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Liu Y, Shen S, Yan Z, Yan L, Ding H, Wang A, Xu Q, Sun L, Yuan Y. Expression characteristics and their functional role of IGFBP gene family in pan-cancer. BMC Cancer 2023; 23:371. [PMID: 37088808 PMCID: PMC10124011 DOI: 10.1186/s12885-023-10832-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 04/11/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Insulin-like growth factor binding proteins (IGFBPs) are critical regulators of the biological activities of insulin-like growth factors. The IGFBP family plays diverse roles in different types of cancer, which we still lack comprehensive and pleiotropic understandings so far. METHODS Multi-source and multi-dimensional data, extracted from The Cancer Genome Atlas (TCGA), Oncomine, Cancer Cell Line Encyclopedia (CCLE), and the Human Protein Atlas (HPA) was used for bioinformatics analysis by R language. Immunohistochemistry and qRT-PCR were performed to validate the results of the database analysis results. Bibliometrics and literature review were used for summarizing the research progress of IGFBPs in the field of tumor. RESULTS The members of IGFBP gene family are differentially expressed in various cancer types. IGFBPs expression can affect prognosis of different cancers. The expression of IGFBPs expression is associated with multiple signal transduction pathways. The expression of IGFBPs is significantly correlated with tumor mutational burden, microsatellite instability, tumor stemness and tumor immune microenvironment. The qRT-PCR experiments verified the lower expression of IGFBP2 and IGFBP6 in gastric cancer and the lower expression of IGFBP6 in colorectal cancer. Immunohistochemistry validated a marked downregulation of IGFBP2 protein in gastric cancer tissues. The keywords co-occurrence analysis of IGFBP related publications in cancer showed relative research have been more concentrating on the potential of IGFBPs as tumor diagnostic and prognostic markers and developing cancer therapies. CONCLUSIONS These findings provide frontier trend of IGFBPs related research and new clues for identifying novel therapeutic targets for various cancers.
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Affiliation(s)
- Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Shixuan Shen
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Lirong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Hanxi Ding
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Ang Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, China.
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Ragavi R, Muthukumaran P, Nandagopal S, Ahirwar DK, Tomo S, Misra S, Guerriero G, Shukla KK. Epigenetics regulation of prostate cancer: Biomarker and therapeutic potential. Urol Oncol 2023:S1078-1439(23)00090-X. [PMID: 37032230 DOI: 10.1016/j.urolonc.2023.03.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 04/11/2023]
Abstract
Prostate cancer (CaP) is the second leading cause of cancer death and displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. The etiology of most cases of CaP is not understood completely, which makes it imperative to search for the molecular basis of CaP and markers for early diagnosis. Epigenetic modifications, including changes in DNA methylation patterns, histone modifications, miRNAs, and lncRNAs are key drivers of prostate tumorigenesis. These epigenetic defects might be due to deregulated expression of the epigenetic machinery, affecting the expression of several important genes like GSTP1, RASSF1, CDKN2, RARRES1, IGFBP3, RARB, TMPRSS2-ERG, ITGB4, AOX1, HHEX, WT1, HSPE, PLAU, FOXA1, ASC, GPX3, EZH2, LSD1, etc. In this review, we highlighted the most important epigenetic gene alterations and their variations as a diagnostic marker and target for therapeutic intervention of CaP in the future. Characterization of epigenetic changes involved in CaP is obscure and adequate validation studies are still required to corroborate the present results that would be the impending future of transforming basic research settings into clinical practice.
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Affiliation(s)
- Ravindran Ragavi
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | | | - Srividhya Nandagopal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Dinesh Kumar Ahirwar
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Karwar, Jodhpur, Rajasthan, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sanjeev Misra
- Atal Bihari Vajpayee Medical University, Lucknow Uttar Pradesh, India
| | - Giulia Guerriero
- Comparative Endocrinology Lab, Department of Biology, University of Naples Federico II, Naples, Italy
| | - Kamla Kant Shukla
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.
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3
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Ding JF, Sun H, Song K, Zhou Y, Tu B, Shi KH, Lu D, Xu SS, Tao H. IGFBP3 epigenetic promotion induced by METTL3 boosts cardiac fibroblast activation and fibrosis. Eur J Pharmacol 2023; 942:175494. [PMID: 36657656 DOI: 10.1016/j.ejphar.2023.175494] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/11/2022] [Accepted: 01/04/2023] [Indexed: 01/17/2023]
Abstract
Cardiac fibrosis remains an unresolved problem in heart disease. Its etiology is directly caused by the activation and proliferation of cardiac fibroblasts (CFs). However, there is limited information regarding the biological role of cardiac fibroblasts in cardiac fibrosis. Herein, we screened out a gene, IGFBP3, whose expression significantly increased in TGF-β1-stimulated human primary CFs by mining RNA-Seq data for differential and WGCNA. We verified the IGFBP3's expression in transverse aortic constriction (TAC) surgery, isoproterenol (ISO)-induced cardiac fibrosis models, and TGFβ1-stimulated mouse primary CFs. We also found that the knockdown of IGFBP3 could inhibit the migration and proliferation ability of CFs. Furthermore, we found that aberrant N6-methyladenosine(m6A) mRNA modifications in the animal model and activated CFs may regulate the expression of IGFBP3 in developing cardiac fibrosis. Silencing METTL3 could downregulate the expression of IGFBP3 and inhibit the activation of CFs and the degree of cardiac fibrosis both in vitro and in vivo. Indeed, we also verified the expression of METTL3 and IGFBP3 in the atrial tissues of patients with atrial fibrillation (AF). Thus, METTL3 may regulate IGFBP3's expression and CFs activation via RNA epigenetic modifications, laying the foundation for a specific and novel therapeutic target in cardiac fibrosis.
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Affiliation(s)
- Ji-Fei Ding
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China; Department of Cardiothoracic Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, PR China
| | - He Sun
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Kai Song
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Yang Zhou
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Bin Tu
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Kai-Hu Shi
- Department of Cardiothoracic Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, PR China.
| | - Dong Lu
- Department of Interventional Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.
| | - Sheng-Song Xu
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China
| | - Hui Tao
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China; Department of Anesthesiology, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China.
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Chiang CC, Yeh H, Lim SN, Lin WR. Transcriptome analysis creates a new era of precision medicine for managing recurrent hepatocellular carcinoma. World J Gastroenterol 2023; 29:780-799. [PMID: 36816628 PMCID: PMC9932421 DOI: 10.3748/wjg.v29.i5.780] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/23/2022] [Accepted: 01/10/2023] [Indexed: 02/06/2023] Open
Abstract
The high incidence of hepatocellular carcinoma (HCC) recurrence negatively impacts outcomes of patients treated with curative intent despite advances in surgical techniques and other locoregional liver-targeting therapies. Over the past few decades, the emergence of transcriptome analysis tools, including real-time quantitative reverse transcription PCR, microarrays, and RNA sequencing, has not only largely contributed to our knowledge about the pathogenesis of recurrent HCC but also led to the development of outcome prediction models based on differentially expressed gene signatures. In recent years, the single-cell RNA sequencing technique has revolutionized our ability to study the complicated crosstalk between cancer cells and the immune environment, which may benefit further investigations on the role of different immune cells in HCC recurrence and the identification of potential therapeutic targets. In the present article, we summarized the major findings yielded with these transcriptome methods within the framework of a causal model consisting of three domains: primary cancer cells; carcinogenic stimuli; and tumor microenvironment. We provided a comprehensive review of the insights that transcriptome analyses have provided into diagnostics, surveillance, and treatment of HCC recurrence.
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Affiliation(s)
- Chun-Cheng Chiang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, United States
| | - Hsuan Yeh
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Borkowski V, Segal M, Mukhtar M, Mohammed M, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, Mumtaz K. Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data. World J Gastrointest Oncol 2022; 14:1856-1873. [PMID: 36187396 PMCID: PMC9516659 DOI: 10.4251/wjgo.v14.i9.1856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/26/2022] [Accepted: 08/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.
AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.
METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.
RESULTS Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.
CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Eli Cohen
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Naima Hashi
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Sharjeel Syed
- Department of Medicine, University of Chicago Hospitals, Chicago, IL 60637, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno, Fresno, CA 93701, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Frankfort, IL 60423, United States
| | - Emmanuel Boateng
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Mary Nemer
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, United States
| | - Dexter Hadley
- Department of Pathology, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Sajid Jalil
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
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Noncoding RNA actions through IGFs and IGF binding proteins in cancer. Oncogene 2022; 41:3385-3393. [PMID: 35597813 PMCID: PMC9203274 DOI: 10.1038/s41388-022-02353-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 12/17/2022]
Abstract
The insulin-like growth factors (IGFs) and their regulatory proteins—IGF receptors and binding proteins—are strongly implicated in cancer progression and modulate cell survival and proliferation, migration, angiogenesis and metastasis. By regulating the bioavailability of the type-1 IGF receptor (IGF1R) ligands, IGF-1 and IGF-2, the IGF binding proteins (IGFBP-1 to -6) play essential roles in cancer progression. IGFBPs also influence cell communications through pathways that are independent of IGF1R activation. Noncoding RNAs (ncRNAs), which encompass a variety of RNA types including microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs), have roles in multiple oncogenic pathways, but their many points of intersection with IGF axis functions remain to be fully explored. This review examines the functional interactions of miRNAs and lncRNAs with IGFs and their binding proteins in cancer, and reveals how the IGF axis may mediate ncRNA actions that promote or suppress cancer. A better understanding of the links between ncRNA and IGF pathways may suggest new avenues for prognosis and therapeutic intervention in cancer. Further, by exploring examples of intersecting ncRNA-IGF pathways in non-cancer conditions, it is proposed that new opportunities for future discovery in cancer control may be generated.
