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Chia L, Wang B, Kim JH, Luo LZ, Shuai S, Herrera I, Chen SY, Li L, Xian L, Huso T, Heydarian M, Reddy K, Sung WJ, Ishiyama S, Guo G, Jaffee E, Zheng L, Cope LM, Gabrielson K, Wood L, Resar L. HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation. J Clin Invest 2023; 133:151601. [PMID: 36919699 PMCID: PMC10014113 DOI: 10.1172/jci151601] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 01/25/2023] [Indexed: 03/15/2023] Open
Abstract
High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.
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Affiliation(s)
- Lionel Chia
- Pathobiology Graduate Program, Department of Pathology and.,Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Bowen Wang
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jung-Hyun Kim
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Li Z Luo
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shuai Shuai
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Iliana Herrera
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Liping Li
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lingling Xian
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tait Huso
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | | | - Woo Jung Sung
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shun Ishiyama
- Department of Pathology.,Department of Molecular and Comparative Pathobiology
| | - Gongbo Guo
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | | | - Leslie M Cope
- Department of Oncology, and.,Division of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Laura Wood
- Pathobiology Graduate Program, Department of Pathology and.,Department of Pathology.,Department of Oncology, and
| | - Linda Resar
- Pathobiology Graduate Program, Department of Pathology and.,Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Biochemistry and Molecular Biology Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.,Department of Pathology.,Department of Oncology, and
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2
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Wei YG, Yang CK, Wei ZL, Liao XW, He YF, Zhou X, Huang HS, Lan CL, Han CY, Peng T. High-Mobility Group AT-Hook 1 Served as a Prognosis Biomarker and Associated with Immune Infiltrate in Hepatocellular Carcinoma. Int J Gen Med 2022; 15:609-621. [PMID: 35058711 PMCID: PMC8765458 DOI: 10.2147/ijgm.s344858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/23/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The protein high-mobility group AT-hook 1 (HMGA1) has been demonstrated that modulated cellular proliferation, invasion, and apoptosis with a poor prognosis in miscellaneous carcinomas. However, the mechanism of circumstantial carcinogenesis and association with the immune microenvironment of HMGA1 in hepatocellular carcinoma (HCC) had not been extensively explored. METHODS The gene expression, clinicopathological correlation, and prognosis analysis were performed in the data obtained from TCGA. The results were further validated by ICGC and GEO database and external validation cohort from Guangxi. The HMGA1 protein expression was further examined in the HPA database. Biological function analyses were conducted by GSEA, STRING database, and Coexpedia online tool. Using TIMER and CIBERSORT method, the relationship between immune infiltrate and HMGA1 was investigated. RESULTS In HCC, HMGA1 had much higher transcriptional and proteomic expression than in corresponding paraneoplastic tissue. Patients with high HMGA1 expression had a poor prognosis and unpromising clinicopathological features. High HMGA1 expression was closely related to the cell cycle, tumorigenesis, substance metabolism, and immune processes by regulating complex signaling pathways. Notably, HMGA1 may be associated with TP53 mutational carcinogenesis. Moreover, increased HMGA1 expression may lead to an increase in immune infiltration and a decrease in tumor purity in HCC. CIBERSORT analysis elucidated that the amount of B cell naive, B cell memory, T cells gamma delta, macrophages M2, and mast cell resting decreased when HMGA1 expression was high, whereas T cells follicular helper, macrophages M0, and Dendritic cells resting increased. CONCLUSION In conclusions, HMGA1 is a potent prognostic biomarker and a sign of immune infiltration in HCC, which may be a potential immunotherapy target for HCC.
