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1
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Luo X, Shi J, Wang S, Jin X. The role of circular RNA targeting IGF2BPs in cancer-a potential target for cancer therapy. J Mol Med (Berl) 2024; 102:1297-1314. [PMID: 39287635 DOI: 10.1007/s00109-024-02488-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/01/2024] [Accepted: 09/10/2024] [Indexed: 09/19/2024]
Abstract
Circular RNAs (circRNAs) are an interesting class of conserved single-stranded RNA molecules derived from exon or intron sequences produced by the reverse splicing of precursor mRNA. CircRNAs play important roles as microRNA sponges, gene splicing and transcriptional regulators, RNA-binding protein sponges, and protein/peptide translation factors. Abnormal functions of circRNAs and RBPs in tumor progression have been widely reported. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) are a highly conserved family of RBPs identified in humans that function as post-transcriptional fine-tuners of target transcripts. Emerging evidence suggests that IGF2BPs regulate the processing and metabolism of RNA, including its stability, translation, and localization, and participate in a variety of cellular functions and pathophysiology. In this review, we have summarized the roles and molecular mechanisms of circRNAs and IGF2BPs in cancer development and progression. In addition, we briefly introduce the role of other RNAs and IGF2BPs in cancer, discuss the current clinical applications and challenges faced by circRNAs and IGF2BPs, and propose future directions for this promising research field.
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Affiliation(s)
- Xia Luo
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jiaxin Shi
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Siyuan Wang
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, 315211, China.
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2
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Liu Z, Deng K, Su Y, Zhang Z, Shi C, Wang J, Fan Y, Zhang G, Wang F. IGF2BP1-mediated the stability and protein translation of FGFR1 mRNA regulates myogenesis through the ERK signaling pathway. Int J Biol Macromol 2024; 280:135989. [PMID: 39326619 DOI: 10.1016/j.ijbiomac.2024.135989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 08/21/2024] [Accepted: 09/22/2024] [Indexed: 09/28/2024]
Abstract
N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of RNAs and plays a key regulatory role in various biological processes. As a member of the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) family, IGF2BP1 has recently demonstrated its ability to specifically bind m6A-modified sites within mRNAs and effectively regulate their mRNA stability. However, the precise roles of IGF2BP1 in mammalian skeletal muscle development, along with its downstream mRNA targets during myogenesis, have yet to be fully elucidated. Here, we observed that IGF2BP1 expression significantly decreased during myogenic differentiation. Knockdown of IGF2BP1 significantly inhibited myoblast proliferation while promoted myogenic differentiation. In contrast, IGF2BP1 overexpression robustly stimulated myoblast proliferation but suppressed their differentiation. Combined analysis of high-throughput sequencing and RNA stability assays revealed that IGF2BP1 can enhance fibroblast growth factor receptor 1 (FGFR1) mRNA stability and promote its translation in an m6A-dependent manner, thereby regulating its expression level and the Extracellular Signal-Regulated Kinase (ERK) pathway. Additionally, knockdown of FGFR1 rescued the phenotypic changes (namely increased cell proliferation and suppressed differentiation) induced by IGF2BP1 overexpression via attenuating ERK signaling. Taken together, our findings suggest that IGF2BP1 maintains the stability and translation of FGFR1 mRNA in an m6A-dependent manner, thereby inhibiting skeletal myogenesis through activation of the ERK signaling pathway. This study further enriches the understanding of the molecular mechanisms by which RNA methylation regulates myogenesis, providing valuable insights into the role of IGF2BP1-mediated post-transcriptional regulation in muscle development.
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Affiliation(s)
- Zhipeng Liu
- Sanya Research Institute of Nanjing Agricultural University & Hainan Seed Industry laborator, Nanjing Agricultural University, Sanya 572025, China; Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Kaiping Deng
- Sanya Research Institute of Nanjing Agricultural University & Hainan Seed Industry laborator, Nanjing Agricultural University, Sanya 572025, China; Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Yalong Su
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhen Zhang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Congyu Shi
- Sanya Research Institute of Nanjing Agricultural University & Hainan Seed Industry laborator, Nanjing Agricultural University, Sanya 572025, China; Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Jingang Wang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Yixuan Fan
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Guoming Zhang
- Sanya Research Institute of Nanjing Agricultural University & Hainan Seed Industry laborator, Nanjing Agricultural University, Sanya 572025, China; Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China; College of veterinary medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Feng Wang
- Sanya Research Institute of Nanjing Agricultural University & Hainan Seed Industry laborator, Nanjing Agricultural University, Sanya 572025, China; Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China.
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Munroe JA, Doe CQ. Imp is expressed in INPs and newborn neurons where it regulates neuropil targeting in the central complex. Neural Dev 2023; 18:9. [PMID: 38031099 PMCID: PMC10685609 DOI: 10.1186/s13064-023-00177-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023] Open
Abstract
The generation of neuronal diversity remains incompletely understood. In Drosophila, the central brain is populated by neural stem cells derived from progenitors called neuroblasts (NBs). There are two types of NBs, type 1 and 2. T1NBs have a relatively simple lineage, whereas T2NBs expand and diversify the neural population with the generation of intermediate neural progenitors (INPs), contributing many neurons to the adult central complex, a brain region essential for navigation. However, it is not fully understood how neural diversity is created in T2NB and INP lineages. Imp, an RNA-binding protein, is expressed in T2NBs in a high-to-low temporal gradient, while the RNA-binding protein Syncrip forms an opposing gradient. It remains unknown if Imp expression is carried into INPs; whether it forms a gradient similar to NBs; and whether INP expression of Imp is required for generating neuronal identity or morphology. Here, we show that Imp/Syp are both present in INPs, but not always in opposing gradients. We find that newborn INPs adopt their Imp/Syp levels from their parental T2NBs; that Imp and Syp are expressed in stage-specific high-to-low gradients in INPs. In addition, there is a late INP pulse of Imp. We find that neurons born from old INPs (E-PG and PF-R neurons) have altered morphology following both Imp knock-down and Imp overexpression. We conclude that Imp functions in INPs and newborn neurons to determine proper neuronal morphology and central complex neuropil organization.
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Affiliation(s)
- Jordan A Munroe
- Institute of Neuroscience, Howard Hughes Medical Institute, Univ. of Oregon, Eugene, OR, 97403, USA
| | - Chris Q Doe
- Institute of Neuroscience, Howard Hughes Medical Institute, Univ. of Oregon, Eugene, OR, 97403, USA.
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Sun X, Ye G, Li J, Shou H, Bai G, Zhang J. Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer. Clin Transl Med 2023; 13:e1457. [PMID: 37877353 PMCID: PMC10599278 DOI: 10.1002/ctm2.1457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 10/02/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Insulin-like growth Factor 2 mRNA-binding protein 3 (IGF2BP3) is a highly conserved RNA-binding protein and plays a critical role in regulating posttranscriptional modifications. METHODS Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA-immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3. RESULTS IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin-mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation. CONCLUSION IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy.
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Affiliation(s)
- Xin Sun
- Department of Medical OncologyCancer CenterKey Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)HangzhouChina
| | - Guiqin Ye
- Basic Medical SciencesHangzhou Medical CollegeHangzhouChina
| | - Jiuzhou Li
- Department of NeurosurgeryBinzhou People's HospitalBinzhouChina
| | - Huafeng Shou
- Department of GynecologyZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)BinzhouChina
| | - Gongxun Bai
- Key Laboratory of Rare Earth Optoelectronic Materials and Devices of Zhejiang Province, College of Optical and Electronic TechnologyChina Jiliang UniversityHangzhouChina
| | - Jianbin Zhang
- Department of Medical OncologyCancer CenterKey Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)HangzhouChina
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Klein M, Wefers M, Hallermann C, Fischer HJ, Hölzle F, Wermker K. IMP3 Expression as a Potential Tumour Marker in High-Risk Localisations of Cutaneous Squamous Cell Carcinoma: IMP3 in Metastatic cSCC. Cancers (Basel) 2023; 15:4087. [PMID: 37627115 PMCID: PMC10452512 DOI: 10.3390/cancers15164087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/01/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND High IMP3 expression is correlated with a worse outcome. Until now, there have been no data about IMP3 expression and clinical outcome for high-risk localisation of squamous cell carcinoma of the skin (cSCC). METHODS One-hundred twenty-two patients with cSCC of the lip and ear were included, and IMP3 expression in the tumours was immunohistochemically assessed in different evaluation approaches. Subsequently, subgroups were analysed in a matched pair approach and correlated with clinical pathologic parameters. In the following, different IMP3 analysis methods were tested for clinical suitability. RESULTS We found a significant correlation between IMP3 expression and risk for lymph node metastasis, local relapse, and progression-free survival. CONCLUSIONS On basis of our data, we suggest a prognostic benefit cutoff value for high (>50%) and low (<50%) IMP3 expression. Thus, IMP3 expression has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision-making.
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Affiliation(s)
- Maurice Klein
- Department of Oral, Maxillofacial and Facial Plastic Surgery, School of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany;
| | - Merle Wefers
- Orthodontics Meyer, Kurze Straße 6, 48151 Muenster, Germany;
| | - Christian Hallermann
- Laboratory for Dermatopathology and Pathology Hamburg-Niendorf, Tibarg 7, 22459 Hamburg, Germany;
- Department of Dermatology and Histopathology, Fachklinik Hornheide, Dorbaumstrasse 300, 48157 Muenster, Germany
| | - Henrike J. Fischer
- Department of Immunology, School of Medicine, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany;
| | - Frank Hölzle
- Department of Oral, Maxillofacial and Facial Plastic Surgery, School of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany;
| | - Kai Wermker
- Department of Oral and Cranio-Maxillofacial Surgery, Klinikum Osnabrueck GmbH, Am Finkenhuegel 1, 49076 Osnabrueck, Germany;
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Ramesh-Kumar D, Guil S. The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer. Semin Cancer Biol 2022; 86:18-31. [PMID: 35643219 DOI: 10.1016/j.semcancer.2022.05.009] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023]
Abstract
RNA binding proteins that act at the post-transcriptional level display a richness of mechanisms to modulate the transcriptional output and respond to changing cellular conditions. The family of IGF2BP proteins recognize mRNAs modified by methylation and lengthen their lifecycle in the context of stable ribonucleoprotein particles to promote cancer progression. They are emerging as key 'reader' proteins in the epitranscriptomic field, driving the fate of bound substrates under physiological and disease conditions. Recent developments in the field include the recognition that noncoding substrates play crucial roles in mediating the pro-growth features of IGF2BP family, not only as regulated targets, but also as modulators of IGF2BP function themselves. In this review, we summarize the regulatory roles of IGF2BP proteins and link their molecular role as m6A modification readers to the cellular phenotype, thus providing a comprehensive insight into IGF2BP function.