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Ghafouri-Fard S, Abak A, Mohaqiq M, Shoorei H, Taheri M. The Interplay Between Non-coding RNAs and Insulin-Like Growth Factor Signaling in the Pathogenesis of Neoplasia. Front Cell Dev Biol 2021; 9:634512. [PMID: 33768092 PMCID: PMC7985092 DOI: 10.3389/fcell.2021.634512] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/02/2021] [Indexed: 12/11/2022] Open
Abstract
The insulin-like growth factors (IGFs) are polypeptides with similar sequences with insulin. These factors regulate cell growth, development, maturation, and aging via different processes including the interplay with MAPK, Akt, and PI3K. IGF signaling participates in the pathogenesis of neoplasia, insulin resistance, diabetes mellitus, polycystic ovarian syndrome, cerebral ischemic injury, fatty liver disease, and several other conditions. Recent investigations have demonstrated the interplay between non-coding RNAs and IGF signaling. This interplay has fundamental roles in the development of the mentioned disorders. We designed the current study to search the available data about the role of IGF-associated non-coding RNAs in the evolution of neoplasia and other conditions. As novel therapeutic strategies have been designed for modification of IGF signaling, identification of the impact of non-coding RNAs in this pathway is necessary for the prediction of response to these modalities.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Mohaqiq
- School of Advancement, Centennial College, Ashtonbee Campus, Toronto, ON, Canada
- Wake Forest Institute for Regenerative Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, United States
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Biranjd University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Kumar A, Singh P, Pandey A, Gosipatala SB. IGFBP3 gene promoter methylation analysis and its association with clinicopathological characteristics of colorectal carcinoma. Mol Biol Rep 2020; 47:6919-6927. [PMID: 32929656 DOI: 10.1007/s11033-020-05747-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 08/28/2020] [Indexed: 12/24/2022]
Abstract
Promoter methylation mediated silencing of tumor suppressor genes plays an important role in the tumorigenesis of colorectal carcinoma (CRC). Tumor suppressor gene, Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) expression is frequently downregulated in CRC due to promoter methylations. The aim of this study was to analyze the methylation status of IGFBP-3 gene promoter in stage II and III of CRC cases; find its association with clinicopathological characteristics of CRC patients and the methylation patterns as a prognostic biomarker. 58 histopathologically confirmed cases of CRC were included in the study. Methylation status of IGFBP-3 gene promoter was determined by using methylation specific PCR (MS-PCR) and bisulfite sequencing. Kaplan-Meier survival curve and univariate cox regression analysis were used for survival analysis; Chi-square test used for association analysis. IGFBP3 promoter methylation was found in 37 (63.8%) out of 58 CRC cases. This promoter methylation status was significantly associated with lymph-node metastasis (P = 0.013) and the survival period. In stage II CRC cases, unmethylated gene promoter status showed better survival than the methylated. Mean overall survival (OS) of methylated and unmethylated group was 22.23 months, and 49.15 months respectively (P = 0.045), HR = 6.432, 95% CI 0.986-41.943. The IGFBP-3 promoter methylations found in 63.8% CRC cases in this study. The methylations was found to be associated with lymph-node metastasis and overall survival of the patients particularly in stage II CRC patients. However, promoter methylation was not associated with other clinocopathological characteristics such as age, gender, tumor location etc.
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Affiliation(s)
- Alok Kumar
- Department of Biotechnology, School for Bio-Science and Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, 226025, India
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, 226010, India
| | - Pradyumn Singh
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, 226010, India
| | - Anshuman Pandey
- Department of Surgical Gastroenterology, Dr. Ram Manohar Lohia Institute of Medical Science, Lucknow, 226010, India
| | - Sunil Babu Gosipatala
- Department of Biotechnology, School for Bio-Science and Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, 226025, India.
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Jin L, Shen F, Weinfeld M, Sergi C. Insulin Growth Factor Binding Protein 7 (IGFBP7)-Related Cancer and IGFBP3 and IGFBP7 Crosstalk. Front Oncol 2020; 10:727. [PMID: 32500027 PMCID: PMC7242731 DOI: 10.3389/fonc.2020.00727] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/16/2020] [Indexed: 12/17/2022] Open
Abstract
The insulin/insulin-like growth factors (IGFs) have crucial tasks in the growth, differentiation, and proliferation of healthy and pernicious cells. They are involved in coordinated complexes, including receptors, ligands, binding proteins, and proteases. However, the systems can become dysregulated in tumorigenesis. Insulin-like growth factor-binding protein 7 (IGFBP7) is a protein belonging to the IGFBP superfamily (also termed GFBP-related proteins). Numerous studies have provided evidence that IGFBP3 and IGFBP7 are involved in a variety of cancers, including hepatocellular carcinoma (HCC), breast cancer, gastroesophageal cancer, colon cancer, prostate cancer, among many others. Still, very few suggest an interaction between these two molecules. In studying several cancer types in our laboratories, we found that both proteins share some crucial signaling pathways. The objective of this review is to present a comprehensive overview of the relationship between IGFBP7 and cancer, as well as highlighting IGFBP3 crosstalk with IGFBP7 reported in recent studies.
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Affiliation(s)
- Li Jin
- Department of Laboratory Medicine, Shiyan Taihe Hospital, College of Biomedical Engineering, Hubei University of Medicine, Shiyan, China
| | - Fan Shen
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Michael Weinfeld
- Division of Experimental Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Consolato Sergi
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
- Department of Orthopedics, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
- Key Laboratory of Fermentation Engineering, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China
- Stollery Children's Hospital, University Alberta Hospital, Edmonton, AB, Canada
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Raglan O, Assi N, Nautiyal J, Lu H, Gabra H, Gunter MJ, Kyrgiou M. Proteomic analysis of malignant and benign endometrium according to obesity and insulin-resistance status using Reverse Phase Protein Array. Transl Res 2020; 218:57-72. [PMID: 31954096 DOI: 10.1016/j.trsl.2019.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/21/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022]
Abstract
Obesity and hyperinsulinemia are known risk factors for endometrial cancer, yet the biological pathways underlying this relationship are incompletely understood. This study investigated protein expression in endometrial cancer and benign tissue and its correlation with obesity and insulin resistance. One hundred and seven women undergoing hysterectomy for endometrial cancer or benign conditions provided a fasting blood sample and endometrial tissue. We performed proteomic expression according to body mass index, insulin resistance, and serum marker levels. We used linear regression and independent t test for statistical analysis. Proteomic data from 560 endometrial cancer cases from The Cancer Genome Atlas (TCGA) databank were used to assess reproducibility of results. One hundred and twenty seven proteins were significantly differentially expressed between 66 cancer and 26 benign patients. Protein expression involved in cell cycle progression, impacting cytoskeletal dynamics (PAK1) and cell survival (Rab 25), were most significantly altered. Obese women with cancer had increased PRAS40_pT246; a downstream marker of increased PI3K-AKT signaling. Obese women without cancer had increased mitogenic and antiapoptotic signaling by way of upregulation of Mcl-1, DUSP4, and Insulin Receptor-b. This exploratory study identified a number of candidate proteins specific to endometrioid endometrial cancer and benign endometrial tissues. Obesity and insulin resistance in women with benign endometrium leads to specific upregulation of proteins involved in insulin and driver oncogenic signaling pathways such as the PI3K-AKT-mTOR and growth factor signaling pathways which are mitogenic and also disruptive to metabolism.
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Affiliation(s)
- Olivia Raglan
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UK; Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Nada Assi
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France
| | - Jaya Nautiyal
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UK
| | - Haonan Lu
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UK
| | - Hani Gabra
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UK; Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France
| | - Maria Kyrgiou
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UK; Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
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11
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Shen L, Xu L, Zhang J, Jiang D. Preoperative Serum Insulin-Like Growth Factor 1 Level as a Prognostic Factor in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma. J Interferon Cytokine Res 2019; 38:153-160. [PMID: 29638204 DOI: 10.1089/jir.2017.0107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In this study, preoperative serum levels of insulin-like growth factor 1 (IGF-1) were determined in 216 hepatocellular carcinoma (HCC) patients who underwent hepatic resection to investigate a possible contribution of IGF-1 to the increased risk for HCC recurrence and mortality. During January 2010 and December 2013, 216 HCC patients receiving hepatectomy were recruited. The primary endpoint was the HCC recurrences within the 3-year follow-up. The secondary endpoint was all-cause mortality. The multivariate analyses with Cox regression model were applied to explore the clinical significance of IGF-1 serum levels and associated parameters on death and recurrence of HCC patients. The IGF-1 levels of included patients were determined, with a median value of 75.5 ng/mL (IQR, 40.3-93.0 ng/mL). The preoperative serum level of IGF-1 was negatively correlated with tumor size, Child-Pugh class, or tumor stage (P < 0.001 for all). In multivariate models comparing the first, second, and third quartiles with the fourth quartile of IGF-1, the levels of IGF-1 in Q1 and Q2 were associated with HCC recurrence, with an increased risk of 216% [hazard ratios (HR) = 3.16 (95% CI: 1.79-4.28)] and 106% [3.02 (1.36-3.11)]. Similarly, concentrations of IGF-1 in Q1 and Q2 were also related to all-cause mortality, with an increased recurrence risk of 238% [HR = 3.38 (95% CI: 1.85-4.36)] and 117% [3.02 (1.40-3.21)], respectively. Poor prognosis in HCC patients receiving hepatectomy could be indicated by low preoperative serum levels of IGF-1, which would be applied as a predictor.
