: PMC3834550 DOI: 10.3892/ol.2013.1636] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 10/07/2013] [Indexed: 01/17/2023] Open
Abstract
N-myc downstream-regulated gene 1 (NDRG1) has been reported to be a multifunctional protein associated with carcinogenesis and tumor progression. However, the cellular function of NDRG1 remains elusive in human hepatocellular carcinoma (HCC). No NDRG1 expression is observed in normal liver tissue. Overexpression of NDRG1 has been observed in human HCC, particularly with aggressive invasion, metastasis, poor differentiation and short patient survival. In addition, recent studies have shown that NDRG1 exhibits an inhibitory effect on HCC growth in vitro and in vivo, which contrasts with previous reports indicating that NDRG1 promotes the proliferation and invasion of HCC cell lines. Further studies have shown that the localization of NDRG1 is variable, translocating to the nucleus or membrane according to the cell state, which may relate to the diverse function of NDRG1. The present study reviews our current knowledge with regard to the functions of NDRG1 in HCC and other types of human cancer.
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Affiliation(s)
- Yan Song
- Central Laboratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
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29
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Nelson VM, Benson AB. Status of targeted therapies in the adjuvant treatment of colon cancer. J Gastrointest Oncol 2013; 4:245-52. [PMID: 23997937 DOI: 10.3978/j.issn.2078-6891.2013.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 05/21/2013] [Indexed: 01/08/2023] Open
Abstract
Colon cancer is the 4(th) most common malignancy with 80% of patients diagnosed with early stage disease that is potentially curable with surgery and the addition of adjuvant chemotherapy in select Stage II and all Stage III patients. Adjuvant chemotherapy with 5-flurouracil based regimens has been shown to have overall survival benefit in Stage III disease with some benefit shown in certain sub-populations in Stage II disease. In recent years, targeted therapies directed against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EFGR) have shown improved survival in metastatic colon cancer. However, trials of these agents in the adjuvant setting showed no benefit. Reasons for failure of these agents in trials thus far include differences in the molecular biology of macrometastatic versus micrometastatic disease and the lack of biologic predictive markers to target the appropriate patient populations for these agents.
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Affiliation(s)
- Valerie M Nelson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
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30
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Lekva T, Berg JP, Heck A, Lyngvi Fougner S, Olstad OK, Ringstad G, Bollerslev J, Ueland T. Attenuated RORC expression in the presence of EMT progression in somatotroph adenomas following treatment with somatostatin analogs is associated with poor clinical recovery. PLoS One 2013; 8:e66927. [PMID: 23825587 PMCID: PMC3692554 DOI: 10.1371/journal.pone.0066927] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 05/13/2013] [Indexed: 12/02/2022] Open
Abstract
Somatostatin analogs (SA) have been established as the first line medical treatment for acromegaly, but following long-term treatment, SA normalizes GH and IGF-I levels in only 40–60% of patients. The epithelial marker E-cadherin plays a crucial role in the epithelial mesenchymal transition (EMT) and is associated with a poor response to SA treatment. We hypothesized that the characterization of transcripts regulated by SA in somatotroph adenomas with high and low E-cadherin expression may identify signaling pathways and mediators that can explain the poor response to SA treatment. We performed a microarray analysis of sixteen adenomas with different levels of E-cadherin and SA treatment to identify regulated transcripts. Candidate transcripts were further explored in vivo in sixty-five adenomas, and interactions between SA treatment and EMT progression on mRNA expression profiles and associations with clinical recovery were assessed. Finally, the effects of SA treatment on adenoma cells in vitro from acromegalic patients were determined. Microarray analysis of selected adenomas with differential E-cadherin expression, as a marker of EMT progression, identified 172 genes that displayed differential expression that was dependent on SA treatment. The validation of selected candidates in the entire cohort identified 9 transcripts that showed an interaction between E-cadherin expression and SA treatment. Further analysis of the impact of these genes suggests that attenuated RORC expression in somatotroph adenomas is associated with increased tumor size and a blunted clinical response. Our study indicates that attenuated RORC may be involved in the poor clinical response to SA treatment in patients with acromegaly.
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Affiliation(s)
- Tove Lekva
- Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway.