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Affiliation(s)
- Deepthi Ramesh-Kumar
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia 08916, Spain
| | - Sonia Guil
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia 08916, Spain.
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Bekki H, Matsumoto Y, Yoshimoto M, Ishihara S, Kawaguchi K, Yamamoto H, Oda Y, Nakashima Y, Harimaya K. The Expression of Insulin-Like Growth Factor II Messenger RNA-Binding Protein 3 Upregulated in Intradural Extramedullary Schwannomas. Spine Surg Relat Res 2022; 7:36-41. [PMID: 36819630 PMCID: PMC9931417 DOI: 10.22603/ssrr.2022-0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/13/2022] [Indexed: 11/05/2022] Open
Abstract
Introduction Tumor size is an important factor in determining the appropriate clinical management of intradural-extramedullary schwannoma. A tumor volume reduction may be achieved by conservative targeted therapy instead of invasive surgery if a molecular event related to tumor size is discovered. Insulin-like growth factor II messenger RNA-binding protein 3 (IMP3), an oncofetal tumor-associated antigen that is expected to be a target for immunotherapy, was focused on in this study. Methods The IMP3 status was assessed by immunohistochemistry in 64 samples of intradural-extramedullary schwannoma, and the correlation between IMP3 expression and tumor size was evaluated. Results Immunohistochemically, high IMP3 expression was observed in ～85% of schwannomas. The maximum tumor diameter of the high IMP3 expression group was significantly larger than that of the low IMP3 expression group (34.3 mm vs 18.5 mm, p=0.002). The receiver operating characteristic curve demonstrated that a maximum tumor diameter of 24 mm was a predictable factor for IMP3 expression (sensitivity, 0.7; 1-specificity, 0.2; area under the curve, 0.82). Conclusions Upregulated IMP3 expression was associated with large tumor size, suggesting a possible therapeutic approach.
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Affiliation(s)
- Hirofumi Bekki
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Matsumoto
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Masato Yoshimoto
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Shin Ishihara
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Kenichi Kawaguchi
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Yasuharu Nakashima
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Katsumi Harimaya
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan,Department of Orthopaedic Surgery, Kyushu University Beppu Hospital, Oita, Japan
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Gou J, Li H, Bi J, Pang X, Li X, Wang Y. Transfer of IGF2BP3 Through Ara-C-Induced Apoptotic Bodies Promotes Survival of Recipient Cells. Front Oncol 2022; 12:801226. [PMID: 35615150 PMCID: PMC9124970 DOI: 10.3389/fonc.2022.801226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 03/30/2022] [Indexed: 01/11/2023] Open
Abstract
Cytosine arabinoside (Ara-C) has been the standard therapeutic agent for myelodysplastic syndromes (MDS) and adult acute myeloid leukemia (AML) patients for decades. Considerable progress has been made in development of new treatments for MDS/AML patients, but drug resistance remains a major clinical problem. Apoptotic bodies (ABs), produced by late apoptotic cells, can enclose bioactive components that affect cell-cell interactions and disease progression. We isolated and identified drug-induced ABs from Ara-C-tolerance cells. Treatment of sensitive cells with Ara-C-induced ABs resulted in Ara-C-resistant phenotype. We further investigated components and functions of Ara-C-induced ABs. Proteomics analysis in combination with mass spectrometry revealed that Ara-C-induced ABs carried numerous RNA-binding proteins, notably including insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Delivery of AB-encapsulated IGF2BP3 promoted survival of recipient cells by activating PI3K-AKT and p42-44 MAPK pathways. High IGF2BP3 level in ABs from MDS/AML patient plasma was correlated with poor overall survival. Our findings demonstrate that AB-derived IGF2BP3 plays an essential role in acquired Ara-C resistance in MDS/AML patients, and is a potential therapeutic target for suppression of Ara-C resistance.
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Affiliation(s)
- Junjie Gou
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi’an, China
| | - Hongjiao Li
- Institute of Hematology, School of Medicine, Northwest University, Xi’an, China
| | - Jingjing Bi
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi’an, China
| | - Xingchen Pang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi’an, China
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi’an, China
- *Correspondence: Xiang Li, ; Yi Wang,
| | - Yi Wang
- Department of Hematology, Provincial People’s Hospital, Xi’an, China
- *Correspondence: Xiang Li, ; Yi Wang,
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Mäkinen A, Nikkilä A, Haapaniemi T, Oksa L, Mehtonen J, Vänskä M, Heinäniemi M, Paavonen T, Lohi O. IGF2BP3 Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia. Cancers (Basel) 2021; 13:1505. [PMID: 33805930 PMCID: PMC8037952 DOI: 10.3390/cancers13071505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/11/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
The oncofetal protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) belongs to a family of RNA-binding proteins involved in localization, stability, and translational regulation of target RNAs. IGF2BP3 is used as a diagnostic and prognostic marker in several malignancies. Although the prognosis of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved, a subgroup of patients exhibits high-risk features and suffer from disease recurrence. We sought to identify additional biomarkers to improve diagnostics, and we assessed expression of IGF2BP3 in a population-based pediatric cohort of B-ALL using a tissue microarray platform. The majority of pediatric B-ALL cases were positive for IGF2BP3 immunohistochemistry and were associated with an increased proliferative phenotype and activated STAT5 signaling pathway. Two large gene expression data sets were probed for the expression of IGF2BP3-the highest levels were seen among the B-cell lymphomas of a germinal center origin and well-established (KMT2A-rearranged and ETV6-RUNX1) and novel subtypes of B-ALL (e.g., NUTM1 and ETV6-RUNX1-like). A high mRNA for IGF2BP3 was associated with a proliferative "metagene" signature and a high expression of CDK6 in B-ALL. A low expression portended inferior survival in a high-risk cohort of pediatric B-ALL. Overall, our results show that IGF2BP3 shows subtype-specificity in expression and provides prognostic utility in high-risk B-ALL.
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Affiliation(s)
- Artturi Mäkinen
- Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.N.); (L.O.); (O.L.)
- Fimlab Laboratories, Department of Pathology, Tampere University Hospital, 33520 Tampere, Finland; (T.H.); (T.P.)
| | - Atte Nikkilä
- Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.N.); (L.O.); (O.L.)
| | - Teppo Haapaniemi
- Fimlab Laboratories, Department of Pathology, Tampere University Hospital, 33520 Tampere, Finland; (T.H.); (T.P.)
- Department of Biological and Environmental Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland
| | - Laura Oksa
- Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.N.); (L.O.); (O.L.)
| | - Juha Mehtonen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland; (J.M.); (M.H.)
| | - Matti Vänskä
- Department of Internal Medicine, Tampere University Hospital, 33520 Tampere, Finland;
| | - Merja Heinäniemi
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland; (J.M.); (M.H.)
| | - Timo Paavonen
- Fimlab Laboratories, Department of Pathology, Tampere University Hospital, 33520 Tampere, Finland; (T.H.); (T.P.)
- Department of Pathology, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland
| | - Olli Lohi
- Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.N.); (L.O.); (O.L.)
- Tays Cancer Centre, Tampere University Hospital, 33520 Tampere, Finland
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Yao L, Yin H, Hong M, Wang Y, Yu T, Teng Y, Li T, Wu Q. RNA methylation in hematological malignancies and its interactions with other epigenetic modifications. Leukemia 2021; 35:1243-1257. [PMID: 33767371 DOI: 10.1038/s41375-021-01225-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 02/12/2021] [Accepted: 03/11/2021] [Indexed: 01/18/2023]
Abstract
Hematological malignancies are a class of malignant neoplasms attributed to abnormal differentiation of hematopoietic stem cells (HSCs). The systemic involvement, poor prognosis, chemotherapy resistance, and recurrence common in hematological malignancies urge researchers to look for novel treatment targets and mechanisms. In recent years, epigenetic abnormalities have been shown to play a vital role in tumorigenesis and progression in hematological malignancies. In addition to DNA methylation and histone modifications, which are most studied, RNA methylation has become increasingly significant. In this review, we elaborate recent advances in the understanding of RNA modification in the pathogenesis, diagnosis and molecular targeted therapies of hematological malignancies and discuss its intricate interactions with other epigenetic modifications, including DNA methylation, histone modifications and noncoding RNAs.
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Affiliation(s)
- Lan Yao
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Yin
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mei Hong
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yajun Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Yu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yao Teng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiuling Wu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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11
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Novel Regulators of the IGF System in Cancer. Biomolecules 2021; 11:biom11020273. [PMID: 33673232 PMCID: PMC7918569 DOI: 10.3390/biom11020273] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.
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12
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Khan K, Javed Z, Sadia H, Sharifi-Rad J, Cho WC, Luparello C. Quercetin and MicroRNA Interplay in Apoptosis Regulation in Ovarian Cancer. Curr Pharm Des 2021; 27:2328-2336. [PMID: 33076802 DOI: 10.2174/1381612826666201019102207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 09/20/2020] [Indexed: 11/22/2022]
Abstract
The multifaceted nature of ovarian cancer has severely hampered the development of effective therapeutics over the years. The complicate nature of ovarian cancer makes it therapeutically challenging, therefore, there has been a renewed interest in phytochemistry. Phytochemicals have emerged as a potential therapeutic option due to less side effects. Moreover, the signaling inhibition properties have also been studied extensively in recent times. A growing number of data obtained via high-throughput technologies has started to delineate the complex oncogenic signaling networks, thus broadening the therapeutic opportunities. Within the network, microRNAs (miRNAs) have been shown to play a versatile role in the regulation of cancer. Quercetin has been in the spotlight over the years because of its high pharmacological values and substantial evidence has demonstrated its anti-proliferative effect against various types of cancers. Despite the versatility of quercetin, little is known about its anti-proliferative potential towards ovarian cancer. This review sheds some light on quercetin as an alternative therapeutic approach to cancer. Furthermore, we also addresss the interplay between miRNAs and quercetin in the regulation of apoptosis in ovarian cancer.