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Affiliation(s)
- Lan Shen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jiaxing University , Jiaxing, People's Republic of China
| | - Liu Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jiaxing University , Jiaxing, People's Republic of China
| | - Jie Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jiaxing University , Jiaxing, People's Republic of China
| | - Dawei Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jiaxing University , Jiaxing, People's Republic of China
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12
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Matsumoto M, Nagano N, Awano H, Ohyama S, Fujioka K, Iwatani S, Urakami T, Iijima K, Morioka I. Incidence and Neonatal Risk factors of Short Stature and Growth Hormone treatment in Japanese Preterm Infants Born Small for Gestational Age. Sci Rep 2019; 9:12238. [PMID: 31439925 PMCID: PMC6706397 DOI: 10.1038/s41598-019-48785-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 08/12/2019] [Indexed: 12/18/2022] Open
Abstract
Incidence and neonatal risk factors for short stature in preterm children born small for gestational age (SGA) have not been fully investigated in Japan. In this prospective study, infants born ≤32 weeks' gestational age (GA) from 2004-2015 were enrolled and followed for 3 years. Incidence of short children born SGA and short stature treated with growth hormone (GH) were investigated. Neonatal risk factors were analysed using univariate and multivariate analyses. GA cut-off value was determined using receiver operating characteristic (ROC) curve analyses. Of 604 infants born ≤32 weeks' GA, 76 (13%) were SGA at birth. Twenty-seven infants (36%) developed short stature at age 2 and 14 infants (19%) received GH treatment at age 3. GA, birthweight, birth length, birth head circumference, and chronic lung disease at 36 weeks' corrected GA were determined as risk factors by univariate analyses (p < 0.01). Multivariate analyses only revealed low GA as an independent risk factor. ROC curve analysis determined a cut-off value of 24 weeks' GA. Nineteen percent of preterm SGA infants ≤32 weeks' GA developed short stature treated with GH. A low GA at birth could be an early detection marker for short stature that requires GH treatment in preterm infants born SGA.
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Affiliation(s)
- Masaaki Matsumoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nobuhiko Nagano
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Hiroyuki Awano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shohei Ohyama
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumichi Fujioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Sota Iwatani
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tatsuhiko Urakami
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ichiro Morioka
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.
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13
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Watanabe K, Panchy N, Noguchi S, Suzuki H, Hong T. Combinatorial perturbation analysis reveals divergent regulations of mesenchymal genes during epithelial-to-mesenchymal transition. NPJ Syst Biol Appl 2019; 5:21. [PMID: 31275609 PMCID: PMC6570767 DOI: 10.1038/s41540-019-0097-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 05/28/2019] [Indexed: 12/14/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT), a fundamental transdifferentiation process in development, produces diverse phenotypes in different physiological or pathological conditions. Many genes involved in EMT have been identified to date, but mechanisms contributing to the phenotypic diversity and those governing the coupling between the dynamics of epithelial (E) genes and that of the mesenchymal (M) genes are unclear. In this study, we employed combinatorial perturbations to mammary epithelial cells to induce a series of EMT phenotypes by manipulating two essential EMT-inducing elements, namely TGF-β and ZEB1. By measuring transcriptional changes in more than 700 E-genes and M-genes, we discovered that the M-genes exhibit a significant diversity in their dependency to these regulatory elements and identified three groups of M-genes that are controlled by different regulatory circuits. Notably, functional differences were detected among the M-gene clusters in motility regulation and in survival of breast cancer patients. We computationally predicted and experimentally confirmed that the reciprocity and reversibility of EMT are jointly regulated by ZEB1. Our integrative analysis reveals the key roles of ZEB1 in coordinating the dynamics of a large number of genes during EMT, and it provides new insights into the mechanisms for the diversity of EMT phenotypes.
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Affiliation(s)
- Kazuhide Watanabe
- RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
| | - Nicholas Panchy
- Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Knoxville, TN 37996 USA
- National Institute for Mathematical and Biological Synthesis, Knoxville, TN 37996 USA
| | - Shuhei Noguchi
- RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
| | - Harukazu Suzuki
- RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
| | - Tian Hong
- Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Knoxville, TN 37996 USA
- National Institute for Mathematical and Biological Synthesis, Knoxville, TN 37996 USA
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14
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Scully T, Scott CD, Firth SM, Pintar JE, Twigg SM, Baxter RC. Contrasting effects of IGF binding protein-3 expression in mammary tumor cells and the tumor microenvironment. Exp Cell Res 2018; 374:38-45. [PMID: 30419192 DOI: 10.1016/j.yexcr.2018.11.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/02/2018] [Accepted: 11/06/2018] [Indexed: 11/29/2022]
Abstract
IGFBP-3 has both stimulatory and inhibitory effects on cancer progression. The growth of EO771 mammary carcinoma cells as syngeneic tumors in C57BL/6 mice is reduced in Igfbp3-null (BP3KO) mice, suggesting that systemic IGFBP-3 enhances tumor progression. In this study we assessed the growth of EO771 cells expressing human IGFBP-3 in BP3KO mice. Cells expressing hIGFBP-3 showed decreased proliferation in vitro and increased levels of IGF-1 receptor (IGF1R) protein but not mRNA, consistent with sequestration of endogenous IGF by IGFBP-3. The growth rate of these cells was restored by exposure to IGF-1 or analogues with reduced affinity for IGFBP-3 (long Arg3-IGF-1) or IGF1R (Leu24-IGF-1). In EO771 cells implanted orthotopically into mice, hIGFBP-3 expression by the cells inhibited tumor establishment in BP3KO but not wild-type mice. For tumors that successfully established, final weight was not affected significantly by hIGFBP-3 expression. However, final tumor weight was inversely related to intratumoral T cell counts, and sera from BP3KO mice with tumors showed low-titer immunoreactivity against IGFBP-3. The contrasting effects on tumor establishment and progression of IGFBP-3 expressed by mammary carcinoma cells, compared to systemic stromal and circulating IGFBP-3, highlights the complexity of growth regulation by IGFBP-3 in mammary tumors.
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Affiliation(s)
- Tiffany Scully
- Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
| | - Carolyn D Scott
- Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
| | - Sue M Firth
- Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
| | - John E Pintar
- Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, NJ 08854, USA.
| | - Stephen M Twigg
- Charles Perkins Centre, Sydney Medical School, University of Sydney, New South Wales 2006, Australia.
| | - Robert C Baxter
- Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia.
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15
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Julovi SM, Martin JL, Baxter RC. Nuclear Insulin-Like Growth Factor Binding Protein-3 As a Biomarker in Triple-Negative Breast Cancer Xenograft Tumors: Effect of Targeted Therapy and Comparison With Chemotherapy. Front Endocrinol (Lausanne) 2018; 9:120. [PMID: 29623068 PMCID: PMC5874320 DOI: 10.3389/fendo.2018.00120] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/09/2018] [Indexed: 12/22/2022] Open
Abstract
Triple-negative breast cancer (TNBC) typically has a worse outcome than other breast cancer subtypes, in part owing to a lack of approved therapeutic targets or prognostic markers. We have previously described an oncogenic pathway in basal-like TNBC cells, initiated by insulin-like growth factor binding protein-3 (IGFBP-3), in which the epidermal growth factor receptor (EGFR) is transactivated by sphingosine-1-phosphate (S1P) resulting from sphingosine kinase (SphK)-1 activation. Oncogenic IGFBP-3 signaling can be targeted by combination treatment with the S1P receptor modulator and SphK inhibitor, fingolimod, and the EGFR kinase inhibitor, gefitinib (F + G). However, the interaction of this treatment with chemotherapy has not been documented. Since we observed nuclear localization of IGFBP-3 in some TNBC tumors, this study aimed to evaluate the prognostic significance of nuclear IGFBP-3 in pre-clinical models of basal-like TNBC treated with F + G and doxorubicin. Orthotopic xenograft tumors were grown in nude mice from the human basal-like TNBC cell lines MDA-MB-468 and HCC1806, and were treated with gefitinib, 25 mg/Kg, plus fingolimod, 5 mg/Kg, 3-times weekly. In some studies, doxorubicin was also administered once weekly for 6 weeks. Tumor tissue proteins were quantitated by immunohistochemistry (IHC). Interaction between doxorubicin and F + G was also studied in proliferation assays in vitro. In both tumor models, tissue staining for IGFBP-3 was predominantly nuclear. Combination of F + G significantly enhanced mouse survival, decreased nuclear IGFBP-3 and Ki67 staining, and increased apoptosis (cleaved caspase-3) staining. Kaplan-Meier survival analysis showed that a high tumor IGFBP-3 IHC score (>median), like a high Ki67 score, was significantly associated with shorter survival time, whereas a high apoptosis score was associated with prolonged survival. Studied in vitro in both cell lines, low-dose doxorubicin that had little effect alone, strongly enhanced the cytostatic effect of low-dose F + G combination. However, in both in vivo models, doxorubicin at maximum-tolerated dose neither inhibited tumor growth when administered alone, nor enhanced the significant inhibitory effect of F + G. We conclude that doxorubicin may not add benefit to the inhibitory effect of F + G unless its dose-limiting toxicity can be overcome. Nuclear IGFBP-3 appears to have potential as a prognostic marker in TNBC and could be evaluated for clinical utility.
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16
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Cervello M, Augello G, Cusimano A, Emma MR, Balasus D, Azzolina A, McCubrey JA, Montalto G. Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma. Adv Biol Regul 2017; 65:59-76. [PMID: 28619606 DOI: 10.1016/j.jbior.2017.06.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/24/2017] [Accepted: 06/04/2017] [Indexed: 06/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and represents the second most frequently cancer and third most common cause of death from cancer worldwide. At advanced stage, HCC is a highly aggressive tumor with a poor prognosis and with very limited response to common therapies. Therefore, there is still the need for new effective and well-tolerated therapeutic strategies. Molecular-targeted therapies hold promise for HCC treatment. One promising molecular target is the multifunctional serine/threonine kinase glycogen synthase kinase 3 (GSK-3). The roles of GSK-3β in HCC remain controversial, several studies suggested a possible role of GSK-3β as a tumor suppressor gene in HCC, whereas, other studies indicate that GSK-3β is a potential therapeutic target for this neoplasia. In this review, we will focus on the different roles that GSK-3 plays in HCC and its interaction with signaling pathways implicated in the pathogenesis of HCC, such as Insulin-like Growth Factor (IGF), Notch, Wnt/β-catenin, Hedgehog (HH), and TGF-β pathways. In addition, the pivotal roles of GSK3 in epithelial-mesenchymal transition (EMT), invasion and metastasis will be also discussed.