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31
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Savas S, Liu G, Xu W. Special considerations in prognostic research in cancer involving genetic polymorphisms. BMC Med 2013; 11:149. [PMID: 23773794 PMCID: PMC3729672 DOI: 10.1186/1741-7015-11-149] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 05/01/2013] [Indexed: 01/08/2023] Open
Abstract
Analysis of genetic polymorphisms may help identify putative prognostic markers and determine the biological basis of variable prognosis in patients. However, in contrast to other variables commonly used in the prognostic studies, there are special considerations when studying genetic polymorphisms. For example, variable inheritance patterns (recessive, dominant, codominant, and additive genetic models) need to be explored to identify the specific genotypes associated with the outcome. In addition, several characteristics of genetic polymorphisms, such as their minor allele frequency and linkage disequilibrium among multiple polymorphisms, and the population substructure of the cohort investigated need to be accounted for in the analyses. In addition, in cancer research due to the genomic differences between the tumor and non-tumor DNA, differences in the genetic information obtained using these tissues need to be carefully assessed in prognostic studies. In this article, we review these and other considerations specific to genetic polymorphism by focusing on genetic prognostic studies in cancer.
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Affiliation(s)
- Sevtap Savas
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St, John's, Newfoundland, Canada.
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Tang MK, Liang YJ, Chan JYH, Wong SW, Chen E, Yao Y, Gan J, Xiao L, Leung HC, Kung HF, Wang H, Lee KKH. Promyelocytic leukemia (PML) protein plays important roles in regulating cell adhesion, morphology, proliferation and migration. PLoS One 2013; 8:e59477. [PMID: 23555679 PMCID: PMC3605454 DOI: 10.1371/journal.pone.0059477] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Accepted: 02/15/2013] [Indexed: 12/22/2022] Open
Abstract
PML protein plays important roles in regulating cellular homeostasis. It forms PML nuclear bodies (PML-NBs) that act like nuclear relay stations and participate in many cellular functions. In this study, we have examined the proteome of mouse embryonic fibroblasts (MEFs) derived from normal (PML+/+) and PML knockout (PML−/−) mice. The aim was to identify proteins that were differentially expressed when MEFs were incapable of producing PML. Using comparative proteomics, total protein were extracted from PML−/− and PML+/+ MEFs, resolved by two dimensional electrophoresis (2-DE) gels and the differentially expressed proteins identified by LC-ESI-MS/MS. Nine proteins (PML, NDRG1, CACYBP, CFL1, RSU1, TRIO, CTRO, ANXA4 and UBE2M) were determined to be down-regulated in PML−/− MEFs. In contrast, ten proteins (CIAPIN1, FAM50A, SUMO2 HSPB1 NSFL1C, PCBP2, YWHAG, STMN1, TPD52L2 and PDAP1) were found up-regulated. Many of these differentially expressed proteins play crucial roles in cell adhesion, migration, morphology and cytokinesis. The protein profiles explain why PML−/− and PML+/+ MEFs were morphologically different. In addition, we demonstrated PML−/− MEFs were less adhesive, proliferated more extensively and migrated significantly slower than PML+/+ MEFs. NDRG1, a protein that was down-regulated in PML−/− MEFs, was selected for further investigation. We determined that silencing NDRG1expression in PML+/+ MEFs increased cell proliferation and inhibited PML expression. Since NDRG expression was suppressed in PML−/− MEFs, this may explain why these cells proliferate more extensively than PML+/+ MEFs. Furthermore, silencing NDRG1expression also impaired TGF-β1 signaling by inhibiting SMAD3 phosphorylation.
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Affiliation(s)
- Mei Kuen Tang
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
- * E-mail: (MKT); (KKHL)
| | - Yong Jia Liang
- Joint JNU-CUHK Key Laboratories for Regenerative Medicine, Ministry of Education, JiNan University, Guangzhou, China
| | - John Yeuk Hon Chan
- Joint JNU-CUHK Key Laboratories for Regenerative Medicine, Ministry of Education, JiNan University, Guangzhou, China
| | - Sing Wan Wong
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Elve Chen
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Yao Yao
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Jingyi Gan
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Lihai Xiao
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Hin Cheung Leung
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Hsiang Fu Kung
- Division of Infectious Diseases, School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Hua Wang
- Division of Infectious Diseases, School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | - Kenneth Ka Ho Lee
- Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong
- Joint JNU-CUHK Key Laboratories for Regenerative Medicine, Ministry of Education, JiNan University, Guangzhou, China
- * E-mail: (MKT); (KKHL)
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Miao X, Yang ZL, Xiong L, Zou Q, Yuan Y, Li J, Liang L, Chen M, Chen S. Nectin-2 and DDX3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2013; 6:179-190. [PMID: 23330003 PMCID: PMC3544223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 11/08/2012] [Indexed: 06/01/2023]
Abstract
The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder have not been well documented because it is a rare subtype of gallbladder cancer. In this study, the protein expression of Nectin-2 and DDX3 in 46 SC/ASCs and 80 adenocarcinomas was measured using immunohistochemistry. We demonstrated that positive Nectin-2 and DDX3 expression was significantly associated with large tumor size, high TNM stage, and lymph node metastasis of SC/ASC and AC. Positive Nectin-2 and DDX3 expression was significantly associated with invasion and surgical curability of AC. Univariate Kaplan-Meier analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with post-operative survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and no surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive Nectin-2 and DDx3 expression is closely correlated with clinical, pathological, and biological behaviors as well as poor-prognosis of gallbladder cancer.