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Affiliation(s)
- Khushbukhat Khan
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Zeeshan Javed
- Office for Research Innovation and Commercialization (ORIC) Lahore Garrison University, Sector-c Phase VI, DHA, Lahore, Pakistan
| | - Haleema Sadia
- Department of Biotechnology BUITEMS, Quetta, Baluchistan, Pakistan
| | | | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong
| | - Claudio Luparello
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita di Palermo, Vialedelle Scienze, 90128 Palermo, Italy
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13
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Cui XH, Hu SY, Zhu CF, Qin XH. Expression and prognostic analyses of the insulin-like growth factor 2 mRNA binding protein family in human pancreatic cancer. BMC Cancer 2020; 20:1160. [PMID: 33246429 PMCID: PMC7694419 DOI: 10.1186/s12885-020-07590-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/29/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Despite advances in early diagnosis and treatment, cancer remains the leading cause of mortality worldwide. The insulin-like growth factor 2 mRNA binding protein (IGF2BP) family has been reported to be involved in a variety of human malignant tumours. However, little is known about their expression and prognostic value in human pancreatic cancer. Therefore, we performed a detailed cancer versus normal differential analysis. METHODS The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyse the mRNA expression levels of the IGF2BP family in various cancers, including pancreatic cancer. Then, the LinkedOmics and GEPIA databases were used to assess the relation between the expression levels of IGF2BPs and overall survival (OS). Then, univariate and multivariate Cox regression analyses were performed, and subgroups based on grade and stage were analysed. The signalling pathways associated with IGF2BP2 and IGF2BP3 were then investigated via gene set enrichment analysis (GSEA). RESULTS IGF2BP2 and IGF2BP3 were associated with each subset of OS based on grade and stage. Further clinical correlation analysis of IGF2BP2 and IGF2BP3 confirmed that IGF2BP2 and IGF2BP3 are fundamental factors in promoting pancreatic cancer progression. CONCLUSION IGF2BP2 and IGF2BP3 are key factors in promoting the progression of pancreatic cancer and are closely related to overall survival.
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Affiliation(s)
- Xiao-Han Cui
- Department of General Surgery, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 68 Pohu Middle Road, Changzhou, Jiangsu, 213000, P.R. China
- Nanjing Medical University, Nanjing, Jiangsu, 211166, P.R. China
| | - Shu-Yi Hu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Chun-Fu Zhu
- Department of General Surgery, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 68 Pohu Middle Road, Changzhou, Jiangsu, 213000, P.R. China.
| | - Xi-Hu Qin
- Department of General Surgery, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 68 Pohu Middle Road, Changzhou, Jiangsu, 213000, P.R. China.
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14
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Berberine inhibits proliferation and induces G0/G1 phase arrest in colorectal cancer cells by downregulating IGF2BP3. Life Sci 2020; 260:118413. [PMID: 32926933 DOI: 10.1016/j.lfs.2020.118413] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/01/2020] [Accepted: 09/06/2020] [Indexed: 12/24/2022]
Abstract
AIMS Berberine (BBR) is one of isoquinoline alkaloids from Coptidis Rhizoma and possesses extensive pharmacological activities, including anti-colorectal cancer (CRC) activity. However, the detailed mechanisms remain to be determined. The current study aims to investigate the ability and the potential mechanism of BBR against CRC. MAIN METHODS By mining recognized CRC datasets and RNA-seq results of cells and tumors treated with BBR for perform bioinformatics analysis to find key targets IGF2BP3. Overexpression and knockdown of IGF2BP3 assays were used to explore the biological role of IGF2BP3 in the process of BBR against CRC. KEY FINDINGS Our results showed that BBR inhibits proliferation and induces G0/G1 phase arrest in CRC cells by downregulating IGF2BP3. Specifically, Knockdown of IGF2BP3 could suppress the PI3K/AKT pathway to inhibit cell proliferation and cycle transition. The negative effects of BBR in CRC cells could be rescued by overexpressing IGF2BP3. SIGNIFICANCE Our data might provide a theoretical basis for the future use of BBR in colorectal cancer prevention.
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15
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Ubiquitination of IGF2BP3 by E3 ligase MKRN2 regulates the proliferation and migration of human neuroblastoma SHSY5Y cells. Biochem Biophys Res Commun 2020; 529:43-50. [PMID: 32560817 DOI: 10.1016/j.bbrc.2020.05.112] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/15/2020] [Indexed: 11/22/2022]
Abstract
Neuroblastoma (NB) is a paediatric tumour that shows great biomolecule and clinical heterogeneity, and patients with NB often develop various neurological complications. Currently, the disease is mainly treated by surgery and still lacks specific therapeutic drugs; therefore, targets are urgently needed. Makorin ring finger protein 2 (MKRN2) is an E3 ligase whose effects on neuroblastoma have not been illustrated. shRNAs for MKRN2 have been designed, and MKRN2-knockdown human neuroblastoma SHSY5Y cells were established. MKRN2 knockdown promotes the proliferation and migration of SHSY5Y cells. Because MKRN2 is an E3 ligase, we performed a series of experiments, and Insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) was identified as a new substrate for MKRN2. IGF2BP3 is an RNA-binding protein that regulates the stability of many mRNAs, including CD44 and PDPN, and our study demonstrated that MKRN2 regulates the expression of CD44 and PDPN in an IGF2BP3-dependent manner. These results suggest that MKRN2 might be a potential therapeutic target for neuroblastoma.
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16
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Thomas D, Radhakrishnan P. Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer. Cancers (Basel) 2020; 12:E1228. [PMID: 32414222 PMCID: PMC7281733 DOI: 10.3390/cancers12051228] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.
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Affiliation(s)
- Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA;
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
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17
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Prieto C, Kharas MG. RNA Regulators in Leukemia and Lymphoma. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a034967. [PMID: 31615866 DOI: 10.1101/cshperspect.a034967] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Posttranscriptional regulation of mRNA is a powerful and tightly controlled process in which cells command the integrity, diversity, and abundance of their protein products. RNA-binding proteins (RBPs) are the principal players that control many intermediary steps of posttranscriptional regulation. Recent advances in this field have discovered the importance of RBPs in hematological diseases. Herein we will review a number of RBPs that have been determined to play critical functions in leukemia and lymphoma. Furthermore, we will discuss the potential therapeutic strategies that are currently being studied to specifically target RBPs in these diseases.
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Affiliation(s)
- Camila Prieto
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Michael G Kharas
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
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18
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Wang PF, Wang X, Liu M, Zeng Z, Lin C, Xu W, Ma W, Wang J, Xiang Q, Johnston RN, Liu H, Liu SL. The Oncogenic Functions of Insulin-like Growth Factor 2 mRNA-Binding Protein 3 in Human Carcinomas. Curr Pharm Des 2020; 26:3939-3954. [PMID: 32282295 DOI: 10.2174/1381612826666200413080936] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 04/01/2020] [Indexed: 02/07/2023]
Abstract
IGF2BP3 (also known as IMP3, KOC), a member of the insulin-like growth factor mRNA-binding protein family (IMPs), has been a research target in recent studies of promoting embryo development and exacerbating cancer. IGF2BP3 is ubiquitously expressed in early embryogenesis stages but limited in postembryonic stages, which is important in many physiological aspects such as stem cell renewal, morphological development and metabolism. A large number of studies show that IGF2BP3 interacts with many kinds of non-coding RNAs and proteins to promote cancer cell proliferation and metastasis and inhibit cancer cell apoptosis. As IGF2BP3 is highly expressed in advanced cancers and associated with poor overall survival rates of patients, it may be a potential molecular marker in cancer diagnosis for the detection of cancerous tissues and an indicator of cancer stages. Therefore, anti-IGF2BP3 drugs or monoclonal antibodies are expected as new therapeutic methods in cancer treatment. This review summarizes recent findings among IGF2BP3, RNA and proteins in cancer processes, with a focus on its cancer-promoting mechanisms and potential application as a new biomarker for cancer diagnosis and treatment.
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Affiliation(s)
- Peng-Fei Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xiaoyu Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Min Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Zheng Zeng
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Caiji Lin
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Wenwen Xu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Wenqing Ma
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Jiali Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Qian Xiang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Randal N Johnston
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, T2N1N4, Canada
| | - Huidi Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Shu-Lin Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
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19
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Mancarella C, Scotlandi K. IGF2BP3 From Physiology to Cancer: Novel Discoveries, Unsolved Issues, and Future Perspectives. Front Cell Dev Biol 2020; 7:363. [PMID: 32010687 PMCID: PMC6974587 DOI: 10.3389/fcell.2019.00363] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/12/2019] [Indexed: 12/24/2022] Open
Abstract
RNA network control is a key aspect of proper cellular homeostasis. In this context, RNA-binding proteins (RBPs) play a major role as regulators of the RNA life cycle due to their capability to bind to RNA sequences and precisely direct nuclear export, translation/degradation rates, and the intracellular localization of their target transcripts. Alterations in RBP expression or functions result in aberrant RNA translation and may drive the emergence and progression of several pathological conditions, including cancer. Among the RBPs, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is of particular interest in tumorigenesis and tumor progression. This review highlights the molecular mechanisms underlying the oncogenic functions of IGF2BP3, summarizes the therapeutic potential related to its inhibition and notes the fundamental issues that remain unanswered. To fully exploit IGF2BP3 for tumor diagnosis and therapy, it is crucial to dissect the mechanisms governing IGF2BP3 re-expression and to elucidate the complex interactions between IGF2BP3 and its target mRNAs as normal cells become tumor cells.
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Affiliation(s)
- Caterina Mancarella
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Katia Scotlandi
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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20
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Liu J, Liu Y, Gong W, Kong X, Wang C, Wang S, Liu A. Prognostic value of insulin-like growth factor 2 mRNA-binding protein 3 and vascular endothelial growth factor-A in patients with primary non-small-cell lung cancer. Oncol Lett 2019; 18:4744-4752. [PMID: 31611984 PMCID: PMC6781568 DOI: 10.3892/ol.2019.10835] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 07/01/2019] [Indexed: 12/19/2022] Open
Abstract
Insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) and vascular endothelial growth factor-A (VEGF-A) may play important roles in the process of tumor progression and tumor angiogenesis. The aim of the present study was to examine the co-expression of IMP3 and VEGF-A in primary human non-small cell lung cancer (NSCLC), to investigate the association between these two expression levels and determine the clinicopathological implications, including changes to microvessel density (MVD), and to assess the prognostic value of co-expression. Using immunohistochemical staining, the expression of IMP3, VEGF-A and CD34 expression was detected in 128 primary NSCLC tissue samples. According to the expression of IMP3 and VEGF-A, the cases were divided into four groups. Next, the clinicopathological features, MVD and survival time were investigated across the different groups. The immunohistochemical analyses demonstrated that there was a significant correlation between IMP3 and VEGF-A expression in NSCLC (r=0.181; P=0.041). Co-expression of IMP3 and VEGF-A was significantly associated with larger primary tumor size (P=0.016), poorer differentiation (P=0.014), more advanced Tumor-Node-Metastasis stage (P=0.012), increased MVD (P=0.004) and positive lymph node metastasis (P=0.002). Survival analysis demonstrated that cases with IMP3 and VEGF-A double-positive staining were significantly associated with lower survival rates compared with cases with double-negative staining (P=0.039). In the early NSCLC (I–IIa) subgroup, the mean survival time of the double-positive staining group was significantly shorter compared with that of the double-negative staining group (P=0.015). Co-expression of IMP3 and VEGF-A was associated with angiogenesis and a poorer prognosis in NSCLC, and may therefore play a critical role in NSCLC progression.