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Affiliation(s)
- Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
| | - Giuseppa Augello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Maria Rita Emma
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Daniele Balasus
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Antonina Azzolina
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Giuseppe Montalto
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy; Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy
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17
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Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3956485. [PMID: 28105421 PMCID: PMC5220417 DOI: 10.1155/2016/3956485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 11/30/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.
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18
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Yen YC, Hsiao JR, Jiang SS, Chang JS, Wang SH, Shen YY, Chen CH, Chang IS, Chang JY, Chen YW. Insulin-like growth factor-independent insulin-like growth factor binding protein 3 promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin β1. Oncotarget 2016; 6:41837-55. [PMID: 26540630 PMCID: PMC4747192 DOI: 10.18632/oncotarget.5995] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 10/05/2015] [Indexed: 12/15/2022] Open
Abstract
Frequent metastasis to the cervical lymph nodes leads to poor survival of patients with oral squamous cell carcinoma (OSCC). To understand the underlying mechanisms of lymph node metastasis, two sublines were successfully isolated from cervical lymph nodes of nude mice through in vivo selection, and identified as originating from poorly metastatic parental cells. These two sublines specifically metastasized to cervical lymph nodes in 83% of mice, whereas OEC-M1 cells did not metastasize after injection into the oral cavity. After gene expression analysis, we identified insulin-like growth factor binding protein 3 (IGFBP3) as one of the significantly up-regulated genes in the sublines in comparison with their parental cells. Consistently, meta-analysis of the public microarray datasets and IGFBP3 immunohistochemical analysis revealed increased both levels of IGFBP3 mRNA and protein in human OSCC tissues when compared to normal oral or adjacent nontumorous tissues. Interestingly, the up-regulated IGFBP3 mRNA expression was significantly associated with OSCC patients with lymph node metastasis. IGFBP3 knockdown in the sublines impaired and ectopic IGFBP3 expression in the parental cells promoted migration, transendothelial migration and lymph node metastasis of orthotopic transplantation. Additionally, ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions. Results indicated that IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions.
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Affiliation(s)
- Yi-Chen Yen
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Jenn-Ren Hsiao
- Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shih Sheng Jiang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Jeffrey S Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Ssu-Han Wang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Ying-Ying Shen
- Pathology Core Laboratory, National Health Research Institutes, Miaoli, Taiwan
| | - Chung-Hsing Chen
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - I-Shou Chang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.,Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Jang-Yang Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan
| | - Ya-Wen Chen
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.,Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
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19
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Lee SM, Kim-Ha J, Choi WY, Lee J, Kim D, Lee J, Choi E, Kim YJ. Interplay of genetic and epigenetic alterations in hepatocellular carcinoma. Epigenomics 2016; 8:993-1005. [PMID: 27411963 DOI: 10.2217/epi-2016-0027] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Genetic and epigenetic alterations play prominent roles in hepatocarcinogenesis and their appearance varies depending on etiological factors, race and tumor progression. Intriguingly, distinct patterns of these genetic and epigenetic mutations are coupled not only to affect each other, but to trigger different types of tumorigenesis. The patterns and frequencies of somatic variations vary depending on the nature of the surrounding chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutation. Therefore, genetic mutations and epigenetic alterations in hepatocellular carcinoma appear to be inseparable factors that accelerate tumorigenesis synergistically. We have summarized recent findings on genetic and epigenetic modifications, their influences on each other's alterations and putative roles in liver tumorigenesis.
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Affiliation(s)
- Sun-Min Lee
- Department of Biochemistry, College of Life Science & Technology, Yonsei University, Seoul, Korea
| | - Jeongsil Kim-Ha
- Department of Integrative Bioscience & Biotechnology, College of Life Sciences, Sejong University, Seoul, Korea
| | - Won-Young Choi
- Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea
| | - Jungwoo Lee
- Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea
| | - Dawon Kim
- Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea
| | - Jinyoung Lee
- Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea
| | - Eunji Choi
- Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science & Technology, Yonsei University, Seoul, Korea.,Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea
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20
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Han JJ, Xue DW, Han QR, Liang XH, Xie L, Li S, Wu HY, Song B. Induction of apoptosis by IGFBP3 overexpression in hepatocellular carcinoma cells. Asian Pac J Cancer Prev 2015; 15:10085-9. [PMID: 25556430 DOI: 10.7314/apjcp.2014.15.23.10085] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The insulin-like growth factor (IGF) system comprises a group of proteins that play key roles in regulating cell growth, differentiation, and apoptosis in a variety of cellular systems. The aim of this study was to investigate the role of insulin-like growth factor binding protein 3 (IGFBP3) in hepatocellular carcinoma. MATERIALS AND METHODS Expression of IGF2, IGFBP3, and PTEN was analyzed by qRT-PCR. Lentivirus vectors were used to overexpress IGFBP3 in hepatocellular carcinoma cell (HCC) lines. The effect of IGFBP3 on proliferation was investigated by MTT and colony formation assays. RESULTS Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells. CONCLUSIONS Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/ trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells.
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Affiliation(s)
- Jian-Jun Han
- Department of Cancer Intervention Treatment Center, Shandong Cancer Hospital and Institute, Jinan, China E-mail :
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21
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Kim ST, Jang HL, Lee J, Park SH, Park YS, Lim HY, Choi MG, Bae JM, Sohn TS, Noh JH, Kim S, Kim KM, Kang WK, Park JO. Clinical Significance of IGFBP-3 Methylation in Patients with Early Stage Gastric Cancer. Transl Oncol 2015; 8:288-94. [PMID: 26310375 PMCID: PMC4562974 DOI: 10.1016/j.tranon.2015.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/11/2015] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND: IGFBP-3 is a multifunctional protein that inhibits growth and induces apoptosis of cancer cells. Hypermethylation of the promoter represses expression of the IGFBP-3 gene. We undertook this study to assess the impact of IGFBP-3 methylation on survival of early stage gastric cancer patients. METHODS: Of the 482 tissue samples from gastric cancer patients who underwent curative surgery, IGFBP-3 methylation was tested in 138 patients with stage IB/II gastric cancer. We also analyzed IGFBP-3 methylation in 26 gastric cancer cell lines. IGFBP-3 methylation was evaluated by methylation-specific polymerase chain reaction (MethyLight). Statistical analyses, all two-sided, were performed to investigate the prognostic effects of methylation status of the IGFBP-3 promoter on various clinical parameters. RESULTS: Hypermethylation of IGFBP-3 was observed in 26 (19%) of the 138 stage IB/II gastric cancer patients. Clinicopathological factors such as age, Lauren classification, sex, tumor infiltration, lymph node metastasis, and histologic grade did not show a statistically significant association with the methylation status of the IGFBP-3 promoter. Patients with a hypermethylated IGFBP-3 promoter had similar 8-year disease-free survival compared with those without a hypermethylated IGFBP-3 promoter (73% vs 75%, P = .78). In subgroup analyses, females, but not males, seemed to have poorer prognosis for DFS and OS in the subset of patients with IGFBP-3 methylation as compared with those without IGFBP-3 methylation (8-year DFS: 55.6% vs 71.6%, P = .3694 and 8-year overall survival: 55.6% vs 68.4%, P = .491, respectively) even with no statistical significance. CONCLUSIONS: The status of IGFBP-3 methylation as measured by methylation-specific polymerase chain reaction proposed the modest role for predicting survival in specific subgroups of patients with early-stage gastric cancer who undergo curative surgery. However, this needs further investigation.
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye-Lim Jang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Seoul, Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Hyung Noh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Perks CM, Holly JM. Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer. J Cell Commun Signal 2015; 9:159-66. [PMID: 25920743 DOI: 10.1007/s12079-015-0294-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 04/21/2015] [Indexed: 12/17/2022] Open
Abstract
Epigenetics refers to heritable changes in gene expression that are independent of alterations in DNA sequence. It is now accepted that disruption of epigenetic mechanisms plays a key role in the pathogenesis of cancer: culminating in altered gene function and malignant cellular transformation. DNA methylation and histone modifications are the most widely studied changes but non-coding RNAs such as miRNAs are also considered part of the epigenetic machinery. The insulin-like growth factor (IGF) axis is composed of two ligands, IGF-I and -II, their receptors and six high affinity IGF binding proteins (IGFBPs). The IGF axis plays a key role in cancer development and progression. As IGFBP genes have consistently been identified among the most common to be aberrantly altered in tumours, this review will focus on epigenetic regulation of IGFBP-3 in cancer for which the majority of evidence has been obtained.
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Affiliation(s)
- Claire M Perks
- IGF & Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK,
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23
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Yulyana Y, Ho IAW, Sia KC, Newman JP, Toh XY, Endaya BB, Chan JKY, Gnecchi M, Huynh H, Chung AYF, Lim KH, Leong HS, Iyer NG, Hui KM, Lam PYP. Paracrine factors of human fetal MSCs inhibit liver cancer growth through reduced activation of IGF-1R/PI3K/Akt signaling. Mol Ther 2015; 23:746-56. [PMID: 25619723 DOI: 10.1038/mt.2015.13] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 12/16/2014] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. The multikinase inhibitor sorafenib only demonstrated marginal improvement in overall survival for advanced disease prompted the search for alternative treatment options. Human mesenchymal stem cells (MSCs) have the ability to home to tumor cells. However, its functional roles on the tumor microenvironment remain controversial. Herein, we showed that conditioned media derived from human fetal MSC (CM-hfMSCs) expressed high level of the insulin growth factor binding proteins IGFBPs and can sequester free insulin-like growth factors (IGFs) to inhibit HCC cell proliferation. The inhibitory effect of IGFBPs on IGF signaling was further evident from the reduction of activated IGF-1R and PI3K/Akt, leading eventually to the induction of cell cycle arrest. We also demonstrated that CM-hfMSCs could enhance the therapeutic efficacy of sorafenib and sunitinib. To the best of our knowledge, this is the first report to show that CM-hfMSCs has a tumor-specific, antiproliferative effect that is not observed with normal human hepatocyte cells and patient-derived matched normal tissues. Our results thus suggest that CM-hfMSCs can provide a useful tool to design alternative/adjuvant treatment strategies for HCC, especially in related function to potentiate the effects of chemotherapeutic drugs.
