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Tsukamoto S, Huaze Y, Weisheng Z, Machinaga A, Kakiuchi N, Ogawa S, Seno H, Higashiyama S, Matsuda M, Hiratsuka T. Quantitative Live Imaging Reveals Phase Dependency of PDAC Patient-Derived Organoids on ERK and AMPK Activity. Cancer Sci 2025; 116:724-735. [PMID: 39731327 PMCID: PMC11875792 DOI: 10.1111/cas.16439] [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: 08/24/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 12/29/2024] Open
Abstract
Patient-derived organoids represent a novel platform to recapitulate the cancer cells in the patient tissue. While cancer heterogeneity has been extensively studied by a number of omics approaches, little is known about the spatiotemporal kinase activity dynamics. Here we applied a live imaging approach to organoids derived from 10 pancreatic ductal adenocarcinoma (PDAC) patients to comprehensively understand their heterogeneous growth potential and drug responses. By automated wide-area image acquisitions and analyses, the PDAC cells were non-selectively observed to evaluate their heterogeneous growth patterns. We monitored single-cell ERK and AMPK activities to relate cellular dynamics to molecular dynamics. Furthermore, we evaluated two anti-cancer drugs, a MEK inhibitor, PD0325901, and an autophagy inhibitor, hydroxychloroquine (HCQ), by our analysis platform. Our analyses revealed a phase-dependent regulation of PDAC organoid growth, where ERK activity is necessary for the early phase and AMPK activity is necessary for the late stage of organoid growth. Consistently, we found PD0325901 and HCQ target distinct organoid populations, revealing their combination is widely effective to the heterogeneous cancer cell population in a range of PDAC patient-derived organoid lines. Together, our live imaging quantitatively characterized the growth and drug sensitivity of human PDAC organoids at multiple levels: in single cells, single organoids, and individual patients. This study will pave the way for understanding the cancer heterogeneity and promote the development of new drugs that eradicate intractable cancer.
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Affiliation(s)
- Shoko Tsukamoto
- Laboratory of Cell Cycle Regulation, Graduate School of BiostudiesKyoto UniversityKyotoJapan
| | - Ye Huaze
- Department of Molecular Oncology, Graduate School of MedicineOsaka UniversityOsakaJapan
| | - Zhang Weisheng
- Department of Molecular Oncology, Graduate School of MedicineOsaka UniversityOsakaJapan
| | - Akihito Machinaga
- Oncology Tsukuba Research Department, Discovery, Medicine CreationOBG, Eisai Co. Ltd.TsukubaJapan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Graduate School of MedicineKyoto UniversityKyotoJapan
- The Hakubi Center for Advanced ResearchKyoto UniversityKyotoJapan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroshi Seno
- The Hakubi Center for Advanced ResearchKyoto UniversityKyotoJapan
| | - Shigeki Higashiyama
- Department of Oncogenesis and Growth Regulation, Research CenterOsaka International Cancer InstituteOsakaJapan
| | - Michiyuki Matsuda
- Laboratory of Cell Cycle Regulation, Graduate School of BiostudiesKyoto UniversityKyotoJapan
- Affiliated Graduate School, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Toru Hiratsuka
- Department of Molecular Oncology, Graduate School of MedicineOsaka UniversityOsakaJapan
- Department of Oncogenesis and Growth Regulation, Research CenterOsaka International Cancer InstituteOsakaJapan
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2
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Fang J, Huang J, Zhang J, Chen L, Deng J. Comprehensive Analysis of Tertiary Lymphoid Structures in Pancreatic Cancer: Molecular Characteristics and Prognostic Implications. CURR PROTEOMICS 2024; 21:230-250. [DOI: 10.2174/0115701646317271240821071544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/16/2024] [Accepted: 07/23/2024] [Indexed: 01/07/2025]
Abstract
Purpose:
The molecular properties of TLSs in pancreatic cancer are still not well comprehended.
This research delved into the molecular properties of intratumoral TLSs in pancreatic
cancer through the exploration of multi-omics data.
Methods:
Seven key genes were identified through Cox regression analysis and random survival
forest analysis from a total of 5908 genes related to TLSs. These genes were utilized to construct a
prognosis model, which was subsequently validated in two independent cohorts. Additionally, the
study investigated the molecular features of different populations of TLSs from multiple perspectives.
The model’ s forecasting accuracy was verified by analyzing nomogram and decision curves,
taking into account the patients’ clinical traits.
Results:
The analysis of immune cell infiltration showed a notably greater presence of Macrophage
M0 cells in the group at high risk than in the low-risk group. The pathway enrichment analysis
demonstrated the activation among common cancer-related pathways, including ECM receptor interaction,
pathways in cancer, and focal adhesion, in the high-risk group. Additionally, the methylation
study revealed notable disparities in DNA methylation between two TLS groups across four
regions: TSS200, 5’ UTR, 1stExon, and Body. A variety of notably distinct sites were linked with
PVT1. Furthermore, by constructing a competing endogenous RNA network, several mRNAs and
lncRNAs were identified that compete for the binding of hsa-mir-221.
Conclusion:
Overall, this research sheds light on the molecular properties of TLSs across various
pancreatic cancer stages and suggests possible focal points for the treatment of pancreatic cancer.
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Affiliation(s)
- Jiana Fang
- College of Mathematics and Informatics, South China Agricultural University, Guangzhou, 510642, China
| | - Jingru Huang
- College of Mathematics and Informatics, South China Agricultural University, Guangzhou, 510642, China
| | - Jiazhong Zhang
- College of Mathematics and Informatics, South China Agricultural University, Guangzhou, 510642, China
| | - Lin Chen
- Department of General Practice, Sun Yat-Sen Memorial Hospital, Guangzhou,
510120, China
| | - Jin Deng
- College of Mathematics and Informatics, South China Agricultural University, Guangzhou, 510642, China
- Pazhou
Lab, Guangzhou, 510330, China
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3
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Biswas S, Afrose S, Mita MA, Hasan MR, Shimu MSS, Zaman S, Saleh MA. Next-Generation Sequencing: An Advanced Diagnostic Tool for Detection of Pancreatic Disease/Disorder. JGH Open 2024; 8:e70061. [PMID: 39605899 PMCID: PMC11599877 DOI: 10.1002/jgh3.70061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
The pancreas is involved in digestion and glucose regulation in the human body. Given the recognized link between chronic pancreatitis and pancreatic cancer, addressing pancreatic disorders and pancreatic cancer is particularly challenging. This review aims to highlight the limitations of traditional methods in diagnosing pancreatic disorders and cancer and explore several next-generation sequencing (NGS) approaches as a promising alternative. There are distinct clinical symptoms that are shared by a number of clinical phenotypes of pancreatic illness induced by particular genetic mutations. Traditional diagnostic methods encompass computed tomography, magnetic resonance imaging, contrast-enhanced Doppler ultrasound, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, transabdominal ultrasound, laparoscopy, and positron emission tomography have a prognostic ability of only 5% or less and a 5-year survival rate. Genetic sequencing can be employed as an alternative to conventional diagnostic techniques. Sanger sequencing and NGS are currently largely operated genome analysis, with no exception for pancreatic disease diagnosis. The NGS methods can sequence millions to billions of short DNA fragments, enabling enormous sample screening in a short amount of time with low-abundance detection, like in 0.1%-1% mutation prevalence declining approximate cost. Whole-genome sequencing, whole-exome sequencing, RNA sequencing, and single-cell NGS are a few NGS methods utilized to diagnose pancreatic disease. For both research and clinical applications, the NGS techniques can provide a precise diagnosis of pancreatic disorders in a short amount of time at a reasonable expenditure.
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Affiliation(s)
- Suvro Biswas
- Miocrobiology Laboratory, Department of Genetic Engineering and BiotechnologyUniversity of RajshahiBangladesh
| | - Shamima Afrose
- Department of Genetic Engineering and BiotechnologyUniversity of RajshahiRajshahiBangladesh
| | - Mohasana Akter Mita
- Department of Genetic Engineering and BiotechnologyUniversity of RajshahiRajshahiBangladesh
| | - Md. Robiul Hasan
- Department of Genetic Engineering and BiotechnologyUniversity of RajshahiRajshahiBangladesh
| | | | - Shahriar Zaman
- Miocrobiology Laboratory, Department of Genetic Engineering and BiotechnologyUniversity of RajshahiBangladesh
| | - Md. Abu Saleh
- Miocrobiology Laboratory, Department of Genetic Engineering and BiotechnologyUniversity of RajshahiBangladesh
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4
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Romashin DD, Tolstova TV, Varshaver AM, Kozhin PM, Rusanov AL, Luzgina NG. Keratins 6, 16, and 17 in Health and Disease: A Summary of Recent Findings. Curr Issues Mol Biol 2024; 46:8627-8641. [PMID: 39194725 DOI: 10.3390/cimb46080508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 08/29/2024] Open
Abstract
Keratins 6, 16, and 17 occupy unique positions within the keratin family. These proteins are not commonly found in the healthy, intact epidermis, but their expression increases in response to damage, inflammation, and hereditary skin conditions, as well as cancerous cell transformations and tumor growth. As a result, there is an active investigation into the potential use of these proteins as biomarkers for different pathologies. Recent studies have revealed the role of these keratins in regulating keratinocyte migration, proliferation, and growth, and more recently, their nuclear functions, including their role in maintaining nuclear structure and responding to DNA damage, have also been identified. This review aims to summarize the latest research on keratins 6, 16, and 17, their regulation in the epidermis, and their potential use as biomarkers in various skin conditions.
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Affiliation(s)
| | | | | | - Peter M Kozhin
- Institute of Biomedical Chemistry, Moscow 119121, Russia
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Zhou Y, He Z, Li T, Choppavarapu L, Hu X, Cao R, Leone GW, Kahn M, Jin VX. 3D Chromatin Alteration by Disrupting β-Catenin/CBP Interaction Is Enriched with Insulin Signaling in Pancreatic Cancer. Cancers (Basel) 2024; 16:2202. [PMID: 38927910 PMCID: PMC11201718 DOI: 10.3390/cancers16122202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/02/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of how the functional crosstalk between the antagonist and the β-catenin/CBP interaction affects changes in 3D chromatin architecture and, thereby, gene expression and downstream effects remains to be elucidated. Here, we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate that the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1-a key insulin signaling gene-significantly impeding pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
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Affiliation(s)
- Yufan Zhou
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (Z.H.); (T.L.)
| | - Zhijing He
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (Z.H.); (T.L.)
- Department of Stomatology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Tian Li
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (Y.Z.); (Z.H.); (T.L.)
| | - Lavanya Choppavarapu
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Xiaohui Hu
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China;
| | - Ruifeng Cao
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, The State University of New Jersey, Piscataway, NJ 08854, USA;
| | - Gustavo W. Leone
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;
| | - Victor X. Jin
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Fu MS, Pan SX, Cai XQ, Lv CT, Pan QC. ARHGAP4 Inhibits Proliferation and Growth of SW620 Colon Cancer Cells by Cell Cycle and Differentiation Pathways. SCIENTIFICA 2024; 2024:5791613. [PMID: 38938545 PMCID: PMC11208814 DOI: 10.1155/2024/5791613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 06/29/2024]
Abstract
The aim of this study is to explore the mechanism by which ARHGAP4 regulates the proliferation and growth of colon cancer cells, and it relates to the metastasis of colorectal cancer (CRC). Various techniques including western blot, CCK8, qRT-PCR, RNA seq assay, plate cloning, subcutaneous tumorigenesis assays, and bioinformatics tools were employed to identify genes that were upregulated or downregulated upon ARHGAP4 knockdown and their involvement in tumor cell proliferation and growth. The expression of ARHGAP4 in T and M stages of CRC uses immunohistochemistry. The expression levels of ARHGAP4 were found to be high in SW620, SW480, and HCT116 cell lines, while they were being low in HT29, LoVo, and NCM460 cell lines. Depletion of ARHGAP4 resulted in inhibited proliferation and growth in SW620 cells and inhibited subcutaneous tumorigenesis in nude mice, whereas overexpression of ARHGAP4 promoted proliferation and growth in HT29 cells and promoted subcutaneous tumorigenesis in nude mice. A total of 318 upregulated genes and 637 downregulated genes were identified in SW620 cells upon ARHGAP4 knockdown. The downregulated genes were primarily associated with cell cycle pathways, while the upregulated genes were enriched in differentiation-related pathways. Notable upregulated genes involved in cell differentiation included KRT10, KRT13, KRT16, IVL, and CD24, while significant downregulation was observed in genes related to the cell cycle such as CCNA2, CDKN2C, CDKN3, CENPA, and CENPF. ARHGAP4 expression is markedly elevated in the M1 stage of CRC compared to the M0 stage, suggesting ARHGAP4 linked to the metastatic in CRC. ARHGAP4 regulates the proliferation and growth of colon cancer cells by up- and downregulated cell cycle and differentiation-related molecules, which may be related to the metastasis of CRC.