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Affiliation(s)
- Jiannan Liu
- Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Ying Liu
- Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Wenjing Gong
- Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Xiangshuo Kong
- Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Congcong Wang
- Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Shuhua Wang
- Department of Medical Record Information, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Aina Liu
- Department of Oncology, Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
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21
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Waly AA, El-Ekiaby N, Assal RA, Abdelrahman MM, Hosny KA, El Tayebi HM, Esmat G, Breuhahn K, Abdelaziz AI. Methylation in MIRLET7A3 Gene Induces the Expression of IGF-II and Its mRNA Binding Proteins IGF2BP-2 and 3 in Hepatocellular Carcinoma. Front Physiol 2019; 9:1918. [PMID: 30733684 PMCID: PMC6353855 DOI: 10.3389/fphys.2018.01918] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/20/2018] [Indexed: 01/08/2023] Open
Abstract
miR-let-7a is a tumor suppressor miRNA with reduced expression in most cancers. Methylation of MIRLET7A3 gene was reported to be the cause of this suppression in several cancers; however, it was not explicitly investigated in hepatocellular carcinoma (HCC). We aimed at investigating miR-let-7a expression and molecular mode in HCC, identifying drug-targetable networks, which might be affected by its abundance. Our results illustrated a significant repression of miR-let-7a, which correlated with hypermethylation of its gene of origin MIRLRT7A3. This was further supported by the induction of miR-let-7a expression upon treatment of HCC cells with a DNA-methyltransferase inhibitor. Using a computational approach, insulin-like growth factor (IGF)-II and IGF-2 mRNA binding proteins (IGF2BP)-2/-3 were identified as potential targets for miR-let-7a that was further confirmed experimentally. Indeed, miR-let-7a mimics diminished IGF-II as well as IGF2BP-2/-3 expression. Direct binding of miR-let-7a to each respective transcript was confirmed using a luciferase reporter assay. In conclusion, this study suggests that DNA hypermethylation leads to epigenetic repression of miR-let-7a in HCC cells, which induces the oncogenic IGF-signaling pathway.
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Affiliation(s)
- Amr A. Waly
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | | | - Reem A. Assal
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | | | - Karim A. Hosny
- Department of General Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend M. El Tayebi
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepatology, Cairo University, Cairo, Egypt
| | - Kai Breuhahn
- Molecular Hepatopathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Ahmed I. Abdelaziz
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
- School of Medicine, Newgiza University, Cairo, Egypt
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22
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Bhargava S, Visvanathan A, Patil V, Kumar A, Kesari S, Das S, Hegde AS, Arivazhagan A, Santosh V, Somasundaram K. IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65. Oncotarget 2018; 8:40469-40485. [PMID: 28465487 PMCID: PMC5522290 DOI: 10.18632/oncotarget.17118] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 04/03/2017] [Indexed: 01/04/2023] Open
Abstract
The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and an important mediator of IMP3 promoted glioma cell migration. IMP3 increased p65 protein levels without any change in p65 transcript levels, but promoted its polysome association. RIP-PCR demonstrated the binding of IMP3 to p65 transcript. UV crosslinking experiments with in vitro transcribed RNA confirmed the specific and direct binding of IMP3 to sites on p65 3′UTR. Further, IMP3 induced luciferase activity from p65 3′UTR reporter carrying wild type sites but not mutated sites. Exogenous overexpression of p65 from a 3′UTR-less construct rescued the reduced migration of glioma cells in IMP3 silenced condition. In addition, IMP3 silencing inhibited glioma stem-like cell maintenance and migration. The exogenous overexpression of 3′UTR-less p65 significantly alleviated the inhibition of neurosphere formation observed in IMP3 silenced glioma stem-like cells. Further, we show that IMP3 is transcriptionally activated by NF-κB pathway indicating the presence of a positive feedback loop between IMP3 and p65. This study establishes p65 as a novel target of IMP3 in increasing glioma cell migration and underscores the significance of IMP3-p65 feedback loop for therapeutic targeting in GBM.
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Affiliation(s)
- Shruti Bhargava
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Abhirami Visvanathan
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Vikas Patil
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Anuj Kumar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Santosh Kesari
- Department of Translational Neuro-Oncology and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
| | - Alangar S Hegde
- Sri Satya Sai Institute of Higher Medical Sciences, Bangalore, India
| | - Arimappamagan Arivazhagan
- Departments of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Vani Santosh
- Departments of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Kumaravel Somasundaram
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
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Bhargava S, Patil V, Mahalingam K, Somasundaram K. Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma. Oncotarget 2017; 8:16650-16668. [PMID: 28035070 PMCID: PMC5369992 DOI: 10.18632/oncotarget.14287] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 11/30/2016] [Indexed: 01/03/2023] Open
Abstract
RNA binding proteins (RBPs) have been implicated in cancer development. An integrated bioinformatics analysis of RBPs (n = 1756) in various datasets (n = 11) revealed several genetic and epigenetically altered events among RBPs in glioblastoma (GBM). We identified 13 mutated and 472 differentially regulated RBPs in GBM samples. Mutations in AHNAK predicted poor prognosis. Copy number variation (CNV), DNA methylation and miRNA targeting contributed to RBP differential regulation. Two sets of differentially regulated RBPs that may be implicated in initial astrocytic transformation and glioma progression were identified. We have also identified a four RBP (NOL3, SUCLG1, HERC5 and AFF3) signature, having a unique expression pattern in glioma stem-like cells (GSCs), to be an independent poor prognostic indicator in GBM. RBP risk score derived from the signature also stratified GBM into low-risk and high-risk groups with significant survival difference. Silencing NOL3, SUCLG1 and HERC5 inhibited GSC maintenance. Gene set enrichment analysis of differentially regulated genes between high-risk and low-risk underscored the importance of inflammation, EMT and hypoxia in high-risk GBM. Thus, we provide a comprehensive overview of genetic and epigenetic regulation of RBPs in glioma development and progression.
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Affiliation(s)
- Shruti Bhargava
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India
| | - Vikas Patil
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India
- Department of Bio-Medical Sciences, School of Biosciences and Technology, VIT University, Vellore-632014, India
| | - Kulandaivelu Mahalingam
- Department of Bio-Medical Sciences, School of Biosciences and Technology, VIT University, Vellore-632014, India
| | - Kumaravel Somasundaram
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India
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Er LM, Li Y, Wu ML, Zhao Q, Tan BB, Wang XL, Wang SJ. Expression of IMP3 as a marker for predicting poor outcome in gastroenteropancreatic neuroendocrine neoplasms. Oncol Lett 2017; 13:2391-2396. [PMID: 28454409 DOI: 10.3892/ol.2017.5735] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/30/2016] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to investigate the expression and clinical significance of oncofetal protein insulin-like growth factor (IGF) II mRNA-binding protein 3 (IMP3) in the differentiation of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). A total of 162 patients who were diagnosed with GEP-NEN, and who underwent surgical or endoscopic resection from January 2006 to March 2013, were enrolled in the study, including 85 cases of grade (G)1 neuroendocrine tumors, 40 cases of G2 neuroendocrine tumors, 28 cases of G3 neuroendocrine carcinomas and 9 cases of mixed stage adenoneuroendocrine carcinomas. The clinical and pathological data were recorded for analysis. The expression of IMP3, cluster of differentiation (CD)44, IGF1 receptor (IGF1R) and matrix metalloproteinase (MMP)2 was determined by immunohistochemistry. SPSS 13.0 software was used for data processing and analyses, and P<0.05 was used to determine significance. Oncofetal protein IMP3 exhibited a high expression rate (74.69%) in GEP-NEN. IMP3-positive cases demonstrated significantly decreased overall and disease-free survival times, as compared with IMP3-negative cases (P=0.012). Overexpression of IMP3 was correlated with tumor grade, clinical stage, tumor size and poor prognosis (all P<0.05). Therefore, patients with overexpressed IMP3 had a poorer prognosis (P<0.01); COX regression analysis revealed that the overexpression of IMP3, the tumor grade, tumor size and metastasis of GEP-NEN were each associated with the clinical outcomes. The results also indicated that the expression rates of CD44, IGF1R and MMP2 in GEP-NEN were 19.75, 53.7 and 55.56%, respectively. While it was negatively associated with the expression of CD44 (r=-0.131; P=0.096), the expression of IMP3 was positively correlated with the expression of IGF1R and MMP2 (r=0.288, P<0.01; r=0.208, P=0.008). In addition, the expression levels of IGF1R and MMP2 were positively associated (r=0.687; P<0.01). In conclusion, high IMP3 expression levels were determined to be associated with a high disease stage in patients with GEP-NEN, thus it may serve as a predictor for metastasis and poor clinical outcomes in GEP-NEN.
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Affiliation(s)
- Li-Mian Er
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yong Li
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Ming-Li Wu
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Qun Zhao
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Bi-Bo Tan
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xiao-Ling Wang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Shi-Jie Wang
- Department of Endoscopy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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Tarsitano A, Asioli S, Morandi L, Monti V, Righi A, Morselli Labate AM, Nardi E, Foschini MP, Marchetti C. Laminin-5 and insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression in preoperative biopsy specimens from oral cancer patients: Their role in neural spread risk and survival stratification. J Craniomaxillofac Surg 2016; 44:1896-1902. [PMID: 27863864 DOI: 10.1016/j.jcms.2016.07.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 06/08/2016] [Accepted: 07/13/2016] [Indexed: 11/29/2022] Open
Abstract
Perineural invasion (PNI) hinders the ability to establish local control of oral squamous cell carcinoma (OSCC). To date, PNI can be evaluated only in surgical specimens and not in preoperative biopsy material, rendering timely therapeutic planning impossible. Insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression appears to be of diagnostic and prognostic utility for many solid tumours, and laminin-5 expression in surgical specimens has been identified as a valid predictor of neural spread of head-and-neck neoplasms. The ability to use preoperative biopsy material to identify patients exhibiting PNI is fundamental for good management of OSCC. We examined a series of 64 consecutive patients treated (primarily via surgery) for OSCC between 2009 and 2014 at the Maxillofacial Surgery Unit, University of Bologna. We evaluated IMP3 and laminin-5 expression in preoperative biopsy material using immunohistochemistry and quantitative reverse transcription polymerase chain reaction. We sought to correlate expression of IMP3 and laminin-5 with PNI evident in surgical specimens. Expression of IMP3 and laminin-5 in preoperative biopsy material appeared to be predictive of PNI in patients with OSCC (P < 0.001). Additionally, the results of multivariate analyses showed that IMP3 status was an independent predictor of death of patients with OSCC (P = 0.001). The present study demonstrates that IMP3 and laminin-5 expression in preoperative biopsy material correlate well with PNI status and may allow accurate preoperative risk stratification of patients with OSCC.