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Affiliation(s)
- Yulyana Yulyana
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore
| | - Ivy A W Ho
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore
| | - Kian Chuan Sia
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore
| | - Jennifer P Newman
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore
| | - Xin Yi Toh
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore
| | - Berwini B Endaya
- Griffith University, Griffith Health Institute, School of Medical Science, Southport, Australia
| | - Jerry K Y Chan
- 1] Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [2] Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore [3] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
| | - Massimiliano Gnecchi
- 1] Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy [2] Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy [3] Department of Medicine, University of Cape Town, South Africa
| | - Hung Huynh
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore
| | | | - Kiat Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore
| | - Hui Sun Leong
- Division of Medical Sciences, National Cancer Centre, Singapore
| | | | - Kam Man Hui
- 1] Division of Cellular and Molecular Research, National Cancer Centre, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore [3] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [4] Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore
| | - Paula Y P Lam
- 1] Division of Cellular and Molecular Research, National Cancer Centre, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore [3] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Enguita-Germán M, Fortes P. Targeting the insulin-like growth factor pathway in hepatocellular carcinoma. World J Hepatol 2014; 6:716-737. [PMID: 25349643 PMCID: PMC4209417 DOI: 10.4254/wjh.v6.i10.716] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/14/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.
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25
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Johnson MA, Firth SM. IGFBP-3: a cell fate pivot in cancer and disease. Growth Horm IGF Res 2014; 24:164-173. [PMID: 24953254 DOI: 10.1016/j.ghir.2014.04.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/21/2014] [Indexed: 12/19/2022]
Abstract
One of the hallmarks in the advancement of cancer cells is an ability to overcome and acquire resistance to adverse conditions. There has been a large amount of cancer research on IGFBP-3 as a pro-apoptotic molecule in vitro. These pro-apoptotic properties, however, do not correlate with several studies linking high IGFBP-3 levels in breast cancer tissue to rapid growth and poor prognosis. Evidence is emerging that IGFBP-3 also exhibits pro-survival and growth-promoting properties in vitro. How IGFBP-3 pivots cell fate to either death or survival, it seems, comes down to a complex interplay between cells' microenvironments and the presence of cellular IGFBP-3 binding partners and growth factor receptors. The cytoprotective actions of IGFBP-3 are not restricted to cancer but are also observed in other disease states, such as retinopathy and brain ischaemia. Here we review the literature on this paradoxical nature of IGFBP-3, its pro-apoptotic and growth-inhibitory actions versus its cytoprotective and growth-potentiating properties, and discuss the implications of targeting IGFBP-3 for treatment of disease.
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Affiliation(s)
- Michael A Johnson
- Hormones and Cancer, Kolling Institute of Medical Research, The University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - Sue M Firth
- Hormones and Cancer, Kolling Institute of Medical Research, The University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
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26
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Pivonello C, De Martino MC, Negri M, Cuomo G, Cariati F, Izzo F, Colao A, Pivonello R. The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets. Infect Agent Cancer 2014; 9:27. [PMID: 25225571 PMCID: PMC4164328 DOI: 10.1186/1750-9378-9-27] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 06/23/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.
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Affiliation(s)
- Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | | | - Federica Cariati
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Francesco Izzo
- National Cancer Institute G Pascale Foundation, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
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IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer. PLoS One 2014; 9:e104285. [PMID: 25127039 PMCID: PMC4134211 DOI: 10.1371/journal.pone.0104285] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 07/07/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIM Aberrant hypermethylation of cancer-related genes has emerged as a promising strategy for the development of diagnostic, prognostic and predictive biomarkers in human cancer, including colorectal cancer (CRC). The aim of this study was to perform a systematic and comprehensive analysis of a panel of CRC-specific genes as potential diagnostic, prognostic and predictive biomarkers in a large, population-based CRC cohort. PATIENTS AND METHODS Methylation status of the SEPT9, TWIST1, IGFBP3, GAS7, ALX4 and miR137 genes was studied by quantitative bisulfite pyrosequencing in a population-based cohort of 425 CRC patients. RESULTS Methylation levels of all genes analyzed were significantly higher in tumor tissues compared to normal mucosa (p<0.0001); however, cancer-associated hypermethylation was most frequently observed for miR137 (86.7%) and IGFBP3 (83%) in CRC patients. Methylation analysis using the combination of these two genes demonstrated greatest accuracy for the identification of colonic tumors (sensitivity 95.5%; specificity 90.5%). Low levels of IGFBP3 promoter methylation emerged as an independent risk factor for predicting poor disease free survival in stage II and III CRC patients (HR = 0.49, 95% CI: 0.28-0.85, p = 0.01). Our results also suggest that stage II & III CRC patients with high levels of IGFBP3 methylation do not benefit from adjuvant 5FU-based chemotherapy. CONCLUSION By analyzing a large, population-based CRC cohort, we demonstrate the potential clinical significance of miR137 and IGFBP3 hypermethylation as promising diagnostic biomarkers in CRC. Our data also revealed that IGFBP3 hypermethylation may serve as an independent prognostic and predictive biomarker in stage II and III CRC patients.
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28
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Anwar SL, Lehmann U. DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma. World J Gastroenterol 2014; 20:7894-7913. [PMID: 24976726 PMCID: PMC4069317 DOI: 10.3748/wjg.v20.i24.7894] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 01/24/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC.
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29
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Sung HY, Choi EN, Lyu D, Mook-Jung I, Ahn JH. Amyloid beta-mediated epigenetic alteration of insulin-like growth factor binding protein 3 controls cell survival in Alzheimer's disease. PLoS One 2014; 9:e99047. [PMID: 24964199 PMCID: PMC4070895 DOI: 10.1371/journal.pone.0099047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 05/11/2014] [Indexed: 12/30/2022] Open
Abstract
Swedish double mutation (KM670/671NL) of amyloid precursor protein (APP) is reported to increase toxic amyloid β (Aβ) production via aberrant cleavage at the β-secretase site and thereby cause early-onset Alzheimer's disease (AD). However, the underlying molecular mechanisms leading to AD pathogenesis remains largely unknown. Previously, our transcriptome sequence analyses revealed global expressional modifications of over 600 genes in APP-Swedish mutant-expressing H4 (H4-sw) cells compared to wild type H4 cells. Insulin-like growth factor binding protein 3 (IGFBP3) is one gene that showed significantly decreased mRNA expression in H4-sw cells. In this study, we investigated the functional role of IGFBP3 in AD pathogenesis and elucidated the mechanisms regulating its expression. We observed decreased IGFBP3 expression in the H4-sw cell line as well as the hippocampus of AD model transgenic mice. Treatment with exogenous IGFBP3 protein inhibited Aβ1–42- induced cell death and caspase-3 activity, whereas siRNA-mediated suppression of IGFBP3 expression induced cell death and caspase-3 cleavage. In primary hippocampal neurons, administration of IGFBP3 protein blocked apoptotic cell death due to Aβ1–42 toxicity. These data implicate a protective role for IGFBP3 against Aβ1–42-mediated apoptosis. Next, we investigated the regulatory mechanisms of IGFBP3 expression in AD pathogenesis. We observed abnormal IGFBP3 hypermethylation within the promoter CpG island in H4-sw cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine restored IGFBP3 expression at both the mRNA and protein levels. Chronic exposure to Aβ1–42 induced IGFBP3 hypermethylation at CpGs, particularly at loci −164 and −173, and subsequently suppressed IGFBP3 expression. Therefore, we demonstrate that expression of anti-apoptotic IGFBP3 is regulated by epigenetic DNA methylation, suggesting a mechanism that contributes to AD pathogenesis.
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Affiliation(s)
- Hye Youn Sung
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Eun Nam Choi
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Dahyun Lyu
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Inhee Mook-Jung
- Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hyuck Ahn
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
- Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
- * E-mail:
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Abstract
The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival - they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.
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Affiliation(s)
- Robert C Baxter
- Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia
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31
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Lima F, Ding D, Goetz W, Yang AJ, Baulch JE. High LET (56)Fe ion irradiation induces tissue-specific changes in DNA methylation in the mouse. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2014; 55:266-77. [PMID: 24723241 DOI: 10.1002/em.21832] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 07/12/2013] [Accepted: 11/15/2013] [Indexed: 05/15/2023]
Abstract
DNA methylation is an epigenetic mechanism that drives phenotype and that can be altered by environmental exposures including radiation. The majority of human radiation exposures occur in a relatively low dose range; however, the biological response to low dose radiation is poorly understood. Based on previous observations, we hypothesized that in vivo changes in DNA methylation would be observed in mice following exposure to doses of high linear energy transfer (LET) (56) Fe ion radiation between 10 and 100 cGy. We evaluated the DNA methylation status of genes for which expression can be regulated by methylation and that play significant roles in radiation responses or carcinogenic processes including apoptosis, metastasis, cell cycle regulation, and DNA repair (DAPK1, EVL, 14.3.3, p16, MGMT, and IGFBP3). We also evaluated DNA methylation of repeat elements in the genome that are typically highly methylated. No changes in liver DNA methylation were observed. Although no change in DNA methylation was observed for the repeat elements in the lungs of these same mice, significant changes were observed for the genes of interest as a direct effect and a delayed effect of irradiation 1, 7, 30, and 120 days post exposure. At delayed times, differences in methylation profiles among genes were observed. DNA methylation profiles also significantly differed based on dose, with the lowest dose frequently affecting the largest change. The results of this study are the first to demonstrate in vivo high LET radiation-induced changes in DNA methylation that are tissue and locus specific, and dose and time dependent.