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Affiliation(s)
- Xiongying Miao
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University Changsha, Hunan 410011, PR China
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Hsu HY, Lin JH, Li CJ, Tsang SF, Tsai CH, Chyuan JH, Chiu SJ, Chuang SE. Antimigratory Effects of the Methanol Extract from Momordica charantia on Human Lung Adenocarcinoma CL1 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2012; 2012:819632. [PMID: 23320038 PMCID: PMC3535856 DOI: 10.1155/2012/819632] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2012] [Revised: 10/26/2012] [Accepted: 11/12/2012] [Indexed: 11/17/2022]
Abstract
Momordica charantia has been found to exhibit anticancer activity, in addition to its well-known therapeutic functions. We have demonstrated that the leaf extract of Momordica charantia (MCME) induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. In this study, a different susceptibility to MCME was found in human lung adenocarcinoma CL1 cells with different metastatic ability, leading to the significant difference of cell viability and invasiveness between MCME-treated CL1-0 and CL1-5 cells. MCME was found to upregulate the expression of Wnt-2 and affect the migratory and invasive ability of CL1 cells through suppressed MMP-2 and MMP-9 enzymatic activities. We proposed that MCME mediates inhibition against migration of CL1 cells by reducing the expression and activation of Src and FAK to decrease the expression of downstream Akt, β-catenin, and MMPs.
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Affiliation(s)
- Hsue-Yin Hsu
- Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan
- Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
| | - Jung-Hsuan Lin
- Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan
| | - Chia-Jung Li
- Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
| | | | - Chun-Hao Tsai
- Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan
| | - Jong-Ho Chyuan
- Hualien District Agricultural Research and Extension Station, Hualien, Taiwan
| | - Shu-Jun Chiu
- Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan
| | - Shuang-En Chuang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
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35
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Long K, Abuelenen T, Pava L, Bastille M, Blanck G. Size matters: sequential mutations in tumorigenesis may reflect the stochastic effect of mutagen target sizes. Genes Cancer 2012; 2:927-31. [PMID: 22701759 DOI: 10.1177/1947601911436200] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2011] [Accepted: 12/11/2011] [Indexed: 11/16/2022] Open
Abstract
We tallied the number of possible mutant amino acids in proteins thought to be inactivated early in tumorigenesis and in proteins thought to be inactivated late in tumorigenesis, respectively. Proteins thought to be inactivated early in tumorigenesis, on average, have a greater number of alternative, mutant possibilities, which raises the possibility that the sequential order of mutations associated with cancer development reflects the random chance, throughout life, of a mutagen inactivating a larger versus a smaller target. The hypothesis that the temporal order of genetic changes in cancer reflects mutagen target sizes leads to novel considerations of 1) the mechanisms of the acquisition of cancer hallmarks and 2) cancer screening strategies.
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36
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Said HM, Polat B, Stein S, Guckenberger M, Hagemann C, Staab A, Katzer A, Anacker J, Flentje M, Vordermark D. Inhibition of N-Myc down regulated gene 1 in in vitro cultured human glioblastoma cells. World J Clin Oncol 2012; 3:104-10. [PMID: 22787578 PMCID: PMC3394081 DOI: 10.5306/wjco.v3.i7.104] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 12/10/2011] [Accepted: 06/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study short dsRNA oligonucleotides (siRNA) as a potent tool for artificially modulating gene expression of N-Myc down regulated gene 1 (NDRG1) gene induced under different physiological conditions (Normoxia and hypoxia) modulating NDRG1 transcription, mRNA stability and translation.