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Affiliation(s)
- Achille Tarsitano
- Department of Biomedical and Neuromotor Sciences, Section of Maxillofacial Surgery, University of Bologna, Policlinico S. Orsola, Bologna, Italy.
| | - Sofia Asioli
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Luca Morandi
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Valentina Monti
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Alberto Righi
- Unit of Anatomic Pathology, Istituto Ortopedico Rizzoli, Bologna, Italy
| | | | - Elena Nardi
- Laboratory of Biostatistics, Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Maria Pia Foschini
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Claudio Marchetti
- Department of Biomedical and Neuromotor Sciences, Section of Maxillofacial Surgery, University of Bologna, Policlinico S. Orsola, Bologna, Italy
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Insulin-like growth factor II messenger RNA-binding protein-3 is an indicator of malignant phyllodes tumor of the breast. Hum Pathol 2016; 55:30-8. [DOI: 10.1016/j.humpath.2016.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 03/30/2016] [Accepted: 04/13/2016] [Indexed: 01/09/2023]
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Stoskus M, Vaitkeviciene G, Eidukaite A, Griskevicius L. ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia. Blood Cells Mol Dis 2016; 57:30-4. [PMID: 26852652 DOI: 10.1016/j.bcmd.2015.11.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Revised: 11/13/2015] [Accepted: 11/13/2015] [Indexed: 11/19/2022]
Abstract
The oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA binding protein 1) is overexpressed in a subset of cancers and promotes cell cycle, migration and aggressive phenotype by regulating post-transcriptionally a number of key mRNAs (e. g, ACTB, CD44, CTNNB1, KRAS, MAPK4, MYC, PTEN and others). IGF2BP1 is also overexpressed in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia (ALL), but the biological significance of this phenomenon has not been addressed so far. We have identified leukemia fusion gene ETV6/RUNX1 mRNA to be highly enriched in immunoprecipitated fraction of endogenous IGF2BP1 from a model cell line REH and t(12;21)(p13;q22)-positive ALL samples. Furthermore, downregulation of IGF2BP1 by two-fold has resulted in a corresponding decrease of ETV6/RUNX1 mRNA validating this transcript as a target of IGF2BP1 protein in t(12;21)(p13;q22)-positive ALL. These data infer that IGF2BP1 is a potent regulator of ETV6/RUNX1 mRNA stability and potentially link this evolutionary-highly conserved protein to cell transformation events in ETV6/RUNX1-mediated leukemogenesis of t(12;21)(p13;q22)-positive ALL.
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MESH Headings
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Cell Line, Tumor
- Chromosomes, Human, Pair 12
- Chromosomes, Human, Pair 21
- Core Binding Factor Alpha 2 Subunit/genetics
- Core Binding Factor Alpha 2 Subunit/metabolism
- Gene Expression Regulation, Leukemic
- Humans
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Protein Binding
- Proto-Oncogene Proteins c-ets/genetics
- Proto-Oncogene Proteins c-ets/metabolism
- RNA Stability
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Translocation, Genetic
- ETS Translocation Variant 6 Protein
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Affiliation(s)
- Mindaugas Stoskus
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania; Department of Immunology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
| | - Goda Vaitkeviciene
- Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania
| | - Audrone Eidukaite
- Department of Immunology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania
| | - Laimonas Griskevicius
- Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania; Clinics of Internal, Family Medicine and Oncology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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28
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Grothaus K, Kanber D, Gellhaus A, Mikat B, Kolarova J, Siebert R, Wieczorek D, Horsthemke B. Genome-wide methylation analysis of retrocopy-associated CpG islands and their genomic environment. Epigenetics 2016; 11:216-26. [PMID: 26890210 DOI: 10.1080/15592294.2016.1145330] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Gene duplication by retrotransposition, i.e., the reverse transcription of an mRNA and integration of the cDNA into the genome, is an important mechanism in evolution. Based on whole-genome bisulfite sequencing of monocyte DNA, we have investigated the methylation state of all CpG islands (CGIs) associated with a retrocopy (n = 1,319), their genomic environment, as well as the CGIs associated with the ancestral genes. Approximately 10% of retrocopies are associated with a CGI. Whereas almost all CGIs of the human genome are unmethylated, 68% of the CGIs associated with a retrocopy are methylated. In retrocopies resulting from multiple retrotranspositions of the same ancestral gene, the methylation state of the CGI often differs. There is a strong positive correlation between the methylation state of the CGI/retrocopy and their genomic environment, suggesting that the methylation state of the integration site determined the methylation state of the CGI/retrocopy, or that methylation of the retrocopy by a host defense mechanism has spread into the adjacent regions. Only a minor fraction of CGI/retrocopies (n = 195) has intermediate methylation levels. Among these, the previously reported CGI/retrocopy in intron 2 of the RB1 gene (PPP1R26P1) as well as the CGI associated with the retrocopy RPS2P32 identified in this study carry a maternal methylation imprint. In conclusion, these findings shed light on the evolutionary dynamics and constraints of DNA methylation.
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Affiliation(s)
- Katrin Grothaus
- a Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen , Essen , Germany
| | - Deniz Kanber
- a Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen , Essen , Germany
| | - Alexandra Gellhaus
- b Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Essen , Essen , Germany
| | - Barbara Mikat
- a Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen , Essen , Germany
| | - Julia Kolarova
- c Institut für Humangenetik, Christian-Albrechts-Universität Kiel & Universitätsklinikum Schleswig-Holstein , Campus Kiel, Kiel , Germany
| | - Reiner Siebert
- c Institut für Humangenetik, Christian-Albrechts-Universität Kiel & Universitätsklinikum Schleswig-Holstein , Campus Kiel, Kiel , Germany
| | - Dagmar Wieczorek
- a Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen , Essen , Germany
| | - Bernhard Horsthemke
- a Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen , Essen , Germany
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Fawzy IO, Hamza MT, Hosny KA, Esmat G, Abdelaziz AI. Abrogating the interplay between IGF2BP1, 2 and 3 and IGF1R by let-7i arrests hepatocellular carcinoma growth. Growth Factors 2016; 34:42-50. [PMID: 27126374 DOI: 10.3109/08977194.2016.1169532] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
IGF2BP 1, 2 and 3 control the fate of many transcripts. Immunoprecipitation studies demonstrated the IGF2BPs to bind to IGF1R mRNA, and our laboratory has recently shown them to post-transcriptionally regulate IGF1R. This study sought to identify a microRNA regulating the IGF2BPs and consequently IGF1R. All three IGF2BPs were among the top-ranked predicted targets of let-7i. Let-7i was downregulated in HCC tissues, and transfection of HuH-7 with let-7i inhibited malignant cell behaviors and decreased IGF2BPs transcripts. Direct binding of let-7i to IGF2BP2 and IGF2BP3 3'UTRs was confirmed, and the effect of let-7i caused a decrease in the IGF2BPs' target gene, the IGF1R. IGF1R mRNA was inversely correlated with let-7i in HCC tissues and was reduced upon let-7i transfection into HuH-7. Reporter assays validated IGF1R as a target of let-7i. Therefore, let-7i may control HCC tumorigenesis by regulating IGF1R directly and indirectly by interrupting the interplay between IGF1R and the IGF2BPs.
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Affiliation(s)
- Injie Omar Fawzy
- a Department of Pharmacology and Toxicology , German University in Cairo, Main Entrance Al Tagamoa Al Khames , Cairo , Egypt
| | - Mohammed Tarif Hamza
- b Department of Clinical Pathology , Ain Shams University , Khalifa El-Maamoun St, Abbasiya Square , Cairo , Egypt
| | - Karim Adel Hosny
- c Department of Endemic Medicine and Hepatology , Cairo University , Kasr El-Aini St , Cairo , Egypt , and
| | - Gamal Esmat
- c Department of Endemic Medicine and Hepatology , Cairo University , Kasr El-Aini St , Cairo , Egypt , and
| | - Ahmed Ihab Abdelaziz
- d Department of Biology , American University in Cairo , AUC Avenue , New Cairo City, Cairo , Egypt
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30
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IMP3 Predicts Invasion and Prognosis in Human Lung Adenocarcinoma. Lung 2015; 194:137-46. [PMID: 26608347 DOI: 10.1007/s00408-015-9829-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 11/21/2015] [Indexed: 02/03/2023]
Abstract
PURPOSE Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with several aggressive and advanced cancers. Whether IMP3 can predict invasion, and prognosis in patients with human lung adenocarcinoma (LAC) remains unclear. METHODS Ninety-five LAC and 75 non-tumor lung tissue samples were included in a tissue microarray. IMP3 expression was assessed by immunohistochemical examination. Correlation between IMP3 expression levels, clinicopathological characteristics, and overall prognosis was evaluated. In a separate in vitro study, RNA interference method was applied for knockdown of IMP3 gene in human LAC cell lines. Invasive potential of LAC cells was then evaluated by transwell migration assay. RESULTS IMP3 immunoreactivity was observed in 39 out of 95 (41.1 %) LAC patients, but not in non-tumor lung tissues. IMP3 expression levels were closely associated with histological grade (P = 0.037), TNM stage (P = 0.034), and lymph node metastasis (P = 0.011). Patients presenting with positive IMP3 expression (P = 0.000), an advanced TNM stage (P = 0.000), and lymph node metastasis (P = 0.001) had a worse overall survival, compared to those lacking these characteristics. Both IMP3 expression (hazard ratio [HR], 2.310; 95 % confidence interval [CI] 1.192-4.476; P = 0.013) and TNM stage (HR 2.338; 95 % CI 1.393-3.925; P = 0.001) were independent predictors of poor prognosis. The invasive potential of LAC cells was significantly inhibited by IMP3 knockdown. CONCLUSION IMP3 appears to play an important role in tumor invasion in patients with LAC and may serve as a useful prognostic biomarker in these patients.