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Affiliation(s)
- Florence Lima
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky
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Lee H, Kim SR, Oh Y, Cho SH, Schleimer RP, Lee YC. Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways. A novel therapeutic approach for asthma. Am J Respir Cell Mol Biol 2014; 50:667-77. [PMID: 24219511 PMCID: PMC5455301 DOI: 10.1165/rcmb.2013-0397tr] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 11/05/2013] [Indexed: 02/04/2023] Open
Abstract
Insulin-like growth factor (IGF)-I has been recognized to play critical roles in the pathogenesis of asthma, whereas IGF-binding protein (IGFBP)-3 blocks crucial physiologic manifestations of asthma. IGF-I enhances subepithelial fibrosis, airway inflammation, airway hyperresponsiveness, and airway smooth muscle hyperplasia by interacting with various inflammatory mediators and complex signaling pathways, such as intercellular adhesion molecule-1, and the hypoxia-inducible factor/vascular endothelial growth factor axis. On the other hand, IGFBP-3 decreases airway inflammation and airway hyperresponsiveness through IGFBP-3 receptor-mediated activation of caspases, which subsequently inhibits NF-κB signaling pathway. It also inhibits the IGF-I/hypoxia-inducible factor/vascular endothelial growth factor axis via IGF-I-dependent and/or IGF-I-independent mechanisms. This Translational Review summarizes the role of IGF-I and IGFBP-3 in the context of allergic airway disease, and discusses the therapeutic potential of various strategies targeting the IGF-I and IGFBP-3 signaling pathways for the management of asthma.
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Affiliation(s)
- Hyun Lee
- Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea
| | - So Ri Kim
- Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea
| | - Youngman Oh
- Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia; and
| | - Seong Ho Cho
- Division of Allergy–Immunology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Robert P. Schleimer
- Division of Allergy–Immunology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Yong Chul Lee
- Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea
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Akiel M, Rajasekaran D, Gredler R, Siddiq A, Srivastava J, Robertson C, Jariwala NH, Fisher PB, Sarkar D. Emerging role of insulin-like growth factor-binding protein 7 in hepatocellular carcinoma. J Hepatocell Carcinoma 2014; 1:9-19. [PMID: 27508172 PMCID: PMC4918263 DOI: 10.2147/jhc.s44460] [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] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a vicious and highly vascular cancer with a dismal prognosis. It is a life-threatening illness worldwide that ranks fifth in terms of cancer prevalence and third in cancer deaths. Most patients are diagnosed at an advanced stage by which time conventional therapies are no longer effective. Targeted molecular therapies, such as the multikinase inhibitor sorafenib, provide a modest increase in survival for advanced HCC patients and display significant toxicity. Thus, there is an immense need to identify novel regulators of HCC that might be targeted effectively. The insulin-like growth factor (IGF) axis is commonly abnormal in HCC. Upon activation, the IGF axis controls metabolism, tissue homeostasis, and survival. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein of a family of low-affinity IGF-binding proteins termed “IGFBP-related proteins” that have been identified as a potential tumor suppressor in HCC. IGFBP7 has been implicated in regulating cellular proliferation, senescence, and angiogenesis. In this review, we provide a comprehensive discussion of the role of IGFBP7 in HCC and the potential use of IGFBP7 as a novel biomarker for drug resistance and as an effective therapeutic strategy.
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Affiliation(s)
- Maaged Akiel
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Devaraja Rajasekaran
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rachel Gredler
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Ayesha Siddiq
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jyoti Srivastava
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Chadia Robertson
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Nidhi Himanshu Jariwala
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
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Antitumor activity and immunogenicity of recombinant vaccinia virus expressing HPV 16 E7 protein SigE7LAMP is enhanced by high-level coexpression of IGFBP-3. Cancer Gene Ther 2014; 21:115-25. [PMID: 24556712 DOI: 10.1038/cgt.2014.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 01/31/2014] [Accepted: 01/31/2014] [Indexed: 01/21/2023]
Abstract
We constructed recombinant vaccinia viruses (VACVs) coexpressing the insulin-like growth factor-binding protein-3 (IGFBP-3) gene and the fusion gene encoding the SigE7Lamp antigen. The expression of the IGFBP-3 transgene was regulated either by the early H5 promoter or by the synthetic early/late (E/L) promoter. We have shown that IGFBP-3 expression regulated by the H5 promoter yielded higher amount of IGFBP-3 protein when compared with the E/L promoter. The immunization with P13-SigE7Lamp-H5-IGFBP-3 virus was more effective in inhibiting the growth of TC-1 tumors in mice and elicited higher T-cell response against VACV-encoded antigen than the P13-SigE7Lamp-TK(-) control virus. We found that high-level production of IGFBP-3 enhanced virus replication both in vitro and in vivo, resulting in more profound antigen stimulation. Production of IGFBP-3 was associated with a higher adsorption rate of P13-SigE7Lamp-H5-IGFBP-3 to CV-1 cells when compared with P13-SigE7Lamp-TK(-). Intracellular mature virions (IMVs) of the IGFBP-3-expressing virus P13-SigE7Lamp-H5-IGFBP-3 have two structural differences: they incorporate the IGFBP-3 protein and they have elevated phosphatidylserine (PS) exposure on outer membrane that could result in increased uptake of IMVs by macropinocytosis. The IMV PS content was measured by flow cytometry using microbeads covered with immobilized purified VACV virions.
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Shahjee HM, Bhattacharyya N. Activation of various downstream signaling molecules by IGFBP-3. ACTA ACUST UNITED AC 2014; 5:830-835. [PMID: 25254143 DOI: 10.4236/jct.2014.59091] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Insulin-like growth factor binding protein-3 (IGFBP-3), a secretory protein, is the most abundant IGF binding protein present in human serum among all IGF binding proteins. IGFBP-3 shows decreased level of expression in cancerous cells but has been known to be present in significant amounts in normal or non-cancerous cells. IGFBP-3 can induce apoptosis in prostate cancer cells either in an IGF-dependent manner or independently of IGF binding. Although putative cell death specific Insulin-like growth factor binding protein-3 (IGFBP-3R) receptor(s) has recently been identified by which IGFBP-3 may induce its anti-tumor effects, IGFBP-3 has also been known to activate various downstream intracellular signaling molecules via a different mechanistic pathway. Stat-1 has been known to be one of the candidate molecules activated by IGFBP-3. IGFBP-3 can also inhibit Akt/IGF-1 survival pathway in MCF- 7 breast cancer cells which ultimately leads to the induction of apoptosis in these cells. All these studies clearly demonstrate that IGFBP-3 regulates cell proliferation and promotes its pro-apoptotic effects in cancer cells in two different pathways,1) sequester IGF-I to bind to IGF-I receptor to inhibit cell proliferation and induce apoptosis, 2) independent of IGF-I pathway, IGFBP-3 binds to some putative receptor and activate various downstream pro-apoptotic molecules involved in cell death.
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Affiliation(s)
- Hanief Mohammad Shahjee
- Diabetes Branch, NIDDK, National Institutes of Health, Bldg 10-Room 8D12, 9000 Rockville Pike, MSC 1758, Bethesda, MD 20892, United States
| | - Nisan Bhattacharyya
- Diabetes Branch, NIDDK, National Institutes of Health, Bldg 10-Room 8D12, 9000 Rockville Pike, MSC 1758, Bethesda, MD 20892, United States
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CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene 2013; 34:104-18. [PMID: 24292684 DOI: 10.1038/onc.2013.522] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 10/16/2013] [Accepted: 10/18/2013] [Indexed: 12/16/2022]
Abstract
Cullin 4B (CUL4B) is a component of the Cullin4B-Ring E3 ligase complex (CRL4B) that functions in proteolysis and is implicated in tumorigenesis. Here, we report that CRL4B is associated with histone methyltransferase SUV39H1, heterochromatin protein 1 (HP1) and DNA methyltransferases 3A (DNMT3A). We showed that CRL4B, through catalyzing H2AK119 monoubiquitination, facilitates H3K9 tri-methylation and DNA methylation, two key epigenetic modifications involved in DNA methylation-based gene silencing. Depletion of CUL4B resulted in loss of not only H2AK119 monoubiquitination but also H3K9 trimethylation and DNA methylation, leading to derepression of a collection of genes, including the tumor suppressor IGFBP3. We demonstrated that CUL4B promotes cell proliferation and invasion, which are consistent with a tumorigenic phenotype, at least partially by repressing IGFBP3. We found that the expression of CUL4B is markedly upregulated in samples of human cervical carcinoma and is negatively correlated with the expression of IGFBP3. Our experiments unveiled a coordinated action between histone ubiquitination/methylation and DNA methylation in transcription repression, providing a mechanism for CUL4B in tumorigenesis.
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Harada A, Jogie-Brahim S, Oh Y. Tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone suppresses a newly identified anti-tumor IGFBP-3/IGFBP-3R system in lung cancer cells. Lung Cancer 2013; 80:270-7. [PMID: 23498137 DOI: 10.1016/j.lungcan.2013.02.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 02/18/2013] [Indexed: 12/20/2022]
Abstract
IGFBP-3 is a tumor suppressor whose expression is frequently suppressed in lung cancer. NNK, the most potent tobacco carcinogen, enhanced cell proliferation of BEAS-2B normal lung epithelial cells and concomitantly suppressed IGFBP-3 expression through DNA methylation. Decreased IGFBP-3 expression and elevated levels of phospho-Akt, phospho-p65-NF-κB, and cyclin D1 were detected in tobacco carcinogen-induced tumorigenic derivatives of BEAS-2B. Overexpression of IGFBP-3 in NNKA, one of the derivatives, suppressed NF-κB activity and induced apoptosis, which was hindered by knocking-down of endogenous IGFBP-3R, an IGFBP-3 specific receptor. These results suggest that NNK inhibits IGFBP-3 expression to abrogate anti-tumor actions of the IGFBP-3/IGFBP-3R system in smoking-induced lung cancer.