METHODS: A cell line established from a patient with glioblastoma multiforme. Plasmid DNA for transfections was prepared with the Endofree Plasmid Maxi kit. From plates containing 5 × 107 cells, nuclear extracts were prepared according to previous protocols. The pSUPER-NDRG1 vectors were designed, two sequences were selected from the human NDRG1 cDNA (5’-GCATTATTGGCATGGGAAC-3’ and 5’-ATGCAGAGTAACGTGGAAG-3’. reverse transcription polymerase chain reaction was performed using primers designed using published information on β-actin and hypoxia-inducible factor (HIF)-1α mRNA sequences in GenBank. NDRG1 mRNA and protein level expression results under different conditions of hypoxia or reoxygenation were compared to aerobic control conditions using the Mann-Whitney U test. Reoxygenation values were also compared to the NDRG1 levels after 24 h of hypoxia (P < 0.05 was considered significant).
RESULTS: siRNA- and iodoacetate (IAA)-mediated downregulation of NDRG1 mRNA and protein expression in vitro in human glioblastoma cell lines showed a nearly complete inhibition of NDRG1 expression when compared to the results obtained due to the inhibitory role of glycolysis inhibitor IAA. Hypoxia responsive elements bound by nuclear HIF-1 in human glioblastoma cells in vitro under different oxygenation conditions and the clearly enhanced binding of nuclear extracts from glioblastoma cell samples exposed to extreme hypoxic conditions confirmed the HIF-1 Western blotting results.
CONCLUSION: NDRG1 represents an additional diagnostic marker for brain tumor detection, due to the role of hypoxia in regulating this gene, and it can represent a potential target for tumor treatment in human glioblastoma. The siRNA method can represent an elegant alternative to modulate the expression of the hypoxia induced NDRG1 gene and can help to monitor the development of the cancer disease treatment outcome through monitoring the expression of this gene in the patients undergoing the different therapeutic treatment alternatives available nowadays.
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Affiliation(s)
- Harun M Said
- Department of Radiation Oncology, University of Wuerzburg, 97080 Würzburg, Germany.
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Su B, Gao L, Meng F, Guo LW, Rothschild J, Gelman IH. Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from FAK complexes to lipid rafts by SSeCKS/AKAP12. Oncogene 2012; 32:2016-26. [PMID: 22710722 PMCID: PMC3449054 DOI: 10.1038/onc.2012.218] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Metastatic cell migration and invasion are regulated by altered adhesion-mediated signaling to the actin-based cytoskeleton via activated Src-FAK complexes. SSeCKS (the rodent orthologue of human Gravin/AKAP12), whose expression is downregulated by oncogenic Src and in many human cancers, antagonizes oncogenic Src pathways including those driving neovascularization at metastatic sites, metastatic cell motility and invasiveness. This is likely manifested through its function as a scaffolder of F-actin and signaling proteins such as cyclins, calmodulin, protein kinase (PK) C and PKA. Here, we show that in contrast to its ability to inhibit haptotaxis, SSeCKS increased prostate cancer cell adhesion to fibronectin (FN) and type I collagen in a FAK-dependent manner, correlating with a relative increase in FAKpoY397 levels. In contrast, SSeCKS suppressed adhesion-induced Src activation (SrcpoY416) and phosphorylation of FAK at Y925, a known Src substrate site. SSeCKS also induced increased cell spreading, cell flattening, integrin β1 clustering and formation of mature focal adhesion plaques. An in silico analysis identified a Src-binding domain on SSeCKS (a.a.153–166) that is homologous to the Src binding domain of Caveolin-1, and this region is required for SSeCKS-Src interaction, for SSeCKS-enhanced Src activity and sequestration to lipid rafts, and for SSeCKS-enhanced adhesion of MAT-LyLu and CWR22Rv1 prostate cancer cells. Our data suggest a model in which SSeCKS suppresses oncogenic motility by sequestering Src to caveolin-rich lipid rafts, thereby disengaging Src from FAK-associated adhesion and signaling complexes.
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Affiliation(s)
- B Su
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
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38
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Abstract
Standard chemotherapy for adrenocortical cancer currently is under evaluation in the context of the recently completed FIRM-ACT evaluating the combination of mitotane with either streptozocin or etoposide, cisplatin, and doxorubicin. New agents are eagerly sought by the ACC community that hopes to make progress against this deadly disease. Investigators have begun to dissect the molecular and genomic context of ACC with a goal of identifying potential novel therapeutic agents. One gene consistently overexpressed in ACC is insulin growth factor type 2. Targeting its receptor IGF1R has shown encouraging results in ACC cell lines and against murine xenografts. As a result, clinical trials to evaluate agents targeting the IGF1R have been done including mitotane and IMC-A12 (a monoclonal antibody) and the GALACCTIC trial that has just completed accrual to evaluate OSI-906, a small molecule IGF1R antagonist. On the horizon are other agents targeting other tyrosine kinases, including EGF and FGF, and novel strategies such as individualized tumor analysis to select treatment.