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Affiliation(s)
- Yong-Guang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Zhong-Liu Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Yong-Fei He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chen-Lu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
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Tian Z, Liu Z, Fang X, Cao K, Zhang B, Wu R, Wen X, Wen Q, Shi H, Wang R. ANP32A promotes the proliferation, migration and invasion of hepatocellular carcinoma by modulating the HMGA1/STAT3 pathway. Carcinogenesis 2021; 42:493-506. [PMID: 33332531 DOI: 10.1093/carcin/bgaa138] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022] Open
Abstract
Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) has been reported to play an essential role in the development and progression of various human cancers. However, its expression pattern and possible mechanism in human hepatocellular carcinoma (HCC) remain to be elucidated. In this study, we used western blot and immunohistochemical staining to detect protein expression. The effects of ANP32A on the proliferation, migration and invasion of HCC cells were examined using 5-ethynyl-20-deoxyuridine (EdU), colony formation, CCK-8, and transwell assays. RT-qPCR was performed to detect mRNA expression. The interaction between ANP32A and the high mobility group A1 (HMGA1) mRNA was assessed using RNA immunoprecipitation (RIP). The tumorigenicity of ANP32A was assessed by establishing a xenograft tumor model in Balb/c nude mice. We found that the ANP32A protein was expressed at high levels in patients with HCC, which was associated with a poor prognosis. Functional experiments revealed that the silencing of ANP32A inhibited the proliferation, migration, and invasion of HCC cells, whereas overexpression of ANP32A promoted these processes. Further investigations indicated that ANP32A bound the HMGA1 mRNA and maintained its stability to promote the expression of HMGA1, thereby increasing the expression and activation of STAT3. Finally, a xenograft tumor model of Balb/c nude mice confirmed the tumorigenicity of ANP32A. This study found that ANP32A is up-regulated in patients with HCC and may accelerate the proliferation, migration and invasion of HCC cells by modulating the HMGA1/STAT3 pathway.
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Affiliation(s)
- Zilu Tian
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhiyi Liu
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaokang Fang
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kuan Cao
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bin Zhang
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Rui Wu
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xin Wen
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Quan Wen
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hengliang Shi
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Central Laboratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renhao Wang
- Institute of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
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4
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De Martino M, Fusco A, Esposito F. HMGA and Cancer: A Review on Patent Literatures. Recent Pat Anticancer Drug Discov 2020; 14:258-267. [PMID: 31538905 DOI: 10.2174/1574892814666190919152001] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/04/2019] [Accepted: 09/11/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins. OBJECTIVE Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment. METHODS We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. RESULTS HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions. CONCLUSION Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.
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Affiliation(s)
- Marco De Martino
- Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy.,Department of Psychology, University of Campania, Caserta 81100, Italy
| | - Alfredo Fusco
- Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy
| | - Francesco Esposito
- Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy
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5
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Elmallah MIY, Cordonnier M, Vautrot V, Chanteloup G, Garrido C, Gobbo J. Membrane-anchored heat-shock protein 70 (Hsp70) in cancer. Cancer Lett 2019; 469:134-141. [PMID: 31669516 DOI: 10.1016/j.canlet.2019.10.037] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/18/2019] [Accepted: 10/22/2019] [Indexed: 12/19/2022]
Abstract
Hsp70 is a highly conserved and inducible heat shock protein that belongs to the HSP70 family of molecular chaperones and plays a central role in protein homeostasis. The main function of Hsp70 is to protect cells from physiological, pathological and environmental insults, as it assists an ATP-dependent manner the process of protein folding. Since Hsp70 provides critical cell survival functions, cancer cells are assumed to rely on this chaperone. Strong evidence suggests that Hsp70 is upregulated in different type of cancers and is involved in tumor growth, invasion, migration and resistance to anti-cancer therapy. Interestingly, this Hsp70 upregulation induces Hsp70 re-location into plasma membrane. In this review, the role of Hsp70 in cancer will be discussed focusing particularly on the extracellular membrane-bound Hsp70. The mechanism by which Hsp70 is translocated to plasma membrane of tumor cells and the recent discoveries of drugs targeting this Hsp70 in cancer therapy will be also highlighted.
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Affiliation(s)
- Mohammed I Y Elmallah
- INSERM 1231, Label Ligue National contre le Cancer and Label d'excellence LipSTIC, 7 Bd Jeanne d'Arc, 21000, Dijon, France; Anti-cancer Center Georges-François Leclerc, Dijon, France; Chemistry Department, Faculty of Science, Helwan University, 11795, Ain Helwan, Cairo, Egypt.