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Affiliation(s)
- Aki Harada
- Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
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Zhang Q, Steinle JJ. DNA-PK phosphorylation of IGFBP-3 is required to prevent apoptosis in retinal endothelial cells cultured in high glucose. Invest Ophthalmol Vis Sci 2013; 54:3052-7. [PMID: 23557743 DOI: 10.1167/iovs.12-11533] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
PURPOSE The goal of this study was to determine whether Compound 49b stimulates insulin-like growth factor binding protein-3 (IGFBP-3) activation in retinal endothelial cells (REC) through DNA-dependent protein kinase (DNA-PK). METHODS REC were grown in a normal glucose (5 mM) or high glucose medium (25 mM). Some cells were transfected with protein kinase A (PKA) siRNA, following treatment with 50 nM Compound 49b, a novel β-adrenergic receptor agonist. Cell proteins were extracted and analyzed for DNA-PK expression by Western blotting. Additional cells were treated with or without NU7441 (a specific DNA-PK inhibitor) prior to Compound 49b treatment. Cell lysates were processed for IGFBP-3 ELISA analyses and Western blotting to measure casein kinase 2 (CK2). Immunoprecipitation for total and phospho-IGFBP-3, cell proliferation and cell death measurements were done after transfection with the S(156)A IGFBP-3 mutation (key phosphorylation site involved in DNA-PK) plasmid DNA. RESULTS Compound 49b required DNA-PK to activate IGFBP-3 in REC. IGFBP-3 activation was significantly reduced following treatment with either the DNA-PK inhibitor or following transfection with the IGFBP-3 S(156)A mutant plasmid (P < 0.05). Significant increases in cell death and decreases in cell proliferation were also observed in cells transfected with the IGFBP-3 S(156)A mutant plasmid (P < 0.05). Casein kinase levels were not altered after treatment with NU7741 or Compound 49b. CONCLUSIONS Our findings suggest Compound 49b induces DNA-PK levels through PKA activity. DNA-PK is required for Compound 49b-induced IGFBP-3 expression, leading to inhibition of REC cell death.
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Affiliation(s)
- Qiuhua Zhang
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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Liu YX, Zhang SF, Ji YH, Guo SJ, Wang GF, Zhang GW. Whole-exome sequencing identifies mutated PCK2 and HUWE1 associated with carcinoma cell proliferation in a hepatocellular carcinoma patient. Oncol Lett 2012. [PMID: 23205112 DOI: 10.3892/ol.2012.825] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is diagnosed in more than half a million individuals worldwide every year. It is often invasive and metastatic, resulting in a poor prognosis. Our knowledge of the genomic alterations implicated in HCC initiation and progression is fragmentary, and few molecular alterations unique to HCC are known. We performed whole-exome sequencing for a pleomorphic cell-type HCC tissue and matched normal tissue, and uncovered seven non-synonymous somatic variants in SPATA21, PPCS, CDH12, OR1L3, PCK2, HUWE1 and PHF16. These variants were validated by PCR and sequencing, with the exception of that in PPCS. We further performed a bioinformatics analysis of the six validated variants. The results suggested that the function of the proteins of the three mutated genes, PCK2, HUWE1 and PHF16, may be changed significantly. Among these genes, PCK2, within the insulin signaling pathway, and HUWE1, within the ubiquitin-mediated proteolysis pathway, may be essential for cell proliferation. These pathways are known to be important for hepatocarcinogenesis. Hence, we suggest that PCK2 and HUWE1 are associated with carcinoma cell proliferation in HCC.
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Affiliation(s)
- Yan-Xuan Liu
- Department of Genetic Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100
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Grise F, Sena S, Bidaud-Meynard A, Baud J, Hiriart JB, Makki K, Dugot-Senant N, Staedel C, Bioulac-Sage P, Zucman-Rossi J, Rosenbaum J, Moreau V. Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion. Hepatology 2012; 55:1766-75. [PMID: 22234932 DOI: 10.1002/hep.25568] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
UNLABELLED We performed a review of public microarray data that revealed a significant down-regulation of Rnd3 expression in hepatocellular carcinoma (HCC), as compared to nontumor liver. Rnd3/RhoE is an atypical RhoGTPase family member because it is always under its active GTP-bound conformation and not sensitive to classical regulators. Rnd3 down-regulation was validated by quantitative real-time polymerase chain reaction in 120 independent tumors. Moreover, Rnd3 down-expression was confirmed using immunohistochemistry on tumor sections and western blotting on human tumor and cell-line extracts. Rnd3 expression was significantly lower in invasive tumors with satellite nodules. Overexpression and silencing of Rnd3 in Hep3B cells led to decreased and increased three-dimensional cell motility, respectively. The short interfering RNA-mediated down-regulation of Rnd3 expression induced a loss of E-cadherin at cell-cell junctions that was linked to epithelial-mesenchymal transition through the up-regulation of the zinc finger E-box binding homeobox protein, ZEB2, and the down-regulation of miR-200b and miR-200c. Rnd3 knockdown mediated tumor hepatocyte invasion in a matrix-metalloproteinase-independent, and Rac1-dependent manner. CONCLUSION Rnd3 down-regulation provides an invasive advantage to tumor hepatocytes, suggesting that RND3 might represent a metastasis suppressor gene in HCC.
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Affiliation(s)
- Florence Grise
- INSERM, Physiopathologie du Cancer du Foie, U1053, Bordeaux, France
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Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. Adenoviral gene therapy in hepatocellular carcinoma: a review. Hepatol Int 2012. [DOI: 10.1007/s12072-012-9367-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Regel I, Eichenmüller M, Joppien S, Liebl J, Häberle B, Müller-Höcker J, Vollmar A, von Schweinitz D, Kappler R. IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors. Mol Cancer 2012; 11:9. [PMID: 22401581 PMCID: PMC3349592 DOI: 10.1186/1476-4598-11-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 03/08/2012] [Indexed: 12/16/2022] Open
Abstract
Background Hepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. We and others have previously shown that the overexpression of insulin-like growth factor 2 (IGF2), loss of imprinting at the IGF2/H19 locus, and amplification of pleomorphic adenoma gene 1 (PLAG1) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis. In this study, we investigated the role of the insulin-like growth factor binding protein 3 (IGFBP3), a known competitor of the IGF axis, in pediatric liver cancers. Results The IGFBP3 gene was highly expressed in normal pediatric livers but was heavily downregulated in four HB cell lines and the majority of HB primary tumors (26/36). Detailed methylation analysis of CpG sites in the IGFBP3 promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of IGFBP3 in HB cell lines. Consequently, the treatment of HB cell lines with 5-aza-2'-deoxycytidine resulted in DNA demethylation and reactivation of the epigenetically silenced IGFBP3 expression. Interestingly, IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring IGFBP3 expression in HB cells resulted in reduced colony formation, migration, and invasion. Conclusion This study provides the first direct evidence that the reactivation of IGFBP3 decreases aggressive properties of pediatric liver cancer cells and that IGFBP3 promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.
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Affiliation(s)
- Ivonne Regel
- Department of Pediatric Surgery, Dr, von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, 80337 Munich, Federal Republic of Germany
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Ohashi H, Adachi Y, Yamamoto H, Taniguchi H, Nosho K, Suzuki H, Arimura Y, Imai K, Carbone DP, Shinomura Y. Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers. Cancer Sci 2012; 103:252-261. [PMID: 22044563 DOI: 10.1111/j.1349-7006.2011.02138.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility.
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Affiliation(s)
- Hirokazu Ohashi
- First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
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Aleem E, Elshayeb A, Elhabachi N, Mansour AR, Gowily A, Hela A. Serum IGFBP-3 is a more effective predictor than IGF-1 and IGF-2 for the development of hepatocellular carcinoma in patients with chronic HCV infection. Oncol Lett 2011; 3:704-712. [PMID: 22740980 DOI: 10.3892/ol.2011.546] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 12/19/2011] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) contributes to 14.8% of all cancer mortality in Egypt, which has a high prevalence of hepatitis C virus (HCV). We have previously shown alterations in the insulin-like growth factor-1 (IGF-1) receptor signalling pathway during experimental hepatocarcinogenesis. The aim of this study was to determine whether serum levels of IGF-1, IGF-2 and IGFBP-3 can be used to discriminate between HCC and the stages of hepatic dysfunction in patients with liver cirrhosis assessed by the Child-Pugh (CP) score, and to correlate these levels with HCC stages. We recruited 241 subjects to the present study; 79 with liver cirrhosis, 62 with HCV-induced HCC and 100 age-matched controls. Results showed that serum levels of IGF-1, IGF-2 and IGFBP-3 were reduced significantly in cirrhosis and HCC patients in comparison to the controls, and that this reduction negatively correlated with the CP scores. However, only IGFBP-3 levels showed significant negative correlation with α-fetoprotein levels. The reduction in IGF-1 and IGFBP-3 but not IGF-2 levels was significant in HCC in comparison to patients with cirrhosis. None of the parameters significantly correlated with the HCC stage. IGFBP-3 levels discriminated between cirrhosis and HCC at a sensitivity of 87%, a specificity of 80% and a cut-off value of <682.6 ng/ml. In conclusion, although our results showed that serum IGF-1, IGF-2 and IGFBP-3 are reduced with the progression of hepatic dysfunction, only IGFBP-3 may be considered as the most promising serological marker for the prediction of the development of HCC in the chronic HCV patients with liver cirrhosis.