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Fawzy IO, Hamza MT, Hosny KA, Esmat G, El Tayebi HM, Abdelaziz AI. miR-1275: A single microRNA that targets the three IGF2-mRNA-binding proteins hindering tumor growth in hepatocellular carcinoma. FEBS Lett 2015; 589:2257-2265. [PMID: 26160756 DOI: 10.1016/j.febslet.2015.06.038] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 06/24/2015] [Accepted: 06/26/2015] [Indexed: 01/08/2023]
Abstract
This study aimed to identify a single miRNA or miR (microRNA) which regulates the three insulin-like growth factor-2-mRNA-binding proteins (IGF2BP1, 2 and 3). Bioinformatics predicted miR-1275 to simultaneously target the three IGF2BPs, and screening revealed miR-1275 to be underexpressed in hepatocellular carcinoma (HCC) tissues. Transfection of HuH-7 cells with miR-1275 suppressed IGF2BPs expression and all three IGF2BPs were confirmed as targets of miR-1275. Ectopic expression of miR-1275 and knockdown of IGF2BPs inhibited malignant cell behaviors, and also reduced IGF1R protein and mRNA. Finally IGF1R was validated as a direct target of miR-1275. These findings indicate that the tumor-suppressor miR-1275 can control HCC tumor growth partially through simultaneously regulating the oncogenic IGF2BPs and IGF1R.
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MESH Headings
- 3' Untranslated Regions/genetics
- Adult
- Base Sequence
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation/genetics
- Cell Survival/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- MicroRNAs/genetics
- Middle Aged
- RNA Interference
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Receptor, IGF Type 1
- Receptors, Somatomedin/genetics
- Receptors, Somatomedin/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Nucleic Acid
- Tumor Burden/genetics
- Young Adult
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Affiliation(s)
- Injie Omar Fawzy
- The Molecular Pathology Research Group, Department of Pharmacology, German University in Cairo, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt
| | - Mohammed Tarif Hamza
- Department of Clinical Pathology, Ain Shams University, Khalifa El-Maamoun St., Abbasiya Square, 11566 Cairo, Egypt
| | - Karim Adel Hosny
- Department of Endemic Medicine and Hepatology, Cairo University, Kasr El-Aini St., 11562 Cairo, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepatology, Cairo University, Kasr El-Aini St., 11562 Cairo, Egypt
| | - Hend Mohamed El Tayebi
- The Molecular Pathology Research Group, Department of Pharmacology, German University in Cairo, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt
| | - Ahmed Ihab Abdelaziz
- The Molecular Pathology Research Group, Department of Pharmacology, German University in Cairo, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt.
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Liu FY, Zhou SJ, Deng YL, Zhang ZY, Zhang EL, Wu ZB, Huang ZY, Chen XP. MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway. Cell Death Dis 2015; 6:e1670. [PMID: 25741595 PMCID: PMC4385924 DOI: 10.1038/cddis.2015.46] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 01/01/2015] [Accepted: 01/21/2015] [Indexed: 02/06/2023]
Abstract
This study aims to investigate the expression status of miRNA-216b in familial hepatocellular carcinoma (HCC) and the correlation between miRNA-216b expression and pathogenesis, as well as the progression of HCC. The expression profile of miRNAs in plasma of peripheral blood between HCC patients with HCC family history and healthy volunteers without HCC family history was determined by microarray. Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers. Next, miR-216b expression and the clinicopathological features of HCC were evaluated. The effect of miR-216b expression on tumor cells was investigated by regulating miR-216b expression in SMMC-7721 and HepG2 in vitro and in vivo. Finally, we explored mRNA targets of miR-216b. In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues. The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032). The 5-year disease-free survival and overall rates after liver resection in low expression and high expression groups of miR-216b are 62% and 54%, 25% and 20%, respectively. MiR-216b overexpression inhibited cell proliferation, migration and invasion, and miR-216b inhibition did the opposite. The expression of hepatitis B virus x protein (HBx) has tight correlation with downregulation of miR-216b. Furthermore, miR-216b downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and exerted its tumor-suppressor function through inhibition of protein kinase B and extracellular signal-regulated kinase signaling downstream of IGF2. MiR-216b inhibits cell proliferation, migration and invasion of HCC by regulating IGF2BP2 and it is regulated by HBx.
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Affiliation(s)
- F-y Liu
- Department of Surgery, Wuhan Center Hospital, Wuhan, Hubei, China
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
| | - S-j Zhou
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
| | - Y-l Deng
- Department of Gastroenterology, Wuhan Center Hospital, Wuhan, Hubei, China
| | - Z-y Zhang
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
| | - E-l Zhang
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
| | - Z-b Wu
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
| | - Z-y Huang
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
| | - X-p Chen
- Research Laboratory and Hepatic Surgical Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China
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Zhang J, Ou Y, Ma Y, Zheng L, Zhang X, Xia R, Kong F, Shen Y, Wang S, Lin L. Clinical implications of insulin-like growth factor II mRNA-binding protein 3 expression in non-small cell lung carcinoma. Oncol Lett 2015; 9:1927-1933. [PMID: 25789070 PMCID: PMC4356331 DOI: 10.3892/ol.2015.2910] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 01/08/2015] [Indexed: 01/16/2023] Open
Abstract
In order to examine the role of insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression for the prognostic evaluation of non-small cell lung carcinoma (NSCLC), a total of 186 breast cancer patients, with adjacent non-tumor lung tissues, were selected for immunohistochemical staining of IMP3 protein. The NSCLC tissues and paired adjacent non-tumor tissues of six patients were quantified using reverse transcription quantitative polymerase chain reaction. The correlations between IMP3 overexpression and the clinical features of NSCLC were evaluated using the χ2 test and Fisher’s exact test. The survival rate was calculated using the Kaplan-Meier method, and the association between prognostic factors and patient survival was also analyzed by Cox’s proportional hazards models. The results showed that IMP3 protein exhibited a mainly cytoplasmic staining pattern in the NSCLC tissues. The positive rate of IMP3 protein expression was 74.7% (139/186) in the NSCLC tissues and was significantly higher than the rate of 19.9% (37/186) in the adjacent non-tumor tissues. The expression rate of the NQO1 protein was correlated with a large tumor size, poor differentiation, lymph node metastasis, late clinical stage, and disease-free and overall survival rates in the NSCLC patients. In the early- and late-stage NSCLC groups, the disease-free and overall survival rates of the patients with IMP3 expression were significantly lower than those of the patients without IMP3 expression. Further analysis using Cox’s proportional hazard regression model revealed that IMP3 expression was a significant independent hazard factor for the overall survival rate of patients with NSCLC. In conclusion, the present study found that IMP3 plays a significant role in the progression of NSCLC, and that it may potentially be used as an independent biomarker for prognostic evaluation of the cancer.
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Affiliation(s)
- Jinhui Zhang
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Yingfu Ou
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Yibing Ma
- Department of Pathology, Dandong Centre Hospital, Dandong, Liaoning 118000, P.R. China
| | - Linlin Zheng
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Xiaokang Zhang
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Rongjun Xia
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Fanyong Kong
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Yue Shen
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Shiqing Wang
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
| | - Lijuan Lin
- Institute of Molecular Medicine, Medical College, Eastern Liaoning University, Dandong, Liaoning 118000, P.R. China
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Damasceno EAM, Carneiro FP, Magalhães AVD, Carneiro MDV, Takano GHS, Vianna LMDS, Seidler HBK, Castro TMMLD, Muniz-Junqueira MI, Amorim RFB, Ferreira VMM, Motoyama AB. IMP3 expression in gastric cancer: association with clinicopathological features and HER2 status. J Cancer Res Clin Oncol 2014; 140:2163-8. [PMID: 25323937 DOI: 10.1007/s00432-014-1850-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 10/05/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the expression of IMP3, an independent poor prognostic factor for many cancers, and its association with clinicopathological features and HER2 status. METHODS Gastrectomy specimens from 106 patients were evaluated by immunohistochemistry and fluorescence in situ hybridization. RESULTS HER2 overexpression was found in 4.71 % of the samples. A negative association was observed between HER2 overexpression and grade of differentiation. No association was observed between HER2 overexpression and status of surgical margins, vascular invasion, perineural invasion, nodal metastasis and depth of invasion. Among all specimens of gastric cancer, 67.92 % were positive for IMP3. Expression of IMP3 was significantly higher in specimens with vascular invasion, perineural invasion, nodal metastasis and higher depth of invasion. HER2 overexpression was detected in only 5.55 % of IMP3 positive specimens. CONCLUSIONS IMP3 expression was frequently observed in gastric cancer and was associated with poor prognostic clinicopathological features. A survival benefit with HER2 therapy should be expected for the minority of patients with IMP3 positive specimens. Studies should be conducted to evaluate the response to HER2 therapy of gastric cancer expressing IMP3.
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Affiliation(s)
- Emanuel Adelino M Damasceno
- Pathological Anatomy Center, University Hospital of Brasilia (UNB), Via L2 Norte, SGAN 604/605, Brasília, DF, CEP 70840-050, Brazil
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Lederer M, Bley N, Schleifer C, Hüttelmaier S. The role of the oncofetal IGF2 mRNA-binding protein 3 (IGF2BP3) in cancer. Semin Cancer Biol 2014; 29:3-12. [PMID: 25068994 DOI: 10.1016/j.semcancer.2014.07.006] [Citation(s) in RCA: 201] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 07/17/2014] [Indexed: 12/20/2022]
Abstract
The post-transcriptional control of gene expression mediated by RNA-binding proteins (RBPs), long non-coding RNAs (lncRNAs) as well as miRNAs is essential to determine tumor cell fate and thus is a major determinant in cancerogenesis. The IGF2 mRNA binding protein family (IGF2BPs) comprises three RBPs. Two members of the family, IGF2BP1 and IGF2BP3, are bona fide oncofetal proteins, which are de novo synthesized in various human cancers. In vitro studies revealed that IGF2BPs serve as post-transcriptional fine-tuners modulating the expression of genes implicated in the control of tumor cell proliferation, survival, chemo-resistance and metastasis. Consistently, the expression of both IGF2BP family members was reported to correlate with an overall poor prognosis and metastasis in various human cancers. Due to the fact that most reports used a pan-IGF2BP antibody for studying IGF2BP expression in cancer, paralogue-specific functions can barely be evaluated at present. Nonetheless, the accordance of IGF2BPs' role in promoting an aggressive phenotype of tumor-derived cells in vitro and their upregulated expression in aggressive malignancies provides strong evidence that IGF2BPs are powerful post-transcriptional oncogenes enhancing tumor growth, drug-resistance and metastasis. This suggests IGF2BPs as powerful biomarkers and candidate targets for cancer therapy.