| | - Marine Cordonnier
- INSERM 1231, Label Ligue National contre le Cancer and Label d'excellence LipSTIC, 7 Bd Jeanne d'Arc, 21000, Dijon, France; Faculty of Medicine. University of Burgundy-Franche-Comté, France
| | - Valentin Vautrot
- INSERM 1231, Label Ligue National contre le Cancer and Label d'excellence LipSTIC, 7 Bd Jeanne d'Arc, 21000, Dijon, France; Anti-cancer Center Georges-François Leclerc, Dijon, France; University of Bourgogne Franche-Comté, EA 3181, France
| | - Gaëtan Chanteloup
- INSERM 1231, Label Ligue National contre le Cancer and Label d'excellence LipSTIC, 7 Bd Jeanne d'Arc, 21000, Dijon, France; Faculty of Medicine. University of Burgundy-Franche-Comté, France
| | - Carmen Garrido
- INSERM 1231, Label Ligue National contre le Cancer and Label d'excellence LipSTIC, 7 Bd Jeanne d'Arc, 21000, Dijon, France; Anti-cancer Center Georges-François Leclerc, Dijon, France; Faculty of Medicine. University of Burgundy-Franche-Comté, France.
| | - Jessica Gobbo
- INSERM 1231, Label Ligue National contre le Cancer and Label d'excellence LipSTIC, 7 Bd Jeanne d'Arc, 21000, Dijon, France; Anti-cancer Center Georges-François Leclerc, Dijon, France
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6
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Wang Y, Hu L, Zheng Y, Guo L. HMGA1 in cancer: Cancer classification by location. J Cell Mol Med 2019; 23:2293-2302. [PMID: 30614613 PMCID: PMC6433663 DOI: 10.1111/jcmm.14082] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 07/19/2018] [Accepted: 11/16/2018] [Indexed: 12/23/2022] Open
Abstract
The high mobility group A1 (HMGA1) gene plays an important role in numerous malignant cancers. HMGA1 is an oncofoetal gene, and we have a certain understanding of the biological function of HMGA1 based on its activities in various neoplasms. As an architectural transcription factor, HMGA1 remodels the chromatin structure and promotes the interaction between transcriptional regulatory proteins and DNA in different cancers. Through analysis of the molecular mechanism of HMGA1 and clinical studies, emerging evidence indicates that HMGA1 promotes the occurrence and metastasis of cancer. Within a similar location or the same genetic background, the function and role of HMGA1 may have certain similarities. In this paper, to characterize HMGA1 comprehensively, research on various types of tumours is discussed to further understanding of the function and mechanism of HMGA1. The findings provide a more reliable basis for classifying HMGA1 function according to the tumour location. In this review, we summarize recent studies related to HMGA1, including its structure and oncogenic properties, its major functions in each cancer, its upstream and downstream regulation associated with the tumourigenesis and metastasis of cancer, and its potential as a biomarker for clinical diagnosis of cancer.
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Affiliation(s)
- Yuhong Wang
- The First Affiliated Hospital of Soochow University Department of Pathology, Suzhou, Jiangsu, China
| | - Lin Hu
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yushuang Zheng
- The First Affiliated Hospital of Soochow University Department of Pathology, Suzhou, Jiangsu, China
| | - Lingchuan Guo
- The First Affiliated Hospital of Soochow University Department of Pathology, Suzhou, Jiangsu, China
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7
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Sumter TF, Xian L, Huso T, Koo M, Chang YT, Almasri TN, Chia L, Inglis C, Reid D, Resar LMS. The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development. Curr Mol Med 2016; 16:353-93. [PMID: 26980699 DOI: 10.2174/1566524016666160316152147] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 02/15/2016] [Accepted: 03/10/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND & OBJECTIVES Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 "transcriptome" is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer's disease and type-2 diabetes. CONCLUSION Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - L M S Resar
- Department of Medicine, Faculty of the Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 1025, Baltimore, MD 21205-2109, USA.
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8
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Abstract
The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases.