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Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 2012; 307:1383-93. [PMID: 22474202 PMCID: PMC3442260 DOI: 10.1001/jama.2012.385] [Citation(s) in RCA: 358] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CONTEXT Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. OBJECTIVE To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. DESIGN, SETTING, AND PARTICIPANTS A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. MAIN OUTCOME MEASURES Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. RESULTS Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. CONCLUSION Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00079274.
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Affiliation(s)
- Steven R Alberts
- Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
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McAuley EM, Bradke TA, Plopper GE. Phenylboronic acid is a more potent inhibitor than boric acid of key signaling networks involved in cancer cell migration. Cell Adh Migr 2012; 5:382-6. [PMID: 21975546 DOI: 10.4161/cam.5.5.18162] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Previous studies from our lab have shown that both boric (BA) and phenylboronic- acid (PBA) inhibit the migration of prostate cancer cell lines, as well as non-tumorigenic prostate cells. Our results indicate that PBA is more potent than BA in targeting metastatic and proliferative properties of cancer cells. Here we focus on the impact of BA and PBA on Rho family of GTP-binding proteins and their downstream targets. Treatment with 1mM PBA and BA decreases activities of RhoA, Rac1, and Cdc42 in DU-145 metastatic prostate cancer cells, but not in normal RWPE-1 prostate cells. Furthermore, ROCKII activity and phosphorylation of myosin light chain kinase decrease as a result of either PBA or BA treatment in DU-145 cells, suggesting these compounds target actomyosin-based contractility.
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Affiliation(s)
- Erin M McAuley
- Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY USA
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Liu W, Xing F, Iiizumi-Gairani M, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Kobayashi A, Mo YY, Fukuda K, Li Y, Watabe K. N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol Med 2012; 4:93-108. [PMID: 22246988 PMCID: PMC3306556 DOI: 10.1002/emmm.201100190] [Citation(s) in RCA: 172] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 11/15/2011] [Accepted: 11/18/2011] [Indexed: 02/06/2023] Open
Abstract
Wnt signalling has pivotal roles in tumour progression and metastasis; however, the exact molecular mechanism of Wnt signalling in the metastatic process is as yet poorly defined. Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG−/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients. Collectively, we have identified NDRG1 as a novel negative master regulator of Wnt signalling during the metastatic progression, which opens an opportunity to define a potential therapeutic target for metastatic disease.
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Affiliation(s)
- Wen Liu
- Department of Medical Microbiology, Southern Illinois University School of Medicine, Springfield, IL, USA
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The indolic diet-derivative, 3,3'-diindolylmethane, induced apoptosis in human colon cancer cells through upregulation of NDRG1. J Biomed Biotechnol 2011; 2012:256178. [PMID: 22187533 PMCID: PMC3228297 DOI: 10.1155/2012/256178] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Accepted: 08/29/2011] [Indexed: 11/17/2022] Open
Abstract
N-myc downstream regulated gene-1 participates in carcinogenesis, angiogenesis, metastases, and anticancer drug resistance. In the present study, we analyzed the expression pattern of N-myc downstream regulated gene-1 following treatment of human colonic cancer cell lines; HCT-116 (well differentiated with wild-type p53 gene) and Colo-320 (poorly differentiated with mutant p53 gene), with 3,3'-diindolylmethane, a well-established proapoptotic agent product derived from indole-3-carbinol. Treatment of Colo-320 and HCT-116 with 3,3'-diindolylmethane disclosed inhibition of cell viability in a dose-dependent manner, mediated through apoptosis induction. The increased expression of N-myc downstream regulated gene-1 was detected only in poorly differentiated colon cancer cells, Colo-320 cell line. Our results suggest that N-myc downstream regulated gene-1 expression is enhanced by 3,3'-diindolylmethane in poorly differentiated cells and followed by induction of apoptosis. 3,3'-diindolylmethane induced apoptosis may represent a new regulator of N-myc downstream regulated gene-1 in poorly differentiated colonic cancer cells.