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Affiliation(s)
- Marcell Lederer
- Division of Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 1, 06120 Halle, Germany
| | - Nadine Bley
- Division of Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 1, 06120 Halle, Germany; Core Facility Imaging (CFI) of the Medical Faculty, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 1, 06120 Halle, Germany
| | - Christian Schleifer
- Division of Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 1, 06120 Halle, Germany
| | - Stefan Hüttelmaier
- Division of Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 1, 06120 Halle, Germany; Core Facility Imaging (CFI) of the Medical Faculty, Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 1, 06120 Halle, Germany.
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Insulin-like growth factor II messenger RNA–binding protein 3 expression in gastrointestinal mesenchymal tumors. Hum Pathol 2014; 45:481-7. [DOI: 10.1016/j.humpath.2013.10.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 10/08/2013] [Accepted: 10/10/2013] [Indexed: 01/27/2023]
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Vislovukh A, Vargas TR, Polesskaya A, Groisman I. Role of 3’-untranslated region translational control in cancer development, diagnostics and treatment. World J Biol Chem 2014; 5:40-57. [PMID: 24600513 PMCID: PMC3942541 DOI: 10.4331/wjbc.v5.i1.40] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/22/2013] [Accepted: 12/19/2013] [Indexed: 02/05/2023] Open
Abstract
The messenger RNA 3’-untranslated region (3’UTR) plays an important role in regulation of gene expression on the posttranscriptional level. The 3’UTR controls gene expression via orchestrated interaction between the structural components of mRNAs (cis-element) and the specific trans-acting factors (RNA binding proteins and non-coding RNAs). The crosstalk of these factors is based on the binding sequences and/or direct protein-protein interaction, or just functional interaction. Much new evidence that has accumulated supports the idea that several RNA binding factors can bind to common mRNA targets: to the non-overlapping binding sites or to common sites in a competitive fashion. Various factors capable of binding to the same RNA can cooperate or be antagonistic in their actions. The outcome of the collective function of all factors bound to the same mRNA 3’UTR depends on many circumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3’UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological conditions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these alterations and their impact on 3’UTR-directed posttranscriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer diagnostics and therapy based on 3’UTR binding factors and approaches to improve them.
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Yang X, Kandil D, Cosar EF, Khan A. Fibroepithelial tumors of the breast: pathologic and immunohistochemical features and molecular mechanisms. Arch Pathol Lab Med 2014; 138:25-36. [PMID: 24377809 DOI: 10.5858/arpa.2012-0443-ra] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT The 2 main prototypes of fibroepithelial tumors of the breast include fibroadenoma and phyllodes tumor (PT). Although both tumors share some overlapping histologic features, there are significant differences in their clinical behavior and management. Phyllodes tumors have been further divided into clinically relevant subtypes, and there is more than one classification scheme for PT currently in use, suggesting a lack of consistency within different practices. Accurate differentiation between fibroadenoma and PT, as well as the grading of PT, may sometimes be challenging on preoperative core needle biopsy. Some immunohistochemical markers have been suggested to aid in the pathologic classification of these lesions. OBJECTIVE To discuss the salient histopathologic features of fibroepithelial tumors and review the molecular pathways proposed for the initiation, progression, and metastasis of PTs. Also, to provide an update on immunohistochemical markers that may be useful in their differential diagnosis and outline the practice and experience at our institution from a pathologic perspective. DATA SOURCES Sources included published articles from peer-reviewed journals in PubMed (US National Library of Medicine). CONCLUSIONS Fibroepithelial tumor of the breast is a heterogenous group of lesions ranging from fibroadenoma at the benign end of the spectrum to malignant PT. There are overlapping histologic features among various subtypes, and transformation and progression to a more malignant phenotype may also occur. Given the significant clinical differences within various subtypes, accurate pathologic classification is important for appropriate management. Although some immunohistochemical markers may be useful in this differential diagnosis, histomorphology still remains the gold standard.
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Affiliation(s)
- Xiaofang Yang
- From the Department of Pathology, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester
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Wang T, Gao J, Yu J, Shen L. Synergistic inhibitory effect of wogonin and low-dose paclitaxel on gastric cancer cells and tumor xenografts. Chin J Cancer Res 2013; 25:505-13. [PMID: 24255573 DOI: 10.3978/j.issn.1000-9604.2013.08.14] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 05/10/2012] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE To investigate the synergistic inhibitory effects of wogonin (WOG) and chemotherapeutic drugs on growth of gastric cancer cells and tumor xenografts. METHODS The IC50 values of WOG, cisplatin (CDDP) and paclitaxel (PTX) in four gastric cancer cell lines were determined by MTS assay. Hoechst staining and the median effect method of Chou-Talalay were used to assess the apoptosis of cells and the interaction of two drugs, respectively. BGC-823-derived xenografts in nude mice were established to investigate the effects of WOG combined with chemotherapeutic drugs in vivo. RESULTS WOG, CDDP and PTX inhibited the growth of BGC-823, MGC-803, MKN-45 and HGC-27 gastric cancer cells in a dose-dependent manner. WOG combined with CDDP or PTX synergistically inhibited the growth of all gastric cancer cell lines in vitro. In BGC-823, MGC-803, HGC-27 and MKN-45 cell lines, synergisms between WOG and PTX were shown when the fraction affected (Fa) values were <0.45, <0.90, <0.85 and <0.60. While WOG and CDDP had a synergistic inhibitory effect when the Fa values were >0, >0, >0.65 and >0.10. From the results of in vivo experiments using tumor xenografts, WOG and low-dose PTX showed better efficacy than either drug alone. The inhibitory percentages of tumor weight were 61.58%, 20.29%, and 22.28% for the combination, WOG-alone, and low-dose PTX-alone groups, respectively. Notably, WOG combined with CDDP displayed very high toxicity. CONCLUSIONS A synergistic inhibitory effect on growth was observed when WOG was combined with low-dose PTX in gastric cancer cells and tumor xenografts. These findings provide evidence for the design of a clinical trial to test the combination of WOG with low-dose PTX in human gastric cancer.
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Affiliation(s)
- Tingting Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Rivera Vargas T, Boudoukha S, Simon A, Souidi M, Cuvellier S, Pinna G, Polesskaya A. Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization. Oncogene 2013; 33:2866-75. [PMID: 23812426 DOI: 10.1038/onc.2013.252] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 05/17/2013] [Accepted: 05/19/2013] [Indexed: 01/03/2023]
Abstract
RNA-binding proteins of the IMP family (insulin-like growth factor 2 (IGF2) mRNA-binding proteins 1-3) are important post-transcriptional regulators of gene expression. Multiple studies have linked high expression of IMP proteins, and especially of IMP-3, to an unfavorable prognosis in numerous types of cancer. The specific importance of IMP-3 for cancer transformation remains poorly understood. We here show that all three IMPs can directly bind the mRNAs of cyclins D1, D3 and G1 (CCND1, D3 and G1) in vivo and in vitro, and yet only IMP-3 regulates the expression of these cyclins in a significant manner in six human cancer cell lines of different origins. In the absence of IMP-3, the levels of CCND1, D3 and G1 proteins fall dramatically, and the cells accumulate in the G1 phase of the cell cycle, leading to almost complete proliferation arrest. Our results show that, compared with IMP-1 and IMP-2, IMP-3 is enriched in the nucleus, where it binds the transcripts of CCND1, D3 and G1. The nuclear localization of IMP-3 depends on its protein partner HNRNPM and is indispensable for the post-transcriptional regulation of expression of the cyclins. Cytoplasmic retention of IMP-3 and HNRNPM in human cancer cells leads to significant drop in proliferation. In conclusion, a nuclear IMP-3-HNRNPM complex is important for the efficient synthesis of CCND1, D3 and G1 and for the proliferation of human cancer cells.
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Affiliation(s)
- T Rivera Vargas
- 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France
| | - S Boudoukha
- 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France [4] Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
| | - A Simon
- 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France
| | - M Souidi
- 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France
| | - S Cuvellier
- Inserm U1016, Institut Cochin, Département Génétique et Développement, Paris, France
| | - G Pinna
- 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France
| | - A Polesskaya
- 1] CNRS, FRE 3377, Gif-sur-Yvette, France [2] Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France [3] CEA, FRE 3377, Gif-sur-Yvette, France
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The oncofetal protein IMP3: a novel biomarker and triage tool for premalignant atypical endometriotic lesions. Fertil Steril 2013; 99:1974-9. [PMID: 23473990 DOI: 10.1016/j.fertnstert.2013.02.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 01/24/2013] [Accepted: 02/04/2013] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To determine whether the oncofetal protein IMP3 is detectable in endometriomas with or without histological atypia and whether IMP3 staining can be used as a triage tool to identify foci of atypical endometriosis in doubtful cases. DESIGN Retrospective study. SETTING Academic department and referral center for endometriosis. PATIENT(S) A consecutive series of 516 women who underwent excision of 874 endometriomas. INTERVENTION(S) Histological review by three expert pathologists and immunohistochemical staining for IMP3. MAIN OUTCOME MEASURE(S) Test performance of IMP3 immunohistochemistry versus first-round histology. RESULT(S) The prevalence of atypical endometriosis was 1.7% (95% confidence interval [CI], 0.9%-3.3%) based on the number of women and 1.0% (95% CI, 0.5%-1.9%) based on the number of cysts. Three cases of atypical endometriosis were identified at first-round histological examination. Immunohistochemistry detected seven of the eight cases diagnosed as preneoplastic atypia at second-round histology and one case diagnosed as reactive atypia at second-round histology. The sensitivity of first-round histology was 33.3%, compared with 88.9% of IMP3 immunohistochemistry. CONCLUSION(S) Immunohistochemical staining for IMP3 expression is a simple, inexpensive, and sensitive test that can be used in routine clinical practice as a triage tool to discriminate between cytological/structural atypia and confounding benign conditions.