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Affiliation(s)
- Ming-Sheng Fu
- Department of Gastroenterology, Shanghai Fifth People's Hospital Fudan University, No. 801, Heqing Road, Minhang District, Shanghai 200240, China
| | - Shu-Xian Pan
- Department of Anesthesiology, Shanghai Fifth People's Hospital Fudan University, Shanghai 200240, China
| | - Xun-Quan Cai
- Department of Gastroenterology, Shanghai Fifth People's Hospital Fudan University, No. 801, Heqing Road, Minhang District, Shanghai 200240, China
| | - Cui-Ting Lv
- Central Laboratory, Shanghai Fifth People's Hospital Fudan University, Shanghai 200240, China
| | - Qin-Cong Pan
- Department of Gastroenterology, Shanghai Fifth People's Hospital Fudan University, No. 801, Heqing Road, Minhang District, Shanghai 200240, China
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7
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Bertonnier‐Brouty L, Andersson J, Kaprio T, Hagström J, Bsharat S, Asplund O, Hatem G, Haglund C, Seppänen H, Prasad RB, Artner I. E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma. Cancer Med 2024; 13:e7187. [PMID: 38686617 PMCID: PMC11058697 DOI: 10.1002/cam4.7187] [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: 09/18/2023] [Revised: 03/14/2024] [Accepted: 04/02/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. OBJECTIVE Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion. METHODS AND RESULTS Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. CONCLUSION Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
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Affiliation(s)
- Ludivine Bertonnier‐Brouty
- Lund Stem Cell CenterLund UniversityLundSweden
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | | | - Tuomas Kaprio
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
| | - Jaana Hagström
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
- Department of Oral Pathology and RadiologyUniversity of TurkuTurkuFinland
| | - Sara Bsharat
- Lund Stem Cell CenterLund UniversityLundSweden
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | - Olof Asplund
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | - Gad Hatem
- Lund University Diabetes Center, Lund UniversityMalmöSweden
| | - Caj Haglund
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
| | - Hanna Seppänen
- Department of SurgeryHelsinki University HospitalHelsinkiFinland
- Translational Cancer Medicine Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- iCAN, Digital Cancer Precision MedicineUniversity of Helsinki and HUS Helsinki University HospitalHelsinkiFinland
| | | | - Isabella Artner
- Lund Stem Cell CenterLund UniversityLundSweden
- Lund University Diabetes Center, Lund UniversityMalmöSweden
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Zhou Y, Li T, He Z, Choppavarapu L, Hu X, Cao R, Leone GW, Kahn M, Jin VX. Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.10.566585. [PMID: 38013997 PMCID: PMC10680786 DOI: 10.1101/2023.11.10.566585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the β-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
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9
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Jamali E, Safarzadeh A, Hussen BM, Liehr T, Ghafouri-Fard S, Taheri M. Single cell RNA-seq analysis with a systems biology approach to recognize important differentially expressed genes in pancreatic ductal adenocarcinoma compared to adjacent non-cancerous samples by targeting pancreatic endothelial cells. Pathol Res Pract 2023; 248:154614. [PMID: 37329816 DOI: 10.1016/j.prp.2023.154614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/03/2023] [Accepted: 06/10/2023] [Indexed: 06/19/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a cancer that is usually diagnosed at late stages. This highly aggressive tumor is resistant to most therapeutic approaches, necessitating identification of differentially expressed genes to design new therapies. Herein, we have analyzed single cell RNA-seq data with a systems biology approach to identify important differentially expressed genes in PDAC samples compared to adjacent non-cancerous samples. Our approach revealed 1462 DEmRNAs, including 1389 downregulated DEmRNAs (like PRSS1 and CLPS) and 73 upregulated DEmRNAs (like HSPA1A and SOCS3), 27 DElncRNAs, including 26 downregulated DElncRNAs (like LINC00472 and SNHG7) and 1 upregulated DElncRNA (SNHG5). We also listed a number of dysregulated signaling pathways, abnormally expressed genes and aberrant cellular functions in PDAC which can be used as possible biomarkers and therapeutic targets in this type of cancer.
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Affiliation(s)
- Elena Jamali
- Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Safarzadeh
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Iraq
| | - Thomas Liehr
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Iyer MK, Shi C, Eckhoff AM, Fletcher A, Nussbaum DP, Allen PJ. Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification. SCIENCE ADVANCES 2023; 9:eade4582. [PMID: 36930707 PMCID: PMC10022906 DOI: 10.1126/sciadv.ade4582] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 02/10/2023] [Indexed: 06/18/2023]
Abstract
The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor κB (TNF-NFκB) and cell cycle (cycling S and cycling G2-M) programs occurred with relative prominence in PB and INT subtypes, respectively. Together, this study delineates markers of high-risk IPMN and insights into malignant progression.
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Affiliation(s)
| | - Chanjuan Shi
- Department of Pathology, Duke University, Durham, NC, USA
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11
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Alur V, Raju V, Vastrad B, Vastrad C, Kavatagimath S, Kotturshetti S. Bioinformatics Analysis of Next Generation Sequencing Data Identifies Molecular Biomarkers Associated With Type 2 Diabetes Mellitus. Clin Med Insights Endocrinol Diabetes 2023; 16:11795514231155635. [PMID: 36844983 PMCID: PMC9944228 DOI: 10.1177/11795514231155635] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 01/19/2023] [Indexed: 02/23/2023] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is the most common metabolic disorder. The aim of the present investigation was to identify gene signature specific to T2DM. Methods The next generation sequencing (NGS) dataset GSE81608 was retrieved from the gene expression omnibus (GEO) database and analyzed to identify the differentially expressed genes (DEGs) between T2DM and normal controls. Then, Gene Ontology (GO) and pathway enrichment analysis, protein-protein interaction (PPI) network, modules, miRNA (micro RNA)-hub gene regulatory network construction and TF (transcription factor)-hub gene regulatory network construction, and topological analysis were performed. Receiver operating characteristic curve (ROC) analysis was also performed to verify the prognostic value of hub genes. Results A total of 927 DEGs (461 were up regulated and 466 down regulated genes) were identified in T2DM. GO and REACTOME results showed that DEGs mainly enriched in protein metabolic process, establishment of localization, metabolism of proteins, and metabolism. The top centrality hub genes APP, MYH9, TCTN2, USP7, SYNPO, GRB2, HSP90AB1, UBC, HSPA5, and SQSTM1 were screened out as the critical genes. ROC analysis provides prognostic value of hub genes. Conclusion The potential crucial genes, especially APP, MYH9, TCTN2, USP7, SYNPO, GRB2, HSP90AB1, UBC, HSPA5, and SQSTM1, might be linked with risk of T2DM. Our study provided novel insights of T2DM into genetics, molecular pathogenesis, and novel therapeutic targets.
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Affiliation(s)
- Varun Alur
- Department of Endocrinology, J.J.M
Medical College, Davanagere, Karnataka, India
| | - Varshita Raju
- Department of Obstetrics and
Gynecology, J.J.M Medical College, Davanagere, Karnataka, India
| | - Basavaraj Vastrad
- Department of Pharmaceutical Chemistry,
K.L.E. College of Pharmacy, Gadag, Karnataka, India
| | | | - Satish Kavatagimath
- Department of Pharmacognosy, K.L.E.
College of Pharmacy, Belagavi, Karnataka, India
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Bhardwaj A, Josse C, Van Daele D, Poulet C, Chavez M, Struman I, Van Steen K. Deeper insights into long-term survival heterogeneity of pancreatic ductal adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses. Sci Rep 2022; 12:11027. [PMID: 35773268 PMCID: PMC9247075 DOI: 10.1038/s41598-022-14592-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 06/09/2022] [Indexed: 11/22/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is categorized as the leading cause of cancer mortality worldwide. However, its predictive markers for long-term survival are not well known. It is interesting to delineate individual-specific perturbed genes when comparing long-term (LT) and short-term (ST) PDAC survivors and integrate individual- and group-based transcriptome profiling. Using a discovery cohort of 19 PDAC patients from CHU-Liège (Belgium), we first performed differential gene expression analysis comparing LT to ST survivor. Second, we adopted systems biology approaches to obtain clinically relevant gene modules. Third, we created individual-specific perturbation profiles. Furthermore, we used Degree-Aware disease gene prioritizing (DADA) method to develop PDAC disease modules; Network-based Integration of Multi-omics Data (NetICS) to integrate group-based and individual-specific perturbed genes in relation to PDAC LT survival. We identified 173 differentially expressed genes (DEGs) in ST and LT survivors and five modules (including 38 DEGs) showing associations to clinical traits. Validation of DEGs in the molecular lab suggested a role of REG4 and TSPAN8 in PDAC survival. Via NetICS and DADA, we identified various known oncogenes such as CUL1 and TGFB1. Our proposed analytic workflow shows the advantages of combining clinical and omics data as well as individual- and group-level transcriptome profiling.
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Affiliation(s)
- Archana Bhardwaj
- GIGA-R Centre, BIO3 - Medical Genomics, University of Liège, Avenue de L'Hôpital, 11, 4000, Liège, Belgium.
| | - Claire Josse
- Laboratory of Human Genetics, GIGA Research, University Hospital (CHU), Liège, Belgium
- Medical Oncology Department, CHU Liège, Liège, Belgium
| | - Daniel Van Daele
- Department of Gastro-Enterology, University Hospital (CHU), Liège, Belgium
| | - Christophe Poulet
- Laboratory of Human Genetics, GIGA Research, University Hospital (CHU), Liège, Belgium
- Laboratory of Rheumatology, GIGA-R, University Hospital (CHULiege), Liège, Belgium
| | - Marcela Chavez
- Department of Medicine, Division of Hematology, University Hospital (CHU), Liège, Belgium
| | - Ingrid Struman
- GIGA-R Centre, Laboratory of Molecular Angiogenesis, University of Liège, Liège, Belgium
| | - Kristel Van Steen
- GIGA-R Centre, BIO3 - Medical Genomics, University of Liège, Avenue de L'Hôpital, 11, 4000, Liège, Belgium
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Ding R, Duan Z, Yang M, Wang X, Li D, Kan Q. High miR-3609 expression is associated with better prognosis in TNBC based on mining using systematic integrated public sequencing data. Exp Ther Med 2021; 23:54. [PMID: 34934431 PMCID: PMC8652383 DOI: 10.3892/etm.2021.10976] [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: 05/25/2021] [Accepted: 09/09/2021] [Indexed: 12/09/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) are small endogenous RNAs that regulate gene expression post-transcriptionally. Abnormal miR-3609 expression is associated with the occurrence of pancreatic cancer, glioma and other diseases, such as polycystic ovary syndrome. However, the prognostic potential of miR-3609 has been reported in breast cancer. Thus, the present study aimed to investigate the differential expression and prognostic value of miR-3609 in patients with breast cancer from the UALCAN, cBioportal and Kaplan-Meier Plotter databases, respectively. Furthermore, the co-expression genes of miR-3609 in breast cancer were investigated using data from the LinkedOmics database, and functional enrichment analysis was performed using the LinkInterpreter module in LinkedOmics. The co-expression gene network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and the cytoHubba plug-in was used to identify the hub genes, which were visualized using Cytoscape software. The prognoses of the hub genes were performed using the Kaplan-Meier Plotter database. The Cell Counting Kit-8 and cell cycle assays were performed to confirm the functions of miR-3609 mimics transfection in MDA-MB-231 cells. Survival analysis using the Kaplan-Meier Plotter database demonstrated that high miR-3609 expression in triple-negative breast cancer (TNBC) was associated with a better prognosis. Furthermore, the experimental results indicated that high miR-3609 expression inhibited the proliferation of TNBC cells and induced cell cycle arrest of TNBC cells in the G0/G1 phase. Taken together, the results of the present study suggest that miR-3609 plays a vital role in mediating cell cycle arrest and inhibiting the proliferation of TNBC cells.