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9
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Akhter MZ, Luthra K, Rajeswari MR. Molecular aspects on adriamycin interaction with hmga1 regulatory region and its inhibitory effect on HMGA1 expression in human cervical cancer. J Biomol Struct Dyn 2015; 34:877-91. [PMID: 26084422 DOI: 10.1080/07391102.2015.1057617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
High mobility group A1 (HMGA1), a non-histone chromosomal protein, is highly expressed in a wide range of human cancers including cervical, breast, and prostate cancers. Therefore, hmga1 gene is considered as an attractive potential target for anticancer drugs. We have chosen 27 bp DNA sequence from a regulatory region of hmga1 promoter and studied its interaction with adriamycin (ADM) and in vitro expression of HMGA1 in the presence of ADM in HeLa cell line. A variety of biophysical techniques were employed to understand the characteristics of [DNA-ADM] complex. Spectrophotometric titration data, DNA denaturation profiles, and quenching of fluorescence of ADM in the presence of DNA demonstrated a strong complexation between DNA and ADM with a high binding affinity (Ka) of 1.3 × 10(6) M(-1) and a stoichiometry of 1:3 (drug:nucleotide). The energetics of binding obtained from isothermal titration calorimetry and differential scanning calorimetry suggest the binding to be exothermic and enthalpy (∆H, -6.7 ± 2.4 kcal M(-1)) and entropy (TΔS, 18.5 ± 6.4 kcal M(-1)) driven (20°C), which is typical of intercalative mode of binding. Further, results on decreased expression (by ~70%) of HMGA1 both at mRNA and protein levels in association with the observed cell death (by ~75%) in HeLa cell line, clearly confirm that ADM does target hmga1; however, the effect of ADM on genes other than hmga1 either directly or via hmga1-mediated pathways cannot be ruled out in the observed cytotoxicity. Therefore, hmga1 in general and particularly the regulatory region is a promising target for therapeutic strategy in combating cancer.
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Affiliation(s)
- Md Zahid Akhter
- a Department of Biochemistry , All India Institute of Medical Sciences , New Delhi 110029 , India
| | - Kalpana Luthra
- a Department of Biochemistry , All India Institute of Medical Sciences , New Delhi 110029 , India
| | - Moganty R Rajeswari
- a Department of Biochemistry , All India Institute of Medical Sciences , New Delhi 110029 , India
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10
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Akhter MZ, Rajeswari MR. Interaction of doxorubicin with a regulatory element of hmga1 and its in vitro anti-cancer activity associated with decreased HMGA1 expression. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2014; 141:36-46. [DOI: 10.1016/j.jphotobiol.2014.08.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 08/20/2014] [Accepted: 08/23/2014] [Indexed: 11/26/2022]
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11
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Ito R, Ishii Y, Wakiyama S, Shiba H, Fujioka S, Misawa T, Ishida Y, Hano H, Yanaga K. Prognostic significance of receptor for advanced glycation end products expression in hepatocellular carcinoma after hepatectomy. J Surg Res 2014; 192:503-8. [PMID: 25043528 DOI: 10.1016/j.jss.2014.06.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 06/01/2014] [Accepted: 06/17/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The receptor for advanced glycation end products (RAGE) is recognized to be responsible for cancer progression in several human cancers. In this study, we investigated the clinical impact of RAGE expression in patients with hepatocellular carcinoma (HCC) after hepatectomy. MATERIALS AND METHODS Sixty-five consecutive patients who underwent initial hepatectomy for HCC were investigated. The relationships between immunohistochemical expression of RAGE and clinicopathologic features, clinical outcome (overall survival [OS], and disease-free survival [DFS]) were evaluated. RESULTS The cytoplasmic expression of RAGE in HCC cells was observed in 46 patients (70.8%) and correlated with histologic grade (poorly differentiated versus moderately differentiated HCC, P = 0.021). Five-year OS in RAGE-positive and RAGE-negative groups were 72% and 94%, respectively, whereas 5-y DFS were 29% and 55%, respectively. There were significant differences between OS and DFS (P = 0.018 and 0.031, respectively). Multivariate analysis indicated that RAGE was an independent predictor for both OS and DFS (P = 0.048 and 0.032, respectively). CONCLUSIONS Our data suggest for the first time a positive correlation between RAGE expression and poor therapeutic outcome. Furthermore, RAGE downregulation may provide a novel therapeutic target for HCC.
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Affiliation(s)
- Ryusuke Ito
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
| | - Yuji Ishii
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Shigeki Wakiyama
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroaki Shiba
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Shuichi Fujioka
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Takeyuki Misawa
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuichi Ishida
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Hano
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Katsuhiko Yanaga
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
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Huso TH, Resar LMS. The high mobility group A1 molecular switch: turning on cancer - can we turn it off? Expert Opin Ther Targets 2014; 18:541-53. [PMID: 24684280 DOI: 10.1517/14728222.2014.900045] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Emerging evidence demonstrates that the high mobility group A1 (HMGA1) chromatin remodeling protein is a key molecular switch required by cancer cells for tumor progression and a poorly differentiated, stem-like state. Because the HMGA1 gene and proteins are expressed at high levels in all aggressive tumors studied to date, research is needed to determine how to 'turn off' this master regulatory switch in cancer. AREAS COVERED In this review, we describe prior studies that underscore the central role of HMGA1 in refractory cancers and we discuss approaches to target HMGA1 in cancer therapy. EXPERT OPINION Given the widespread overexpression of HMGA1 in diverse, aggressive tumors, further research to develop technology to target HMGA1 holds immense promise as potent anticancer therapy. Previous work in preclinical models indicates that delivery of short hairpin RNA or interfering RNA molecules to 'switch off' HMGA1 expression dramatically impairs cancer cell growth and tumor progression. The advent of nanoparticle technology to systemically deliver DNA or RNA molecules to tumors brings this approach even closer to clinical applications, although further efforts are needed to translate these advances into therapies for cancer patients.