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Identification of CD146 expression, angiogenesis, and lymphangiogenesis as progression, metastasis, and poor-prognosis related markers for gallbladder adenocarcinoma. Tumour Biol 2011; 33:173-82. [PMID: 22076922 DOI: 10.1007/s13277-011-0260-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 10/25/2011] [Indexed: 12/16/2022] Open
Abstract
Gallbladder cancers (GBC) are associated with high disease-specific mortality rates because of no means of early detection and effective therapies. In this study, we investigated CD146 expression, microvessel densities, and lymph vessel densities in 108 adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues using immunohistochemistry. We demonstrated that positive CD146 expression, and average microvessel and lymph vessel counts in gallbladder adenocarcinomas were significantly higher than those in peritumoral tissues, polyps, and chronic cholecystitis (ps < 0.01). Positive CD146 expression, and average microvessel and lymph vessel counts were also significantly lower in cases with well-differentiated adenocarcinoma, maximal tumor diameter <2 cm, no metastasis of lymph node, and no invasion of regional tissues than in cases with poorly differentiated adenocarcinoma, maximal tumor diameter ≥ 2 cm, metastasis in lymph nodes, and invasion of regional tissues (p < 0.05 or p < 0.01). Univariate Kaplan-Meier analysis showed that increased expression of CD146 (p = 0.056), higher average microvessel counts (p < 0.05), and lymph vessel counts (p < 0.05) were associated with decreased overall survival. Multivariate Cox regression analysis showed that average microvessel and lymph vessel counts (ps < 0.05) were independent prognostic predictors in gallbladder adenocarcinoma. Our study suggested that the elevated expression of CD146, angiogenesis, and lymphangiogenesis might be closely related to progression, invasion, metastasis, and prognosis of gallbladder adenocarcinoma.
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Effects of a Chinese Herbal Medicine, Guan-Jen-Huang (Aeginetia indica Linn.), on Renal Cancer Cell Growth and Metastasis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2012:935860. [PMID: 22028734 PMCID: PMC3199064 DOI: 10.1155/2012/935860] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 08/09/2011] [Accepted: 08/09/2011] [Indexed: 01/05/2023]
Abstract
Aeginetia indica Linn. (Guan-Jen-Huang, GJH), a traditional Chinese herb, has the potential to be an immunomodulatory agent. The purpose of this study was to explore the effect of GJH in the treatment of renal cancer. Concentration-effect curves for the influence of GJH on cellular proliferation showed a biphasic shape. Besides, GJH had a synergistic effect on cytotoxicity when combined with 5-fluorouracil (5-FU)which may be due to the alternation of the chemotherapeutic agent resistance-related genes and due to the synergistic effects on apoptosis. In addition, treatment with GJH extract markedly reduced 786-O cell adherence to human umbilical vein endothelial cells (HUVECs) and decreased 786-O cell migration and invasion. In a xenograft animal model, GJH extract had an inhibitory effect on tumor cell-induced metastasis. Moreover, western blot analysis showed that the expression of intercellular adhesion molecule-1 (ICAM-1) in 786-O cells was significantly decreased by treatment with GJH extract through inactivation of nuclear factor-κB (NF–κB). These results suggest that GJH extract has a synergistic effect on apoptosis induced by chemotherapeutic agents and an inhibitory effect on cell adhesion, migration, and invasion, providing evidence for the use of water-based extracts of GJH as novel alternative therapeutic agents in the treatment of human renal cancer.
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Branco MC, Sigano DM, Schneider JP. Materials from peptide assembly: towards the treatment of cancer and transmittable disease. Curr Opin Chem Biol 2011; 15:427-34. [PMID: 21507707 PMCID: PMC3489472 DOI: 10.1016/j.cbpa.2011.03.021] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Revised: 03/22/2011] [Accepted: 03/23/2011] [Indexed: 01/20/2023]
Abstract
As the prevalence of cancer and transmittable disease persists, the development of new and more advanced therapies remains a priority in medical research. An emerging platform for the treatment of these illnesses is the use of materials formed via peptide assembly where the bulk material itself acts as the therapeutic. Higher ordered peptide structures with defined chemistry are capable of cellular targeting, recognition, and internalization. Recent design efforts are being made to exploit the nanoscale definition of the materials formed by assembling peptides to target cancer and microbial cells and to function as vaccines. This review focuses on assembled peptide materials that actively participate in the biological processes important to cancer and transmittable diseases to exert an anticipated functional outcome.