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Affiliation(s)
- Rumeng Ding
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhenfeng Duan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Meng Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xinru Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Duolu Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Quancheng Kan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Inoue H, Eguchi A, Kobayashi Y, Usugi E, Yamada R, Tsuboi J, Akuta T, Horiki N, Iwasa M, Takei Y. Extracellular vesicles from pancreatic ductal adenocarcinoma endoscopic ultrasound-fine needle aspiration samples contain a protein barcode. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:394-403. [PMID: 34555251 DOI: 10.1002/jhbp.1048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/25/2021] [Accepted: 09/03/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND The survival rate of pancreatic ductal adenocarcinoma (PDAC) is very poor because early detection is difficult. Extracellular vesicles (EVs) are released from cells associating with the cellular condition and circulated in the blood. We aimed to identify EV proteins from endoscopic ultrasound-fine needle aspiration (EUS-FNA) biopsy samples in order to develop novel biomarkers for PDAC. METHODS Extracellular vesicles were isolated from EUS-FNA samples of 40 PDAC patients and six autoimmune pancreatitis (AIP) patients to be used as a control. EV proteins were identified using nanoLC-MS/MS. RESULTS Intact EVs approximately 200 nm in diameter were detected from EUS-FNA samples. We identified 2059 or 1032 EV proteins in PDAC or AIP, respectively, and 1071 EV proteins were detected only in PDAC. One hundred and fifty-three EV proteins were significantly different between PDAC and AIP: 64 proteins were down-regulated in PDAC whereas 89 EV proteins were up-regulated in PDAC including mucins, keratins, Ras-related proteins, and olfactomedin-4, which proteins have been reported to be elevated in PDAC tissue/blood, or cultured pancreatic cancer cell lines. Notably, in the 89 up-regulated PDAC EV proteins we identified novel proteins including ADP-ribosylation factor 3, CD55, pyruvate kinase, and lipopolysaccharide-induced tumor necrosis factor. Out of 89 proteins, a total of 13 proteins including Ras-related proteins were significantly elevated in PDAC stages II-IV compared to PDAC stage I, including Ras-related proteins, moesin, and CD55. CONCLUSIONS The EV proteins obtained from EUS-FNA samples contain a PDAC-specific protein barcode. The EV proteins identified from EUS-FNA samples include promising biomarkers for the diagnosis and clinical staging of PDAC.
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Affiliation(s)
- Hiroyuki Inoue
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.,JST, PRETO, Kawaguchi, Japan
| | - Yoshinao Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.,Center for Physical and Mental Health, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Eri Usugi
- Department of Oncologic Pathology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Reiko Yamada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Junya Tsuboi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Teruo Akuta
- Research and Development Division, Kyokuto Pharmaceutical Industrial Co., Ltd., Takahagi-shi, Japan
| | - Noriyuki Horiki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
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15
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A Potential miRNA-mRNA Network for Dementia and Hernia Crosstalk. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4324068. [PMID: 34341761 PMCID: PMC8325595 DOI: 10.1155/2021/4324068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/11/2021] [Accepted: 07/08/2021] [Indexed: 12/13/2022]
Abstract
Background It has been reported that there may be a potential link between hernia and dementia. However, the exact mechanisms of their association have not been established. This study is aimed at constructing miRNA-mRNA networks to elucidate on the potential link between dementia and hernia. Methods Gene expression profiles for dementia, herniation, and skeletal muscle were downloaded from the GEO database after which differentially expressed mRNAs and miRNAs were obtained. In addition, fascia tissue samples were obtained during surgery. A total of 41 patients were recruited in this study, and expression levels of candidate genes were examined using quantitative RT-PCR. Luciferase reporter gene assays were used to identify potential miRNA-mRNA regulatory pathways. Results Differentially expressed mRNAs and miRNAs were screened. A potential miRNA-mRNA network revealing the crosstalk mechanism between herniation and dementia was identified. Single cell analysis revealed that PI16 was highly enriched in adipose tissues, skeletal muscles, and in the skin. GSEA enrichment analysis showed that PI16 is involved in adipose metabolism, muscle functions, and energy metabolism. In clinical samples, PI16 was found to be upregulated in hernia, while miR-4451 was found to be downregulated. The luciferase reporter gene assay revealed that downregulation of circulating miR-4451 may be responsible for the upregulated PI16 expression in hernia sacs. Conclusions We constructed an miRNA-mRNA network that shows the potential association between dementia and hernia. We also found that miR-4451 regulates the PI16 expression, which may be a key target and biomarker for hernia pathogenesis and dementia crosstalk.
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16
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Karpinets TV, Mitani Y, Liu B, Zhang J, Pytynia KB, Sellen LD, Karagiannis DT, Ferrarotto R, Futreal AP, El-Naggar AK. Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations. Clin Cancer Res 2021; 27:3960-3969. [PMID: 34011559 DOI: 10.1158/1078-0432.ccr-20-4071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/27/2021] [Accepted: 05/14/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Salivary gland carcinomas (SGCs) are pathologically classified into several widely diverse subtypes, of which adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), and salivary duct carcinoma (SDC) are the most commonly encountered. A comparative genetic analysis of these subtypes provides detailed information on the genetic alterations that are associated with their tumorigenesis and may lead to the identification of biomarkers to guide tumor-specific clinical trials. EXPERIMENTAL DESIGN Whole-genome sequencing of 58 common SGCs (20 ACCs, 20 SDCs, and 18 MECs) was performed to catalog structural variations, copy number, rearrangements, and driver mutations. Data were bioinformatically analyzed and correlated with clinicopathologic parameters, and selected targets were validated. RESULTS Novel and recurrent type-specific and shared genetic alterations were identified within and among 3 subtypes. Mutually exclusive canonical fusion and nonfusion genomic alterations were identified in both ACC and MEC. In ACCs, loss of chromosome 12q was dominant in MYB or MYBL1 fusion-positive tumors and mutations of NOTCH pathway were more common in these fusion negatives. In MECs, CRTC1-MAML2 fusion-positive tumors showed frequent BAP1 mutation, and tumors lacking this fusion were enriched with LRFN1 mutation. SDCs displayed considerable genetic instability, lacked recurrent chromosomal rearrangements, and demonstrated nonoverlapping TP53 mutation and ERBB2 amplification in a subset of tumors. Limited genetic alterations, including focal amplifications of 8q21-q23, were shared by all subtypes and were associated with poor survival. CONCLUSIONS This study delineates type-specific and shared genetic alterations that are associated with early phenotypic commitment and the biologic progression of common SGCs. These alterations, upon validation, could serve as biomarkers in tumor-specific clinical trials.
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Affiliation(s)
- Tatiana V Karpinets
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yoshitsugu Mitani
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bin Liu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kristen B Pytynia
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Linton D Sellen
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Danice T Karagiannis
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Renata Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrew P Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Adel K El-Naggar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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17
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Sohrabi E, Rezaie E, Heiat M, Sefidi-Heris Y. An Integrated Data Analysis of mRNA, miRNA and Signaling Pathways in Pancreatic Cancer. Biochem Genet 2021; 59:1326-1358. [PMID: 33813720 DOI: 10.1007/s10528-021-10062-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 03/16/2021] [Indexed: 02/06/2023]
Abstract
Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis results also revealed 109 common mRNAs by microarray and mirDIP 4.1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer.
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Affiliation(s)
- Ehsan Sohrabi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Science, Tehran, Iran
| | - Ehsan Rezaie
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Science, P.O. Box 19395-5487, Tehran, Iran.
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Science, Tehran, Iran
| | - Yousef Sefidi-Heris
- Division of Molecular Cell Biology, Department of Biology, Shiraz University, Shiraz, Iran
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18
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Mahananda B, Vinay J, Palo A, Singh A, Sahu SK, Singh SP, Dixit M. SERPINB5 Genetic Variants rs2289519 and rs2289521 are Significantly Associated with Gallbladder Cancer Risk. DNA Cell Biol 2021; 40:706-712. [PMID: 33691472 DOI: 10.1089/dna.2021.0056] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Serine protease inhibitor b5 (SERPINB5) is a tumor suppressor gene that plays a critical role in various cellular processes. In gallbladder cancer (GBC), SERPINB5's aberrant expression is reported but its role in genetic predisposition is not known. We enrolled 270 cases and 296 controls and genotyped them for single nucleotide polymorphisms (SNPs) using direct DNA sequencing, followed by genotype-phenotype analysis in GBC and other cancer cell lines. Luciferase assay was done to determine the role of rs2289521 SNP on expression regulation. We found that two SERPINB5 variants rs2289519 and rs2289521 are significantly associated with GBC and contribute to genetic predisposition. The TT genotype of variant rs2289519 was found to be significantly associated (p = 0.008) with GBC in a recessive model. C allele of rs2289521 increased the risk for GBC significantly at genotypic (CT, p = 0.026) and allelic (p = 0.04) levels. In silico analysis and luciferase assay uncovered the probable regulatory role of the rs2289521 variant on expression. Genotype-phenotype correlation in GBC and breast cancer cell lines showed reduced expression of SERPINB5 in the presence of C allele that was consistent with the result of luciferase assay. Overall, our study reveals the genetic association of two SERPINB5 variants with GBC and rs2289521's possible role in the regulation of expression.
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Affiliation(s)
- Biswaheree Mahananda
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
| | - J Vinay
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
| | - Ananya Palo
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
| | - Ayaskanta Singh
- Department of Gastroenterology and Hepato-Biliary Sciences, IMS & SUM Hospital, Sikshya O Anusandhan University, Bhubaneswar, India
| | - Saroj Kanta Sahu
- Department of Gastroenterology and Hepato-Biliary Sciences, IMS & SUM Hospital, Sikshya O Anusandhan University, Bhubaneswar, India
| | - Shivaram Prasad Singh
- Department of Gastroenterology, Sriram Chandra Bhanja Medical College and Hospital, Cuttack, India
| | - Manjusha Dixit
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India.,Homi Bhabha National Institute, Mumbai, India
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Hong Z, Wang Q, Hong C, Liu M, Qiu P, Lin R, Lin X, Chen F, Li Q, Liu L, Wang C, Chen D. Identification of Seven Cell Cycle-Related Genes with Unfavorable Prognosis and Construction of their TF-miRNA-mRNA regulatory network in Breast Cancer. J Cancer 2021; 12:740-753. [PMID: 33403032 PMCID: PMC7778540 DOI: 10.7150/jca.48245] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC), with complex tumorigenesis and progression, remains the most common malignancy in women. We aimed to explore some novel and significant genes with unfavorable prognoses and potential pathways involved in BC initiation and progression via bioinformatics methods. BC tissue-specific microarray datasets of GSE42568, GSE45827 and GSE54002, which included a total of 651 BC tissues and 44 normal breast tissues, were obtained from the Gene Expression Omnibus (GEO) database, and 124 differentially expressed genes (DEGs) were identified between BC tissues and normal breast tissues via R software and an online Venn diagram tool. Database for Annotation, Visualization and Integration Discovery (DAVID) software showed that 65 upregulated DEGs were mainly enriched in the regulation of the cell cycle, and Search Tool for the Retrieval of Interacting Genes (STRING) software identified the 39 closest associated upregulated DEGs in protein-protein interactions (PPIs), which validated the high expression of genes in BC tissues by the Gene Expression Profiling Interactive Analysis (GEPIA) tool. In addition, 36 out of 39 BC patients showed significantly worse outcomes by Kaplan-Meier plotter (KM plotter), and an additional Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that seven genes (cyclin E2 (CCNE2), cyclin B1 (CCNB1), cyclin B2 (CCNB2), mitotic checkpoint serine/threonine kinase B (BUB1B), dual-specificity protein kinase (TTK), cell division cycle 20 (CDC20), and pituitary tumor transforming gene 1 (PTTG1)) were markedly enriched in the cell cycle pathway. Analysis of the clinicopathological characteristics of hub genes revealed that seven cell cycle-related genes (CCRGs) were significantly highly expressed in four BC subtypes (luminal A, luminal B, HER2-positive and triple-negative (TNBC)), and except for the CCNE2 gene, high expression levels were significantly associated with tumor pathological grade and stage and metastatic events of BC. Furthermore, genetic mutation analysis indicated that genetic alterations of CCRGs could also significantly affect BC patients' prognosis. A quantitative real-time polymerase chain reaction (qRT-PCR) assay found that the seven CCRGs were significantly differentially expressed in BC cell lines. Integration of published multilevel expression data and a bioinformatics computational approach were used to predict and construct a regulation mechanism: a transcription factor (TF)-microRNA (miRNA)-messenger RNA (mRNA) regulation network. The present work is the first to construct a regulatory network of TF-miRNA-mRNA in BC for CCRGs and provides new insights into the molecular mechanism of BC.