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Affiliation(s)
- Tait H Huso
- The Johns Hopkins University School of Medicine, Hematology Division , Ross Research Building, Room 1015, 720 Rutland Avenue, Baltimore MD 21205 , USA
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13
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Overexpression of high mobility group A1 protein in human uveal melanomas: implication for prognosis. PLoS One 2013; 8:e68724. [PMID: 23935884 PMCID: PMC3720810 DOI: 10.1371/journal.pone.0068724] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 06/03/2013] [Indexed: 11/23/2022] Open
Abstract
There is increasing evidence that the high mobility group A1 (HMGA1) protein, which functions as a transcriptional master regulator, plays critical roles in tumor progression. We evaluated HMGA1 expression in 89 primary uveal melanomas (UM) by immunohistochemistry to determine the clinicopathological and prognostic value of HMGA1 in UM after adjusting for other prognostic variables. Nuclear expression of HMGA1 was detected in 44% UMs. High expression levels of HMGA1 were more frequent in UMs with high levels of epithelioid cell pattern, mitoses count, and Ki67 labeling index (P = 0.025, P<0.0001, P = 0.0018; respectively), and HMGA1 expression levels were directly correlated with Ki67 labeling indexes and mitoses counts (R = 0.31, P <0.0001; R = 0.27, P<0.0068; respectively). High expression of HMGA1 was also independently associated with an increased risk of distant metastases as determined using the Cox proportional hazards regression model (multivariate hazard ratio: 3.44; 95% confidence interval: 1.56–7.60; log rank P = 0.0022). Moreover, high HMGA1 expression was associated with shorter UM-specific survival (multivariate hazard ratio: 2.41; 95% confidence interval: 1.10–5.53; log rank P = 0.041). These findings suggest that high levels of HMGA1 are associated with adverse clinical outcomes in UM patients and that further evaluation of HMGA1 as a potential therapeutic target in UM is warranted.
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Cano LQ, Lavery DN, Bevan CL. Mini-review: Foldosome regulation of androgen receptor action in prostate cancer. Mol Cell Endocrinol 2013; 369:52-62. [PMID: 23395916 DOI: 10.1016/j.mce.2013.01.023] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 01/28/2013] [Accepted: 01/29/2013] [Indexed: 11/24/2022]
Abstract
Steroid hormone receptors play diverse roles in many aspects of human physiology including cell division, apoptosis and homeostasis, tissue differentiation, sexual development and response to stress. These ligand-activated transcription factors require the functional activity of numerous chaperone and chaperone-associated proteins, collectively termed the foldosome, at the crucial step of ligand recognition and binding. Since the initial isolation of foldosome components and pioneering research by Pratt, Toft and colleagues we understand much regarding cytosolic receptor function. The classical view, that the role of foldosome components is restricted to the cytosol, has been modified over recent years by research highlighting additional roles of chaperone proteins in nuclear translocation and target gene expression. Further, dysregulation of chaperone activity and expression has been implicated in various cancers, including breast and prostate cancer. Consequently, the foldosome provides an attractive therapeutic target in steroid hormone receptor-driven malignancies. This review summarises current knowledge of how the foldosome impacts upon androgen receptor signalling, which is the key therapeutic target on prostate cancer, and how foldosome components may be used as biomarkers or therapeutic targets in this disease.