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Affiliation(s)
- Monica C Branco
- Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States
| | - Dina M Sigano
- Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States
| | - Joel P Schneider
- Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States
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Liu W, Iiizumi-Gairani M, Okuda H, Kobayashi A, Watabe M, Pai SK, Pandey PR, Xing F, Fukuda K, Modur V, Hirota S, Suzuki K, Chiba T, Endo M, Sugai T, Watabe K. KAI1 gene is engaged in NDRG1 gene-mediated metastasis suppression through the ATF3-NFkappaB complex in human prostate cancer. J Biol Chem 2011; 286:18949-18959. [PMID: 21454613 PMCID: PMC3099710 DOI: 10.1074/jbc.m111.232637] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 03/18/2011] [Indexed: 02/06/2023] Open
Abstract
NDRG1 and KAI1 belong to metastasis suppressor genes, which impede the dissemination of tumor cells from primary tumors to distant organs. Previously, we identified the metastasis promoting transcription factor, ATF3, as a downstream target of NDRG1. Further analysis revealed that the KAI1 promoter contained a consensus binding motif of ATF3, suggesting a possibility that NDRG1 suppresses metastasis through inhibition of ATF3 expression followed by activation of the KAI1 gene. In this report, we found that ectopic expression of NDRG1 was able to augment endogenous KAI1 gene expression in prostate cancer cell lines, whereas silencing NDRG1 was accompanied with significant decrease in KAI1 expression in vitro and in vivo. In addition, our results of ChIP analysis indicate that ATF3 indeed bound to the promoter of the KAI1 gene. Importantly, our promoter-based analysis revealed that ATF3 modulated KAI1 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NFκB). Moreover, loss of KAI1 expression significantly abrogated NDRG1-mediated metastatic suppression in vitro as well as in a spontaneous metastasis animal model, indicating that KA11 is a functional downstream target of the NDRG1 pathway. Our result of immunohistochemical analysis showed that loss of NDRG1 and KAI1 occurs in parallel as prostate cancer progresses. We also found that a combined expression status of these two genes serves as a strong independent prognostic marker to predict metastasis-free survival of prostate cancer patients. Taken together, our result revealed a novel regulatory network of two metastasis suppressor genes, NDRG1 and KAI1, which together concerted metastasis-suppressive activities through an intrinsic transcriptional cascade.
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Affiliation(s)
- Wen Liu
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Megumi Iiizumi-Gairani
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Hiroshi Okuda
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Aya Kobayashi
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Misako Watabe
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Sudha K. Pai
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Puspa R. Pandey
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Fei Xing
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Koji Fukuda
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | - Vishnu Modur
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
| | | | | | | | | | - Tamotsu Sugai
- Diagnostic Pathology, Iwate Medical School, Morioka, Iwate 0208505, Japan
| | - Kounosuke Watabe
- From the Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626 and
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GATA6 promotes colon cancer cell invasion by regulating urokinase plasminogen activator gene expression. Neoplasia 2011; 12:856-65. [PMID: 21076612 DOI: 10.1593/neo.10224] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Revised: 07/09/2010] [Accepted: 07/09/2010] [Indexed: 11/18/2022] Open
Abstract
GATA6 is a zinc finger transcription factor expressed in the colorectal epithelium. We have examined the expression of GATA6 in colon cancers and investigated the mechanisms by which GATA6 regulates colon cancer cell invasion. GATA6 was overexpressed in colorectal polyps and primary and metastatic tumors. GATA6 was strongly expressed in both the nuclear and cytoplasmic compartments of the colon cancer cells. GATA6 expression was upregulated in invasive HT29 and KM12L4 cells compared with the parental HT29 and KM12 cells and positively correlated with urokinase-type plasminogen activator (uPA) gene expression. Small interfering RNA (siRNA) knockdown of GATA6 resulted in reduced uPA gene expression and cell invasion. GATA6 bound to the uPA gene regulatory sequences in vivo and activated uPA promoter activity in vitro. uPA promoter deletion analysis indicated that the promoter proximal Sp1 sites were required for GATA6 activation of the uPA promoter. Accordingly, GATA6 physically associated with Sp1 and siRNA knockdown of Sp1 decreased GATA6 activation of the uPA promoter activity suggesting that Sp1 recruits GATA6 to the uPA promoter and mediates GATA6 induced activation of the uPA promoter activity. On the basis of our results, we conclude that GATA6 is an important regulator of uPA gene expression, and the dysregulated expression of GATA6 contributes to colorectal tumorigenesis and tumor invasion.