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Affiliation(s)
- Zhipeng Hong
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China.,Department of Breast Surgery and General Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian Province, 350001, P. R. China.,Breast Cancer Institute, Fujian Medical University, Fuzhou, Fujian Province, 350001, P.R. China
| | - Qinglan Wang
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Chengye Hong
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Meimei Liu
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Pengqin Qiu
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Rongrong Lin
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Xiaolan Lin
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Fangfang Chen
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Qiuhuang Li
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Lingling Liu
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
| | - Chuan Wang
- Department of Breast Surgery and General Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian Province, 350001, P. R. China.,Breast Cancer Institute, Fujian Medical University, Fuzhou, Fujian Province, 350001, P.R. China
| | - Debo Chen
- Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, P. R. China
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20
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Dang TT, McIntosh AT, Morales JC, Pearson GW. miR614 Expression Enhances Breast Cancer Cell Motility. Int J Mol Sci 2020; 22:ijms22010112. [PMID: 33374314 PMCID: PMC7801944 DOI: 10.3390/ijms22010112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 01/17/2023] Open
Abstract
Using a data driven analysis of a high-content screen, we have uncovered new regulators of epithelial-to-mesenchymal transition (EMT) induced cell migration. Our results suggest that increased expression of miR614 can alter cell intrinsic gene expression to enhance single cell and collective migration in multiple contexts. Interestingly, miR614 specifically increased the expression of the EMT transcription factor Slug while not altering existing epithelial character or inducing other canonical EMT regulatory factors. Analysis of two different cell lines identified a set of genes whose expression is altered by the miR614 through direct and indirect mechanisms. Prioritization driven by functional testing of 25 of the miR614 suppressed genes uncovered the mitochondrial small GTPase Miro1 and the transmembrane protein TAPT1 as miR614 suppressed genes that inhibit migration. Notably, the suppression of either Miro1 or TAPT1 was sufficient to increase Slug expression and the rate of cell migration. Importantly, reduced TAPT1 expression correlated with an increased risk of relapse in breast cancer patients. Together, our results reveal how increased miR614 expression and the suppression of TAPT1 and Miro1 modulate the EMT state and migratory properties of breast cancer cells.
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Affiliation(s)
- Tuyen T. Dang
- Department of Neurosurgery and Stephenson Cancer Center, University of Oklahoma Health Science Center, 1122 NE 13th St., Oklahoma City, OK 73117, USA; (T.T.D.); (J.C.M.)
- Simmons Comprehensive Cancer, University of Texas, Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390, USA
| | - Alec T. McIntosh
- Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, 3970 Reservoir Rd. NW, Washington, DC 20057, USA;
| | - Julio C. Morales
- Department of Neurosurgery and Stephenson Cancer Center, University of Oklahoma Health Science Center, 1122 NE 13th St., Oklahoma City, OK 73117, USA; (T.T.D.); (J.C.M.)
| | - Gray W. Pearson
- Simmons Comprehensive Cancer, University of Texas, Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390, USA
- Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, 3970 Reservoir Rd. NW, Washington, DC 20057, USA;
- Correspondence:
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Randazzo O, Papini F, Mantini G, Gregori A, Parrino B, Liu DSK, Cascioferro S, Carbone D, Peters GJ, Frampton AE, Garajova I, Giovannetti E. "Open Sesame?": Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer. Cancers (Basel) 2020; 12:3206. [PMID: 33142664 PMCID: PMC7692081 DOI: 10.3390/cancers12113206] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/25/2020] [Accepted: 10/26/2020] [Indexed: 01/14/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.
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Affiliation(s)
- Ornella Randazzo
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, 90123 Palermo, Italy; (B.P.); (S.C.); (D.C.)
| | - Filippo Papini
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
| | - Giulia Mantini
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, 56017 Pisa, Italy
| | - Alessandro Gregori
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
| | - Barbara Parrino
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, 90123 Palermo, Italy; (B.P.); (S.C.); (D.C.)
| | - Daniel S. K. Liu
- Division of Cancer, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, London W12 0NN, UK;
| | - Stella Cascioferro
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, 90123 Palermo, Italy; (B.P.); (S.C.); (D.C.)
| | - Daniela Carbone
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, 90123 Palermo, Italy; (B.P.); (S.C.); (D.C.)
| | - Godefridus J. Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Adam E. Frampton
- Division of Cancer, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, London W12 0NN, UK;
- Faculty of Health and Medical Sciences, The Leggett Building, University of Surrey, Guildford GU2 7XH, UK
| | - Ingrid Garajova
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (O.R.); (F.P.); (G.M.); (A.G.); (G.J.P.); (I.G.)
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, 56017 Pisa, Italy
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Comprehensive Analysis of Immunoinhibitors Identifies LGALS9 and TGFBR1 as Potential Prognostic Biomarkers for Pancreatic Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:6138039. [PMID: 33062039 PMCID: PMC7545442 DOI: 10.1155/2020/6138039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 07/21/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) is one of the most deadly cancers worldwide. To uncover the unknown novel biomarker used to indicate early diagnosis and prognosis in the molecular therapeutic field of PC is extremely of importance. Accumulative evidences indicated that aberrant expression or activation of immunoinhibitors is a common phenomenon in malignances, and significant associations have been noted between immunoinhibitors and tumorigenesis or progression in a wide range of cancers. However, the expression patterns and exact roles of immunoinhibitors contributing to tumorigenesis and progression of pancreatic cancer (PC) have not yet been elucidated clearly. In this study, we investigated the distinct expression and prognostic value of immunoinhibitors in patients with PC by analyzing a series of databases, including TISIDB, GEPIA, cBioPortal, and Kaplan-Meier plotter database. The mRNA expression levels of IDO1, CSF1R, VTCN1, KDR, LGALS9, TGFBR1, TGFB1, IL10RB, and PVRL2 were found to be significantly upregulated in patients with PC. Aberrant expression of TGFBR1, VTCN1, and LGALS9 was found to be associated with the worse outcomes of patients with PC. Bioinformatics analysis demonstrated that LGALS9 was involved in regulating the type I interferon signaling pathway, interferon-gamma-mediated signaling pathway, RIG-I-like receptor signaling pathway, NF-kappa B signaling pathway, cytosolic DNA-sensing pathway, and TNF signaling pathway. And TGFB1 was related to mesoderm formation, cell matrix adhesion, TGF-beta signaling pathway, and Hippo signaling pathway. These results suggested that LGALS9 and TGFBR1 might serve as potential prognostic biomarkers and targets for PC.
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23
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He F, Huang L, Xu Q, Xiong W, Liu S, Yang H, Lu W, Xiao R, Hu Z, Cai L. Microarray profiling of differentially expressed lncRNAs and mRNAs in lung adenocarcinomas and bioinformatics analysis. Cancer Med 2020; 9:7717-7728. [PMID: 32869486 PMCID: PMC7571829 DOI: 10.1002/cam4.3369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 06/14/2020] [Accepted: 06/27/2020] [Indexed: 12/11/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) dysregulation leads to malignant progression of lung cancer. Our study profiled differentially expressed lncRNA and mRNA in tumor and normal tissues of lung adenocarcinoma (LUAD). Further, analysis of the gene expression profiles of LUAD tissues (n = 533) and normal tissues (n = 59) from The Cancer Genome Atlas (TCGA). A total of 138 lncRNAs were differentially expressed between LUAD tissues and normal tissues (false discovery rate [FDR] q < 0.05, fold change (FC) ≥ 2), a number of which are key regulators of multiple cancer and biological processes in humans. For example, lncRNA A2M‐AS1 displayed the highest correlation with the co‐expressed mRNAs, indicating that it might play a key role in regulating differential gene expression in LUAD. The data from the current study of the comprehensive lncRNA expression profile in LUAD tissues provided useful information to guide the identification of potential LUAD biomarkers.
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Affiliation(s)
- Fei He
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Environment factors and Cancer, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Liping Huang
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China.,Department of Basic Medicine, Zhangzhou Health Vocational College, Zhangzhou, China
| | - Qiuping Xu
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Weimin Xiong
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Shuang Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Huimin Yang
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Wanting Lu
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Rendong Xiao
- Department of Thoracic Surgery, The first affiliated hospital of Fujian Medical University, Fuzhou, China
| | - Zhijian Hu
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Environment factors and Cancer, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Lin Cai
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Environment factors and Cancer, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
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24
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Differential transcriptome analysis in HPV-positive and HPV-negative cervical cancer cells through CRISPR knockout of miR-214. J Biosci 2020. [DOI: 10.1007/s12038-020-00075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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25
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Lin Y, Nakatochi M, Hosono Y, Ito H, Kamatani Y, Inoko A, Sakamoto H, Kinoshita F, Kobayashi Y, Ishii H, Ozaka M, Sasaki T, Matsuyama M, Sasahira N, Morimoto M, Kobayashi S, Fukushima T, Ueno M, Ohkawa S, Egawa N, Kuruma S, Mori M, Nakao H, Adachi Y, Okuda M, Osaki T, Kamiya S, Wang C, Hara K, Shimizu Y, Miyamoto T, Hayashi Y, Ebi H, Kohmoto T, Imoto I, Kasugai Y, Murakami Y, Akiyama M, Ishigaki K, Matsuda K, Hirata M, Shimada K, Okusaka T, Kawaguchi T, Takahashi M, Watanabe Y, Kuriki K, Kadota A, Okada R, Mikami H, Takezaki T, Suzuki S, Yamaji T, Iwasaki M, Sawada N, Goto A, Kinoshita K, Fuse N, Katsuoka F, Shimizu A, Nishizuka SS, Tanno K, Suzuki K, Okada Y, Horikoshi M, Yamauchi T, Kadowaki T, Yu H, Zhong J, Amundadottir LT, Doki Y, Ishii H, Eguchi H, Bogumil D, Haiman CA, Le Marchand L, Mori M, Risch H, Setiawan VW, Tsugane S, Wakai K, Yoshida T, Matsuda F, Kubo M, Kikuchi S, Matsuo K. Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. Nat Commun 2020; 11:3175. [PMID: 32581250 PMCID: PMC7314803 DOI: 10.1038/s41467-020-16711-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 05/15/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
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Affiliation(s)
- Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan.
| | - Masahiro Nakatochi
- Division of Public Health Informatics, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, 461-8673, Japan.