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Affiliation(s)
- Laia Querol Cano
- Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom
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Kanamori H, Kawakami T, Effendi K, Yamazaki K, Mori T, Ebinuma H, Masugi Y, Du W, Nagasaka K, Ogiwara A, Kyono Y, Tanabe M, Saito H, Hibi T, Sakamoto M. Identification by differential tissue proteome analysis of talin-1 as a novel molecular marker of progression of hepatocellular carcinoma. Oncology 2011; 80:406-15. [PMID: 21846996 DOI: 10.1159/000330734] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 06/15/2011] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is characterized by a multistage process of tumor progression. This study addressed its molecular features to identify novel protein candidates involved in HCC progression. METHODS Using liquid chromatography-tandem mass spectrometry, proteomes of 4 early HCCs and 4 non-HCC tissues derived from 2 cases of liver transplant surgery were compared with respect to the separation profiles of their tryptic peptides. Immunohistochemistry was performed on 106 HCC nodules to confirm the results of the proteomic analysis. RESULTS Statistical analysis of the profiles selected the peptide peaks differentiating HCC from non-HCC. A database search of the tandem mass spectrometry data from those peptide peaks identified 61 proteins, including a cytoskeletal protein, talin-1, as upregulated in HCC. Talin-1 expression levels in HCC nodules were significantly associated with the dedifferentiation of HCC (p = 0.001). A follow-up survey of the examined clinical cases revealed a correlation between talin-1 upregulation and a shorter time to recurrence after resection (p = 0.039), which may be related to the higher rate of portal vein invasion in HCCs with talin-1 up-regulation (p = 0.029). CONCLUSIONS Proteomic analysis led to identification of talin-1 as a promising HCC marker. Talin-1 upregulation is associated with HCC progression and may serve as a prognostic marker.
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Affiliation(s)
- Hideaki Kanamori
- Department of Gastroenterology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Spain
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16
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So A, Hadaschik B, Sowery R, Gleave M. The role of stress proteins in prostate cancer. Curr Genomics 2011; 8:252-61. [PMID: 18645594 DOI: 10.2174/138920207781386951] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2007] [Revised: 04/25/2007] [Accepted: 05/04/2007] [Indexed: 01/22/2023] Open
Abstract
The development of therapeutic resistance, after hormone or chemotherapy for example, is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress related proteins, including small heat shock proteins (HSPs). HSPs interact with various client proteins to assist in their folding and enhance the cellular recovery from stress, thus restoring protein homeostasis and promoting cell survival. The vents of cell stress and cell death are linked, as the induction of molecular chaperones appears to function at key regulatory points in the control of apoptosis. On the basis of these observations and on the role of molecular chaperones in the regulation of steroid receptors, kinases, caspases, and other protein remodelling events involved in chromosome replication and changes in cell structure, it is not surprising that molecular chaperones have been implicated in the control of cell growth and in resistance to various anticancer treatments that induce apoptosis. Recently, several molecular chaperones such as Clusterin and HSP27 have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the molecular and cellular events initiated by treatment induced stress, and discuss the potential role of chaperone proteins as targets for prostate cancer treatment.
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Affiliation(s)
- Alan So
- The Prostate Centre at Vancouver General Hospital, Vancouver, BC, V6H3Z6, Canada
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17
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HMGA1 levels influence mitochondrial function and mitochondrial DNA repair efficiency. Mol Cell Biol 2009; 29:5426-40. [PMID: 19687300 DOI: 10.1128/mcb.00105-09] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
HMGA chromatin proteins, a family of gene regulatory factors found at only low concentrations in normal cells, are almost universally overexpressed in cancer cells. HMGA proteins are located in the nuclei of normal cells except during the late S/G(2) phases of the cell cycle, when HMGA1, one of the members of the family, reversibly migrates to the mitochondria, where it binds to mitochondrial DNA (mtDNA). In many cancer cells, this controlled shuttling is lost and HMGA1 is found in mitochondria throughout the cell cycle. To investigate the effects of HMGA1 on mitochondria, we employed a genetically engineered line of human MCF-7 cells in which the levels of transgenic HMGA1 protein could be reversibly controlled. "Turn-ON" and "turn-OFF" time course experiments were performed with these cells to either increase or decrease intracellular HMGA1 levels, and various mitochondrial changes were monitored. Results demonstrated that changes in both mtDNA levels and mitochondrial mass inversely paralleled changes in HMGA1 concentrations, strongly implicating HMGA1 in the regulation of these parameters. Additionally, the level of cellular reactive oxygen species (ROS) increased and the efficiency of repair of oxidatively damaged mtDNA decreased as consequences of elevated HMGA1 expression. Increased ROS levels and reduced repair efficiency in HMGA1-overexpressing cells likely contribute to the increased occurrence of mutations in mtDNA frequently observed in cancer cells.