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Fadare O, Liang SX, Crispens MA, Jones HW, Khabele D, Gwin K, Zheng W, Mohammed K, Parkash V, Hecht JL, Desouki MM. Expression of the oncofetal protein IGF2BP3 in endometrial clear cell carcinoma: assessment of frequency and significance. Hum Pathol 2013; 44:1508-15. [PMID: 23465280 DOI: 10.1016/j.humpath.2012.12.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 12/06/2012] [Accepted: 12/07/2012] [Indexed: 01/05/2023]
Abstract
Insulin-like growth factor-II messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is a biomarker whose expression has been found to be a negative prognostic factor in several neoplasms including ovarian clear cell carcinoma (CCC). In this study, we analyzed the frequency and clinicopathologic significance of IMP3 expression, as assessed by immunohistochemistry and as scored using a modified H-score system, in a cohort of 50 endometrial CCCs. Cases with scores of 0 to 100, 101 to 200, and 201 to 300 were classified as negative/mildly positive (n = 17), moderately positive (n = 20), and strongly positive (n = 13), respectively. A distinctive pattern of increased staining at the myoinvasive front (relative to the main tumor) was evident in 46% of the cases with evaluable foci of myometrial invasion. Moderate/strong IMP3 staining was associated with a tumor architectural pattern that has been reported to be of poor prognostic significance: at least 10% of the tumor composed of solid architecture or individual infiltrating tumor cells (P = .01). Increasing levels of IMP3 expression showed a trend toward decreasing relapse-free survival (RFS; median survival, 75.6, 81.3, and 48.4 months for the negative/mildly, moderately, and strongly positive groups, respectively [P = .09]). However, IMP3 expression was not significantly associated with reduced overall survival or RFS in a multivariate analytic model. The finding in a subset of our cases of increased IMP3 expression at the tumoral myoinvasive front is consistent with a role for IMP3 in invasiveness, as is the trend toward reduced RFS in cases expressing IMP3 at high levels. These preliminary findings suggest that IMP3 expression may be involved in the pathogenesis of CCC and is worthy of further exploration.
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Affiliation(s)
- Oluwole Fadare
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Kessler SM, Pokorny J, Zimmer V, Laggai S, Lammert F, Bohle RM, Kiemer AK. IGF2 mRNA binding protein p62/IMP2-2 in hepatocellular carcinoma: antiapoptotic action is independent of IGF2/PI3K signaling. Am J Physiol Gastrointest Liver Physiol 2013; 304:G328-36. [PMID: 23257922 DOI: 10.1152/ajpgi.00005.2012] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The insulin-like growth factor II (IGF2) mRNA binding protein (IMP) p62/IMP2-2, originally isolated from a hepatocellular carcinoma (HCC) patient, induces a steatotic phenotype when overexpressed in mouse livers. Still, p62 transgenic livers do not show liver cell damage but exhibit a pronounced induction of Igf2 and activation of the downstream survival kinase AKT. The aim of this study was to investigate the relation between p62 and IGF2 expression in the human system and to study potential antiapoptotic actions of p62. p62 and IGF2 mRNA levels were assessed by real-time RT-PCR. For knockdown and overexpression experiments, human hepatoma HepG2 and PLC/PRF/5 cells were transfected with siRNA or plasmid DNA. Phosphorylated AKT and ERK1/2 were analyzed by Western blot. Investigations of 32 human HCC tissues showed a strong correlation between p62 and IGF2 expression. Of note, p62 expression was increased markedly in patients with poor outcome. In hepatoma cells overexpression of p62 lowered levels of doxorubicin-induced caspase-3-like activity. Vice versa, knockdown of p62 resulted in increased doxorubicin-induced apoptosis. However, neither PI3K inhibitors nor a neutralizing IGF2 antibody showed any effects. Western blot analysis revealed increased levels of phosphorylated ERK1/2 in hepatoma cells overexpressing p62 and decreased levels in p62 knockdown experiments. When p62-overexpressing cells were treated with ERK1/2 inhibitors, the apoptosis-protecting effect of p62 was completely abrogated. Our data demonstrate that p62 exerts IGF2-independent antiapoptotic action, which is facilitated via phosphorylation of ERK1/2. Furthermore, p62 might serve as a new prognostic marker in HCC.
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Affiliation(s)
- Sonja M Kessler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
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Ueki A, Shimizu T, Masuda K, Yamaguchi SI, Ishikawa T, Sugihara E, Onishi N, Kuninaka S, Miyoshi K, Muto A, Toyama Y, Banno K, Aoki D, Saya H. Up-regulation of Imp3 confers in vivo tumorigenicity on murine osteosarcoma cells. PLoS One 2012; 7:e50621. [PMID: 23226335 PMCID: PMC3511546 DOI: 10.1371/journal.pone.0050621] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 10/22/2012] [Indexed: 11/19/2022] Open
Abstract
Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development. We have now identified Igf2 mRNA-binding protein3 (Imp3) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo. Imp3 is consistently up-regulated in tumors formed by AX cells, and its expression in these cells was found to confer malignant properties such as anchorage-independent growth, loss of contact inhibition, and escape from anoikis in vitro. The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells. The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism. Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy.
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Affiliation(s)
- Arisa Ueki
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Takatsune Shimizu
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
- Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
- * E-mail:
| | - Kenta Masuda
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Sayaka I. Yamaguchi
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tomoki Ishikawa
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Kasai R&D Center, Daiichi Sankyo Co. Ltd., Tokyo, Japan
| | - Eiji Sugihara
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Nobuyuki Onishi
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
| | - Shinji Kuninaka
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
| | - Keita Miyoshi
- Department of Molecular Biology, School of Medicine, Keio University, Tokyo, Japan
| | - Akihiro Muto
- Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
| | - Yoshiaki Toyama
- Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
- Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
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Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression? Cell Mol Life Sci 2012; 70:2657-75. [PMID: 23069990 PMCID: PMC3708292 DOI: 10.1007/s00018-012-1186-z] [Citation(s) in RCA: 569] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 09/28/2012] [Accepted: 10/01/2012] [Indexed: 12/21/2022]
Abstract
The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, IGF2BP3) belong to a conserved family of RNA-binding, oncofetal proteins. Several studies have shown that these proteins act in various important aspects of cell function, such as cell polarization, migration, morphology, metabolism, proliferation and differentiation. In this review, we discuss the IGF2BP family’s role in cancer biology and how this correlates with their proposed functions during embryogenesis. IGF2BPs are mainly expressed in the embryo, in contrast with comparatively lower or negotiable levels in adult tissues. IGF2BP1 and IGF2BP3 have been found to be re-expressed in several aggressive cancer types. Control of IGF2BPs’ expression is not well understood; however, let-7 microRNAs, β-catenin (CTNNB1) and MYC have been proposed to be involved in their regulation. In contrast to many other RNA-binding proteins, IGF2BPs are almost exclusively observed in the cytoplasm where they associate with target mRNAs in cytoplasmic ribonucleoprotein complexes (mRNPs). During development, IGF2BPs are required for proper nerve cell migration and morphological development, presumably involving the control of cytoskeletal remodeling and dynamics, respectively. Likewise, IGF2BPs modulate cell polarization, adhesion and migration in tumor-derived cells. Moreover, they are highly associated with cancer metastasis and the expression of oncogenic factors (KRAS, MYC and MDR1). However, a pro-metastatic role of IGF2BPs remains controversial due to the lack of ‘classical’ in vivo studies. Nonetheless, IGF2BPs could provide valuable targets in cancer treatment with many of their in vivo roles to be fully elucidated.
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Regulation of IMP3 by EGFR signaling and repression by ERβ: implications for triple-negative breast cancer. Oncogene 2012; 31:4689-97. [PMID: 22266872 PMCID: PMC3337950 DOI: 10.1038/onc.2011.620] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Insulin-like growth factor II (IGF-II) mRNA binding protein 3 (IMP3) is emerging as a useful indicator of the progression and outcome of several cancers. IMP3 expression is associated with triple-negative breast carcinomas (TNBCs), which are aggressive tumors associated with poor outcome. In this study, we addressed the hypothesis that signaling pathways, which are characteristic of TNBCs, impact the expression of IMP3 and that IMP3 contributes to the function of TNBCs. The data obtained reveal that IMP3 expression is repressed specifically by estrogen receptor β (ERβ) and its ligand 3βA-diol but not by ERα. EGF receptor (EGFR) signaling and consequent activation of the MAP kinase pathway induce IMP3 transcription and expression. Interestingly, we discovered that the EGFR promoter contains an imperfect estrogen response element and that ERβ represses EGFR transcription. These data support a mechanism in which ERβ inhibits IMP3 expression indirectly by repressing the EGFR. This mechanism relates to the biology of TNBC, which is characterized by diminished ERβ and increased EGFR expression. We also demonstrate that IMP3 contributes to the migration and invasion of breast carcinoma cells. Given that IMP3 is an mRNA binding protein, we determined that it binds several key mRNAs that could contribute to migration and invasion including CD164 (endolyn) and MMP9. Moreover, expression of these mRNAs is repressed by ERβ and enhanced by EGFR signaling, consistent with our proposed mechanism for the regulation of IMP3 expression in breast cancer cells. Our findings show that IMP3 is an effector of EGFR-mediated migration and invasion and they provide the first indication of how this important mRNA binding protein is regulated in cancer.
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Chen ST, Jeng YM, Chang CC, Chang HH, Huang MC, Juan HF, Hsu CH, Lee H, Liao YF, Lee YL, Hsu WM, Lai HS. Insulin-like growth factor II mRNA-binding protein 3 expression predicts unfavorable prognosis in patients with neuroblastoma. Cancer Sci 2011; 102:2191-8. [PMID: 21917080 PMCID: PMC11158860 DOI: 10.1111/j.1349-7006.2011.02100.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported to enhance proliferation and invasion in various cancers. The role of IMP3 on neuroblastoma (NB) is unknown. We aimed to clarify the prognostic significance of IMP3 expression in patients with NB. By microarray analysis, high IMP3 expression was found in patients with poor outcome. IMP3 expression in 90 NB samples was analyzed by immunohistochemical staining to correlate with clinical stages, histology, and patient outcome. Positive IMP3 expression was detected in 52 of 90 patients, and was significantly correlated with undifferentiated histology, advanced stages, MYCN amplification, and poor outcome. In subgroups, positive IMP3 expression could predict an even worse prognosis in patients with advanced disease, with normal MYCN status, or with MYCN amplification (P = 0.005, P = 0.001, and P = 0.033, respectively). The IMP3 expression decreased by induction of differentiation with retinoid acid treatment in SK-N-DZ and SK-N-SH cells in vitro. The invasion ability of NB cells also decreased as IMP3 knockdown by using RNA interference in vitro. In summary, high expression of IMP3 in NB might contribute to the undifferentiated phenotype and invasive behaviors, leading to a poor prognosis. Determining IMP3 expression in NB could help to improve a personalized therapy.
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Affiliation(s)
- Szu-Ta Chen
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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