- Department of Nursing, Nagoya University Graduate School of Medicine, Nagoya, 461-8673, Japan.
| | - Yasuyuki Hosono
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
- Department of Descriptive Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Yoichiro Kamatani
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Akihito Inoko
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Hiromi Sakamoto
- Genetics Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Fumie Kinoshita
- Data Science Division, Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, 461-8673, Japan
| | - Yumiko Kobayashi
- Data Science Division, Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, 461-8673, Japan
| | | | - Masato Ozaka
- Department of Hepato-biliary-pancreatic Medicine, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Takashi Sasaki
- Department of Hepato-biliary-pancreatic Medicine, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Masato Matsuyama
- Department of Hepato-biliary-pancreatic Medicine, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Naoki Sasahira
- Department of Hepato-biliary-pancreatic Medicine, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Manabu Morimoto
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, 241-8515, Japan
| | - Satoshi Kobayashi
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, 241-8515, Japan
| | - Taito Fukushima
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, 241-8515, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, 241-8515, Japan
| | - Shinichi Ohkawa
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, 241-8515, Japan
| | - Naoto Egawa
- Department of Gastroenterology, Tokyo Metropolitan Hiroo Hospital, Tokyo, 150-0013, Japan
| | - Sawako Kuruma
- Department of Gastroenterology, Tokyo Metropolitan Komagome Hospital, Tokyo, 113-8677, Japan
| | - Mitsuru Mori
- Hokkaido Chitose College of Rehabilitation, Hokkaido, 066-0055, Japan
| | - Haruhisa Nakao
- Division of Hepatology and Pancreatology, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | | | - Masumi Okuda
- Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan
| | - Takako Osaki
- Department of Infectious Diseases, Kyorin University School of Medicine, Tokyo, 181-8611, Japan
| | - Shigeru Kamiya
- Department of Infectious Diseases, Kyorin University School of Medicine, Tokyo, 181-8611, Japan
| | - Chaochen Wang
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan
| | - Tatsuo Miyamoto
- Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Yuko Hayashi
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Hiromichi Ebi
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Tomohiro Kohmoto
- Department of Human Genetics, Tokushima University Graduate School of Medicine, Tokushima, 770-8503, Japan
- Division of Molecular Genetics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Issei Imoto
- Division of Molecular Genetics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
| | - Yumiko Kasugai
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
- Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Masato Akiyama
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Kazuyoshi Ishigaki
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Koichi Matsuda
- Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Makoto Hirata
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, 104-0045, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan
| | - Takahisa Kawaguchi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Meiko Takahashi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Yoshiyuki Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan
| | - Aya Kadota
- Department of Public Health, Shiga University of Medical Science, Otsu, 520-2192, Japan
| | - Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Haruo Mikami
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan
| | - Toshiro Takezaki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan
| | - Taiki Yamaji
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, 104-0045, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, 104-0045, Japan
| | - Norie Sawada
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, 104-0045, Japan
| | - Atsushi Goto
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, 104-0045, Japan
| | - Kengo Kinoshita
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Nobuo Fuse
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Fumiki Katsuoka
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
| | - Atsushi Shimizu
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, 028-3694, Japan
| | - Satoshi S Nishizuka
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, 028-3694, Japan
| | - Kozo Tanno
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, 028-3694, Japan
- Department of Hygiene and Preventive Medicine, School of Medicine, Iwate Medicalm University, Iwate, 028-3694, Japan
| | - Ken Suzuki
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
- Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Centre for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
| | - Yukinori Okada
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, 565-0871, Japan
| | - Momoko Horikoshi
- Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Centre for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Herbert Yu
- University of Hawaii Cancer Center, Honolulu, HI, 96813, USA
| | - Jun Zhong
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Laufey T Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Hideshi Ishii
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - David Bogumil
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeless, CA, 90033, USA
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeless, CA, 90033, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | | | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Harvey Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA
| | - Veronica W Setiawan
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeless, CA, 90033, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Shoichiro Tsugane
- Center for Public Health Sciences, National Cancer Center, Tokyo, 104-0045, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Teruhiko Yoshida
- Genetics Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Shogo Kikuchi
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
- Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
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26
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Transcriptome analysis of HPV-induced warts and healthy skin in humans. BMC Med Genomics 2020; 13:35. [PMID: 32151264 PMCID: PMC7063766 DOI: 10.1186/s12920-020-0700-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 02/27/2020] [Indexed: 12/20/2022] Open
Abstract
Background The human papillomaviruses (HPV) are a group of viruses that, depending on the strain, can cause cancer or the formation of benign growths known as warts. Scarce information exists with regard to the genetic nature of non-genital cutaneous warts induced by the human papillomavirus (HPV). Methods The main purpose of this study is to investigate the differences between the gene expression profiles of common warts and healthy skin in HPV-positive individuals by RNA sequencing on the Illumina HiSeq 2500. After obtaining shave biopsies of common warts and healthy skin from twelve Arab males, we were able to analyze the transcriptomes of 24 paired cases and controls. Results Common warts were found to possess a highly significant and unique molecular signature. Many of the most up-regulated (KRT16, EPGN, and ABCG4) and down-regulated genes (C15orf59, CYB561A3, and FCGRT) in warts were the subject of little investigation in the published literature. Moreover, the top 500 differentially expressed genes were found to be associated with immune and autoimmune pathways, such as the neutrophil degranulation, toll-like receptor 7/8 (TLR 7/8) cascade, toll-like receptor 9 (TLR9) cascade, and toll-like receptor 10 (TLR10) pathways, among others. Conclusions Our findings are particularly important because they serve as the most comprehensive to date with regard to the modulation of human skin gene expression by HPV infection.
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Wang H, Liu J, Li J, Zang D, Wang X, Chen Y, Gu T, Su W, Song N. Identification of gene modules and hub genes in colon adenocarcinoma associated with pathological stage based on WGCNA analysis. Cancer Genet 2020; 242:1-7. [PMID: 32036224 DOI: 10.1016/j.cancergen.2020.01.052] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/22/2020] [Accepted: 01/30/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the world, in which colon adenocarcinoma (COAD) is the most common histological subtype of CRC. In this study, our aim is to identify gene modules and representative candidate biomarkers for clinical prognosis of patients with COAD, and help to predict prognosis and reveal the mechanisms of cancer progression. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network and identify gene modules correlated with TNM clinical staging of COAD patients. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the module gene. Protein-protein interaction (PPI) network and hub gene identification were explored with Cytoscape software. Finally, the hub gene mRNA level was validated in Oncomine database. Five gene modules, related with the pathological TNM stage, were constructed, and the gene module was enriched in cell proliferation, invasion and migration related GO terms and metabolic related KEGG pathways. A total of top 10 hub genes was identified, and in which six of the hub genes show a significant up-regulation in COAD as compared to normal tissue, including IVL, KRT16, KRT6C, KRT6A, KRT78 and SBSN. In conclusion, we identified five gene modules and six candidate biomarkers correlated with the TNM staging of COAD patients. These findings may help us to understand the tumor progression of COAD and provide prognostic biomarkers as well as therapeutic targets.
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Affiliation(s)
- Haijun Wang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China; School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jia Liu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jinsong Li
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Dan Zang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Xiaohui Wang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yiyang Chen
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Tengteng Gu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Wei Su
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Na Song
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China.
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28
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Roche S, O’Neill F, Murphy J, Swan N, Meiller J, Conlon NT, Geoghegan J, Conlon K, McDermott R, Rahman R, Toomey S, Straubinger NL, Straubinger RM, O’Connor R, McVey G, Moriarty M, Clynes M. Establishment and Characterisation by Expression Microarray of Patient-Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients. Int J Mol Sci 2020; 21:ijms21030962. [PMID: 32024004 PMCID: PMC7037178 DOI: 10.3390/ijms21030962] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer remains among the most lethal cancers worldwide, with poor early detection rates and poor survival rates. Patient-derived xenograft (PDX) models have increasingly been used in preclinical and clinical research of solid cancers to fulfil unmet need. Fresh tumour samples from human pancreatic adenocarcinoma patients were implanted in severe combined immunodeficiency (SCID) mice. Samples from 78% of treatment-naïve pancreatic ductal adenocarcinoma patients grew as PDX tumours and were confirmed by histopathology. Frozen samples from F1 PDX tumours could be later successfully passaged in SCID mice to F2 PDX tumours. The human origin of the PDX was confirmed using human-specific antibodies; however, the stromal component was replaced by murine cells. Cell lines were successfully developed from three PDX tumours. RNA was extracted from eight PDX tumours and where possible, corresponding primary tumour (T) and adjacent normal tissues (N). mRNA profiles of tumour vs. F1 PDX and normal vs. tumour were compared by Affymetrix microarray analysis. Differential gene expression showed over 5000 genes changed across the N vs. T and T vs. PDX samples. Gene ontology analysis of a subset of genes demonstrated genes upregulated in normal vs. tumour vs. PDX were linked with cell cycle, cycles cell process and mitotic cell cycle. Amongst the mRNA candidates elevated in the PDX and tumour vs. normal were SERPINB5, FERMT1, AGR2, SLC6A14 and TOP2A. These genes have been associated with growth, proliferation, invasion and metastasis in pancreatic cancer previously. Cumulatively, this demonstrates the applicability of PDX models and transcriptomic array to identify genes associated with growth and proliferation of pancreatic cancer.
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Affiliation(s)
- Sandra Roche
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
- Correspondence:
| | - Fiona O’Neill
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Jean Murphy
- St. Vincent’s University Hospital, Dublin 4, Ireland
| | - Niall Swan
- St. Vincent’s University Hospital, Dublin 4, Ireland
| | - Justine Meiller
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Neil T. Conlon
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | | | - Kevin Conlon
- St. Vincent’s University Hospital, Dublin 4, Ireland
- Trinity College Dublin, College Green, Dublin 2, Ireland
| | - Ray McDermott
- St. Vincent’s University Hospital, Dublin 4, Ireland
| | - Rozana Rahman
- St. Vincent’s University Hospital, Dublin 4, Ireland
| | - Sinead Toomey
- Department of Molecular Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin 9, Ireland
| | - Ninfa L. Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Robert M. Straubinger
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Robert O’Connor
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Gerard McVey
- St. Vincent’s University Hospital, Dublin 4, Ireland
- St Luke’s Radiation Oncology Network, Dublin 6, Ireland
| | - Michael Moriarty
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
- St Luke’s Radiation Oncology Network, Dublin 6, Ireland
| | - Martin Clynes
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
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29
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Johnson BL, d’Alincourt Salazar M, Mackenzie-Dyck S, D’Apuzzo M, Shih HP, Manuel ER, Diamond DJ. Desmoplasia and oncogene driven acinar-to-ductal metaplasia are concurrent events during acinar cell-derived pancreatic cancer initiation in young adult mice. PLoS One 2019; 14:e0221810. [PMID: 31490946 PMCID: PMC6731019 DOI: 10.1371/journal.pone.0221810] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 08/15/2019] [Indexed: 01/04/2023] Open
Abstract
The five-year survival rate of patients diagnosed with advanced pancreatic ductal adenocarcinoma (PDAC) has remained static at <5% despite decades of research. With the exception of erlotinib, clinical trials have failed to demonstrate the benefit of any targeted therapy for PDAC despite promising results in preclinical animal studies. The development of more refined mouse models of PDAC which recapitulate the carcinogenic progression from non-neoplastic, adult exocrine subsets of pancreatic cells to invasive carcinoma in humans are needed to facilitate the accurate translation of therapies to the clinic. To study acinar cell-derived PDAC initiation, we developed a genetically engineered mouse model of PDAC, called KPT, utilizing a tamoxifen-inducible Cre recombinase/estrogen receptor (ESR1) fusion protein knocked into the Ptf1a locus to activate the expression of oncogenic KrasG12D and Trp53R270H alleles in mature pancreatic acinar cells. Oncogene-expressing acinar cells underwent acinar-to-ductal metaplasia, and formed pancreatic intraepithelial neoplasia lesions following the induction of oncogene expression. After a defined latency period, oncogene-expressing acinar cells initiated the formation of highly differentiated and fibrotic tumors, which metastasized to the lungs and liver. Whole-transcriptome analysis of microdissected regions of acinar-to-ductal metaplasia and histological validation experiments demonstrated that regions of acinar-to-ductal metaplasia are characterized by the deposition of the extracellular matrix component hyaluronan. These results indicate that acinar cells expressing KrasG12D and Trp53R270H can initiate PDAC development in young adult mice and implicate hyaluronan deposition in the formation of the earliest characterized PDAC precursor lesions (and the progression of pancreatic cancer). Further studies are necessary to provide a comprehensive characterization of PDAC progression and treatment response in KPT mice and to investigate whether the KPT model could be used as a tool to study translational aspects of acinar cell-derived PDAC tumorigenesis.