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18
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Grise F, Bidaud A, Moreau V. Rho GTPases in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2009; 1795:137-51. [PMID: 19162129 DOI: 10.1016/j.bbcan.2008.12.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2008] [Revised: 12/21/2008] [Accepted: 12/24/2008] [Indexed: 01/05/2023]
Abstract
Rho GTPases are major regulators of signal transduction pathways and play key roles in processes including actin dynamics, cell cycle progression, cell survival and gene expression, whose deregulation may lead to tumorigenesis. A growing number of in vitro and in vivo studies using tumor-derived cell lines, primary tumors and animal cancer models strongly suggest that altered Rho GTPase signaling plays an important role in the initiation as well as in the progression of hepatocellular carcinoma (HCC), one of the deadliest human cancers in the world. These alterations can occur at the level of the GTPases themselves or of one of their regulators or effectors. The participation into the tumorigenic process can occur either through the over-expression of one of these components which presents an oncogenic activity as illustrated with RhoA and C or through the attenuation of the expression of a component presenting tumor suppressor activity as for Cdc42 or the RhoGAP, DLC-1. Consequently, these observations reflect the heterogeneity and the complexity of liver carcinogenesis. Recently, pharmacological approaches targeting Rho GTPase signaling have been used in HCC-derived models with relative success but remain to be validated in more physiologically relevant systems. Therefore, therapeutic approaches targeting Rho GTPase signaling may provide a novel alternative for anti-HCC therapy.
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Affiliation(s)
- Florence Grise
- INSERM, U889, Bordeaux, 33076 Bordeaux, France; Université Victor Segalen Bordeaux 2, Bordeaux, 33076 Bordeaux, France
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Abstract
The high mobility group A (HMGA) non-histone chromatin proteins alter chromatin structure and thereby regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumours. Conversely, unrearranged HMGA overexpression is a feature of malignant tumours and is also causally related to neoplastic cell transformation. Here, we focus on the role of the HMGA proteins in human neoplastic diseases, the mechanisms by which they contribute to carcinogenesis, and therapeutic strategies based on targeting HMGA proteins.
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Affiliation(s)
- Alfredo Fusco
- Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via Pansini, 5, 80131, Naples, Italy.
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Abstract
AIM: To study at transcriptional level the similarities and differences of the physiological and biochemical activities between liver tumor (LT) and regenerating liver cells.
METHODS: LT-associated genes and their expression changes in LT were obtained from databases and scientific articles, and their expression profiles in rat liver regeneration (LR) were detected using Rat Genome 230 2.0 array. Subsequently their expression changes in LT and LR were compared and analyzed.
RESULTS: One hundred and twenty one LT-associated genes were found to be LR-associated. Thirty four genes were up-regulated, and 14 genes were down-regulated in both LT and regenerating liver; 20 genes up-regulated in LT were down-regulated in regenerating liver; 21 up-regulated genes and 16 down-regulated genes in LT were up-regulated at some time points and down-regulated at others during LR.
CONCLUSION: Results suggested that apoptosis activity suppressed in LT was still active in regenerating liver, and there are lots of similarities and differences between the LT and regenerating liver at the aspects of cell growth, proliferation, differentiation, migration and angiogenesis.
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Affiliation(s)
- Cun-Shuan Xu
- College of Life Science, Henan Normal University, Xinxiang 453007, Henan Province, China.