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Röwer C, Koy C, Hecker M, Reimer T, Gerber B, Thiesen HJ, Glocker MO. Mass spectrometric characterization of protein structure details refines the proteome signature for invasive ductal breast carcinoma. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2011; 22:440-456. [PMID: 21472563 DOI: 10.1007/s13361-010-0031-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 10/30/2010] [Accepted: 11/03/2010] [Indexed: 05/30/2023]
Abstract
Early diagnosis as well as individualized therapies are necessary to reduce the mortality of breast cancer, and personalized patient care strategies rely on novel prognostic or predictive factors. In this study, with six breast cancer patients, 2D gel analysis was applied for studying protein expression differences in order to distinguish invasive ductal breast carcinoma, the most frequent breast tumor subtype, from control samples. In total, 1203 protein spots were assembled in a 2D reference gel. Differentially abundant spots were subjected to peptide mass fingerprinting for protein identification. Twenty proteins with their corresponding 38 differentially expressed 2D gel spots were contained in our previously reported proteome signature, suggesting that distinct protein forms were contributing. In-depth MS/MS measurements enabled analyses of protein structure details of selected proteins. In protein spots that significantly contributed to our signature, we found that glyceraldehyde-3-phosphate dehydrogenase was N-terminally truncated, pyruvate kinase M2 and nucleoside diphosphate kinase A but not other isoforms of these proteins were of importance, and nucleophosmin phosphorylation at serine residues 106 and 125 were clearly identified. Principle component analysis and hierarchical clustering with normalized quantitative data from the 38 spots resulted in accurate separation of tumor from control samples. Thus, separation of tissue samples as in our initial proteome signature could be confirmed even with a different proteome analysis platform. In addition, detailed protein structure investigations enabled refining our proteome signature for invasive ductal breast carcinoma, opening the way to structure-/function studies with respect to disease processes and/or therapeutic intervention.
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Affiliation(s)
- Claudia Röwer
- Proteome Center Rostock, Department for Proteome Research, Institute of Immunology, Medical Faculty, University of Rostock, Schillingallee 69, P.O. Box 100 888, Rostock 18055, Germany
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Aigner A. MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs. J Mol Med (Berl) 2011; 89:445-57. [PMID: 21234533 DOI: 10.1007/s00109-010-0716-0] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Revised: 12/07/2010] [Accepted: 12/20/2010] [Indexed: 12/12/2022]
Abstract
The management of tumor cell invasion and metastasis is instrumental in cancer therapy, since metastases are the prime reason for cancer patient mortality. Various cellular mechanisms and underlying molecular pathways relevant for metastasis have been identified so far, providing a basis for antimetastatic drugs. MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules that have been shown to regulate various cellular processes by interfering with protein expression through posttranscriptional repression or mRNA degradation. More importantly, beyond their roles in physiological processes, many miRNAs are aberrantly expressed in various pathologies including cancer and regulate tumor- and metastasis-associated genes. Their pivotal role in metastasis has emerged only recently. After an introduction into the mechanisms of miRNA action, this review article describes the roles of miRNAs in cancer invasion and metastasis. Various miRNAs are discussed with regard to their upstream regulators, downstream target genes, and pro-/antimetastatic effects. A table provides a comprehensive overview of miRNAs that are misregulated/relevant in metastasis and the current knowledge regarding their underlying molecular effects. Furthermore, therapeutic approaches based on miRNAs, either as drugs or as therapeutic targets, are described prior to the discussion of the delivery of miRNA-based therapeutics as novel strategy in antimetastatic treatment.
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Affiliation(s)
- Achim Aigner
- Institute of Pharmacology, Faculty of Medicine, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, Marburg, Germany.
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50
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Liu YL, Bai WT, Luo W, Zhang DX, Yan Y, Xu ZK, Zhang FL. Downregulation of NDRG1 promotes invasion of human gastric cancer AGS cells through MMP-2. Tumour Biol 2010; 32:99-105. [PMID: 21052891 DOI: 10.1007/s13277-010-0103-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Accepted: 08/10/2010] [Indexed: 12/21/2022] Open
Abstract
The N-myc downstream-regulated gene-1 (NDRG1) has recently been proposed as a metastasis suppressor, but its precise role remains unclear. To investigate whether NDRG1 can indeed influence the metastasis progress, expression of endogenous NDRG1 was knocked down in human AGS gastric adenocarcinoma cells using RNA interference. Stable NDRG1 "silenced" transfectants showed similar growth rates as their control counterparts. By contrast, invasive ability in Matrigel invasion activity and Gelatinolytic activity by matrix metalloproteinase-2 (MMP-2) were markedly increased in NDRG1 "silenced" cells. Moreover, re-expression of NDRG1 by recombinant adenovirus Ad-NDRG1 in NDRG1 "silenced" cells inhibited the increased invasive ability. Further study, we found the induction of MMP-2 by downregulation of NDRG1 was mediated by MT1-MMP. Altogether, our results imply that NDRG-1 could play a key role in the regulation of cellular invasion and metastasis, which may involve the upregulation of matrix metalloproteinases.
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Affiliation(s)
- Yan-Li Liu
- Department of Microbiology, The Fourth Military Medical University, No. 17 Changle West Rd, Xi'an 710032, People's Republic of China
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