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Affiliation(s)
- Benjamin L. Johnson
- Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
| | - Marcela d’Alincourt Salazar
- Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
| | - Sarah Mackenzie-Dyck
- Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
| | - Massimo D’Apuzzo
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, United States of America
| | - Hung Ping Shih
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolic Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
| | - Edwin R. Manuel
- Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
| | - Don J. Diamond
- Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, United States of America
- * E-mail:
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30
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Zaccari P, Cardinale V, Severi C, Pedica F, Carpino G, Gaudio E, Doglioni C, Petrone MC, Alvaro D, Arcidiacono PG, Capurso G. Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas. World J Gastroenterol 2019; 25:4343-4359. [PMID: 31496617 PMCID: PMC6710182 DOI: 10.3748/wjg.v25.i31.4343] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/13/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.
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Affiliation(s)
- Piera Zaccari
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00161 Rome, Italy
| | - Carola Severi
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Federica Pedica
- Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome 00161, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Division of Human Anatomy, Sapienza University of Rome, Rome 00161, Italy
| | - Claudio Doglioni
- Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Maria Chiara Petrone
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome 00161, Italy
| | - Paolo Giorgio Arcidiacono
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Gabriele Capurso
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
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31
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de Santiago I, Yau C, Heij L, Middleton MR, Markowetz F, Grabsch HI, Dustin ML, Sivakumar S. Immunophenotypes of pancreatic ductal adenocarcinoma: Meta-analysis of transcriptional subtypes. Int J Cancer 2019; 145:1125-1137. [PMID: 30720864 PMCID: PMC6767191 DOI: 10.1002/ijc.32186] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 01/21/2019] [Indexed: 01/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5-year survival rate of <5%. Recent studies of PDAC have provided several transcriptomic classifications based on separate analyses of individual patient cohorts. There is a need to provide a unified transcriptomic PDAC classification driven by therapeutically relevant biologic rationale to inform future treatment strategies. Here, we used an integrative meta-analysis of 353 patients from four different studies to derive a PDAC classification based on immunologic parameters. This consensus clustering approach indicated transcriptomic signatures based on immune infiltrate classified as adaptive, innate and immune-exclusion subtypes. This reveals the existence of microenvironmental interpatient heterogeneity within PDAC and could serve to drive novel therapeutic strategies in PDAC including immune modulation approaches to treating this disease.
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Affiliation(s)
- Ines de Santiago
- Cancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUnited Kingdom
| | - Christopher Yau
- Centre for Computational Biology, Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Lara Heij
- GROW School for Oncology and Developmental Biology, Department of PathologyMaastricht University Medical CenterMaastrichtThe Netherlands
- Department of Surgery and TransplantationUniversity Hospital RWTH AachenAachenGermany
| | - Mark R. Middleton
- Department of OncologyUniversity of OxfordOxfordUnited Kingdom
- Oxford NIHR Biomedical Research CentreOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Florian Markowetz
- Cancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUnited Kingdom
| | - Heike I. Grabsch
- GROW School for Oncology and Developmental Biology, Department of PathologyMaastricht University Medical CenterMaastrichtThe Netherlands
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James'sUniversity of LeedsLeedsUnited Kingdom
| | - Michael L. Dustin
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUnited Kingdom
- Department of PathologyNew York University School of MedicineNew YorkNY
| | - Shivan Sivakumar
- Department of OncologyUniversity of OxfordOxfordUnited Kingdom
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUnited Kingdom
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32
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Felix TF, Lopez Lapa RM, de Carvalho M, Bertoni N, Tokar T, Oliveira RA, M. Rodrigues MA, Hasimoto CN, Oliveira WK, Pelafsky L, Spadella CT, Llanos JC, F. Silva G, Lam WL, Rogatto SR, Amorim LS, Drigo SA, Carvalho RF, Reis PP. MicroRNA modulated networks of adaptive and innate immune response in pancreatic ductal adenocarcinoma. PLoS One 2019; 14:e0217421. [PMID: 31150430 PMCID: PMC6544344 DOI: 10.1371/journal.pone.0217421] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/10/2019] [Indexed: 12/14/2022] Open
Abstract
Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC≥2 and p<0.05) (15 down- and 5 up-regulated) in PDAC. miR-216 family (miR-216a-3p, miR-216a-5p, miR-216b-3p and miR-216b-5p) was consistently down-regulated in PDAC. miRNA-modulated pathways are associated with innate and adaptive immune system responses in PDAC. AMP cancers showed 8 down- and 1 up-regulated miRNAs (FDR p<0.05). Most enriched pathways (p<0.01) were RAS and Nerve Growth Factor signaling. PDAC and AMP display different global miRNA expression profiles and miRNA regulated networks/tumorigenesis pathways. The immune response was enriched in PDAC, suggesting the existence of immune checkpoint pathways more relevant to PDAC than AMP.
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Affiliation(s)
- Tainara F. Felix
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
- Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Rainer M. Lopez Lapa
- Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
- Department of Genetics, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Márcio de Carvalho
- Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Natália Bertoni
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
- Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Tomas Tokar
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Rogério A. Oliveira
- Department of Biostatistics, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Maria A. M. Rodrigues
- Department of Pathology, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Cláudia N. Hasimoto
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Walmar K. Oliveira
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Leonardo Pelafsky
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - César T. Spadella
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Juan C. Llanos
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Giovanni F. Silva
- Department of Clinics and Gastroenterology, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Wan L. Lam
- Genetics Unity, Integrative Oncology, British Columbia Cancer Center, Vancouver, BC, Canada
| | - Silvia Regina Rogatto
- Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Denmark, DK
| | | | - Sandra A. Drigo
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
- Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Robson F. Carvalho
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Patricia P. Reis
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
- Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
- * E-mail:
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33
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Banias L, Jung I, Gurzu S. Subcellular expression of maspin – from normal tissue to tumor cells. World J Meta-Anal 2019; 7:142-155. [DOI: 10.13105/wjma.v7.i4.142] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Maspin or SerpinB5, a member of the serine protease inhibitor family, was shown to function as a tumor suppressor, especially in carcinomas. It seems to inhibit invasion, tumor cells motility and angiogenesis, and promotes apoptosis. Maspin can also induce epigenetic changes such as cytosine methylation, de-acetylation, chromatin condensation, and histone modulation. In this review, a comprehensive synthesis of the literature was done to present maspin function from normal tissues to pathologic conditions. Data was sourced from MEDLINE and PubMed. Study eligibility criteria included: Published in English, between 1994 and 2019, specific to humans, and with full-text availability. Most of the 118 studies included in the present review focused on maspin immunostaining and mRNA levels. It was shown that maspin function is organ-related and depends on its subcellular localization. In malignant tumors, it might be downregulated or negative (e.g., carcinoma of prostate, stomach, and breast) or upregulated (e.g., colorectal and pancreatic tumors). Its subcellular localization (nuclear vs cytoplasm), which can be proved using immunohistochemical methods, was shown to influence both tumor behavior and response to chemotherapy. Although the number of maspin-related papers increased, the exact role of this protein remains unknown, and its interpretation should be done with extremely high caution.
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Affiliation(s)
- Laura Banias
- Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology of Tirgu-Mures, Tirgu Mures 540139, Romania
- Department of Pathology, Clinical County Emergency Hospital, Tirgu Mures 540139, Romania
| | - Ioan Jung
- Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology of Tirgu-Mures, Tirgu Mures 540139, Romania
| | - Simona Gurzu
- Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology of Tirgu-Mures, Tirgu Mures 540139, Romania
- Department of Pathology, Clinical County Emergency Hospital, Tirgu Mures 540139, Romania
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34
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Tsai S, McOlash L, Jia S, Zhang J, Simpson P, Kaldunski ML, Aldakkak M, Grewal J, Palen K, Dwinell MB, Johnson BD, Mackinnon A, Hessner MJ, Gershan JA. A Serum-Induced Transcriptome and Serum Cytokine Signature Obtained at Diagnosis Correlates with the Development of Early Pancreatic Ductal Adenocarcinoma Metastasis. Cancer Epidemiol Biomarkers Prev 2018; 28:680-689. [PMID: 30530849 DOI: 10.1158/1055-9965.epi-18-0813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/11/2018] [Accepted: 11/26/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Despite the accessibility of blood, identification of systemic biomarkers associated with cancer progression has been especially challenging. The aim of this study was to determine a difference in baseline serum immune signatures in patients that experienced early pancreatic ductal adenocarcinoma (PDAC) metastasis compared with patients that did not. We hypothesized that immune mediators would differ in the baseline serum of these patient cohorts. To test this hypothesis, novel approaches of systemic immune analysis were performed. METHODS A serum-induced transcriptional assay was used to identify transcriptome signatures. To enable an understanding of the transcriptome data in a global sense, a transcriptome index was calculated for each patient taking into consideration the relationship of up- and downregulated transcripts. For each patient, serum cytokine concentrations were also analyzed globally as a cytokine index (CI). RESULTS A transcriptome signature of innate type I IFN inflammation was identified in patients that experienced early metastatic progression. Patients without early metastatic progression had a baseline transcriptome signature of TGFβ/IL10-regulated acute inflammation. The transcriptome index was greater in patients with early metastasis. There was a significant difference in the CI in patients with and without early metastatic progression. CONCLUSIONS The association of serum-induced transcriptional signatures with PDAC metastasis is a novel finding. Global assessment of serum cytokine concentrations as a CI is a novel approach to assess systemic cancer immunity. IMPACT These systemic indices can be assessed in combination with tumor markers to further define subsets of PDAC that will provide insight into effective treatment, progression, and outcome.
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Affiliation(s)
- Susan Tsai
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Laura McOlash
- Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Shuang Jia
- Department of Pediatrics, Division of Endocrinology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jian Zhang
- Department of Pediatrics, Division of Quantitative Health Services, Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Pippa Simpson
- Department of Pediatrics, Division of Quantitative Health Services, Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Mary L Kaldunski
- Department of Pediatrics, Division of Endocrinology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Mohammed Aldakkak
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jenny Grewal
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Katie Palen
- Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Michael B Dwinell
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Bryon D Johnson
- Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Martin J Hessner
- Department of Pediatrics, Division of Endocrinology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jill A Gershan
- Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
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35
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Pang C, Gu Y, Ding Y, Ma C, Yv W, Wang Q, Meng B. Several genes involved in the JAK-STAT pathway may act as prognostic markers in pancreatic cancer identified by microarray data analysis. Medicine (Baltimore) 2018; 97:e13297. [PMID: 30557977 PMCID: PMC6320066 DOI: 10.1097/md.0000000000013297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This study aimed to identify the underlying mechanisms in pancreatic cancer (PC) carcinogenesis and those as potential prognostic biomarkers, which can also be served as new therapeutic targets of PC. METHODS Differentially expressed genes (DEGs) were identified between PC tumor tissues and adjacent normal tissue samples from a public GSE62452 dataset, followed by functional and pathway enrichment analysis. Then, protein-protein interaction (PPI) network was constructed and prognosis-related genes were screened based on genes in the PPI network, before which prognostic gene-related miRNA regulatory network was constructed. Functions of the prognostic gene in the network were enriched before which Kaplan-Meier plots were calculated for significant genes. Moreover, we predicted related drug molecules based on target genes in the miRNA regulatory network. Furthermore, another independent GSE60979 dataset was downloaded to validate the potentially significant genes. RESULTS In the GSE62452 dataset, 1017 significant DEGs were identified. Twenty-six important prognostic-related genes were found using multivariate Cox regression analysis. Through pathway enrichment analysis and miRNA regulatory analysis, we found that the 5 genes, such as Interleukin 22 Receptor Subunit Alpha 1 (IL22RA1), BCL2 Like 1 (BCL2L1), STAT1, MYC Proto-Oncogene (MYC), and Signal Transducer And Activator Of Transcription 2 (STAT2), involved in the Jak-STAT signaling pathway were significantly associated with prognosis. Moreover, the expression change of these 5 genes was further validated using another microarray dataset. Additionally, we identified camptothecin as an effective drug for PC. CONCLUSION IL22RA1, BCL2L1, STAT1, MYC, and STAT2 involved in the Jak-STAT signaling pathway may be significantly associated with prognosis of PC.