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Liau SS, Jazag A, Ito K, Whang EE. Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells. Br J Cancer 2007; 96:993-1000. [PMID: 17342093 PMCID: PMC2360112 DOI: 10.1038/sj.bjc.6603654] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. Roles of HMGA1 in mediating the malignant phenotype of this cancer are poorly understood. We tested the hypothesis that overexpression of HMGA1 promotes resistance to anoikis (apoptosis induced by anchorage deprivation) in pancreatic cancer cells. HMGA1 cDNA was stably transfected into MiaPaCa2 human pancreatic adenocarcinoma cells (which have low baseline expression levels of HMGA1). Cells were grown in suspension on PolyHEMA-coated plates and their susceptibility to anoikis was assayed using flow cytometry. Overexpression of HMGA1 was associated with marked reductions in susceptibility to anoikis in concert with increases in Akt phosphorylation (Ser473) and in Akt kinase activity and with reductions in caspase 3 activation. Inhibition of phosphoinositidyl-3 (PI3-K)/Akt pathway with either the small molecule inhibitor LY294002 or dominant-negative Akt resulted in reversal of anoikis resistance induced by HMGA1 overexpression. Further, RNA interference-mediated HMGA1 silencing in MiaPaCa2 and BxPC3 (a human pancreatic adenocarcinoma cell line with high baseline levels of HMGA1 expression) cells resulted in significant increases in susceptibility to anoikis. Our findings suggest HMGA1 promotes anoikis resistance through a PI3-K/Akt-dependent mechanism. Given the putative associations between anoikis resistance and metastatic potential, HMGA1 represents a potential therapeutic target in pancreatic adenocarcinoma.
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Affiliation(s)
- S-S Liau
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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Xu J, Shen ZY, Chen XG, Zhang Q, Bian HJ, Zhu P, Xu HY, Song F, Yang XM, Mi L, Zhao QC, Tian R, Feng Q, Zhang SH, Li Y, Jiang JL, Li L, Yu XL, Zhang Z, Chen ZN. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology 2007; 45:269-76. [PMID: 17256759 DOI: 10.1002/hep.21465] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
UNLABELLED Orthotopic liver transplantation (OLT) is the only curative therapy of HCC with underlying cirrhosis, but due to HCC metastasis and recurrence, its benefit is limited to a small population who meet the strict selection criteria. We previously reported that Licartin ([131I] mAb HAb18G/CD147) was safe and effective in treating HCC patients, and its antigen, HAb18G/CD147, was closely related to HCC invasion and metastasis. Here, we reported a randomized controlled trial to assess the post-OLT antirecurrence efficacy of Licartin in advanced HCC patients. We randomized 60 post-OLT patients with HCC, who were at tumor stage 3/4 and outside the Milan criteria before OLT, into 2 groups. Three weeks after OLT, the treatment group received 15.4 MBq/kg of Licartin, while the control group received placebo intravenously for 3 times with an interval of 28 days. At 1-year follow-up, the recurrence rate significantly decreased by 30.4% (P = 0.0174) and the survival rate increased by 20.6% (P = 0.0289) in the treatment group, compared with those in the control group. For the control group versus the treatment group, the hazard ratio for recurrence was 3.60 (95% confidence interval [CI], 1.50-8.60) and that for death was 3.87 (95% CI, 1.23-12.21). Licartin treatment also resulted in an earlier decreased AFP level and a longer time of normal AFP level than placebo (P = 0.0016). No Licartin-related toxic effects were observed. CONCLUSION Licartin is a promising drug for preventing post-OLT tumor recurrence in advanced HCC patients excluded by the currently strict criteria for OLT. HAb18G/CD147 can be a good drug target.
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Affiliation(s)
- Jing Xu
- Cell Engineering Research Centre, Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China
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Liau SS, Jazag A, Whang EE. HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma. Cancer Res 2006; 66:11613-22. [PMID: 17178855 DOI: 10.1158/0008-5472.can-06-1460] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
HMGA1 proteins are architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. We hypothesized that HMGA1 expression is a determinant of cellular invasiveness and metastasis in pancreatic cancer. Stable silencing of HMGA1 in MiaPaCa2 and PANC1 pancreatic adenocarcinoma cells was achieved by transfection of short hairpin RNA-generating vectors. Additionally, stable overexpression of HMGA1 in MiaPaCa2 cells (characterized by low levels of inherent HMGA1 expression) was achieved. HMGA1 silencing resulted in significant reductions in cellular invasiveness through Matrigel; in cellular matrix metalloproteinase-9 (MMP-9) activity, mRNA levels, and gene promoter activity; and in Akt phosphorylation at Ser(473). Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels, and promoter activity; and in Akt phosphorylation at Ser(473). HMGA1 overexpression-induced increases in invasiveness were MMP-9 dependent. The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs. Akt-dependent modulation of MMP-9 activity contributed significantly to HMGA1 overexpression-induced increases in invasive capacity. Furthermore, HMGA1 silencing resulted in reductions in metastatic potential and tumor growth in vivo and in tumoral MMP-9 activity. Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma.
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Affiliation(s)
- Siong-Seng Liau
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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