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Affiliation(s)
- Eiman Aleem
- Molecular Biology Division, Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt
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Zhao L, He LR, Zhang R, Cai MY, Liao YJ, Qian D, Xi M, Zeng YX, Xie D, Liu MZ. Low expression of IGFBP-3 predicts poor prognosis in patients with esophageal squamous cell carcinoma. Med Oncol 2011; 29:2669-76. [PMID: 22167391 DOI: 10.1007/s12032-011-0133-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2011] [Accepted: 12/02/2011] [Indexed: 10/14/2022]
Abstract
Previous studies have suggested that insulin-like growth factor binding protein-3 (IGFBP-3) acts as a tumor suppressor in human esophageal squamous cell carcinoma (ESCC). The present study was designed to investigate the clinical and prognostic significance of IGFBP-3 in ESCC patients. In this study, IGFBP-3 was detected by immunohistochemistry (IHC) in paraffin-embedded tissues from 110 ESCC patients, of which 110 were from primary cancer sites and 56 from matched adjacent non-malignant sites. Differences in IGFBP-3 expression and clinical characteristics were compared by χ2 test. Correlations between prognostic outcomes and with IGFBP-3 expression were investigated using Kaplan-Meier analysis and the Cox proportional hazards model. Among adjacent non-malignant tissues, 83.9% of individual tissue staining was scored as either high for IGFBP-3. However, among ESCC cases, only 51.8% of the cancer tissues were scored as high IGFBP-3 expression. In addition, IGFBP-3 expression inversely correlated with pathological classification (P<0.05 for T, N, and M classifications) and clinical staging (P=0.006). Furthermore, patients with higher levels of IGFBP-3 had prolonged overall survival (P<0.001). In conclusion, reduced IGFBP-3 expression may be a risk factor for advanced clinicopathological classification and poor patient survival. These findings suggest that IGFBP-3 may serve as a useful marker for the prognostic evaluation of ESCC patients.
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Affiliation(s)
- Lei Zhao
- Department of Radiotherapy, Cancer Center, Sun Yat-Sen University, Guangzhou, No 651, Dongfeng road east, Guangzhou, 510060, China
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Lin WH, Martin JL, Marsh DJ, Jack MM, Baxter RC. Involvement of insulin-like growth factor-binding protein-3 in the effects of histone deacetylase inhibitor MS-275 in hepatoma cells. J Biol Chem 2011; 286:29540-7. [PMID: 21737444 DOI: 10.1074/jbc.m111.263111] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Insulin-like growth factor-binding protein-3 (IGFBP-3) expression is frequently suppressed in liver cancers and can be reactivated by histone deacetylase (HDAC) inhibition. This study examined the role of IGFBP-3 in mediating the effects of the HDAC inhibitor MS-275 in liver cancer cells and identified IGFBP-3-dependent proteins that regulate proliferation and migration. In HepG2 cells, MS-275 inhibited DNA synthesis, cell cycle activity, and cell viability concomitantly with increased binding of acetylated histone H3 to IGFBP-3 promoter sequences and induction of IGFBP-3 expression. IGFBP-3 down-regulation by siRNA significantly reversed the inhibition of cell viability and DNA synthesis by MS-275, indicating an intermediary role for IGFBP-3. Induction of the cyclin-dependent kinase inhibitor p21 by MS-275 was attenuated by IGFBP-3 down-regulation, providing an explanation for IGFBP-3-dependent effects of MS-275 on cell cycle activity. In contrast, MS-275 stimulated HepG2 cell migration, an effect also inhibited by IGFBP-3 down-regulation. Among genes whose induction by MS-275 was attenuated by IGFBP-3 down-regulation, LYVE1 and THBS2 (thrombospondin-2) were identified as mediators of IGFBP-3-dependent effects of MS-275. Silencing of either protein had no effect on the inhibition of HepG2 viability by MS-275 but reversed its stimulatory effect on cell migration. We conclude that among genes up-regulated by MS-275, IGFBP-3 is a key mediator of effects on hepatoma cell growth and migration, involving IGFBP-3-dependent proteins p21 (proliferation) and LYVE1 and THBS2 (migration). The enhanced cell motility that accompanies reactivation of IGFBP-3 expression in liver cancer by HDAC inhibition suggests the possibility of increased metastatic spread despite inhibited cell proliferation.
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Affiliation(s)
- Wen Hui Lin
- Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales 2065, Australia
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Safarinejad MR, Shafiei N, Safarinejad S. Relationship of insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) gene polymorphism with the susceptibility to development of prostate cancer and influence on serum levels of IGF-I, and IGFBP-3. Growth Horm IGF Res 2011; 21:146-154. [PMID: 21536469 DOI: 10.1016/j.ghir.2011.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2010] [Revised: 12/23/2010] [Accepted: 03/30/2011] [Indexed: 11/19/2022]
Abstract
The bioavailability of IGF-I is controlled by the binding protein, IGF binding protein-3 (IGFBP-3). In addition, IGFBP-3 is a strong anti-proliferative protein that provokes apoptosis and inhibits cell proliferation in prostate cancer. We conducted this study to investigate the association between IGFBP-3 gene polymorphism and serum levels of IGF-I and IGFBP-3 and the incidence of prostate cancer (PCa) and benign prostatic hyperplasia (BPH). DNA isolation was performed in peripheral blood samples obtained from all participants. Required areas were amplified with polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique by using proper primers belonging to this gene area. We also measured serum IGF-I and IGFBP-3 levels. The IGFBP-3 -202 A/C polymorphism genotype frequencies showed a significant difference between PCa patients and controls (χ(2)=6.27, df=2.0, P=0.026), as well as between BPH patients and controls (χ(2)=11.57, df=4.0, P=0.014). The AA genotype frequency was significantly decreased in PCa and BPH patients compared to control group and the risk of PCa and BPH occurrence of this genotype was decreased accordingly (PCa; OR=0.28, 95% CI=0.17-0.44, P=0.0001; BPH: OR=0.48, 95% CI=0.29-0.77, P=0.001). Age-adjusted mean serum IGFBP-3 concentrations were highest in the individuals with the AA genotype and diminished significantly in a stepwise manner in the presence of 1 or 2 copies of the C allele (4577 ng/ml, 3929 ng/ml and 3349 ng/ml, respectively). Patients with PCa and BPH had lower serum IGF-1 (P=0.001, and P=0.01, respectively) and IGFBP-3 levels (P=0.001, and P=0.01, respectively) compared with controls. The AA genotype at IGFBP-3 gene polymorphism is associated with reduced risks of PCa and BPH. Both IGF-I and IGFBP-3 concentrations, are associated with modified risks of PCa and BPH.
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Chen R, Tan Y, Wang M, Wang F, Yao Z, Dong L, Ye M, Wang H, Zou H. Development of glycoprotein capture-based label-free method for the high-throughput screening of differential glycoproteins in hepatocellular carcinoma. Mol Cell Proteomics 2011; 10:M110.006445. [PMID: 21474793 DOI: 10.1074/mcp.m110.006445] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A robust, reproducible, and high throughput method was developed for the relative quantitative analysis of glycoprotein abundances in human serum. Instead of quantifying glycoproteins by glycopeptides in conventional quantitative glycoproteomics, glycoproteins were quantified by nonglycosylated peptides derived from the glycoprotein digest, which consists of the capture of glycoproteins in serum samples and the release of nonglycopeptides by trypsin digestion of captured glycoproteins followed by two-dimensional liquid chromatography-tandem MS analysis of released peptides. Protein quantification was achieved by comparing the spectrum counts of identified nonglycosylated peptides of glycoproteins between different samples. This method was demonstrated to have almost the same specificity and sensitivity in glycoproteins quantification as capture at glycopeptides level. The differential abundance of proteins present at as low as nanogram per milliliter levels was quantified with high confidence. The established method was applied to the analysis of human serum samples from healthy people and patients with hepatocellular carcinoma (HCC) to screen differential glycoproteins in HCC. Thirty eight glycoproteins were found with substantial concentration changes between normal and HCC serum samples, including α-fetoprotein, the only clinically used marker for HCC diagnosis. The abundance changes of three glycoproteins, i.e. galectin-3 binding protein, insulin-like growth factor binding protein 3, and thrombospondin 1, which were associated with the development of HCC, were further confirmed by enzyme-linked immunosorbent assay. In conclusion, the developed method was an effective approach to quantitatively analyze glycoproteins in human serum and could be further applied in the biomarker discovery for HCC and other cancers.
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Affiliation(s)
- Rui Chen
- Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian 116023, China
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Safarinejad MR, Shafiei N, Safarinejad SH. The association between bladder cancer and a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) gene. Arch Toxicol 2011; 85:1209-18. [DOI: 10.1007/s00204-011-0671-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 02/08/2011] [Indexed: 10/18/2022]
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Safarinejad MR. Insulin-like growth factor binding protein-3 (IGFBP-3) gene variants are associated with renal cell carcinoma. BJU Int 2011; 108:762-70. [PMID: 21314884 DOI: 10.1111/j.1464-410x.2010.10017.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE • To evaluate the A to C nucleotide change located 202 bp upstream to the transcription start site, (-202 A/C polymorphism), in the insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) gene, and its association with renal carinogenesis and with clinicopathological characteristics. PATIENTS AND METHODS • We matched 158 male patients with clear-cell renal cell carcinoma (CCRCC) to 316 healthy controls, and genotyped one single nucleotide polymorphism (rs2854744) using the polymerase chain reaction restriction fragment length polymorphism technique. RESULTS • The alleles and genotypes differed significantly between patients with CCRCC and controls (patients with CCRCC, P= 0.82; controls, P= 0.88). • We found that the frequency of the AA genotype was significantly higher in patients with CCRCC than in controls (odds ratio [OR]= 4.62, 95% confidence interval [CI]= 3.41-7.42, P= 0.001). • The A allele had a gene dose effect in increasing the risk of CCRCC (OR = 4.75, 95% CI = 3.64-7.64, P= 0.001). • The distribution of IGFBP-3 genotypes was also significantly associated with the histological grade (P= 0.001) and clinical stage (P= 0.001). CONCLUSION • In the Iranian population, the polymorphism of the IGFBP-3 gene plays a pivotal role in the development of CCRCC.
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