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Li S, Liu X, Zhou Y, Acharya A, Savkovic V, Xu C, Wu N, Deng Y, Hu X, Li H, Haak R, Schmidt J, Shang W, Pan H, Shang R, Yu Y, Ziebolz D, Schmalz G. Shared genetic and epigenetic mechanisms between chronic periodontitis and oral squamous cell carcinoma. Oral Oncol 2018; 86:216-224. [DOI: 10.1016/j.oraloncology.2018.09.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Revised: 09/15/2018] [Accepted: 09/28/2018] [Indexed: 12/11/2022]
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Lin J, Wu YJ, Liang X, Ji M, Ying HM, Wang XY, Sun X, Shao CH, Zhan LX, Zhang Y. Network-based integration of mRNA and miRNA profiles reveals new target genes involved in pancreatic cancer. Mol Carcinog 2018; 58:206-218. [PMID: 30294829 DOI: 10.1002/mc.22920] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 08/31/2018] [Accepted: 10/03/2018] [Indexed: 12/30/2022]
Abstract
Pancreatic cancer is regarded as the most fatal and aggressive malignancy cancer due to its low 5-year survival rate and poor prognosis. The approaches of early diagnosis and treatment are limited, which makes it urgent to identify the complex mechanism of pancreatic oncogenesis. In this study, we used RNA-seq to investigate the transcriptomic (mRNA and miRNA) profiles of pancreatic cancer in paired tumor and normal pancreatic samples from ten patients. More than 1000 differentially expressed genes were identified, nearly half of which were also found to be differentially expressed in the majority of examined patients. Functional enrichment analysis revealed that these genes were significantly enriched in multicellular organismal and metabolic process, secretion, mineral transport, and intercellular communication. In addition, only 24 differentially expressed miRNAs were found, all of which have been reported to be associated with pancreatic cancer. Furthermore, an integrated miRNA-mRNA interaction network was generated using multiple resources. Based on the calculation of disease correlation scores developed here, several genes present in the largest connected subnetwork, such as albumin, ATPase H+ /K+ exchanging alpha polypeptide and carcinoembryonic antigen-related cell adhesion molecule 1, were considered as novel genes that play important roles in the development of pancreatic cancer. Overall, our data provide new insights into further understanding of key molecular mechanisms underlying pancreatic tumorigenesis.
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Affiliation(s)
- Jie Lin
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong Province, P. R. China.,Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P. R. China
| | - Yan-Jun Wu
- Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P. R. China
| | - Xing Liang
- Department of Pancreatic-Biliary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, P. R. China
| | - Meng Ji
- Department of Pancreatic-Biliary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, P. R. China
| | - Hui-Min Ying
- Department of Endocrinology, Hangzhou Xixi Hospital, Hangzhou, Zhejiang, P. R. China
| | - Xin-Yu Wang
- Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P. R. China
| | - Xia Sun
- Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P. R. China
| | - Cheng-Hao Shao
- Department of Pancreatic-Biliary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, P. R. China
| | - Li-Xing Zhan
- Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P. R. China
| | - Yan Zhang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong Province, P. R. China
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Xu X, Liu H, Gross N, Wei D, Qian Y, Li W, Wei P, Li G, Zhang F, Yang Z, Lei D, Pan X. Overexpression of miRNA 4451 is Associated With a Poor Survival of Patients With Hypopharyngeal Cancer After Surgery With Postoperative Radiotherapy. Transl Oncol 2018; 11:1244-1250. [PMID: 30103154 PMCID: PMC6091437 DOI: 10.1016/j.tranon.2018.07.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 07/24/2018] [Accepted: 07/30/2018] [Indexed: 12/30/2022] Open
Abstract
Hypopharyngeal cancer (HC) is the most common subset of head and neck cancers. These tumors often have an aggressive clinical outcome characterized by local invasion and regional nodal metastasis. Upregulated miRNAs might be useful as biomarkers for prognosis and molecular targets for these tumors. We determined tumor expression of candidate miRNAs using microarray in 8 HC patients and validated in 372 HC patients. We also used paired tumorous and mucosal tissue to verify the miRNA expression. Log-rank test and Cox model were used to evaluate the survival; and Harrell's C-index was used to compare concordance of Cox models. Our results indicated 7 miRNAs aberrantly expressed in HC. Three of these candidate miRNAs (miRNA-4415, miRNA-200a, and miRNA-30b) were selected for further qRT-PCR validation and all of them were frequently found upregulated in HC tumors; with miR-4451 being the most differentially expressed. Moreover, high expression of miR-4451 was positively correlated with advanced tumor stage and increased mortality risk (HR: 1.6, 95% CI: 1.2-2.3; adjusted HR: 1.5, adjusted 95% CI: 1.1-2.1). Finally, significantly higher expression of miR-4451 in tumors compared to in fresh adjacent normal tissues indicates an oncogenic role of miR-4451 in this tumor. Upregulated miR-4451 in HC samples were frequently found and is significantly associated with advanced stage and poor survival of HC, which may indicate an association of this miRNA with the carcinogenesis process in this tumor site; and they could serve as a prognostic biomarker as well as help develop potential new targets for therapy.
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Affiliation(s)
- Xinbo Xu
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China
| | - Heng Liu
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China
| | - Neil Gross
- Department of Head & Neck Surgery, MD Anderson Cancer Center, Houston, TX
| | - Dongmin Wei
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China
| | - Ye Qian
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China
| | - Wenming Li
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Guojun Li
- Department of Head & Neck Surgery, MD Anderson Cancer Center, Houston, TX; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
| | - Fenghua Zhang
- Thyroid and Breast Surgery Department, Hebei General Hospital, Hebei, China.
| | - Zheng Yang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otolaryngology, Beijing, 100730, China
| | - Dapeng Lei
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China
| | - Xinliang Pan
- Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China; NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Jinan, Shandong, China.
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Impact of miRNA-mRNA Profiling and Their Correlation on Medulloblastoma Tumorigenesis. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 12:490-503. [PMID: 30195786 PMCID: PMC6070673 DOI: 10.1016/j.omtn.2018.06.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/01/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023]
Abstract
Medulloblastoma (MB) is a clinically challenging, childhood brain tumor with a diverse genetic makeup and differential miRNA profile. Aiming to identify deregulated miRNAs in MB, the miRNA expression profile of human MB samples was compared to that of normal cerebellar tissues. As a result, 8 upregulated and 64 downregulated miRNAs were identified in MB samples. Although various algorithms have been developed to predict the interaction between miRNA-mRNA pairs, the complexity and fidelity of miRNA-mRNA remain a concern. Therefore, to identify the signatures of miRNA-mRNA interactions essential for MB pathogenesis, miRNA profiling, RNA sequencing, and ingenuity pathway analysis (IPA) were performed in the same primary human MB samples. Further, when miR-217 was inhibited, a significant upregulation of predicted target genes SIRT1, ROBO1, FOXO3, and SMAD7 in HDMB03 cells was observed, confirming the validity of our approach. Functional analysis revealed that the inhibition of miR-217 in HDMB03 cells suppresses colony formation, migration, invasion, promoted apoptosis, and arrested cell population in S phase, indicating that manipulation of miR-217 may have a therapeutic potential for MB patients. Therefore, our study provides an essential platform for future investigations of specific miRNAs responsible for MB pathogenesis.
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Zhou X, Lu Z, Wang T, Huang Z, Zhu W, Miao Y. Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis. Gene 2018; 673:181-193. [PMID: 29913239 DOI: 10.1016/j.gene.2018.06.037] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 06/12/2018] [Indexed: 02/06/2023]
Abstract
The differential expression of microRNAs (miRNAs) in plasma of pancreatic cancer (PC) patients may act as a diagnostic biomarker. A four-stage study was performed to identify plasma miRNAs with potential in detecting PC. Exiqon panels (20 PC vs. 10 normal controls (NCs)) were applied in the screening phase to obtain miRNA profiling. The identified miRNAs were further assessed in the training (40 PC vs. 40 NCs) and testing stages (112 PC vs. 116 NCs) with qRT-PCR assays. A six-miRNA signature including up-regulated miR-122-5p, miR-125b-5p, miR-192-5p, miR-193b-3p, miR-221-3p and miR-27b-3p was identified. The signature could accurately discriminate PC patients from NCs with areas under the receiver operating characteristic curve of 0.848, 0.833 and 0.937 for the training, testing and the external validation stage (41 PC vs. 50 NCs), respectively. The multivariate Cox regression analyses showed that down-regulated plasma miR-125b-5p could predict worse OS independent from late tumor stage and high CA19-9. All the six miRNAs except miR-122-5p showed high expression levels in PC tissues than those in matched normal tissues. MiR-122-5p and miR-193b-3p were up-regulated, while miR-221-3p was down-regulated in plasma exosomes from PC patients. Bioinformatics analysis demonstrated that the miRNAs might involve in several molecular pathways closely related with PC such as p53 signaling pathway, pancreatic cancer, TGF-beta signaling pathway and so on. In conclusion, we identified a six-miRNA signature in plasma which could act as a non-invasive biomarker in diagnosis and prognosis of PC. Plasma miR-125b-5p might act as an independent biomarker in predicting OS of PC patients.
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Affiliation(s)
- Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China.
| | - Zipeng Lu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China; Pancreas Institute, Nanjing Medical University, Nanjing 210029, Jiangsu Province, PR China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China
| | - Zebo Huang
- Department of Oncology, The Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi 214062, Jiangsu Province, PR China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China.
| | - Yi Miao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, PR China; Pancreas Institute, Nanjing Medical University, Nanjing 210029, Jiangsu Province, PR China.
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Zeng W, Rao N, Li Q, Wang G, Liu D, Li Z, Yang Y. Genome-wide Analyses on Single Disease Samples for Potential Biomarkers and Biological Features of Molecular Subtypes: A Case Study in Gastric Cancer. Int J Biol Sci 2018; 14:833-842. [PMID: 29989098 PMCID: PMC6036754 DOI: 10.7150/ijbs.24816] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/06/2018] [Indexed: 02/06/2023] Open
Abstract
Purpose: Based on the previous 3 well-defined subtypes of gastric adenocarcinoma (invasive, proliferative and metabolic), we aimed to find potential biomarkers and biological features of each subtype. Methods: The genome-wide co-expression network of each subtype of gastric cancer was firstly constructed. Then, the functional modules in each genome-wide co-expression network were divided. Next, the key genes were screened from each functional module. Finally, the enrichment analysis was performed on the key genes to mine the biological features of each subtype. Comparative analysis between each pair of subtypes was performed to find the common and unique features among different subtypes. Results: A total of 207 key genes were identified in invasive, 215 key genes in proliferative, and 204 key genes in metabolic subtypes. Most key genes in each subtype were unique and new findings compared with that of the existing related researches. The GO and KEGG enrichment analyses for the key genes of each subtype revealed important biological features of each subtype. Conclusions: For a subtype, most identified key genes and important biological features were unique, which means that the key genes can be used as the potential biomarker of a subtype, and each subtype of gastric cancer might have different occurrence and development mechanisms. Thus, different diagnosis and therapy methods should be applied to the invasive, proliferative and metabolic subtypes of gastric cancer.
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Affiliation(s)
- Wei Zeng
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China.,Department of Biomedical Engineering, School of Automation and Information Engineering, Sichuan University of Science and Engineering, Zigong, 643000, China
| | - Nini Rao
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China.,Institute of Electronic and Information Engineering of UESTC in Guangdong, Dongguan, 523808, China
| | - Qian Li
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Guangbin Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Dingyun Liu
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Zhengwen Li
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Yuntao Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.,Key Laboratory for NeuroInformation of the Ministry of Education, University of Electronic Science and Technology of China, Chengdu 610054, China
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Kao GS, Tu YK, Sung PH, Wang FS, Lu YD, Wu CT, Lin RLC, Yip HK, Lee MS. MicroRNA-mediated interacting circuits predict hypoxia and inhibited osteogenesis of stem cells, and dysregulated angiogenesis are involved in osteonecrosis of the femoral head. INTERNATIONAL ORTHOPAEDICS 2018; 42:1605-1614. [PMID: 29700584 DOI: 10.1007/s00264-018-3895-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 03/13/2018] [Indexed: 01/07/2023]
Abstract
PURPOSE MicroRNAs (miRNAs) are associated with various pathologic conditions and can serve as diagnostic or therapeutic biomarkers. This study tried to identify the differentially expressed miRNAs to predict the possible pathomechanisms involved in osteonecrosis of the femoral head (ONFH). METHODS We compared the peripheral blood miRNAs in 46 patients with ONFH and 85 healthy controls by microarray and droplet digital polymerase chain reaction (ddPCR). Putative interacted networks between the differentially responded miRNAs were analyzed by web-based bioinformatics prediction tools. RESULTS Microarray identified 51 differentially expressed miRNAs with at least twofold change (upregulation in 34 and downregulation in 17), and the results were validated by ddPCR using six selected miRNAs. Bioinformatics genetic network analysis focusing on the six miRNAs found the upregulated miR-18a and miR-19a are associated with angiogenesis after induction of ischemia; the upregulated miR-138-1 can inhibit osteogenic differentiation of mesenchymal stem cells; the most targeted genes, p53 and SERBP1, are associated with hypoxia and hypofibrinolysis. CONCLUSIONS This study combined the miRNA analysis with the bioinformatics and predicts that hypoxia, inhibited osteogenesis of stem cells, and dysregulated angiogenesis might be orchestrated through the miRNA interacting circuits in the pathogenesis of ONFH.
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Affiliation(s)
- Gour-Shenq Kao
- Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan.,Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan
| | - Yuan-Kun Tu
- Department of Orthopedic Surgery, Eda Hospital, Kaohsiung, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohisung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan
| | - Feng-Sheng Wang
- Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan.,Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Yu-Der Lu
- Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan
| | - Chen-Ta Wu
- Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan
| | - Rio L C Lin
- Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan.,Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohisung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan.
| | - Mel S Lee
- Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan.
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Huang J, Lai J, Liang B, Jiang J, Ning C, Liao Y, Zang N, Wang M, Qin F, Yu J, Wei W, Ye L, Liang H. mircoRNA-3162-3p is a potential biomarker to identify new infections in HIV-1-infected patients. Gene 2018; 662:21-27. [PMID: 29627523 DOI: 10.1016/j.gene.2018.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 03/30/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Identification of new HIV infections (HIV incidence) is critical for monitoring AIDS epidemic and assessing the effectiveness of intervention measures. However, current methods for distinguishing new infections from newly diagnosed HIV-1 patients are still imperfect. We explored utilizing miRNAs as biomarker to identify HIV new infections. METHODS According to the HIV-1 status and the estimated duration of infection (EDI), we enrolled participants and divided them into three groups: healthy control, new infection (within 1 year), and old infection (longer than 1 year). Participants were assigned into screening set or validation set. miRNA microarray was performed in screening set and the differentially expressed miRNAs were screened out. The differentially expressed miRNAs were further confirmed in validation set and HIV-1 IIIB-MT2 cells infection system. RESULTS In screening set, 5 miRNAs including miR-1291, miR-3609, miR-3162-3p, miR-874-5p and miR-4258 were screened out for their differential expression in plasma among three groups. In validation set, down- trend of miR-3162-3p was validated from healthy control, new infection to old infection groups. In HIV-1 IIIB-MT2 system, the levels of miR-3162-3p also decreased along with infection duration in vitro. Sensitivity and specificity for miR-3162-3p to distinguish new infection from old infection were 100.0% and 71.43%, respectively, with the cut-off value of 0.916. CONCLUSION miR-3162-3p in plasma could be a potential microRNA biomarker to identify HIV new infections in HIV-1 infected patients.
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Affiliation(s)
- Jiegang Huang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Jingzhen Lai
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Bingyu Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Junjun Jiang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Chuanyi Ning
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Yanyan Liao
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Ning Zang
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Minlian Wang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Fengxiang Qin
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Jun Yu
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Wudi Wei
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Li Ye
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China.
| | - Hao Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, China; Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning 530021, Guangxi, China.
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Zhu Y, Zhang HL, Wang QY, Chen MJ, Liu LB. Overexpression of microRNA-612 Restrains the Growth, Invasion, and Tumorigenesis of Melanoma Cells by Targeting Espin. Mol Cells 2018; 41:119-126. [PMID: 29385671 PMCID: PMC5824021 DOI: 10.14348/molcells.2018.2235] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 11/18/2017] [Accepted: 11/24/2017] [Indexed: 01/04/2023] Open
Abstract
microRNA (miR)-612 shows anticancer activity in several types of cancers, yet its function in melanoma is still unclear. This study was undertaken to investigate the expression of miR-612 and its biological relevance in melanoma cell growth, invasion, and tumorigenesis. The expression and prognostic significance of miR-612 in melanoma were examined. The effects of miR-612 overexpression on cell proliferation, colony formation, tumorigenesis, and invasion were determined. Rescue experiments were conducted to identify the functional target gene(s) of miR-612. miR-612 was significantly downregulated in melanoma tissues compared to adjacent normal tissues. Low miR-612 expression was significantly associated with melanoma thickness, lymph node metastasis, and shorter overall, and disease-free survival of patients. Overexpression of miR-612 significantly decreased cell proliferation, colony formation, and invasion of SK-MEL-28 and A375 melanoma cells. In vivo tumorigenic studies confirmed that miR-612 overexpression retarded the growth of A375 xenograft tumors, which was coupled with a decline in the percentage of Ki-67-positive proliferating cells. Mechanistically, miR-612 targeted Espin in melanoma cells. Overexpression of Espin counteracted the suppressive effects of miR-612 on melanoma cell proliferation, invasion, and tumorigenesis. A significant inverse correlation (r = -0.376, P = 0.018) was observed between miR-612 and Espin protein expression in melanoma tissues. In addition, overexpression of miR-612 and knockdown of Espin significantly increased the sensitivity of melanoma cells to doxorubicin. Collectively, miR-612 suppresses the aggressive phenotype of melanoma cells through downregulation of Espin. Delivery of miR-612 may represent a novel therapeutic strategy against melanoma.
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Affiliation(s)
- Ying Zhu
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou,
China
| | - Hao-liang Zhang
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou,
China
| | - Qi-ying Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou,
China
| | - Min-jing Chen
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou,
China
| | - Lin-bo Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou,
China
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Marcus R, Maitra A, Roszik J. Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas. J Pathol 2017; 243:271-272. [PMID: 28816351 DOI: 10.1002/path.4959] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/09/2017] [Accepted: 08/10/2017] [Indexed: 01/02/2023]
Abstract
Adenosquamous carcinoma of the pancreas (ASCP) is a mixed tumor type which contains squamous cell carcinoma and also ductal adenocarcinoma components. Due to the rarity of this malignancy, only very limited genomic profiling has been performed. A recent paper by Fang et al. published in The Journal of Pathology contributed to our knowledge of genomic alterations by performing whole-genome and -exome sequencing of 17 ASCP tumors. They found major genomic similarities to pancreatic ductal adenocarcinoma; however, the p53 pathway was altered in a greater proportion of cases, while a high frequency of 3p loss was a distinct copy number alteration pattern observed in ASCP. Laser capture microdissection revealed that adenocarcinoma and squamous carcinoma components of ASCP harbor similar genomic variations, indicating that the origin of tumor components is the same or similar. Although the study published by Fang et al. increases our knowledge of this rare mixed tumor type, further investigation, including RNA sequencing, will be needed to fully characterize this malignancy and to aid the development of novel treatment approaches. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Rebecca Marcus
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Anirban Maitra
- Departments of Pathology and Translational Molecular Pathology, Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jason Roszik
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Zhi D, Zhao X, Dong M, Yan C. miR-493 inhibits proliferation and invasion in pancreatic cancer cells and inversely regulated hERG1 expression. Oncol Lett 2017; 14:7398-7404. [PMID: 29344180 PMCID: PMC5755206 DOI: 10.3892/ol.2017.7178] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 10/03/2017] [Indexed: 12/19/2022] Open
Abstract
The human ether-a-go-go-related potassium channel 1 (hERG1) is a component of the voltage-gated Kv11.1 potassium channel, which has been recently indicated to have a crucial role in the tumorigenesis of multiple tumors, including pancreatic carcinoma. Pancreatic carcinoma is one of the most malignant human cancer types, which has an extremely poor prognosis. The present study demonstrated that the expression levels of hERG1 were markedly elevated in pancreatic cancer tissues and pancreatic cancer cell lines, and that the abnormal hERG1 expression was significantly associated with the proliferation and invasion ability of pancreatic cancer. Furthermore, hERG1 was identified to be a direct target of miR-493, which is generally reduced in pancreatic cancer tissues and cell lines. These findings provide a novel insight into the regulatory mechanism of miR-493/hERG1 in pancreatic cancer cell proliferation and invasion, which may aid the development of novel diagnostic and therapeutic strategies for pancreatic cancer in the future.
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Affiliation(s)
- Duo Zhi
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, P.R. China
| | - Xin Zhao
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, P.R. China
| | - Caichuan Yan
- Department of Cancer Molecular and Biology, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150040, P.R. China
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Tang H, Wei P, Chang P, Li Y, Yan D, Liu C, Hassan M, Li D. Genetic polymorphisms associated with pancreatic cancer survival: a genome-wide association study. Int J Cancer 2017; 141:678-686. [PMID: 28470677 DOI: 10.1002/ijc.30762] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 03/28/2017] [Accepted: 04/21/2017] [Indexed: 12/15/2022]
Abstract
Previous findings on the association of genetic factors and pancreatic cancer survival are limited and inconsistent. In a two-stage study, we analyzed the existing genome-wide association study dataset of 868 pancreatic cancer patients from MD Anderson Cancer Center in relation to overall survival using Cox regression. Top hits were selected for replication in another 820 patients from the same institution using the Taqman genotyping method. Functional annotation, pathway analysis and gene expression analysis were conducted using existing software and databases. We discovered genome-wide significant associations of patient survival with three imputed SNPs which, in complete LD (r2 = 1), were intronic SNPs of the PAIP2B (rs113988120) and DYSF genes (rs112493246 and rs138529893) located on Chromosome 2. The variant alleles were associated with a 3.06-fold higher risk of death [95% confidence interval (CI) = 2.10-4.47, p=6.4 × 10-9] after adjusting for clinical factors. Eleven SNPs were tested in the replication study and the association of rs113988120 with survival was confirmed (hazard ratio: 1.57, 95% CI: 1.13-2.20, p=0.008). In silico analysis found rs1139988120 might lead to altered motif. This locus is in LD (D' = 0.77) with three eQTL SNPs near or belong to the NAGK and MCEE genes. According to The Cancer Genome Atlas data and our previous RNA-sequencing data, the mRNA expression level of PAIP2B but not NAGK, MCEE or DYSF was significantly lower in pancreatic tumors than in normal adjacent tissues. Additional validation efforts and functional studies are warranted to demonstrate whether PAIP2B is a novel tumor suppressor gene and a potential therapeutic target for pancreatic cancer.
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Affiliation(s)
- Hongwei Tang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ping Chang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yanan Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dong Yan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Chang Liu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Manal Hassan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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