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Zhou Q, Yu H, Chen Y, Ren J, Lu Y, Sun Y. The CRL3 KCTD10 ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11. Proc Natl Acad Sci U S A 2024; 121:e2320655121. [PMID: 38959043 PMCID: PMC11252818 DOI: 10.1073/pnas.2320655121] [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: 11/24/2023] [Accepted: 05/22/2024] [Indexed: 07/04/2024] Open
Abstract
SLC7A11 is a cystine transporter and ferroptosis inhibitor. How the stability of SLC7A11 is coordinately regulated in response to environmental cystine by which E3 ligase and deubiquitylase (DUB) remains elusive. Here, we report that neddylation inhibitor MLN4924 increases cystine uptake by causing SLC7A11 accumulation, via inactivating Cullin-RING ligase-3 (CRL-3). We identified KCTD10 as the substrate-recognizing subunit of CRL-3 for SLC7A11 ubiquitylation, and USP18 as SLC7A11 deubiquitylase. Upon cystine deprivation, the protein levels of KCTD10 or USP18 are decreased or increased, respectively, contributing to SLC7A11 accumulation. By destabilizing or stabilizing SLC7A11, KCTD10, or USP18 inversely regulates the cystine uptake and ferroptosis. Biologically, MLN4924 combination with SLC7A11 inhibitor Imidazole Ketone Erastin (IKE) enhanced suppression of tumor growth. In human breast tumor tissues, SLC7A11 levels were negatively or positively correlated with KCTD10 or USP18, respectively. Collectively, our study defines how SLC7A11 and ferroptosis is coordinately regulated by the CRL3KCTD10/E3-USP18/DUB axis, and provides a sound rationale of drug combination to enhance anticancer efficacy.
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Affiliation(s)
- Qiyin Zhou
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province310009, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou310029, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou310009, China
| | - Hongfei Yu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou310029, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou310053, China
| | - Yongxia Chen
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou310029, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou310016, China
| | - Jiayi Ren
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou310029, China
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou310016, China
| | - Yan Lu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou310029, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou310006, China
| | - Yi Sun
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province310009, China
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou310029, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou310009, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou310053, China
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Fei Y, Wu Y, Chen L, Yu H, Pan L. Comprehensive pan-carcinoma analysis of ITGB1 distortion and its potential clinical significance for cancer immunity. Discov Oncol 2024; 15:47. [PMID: 38402311 PMCID: PMC10894187 DOI: 10.1007/s12672-024-00901-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 02/20/2024] [Indexed: 02/26/2024] Open
Abstract
The human protein-coding gene ITGB1 (Integrin 1), also known as CD29, has a length of 58048 base pairs. The Integrin family's most prevalent subunit, it participates in the transmission of numerous intracellular signaling pathways. A thorough examination of ITGB1's functions in human malignancies, however, is inadequate and many of their relationships to the onset and development of human cancers remain unknown. In this work, we examined ITGB1's role in 33 human cancers. Finally, a multi-platform analysis revealed that three of the 33 malignancies had significantly altered ITGB1 expression in tumor tissues in comparison to normal tissues. In addition, it was discovered through survival analysis that ITGB1 was a stand-alone prognostic factor in a number of cancers. ITGB1 expression was linked to immune cell infiltration in colon cancer, according to an investigation of immune infiltration in pan-cancer. In the gene co-expression research, ITGB1 showed a positive connection with the majority of the cell proliferation and EMT indicators, indicating that ITGB1 may have an essential function in controlling cancer metastasis and proliferation. Our pan-cancer analysis of ITGB1 gives evidence in favor of a further investigation into its oncogenic function in various cancer types.
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Affiliation(s)
- Yuchang Fei
- Department of Integrated Chinese and Western Medicine, The First People's Hospital of Jiashan, Jiashan Hospital Affiliated of Jiaxing University, Jiashan, Zhejiang, China.
| | - Yulun Wu
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Luting Chen
- Department of Integrated Chinese and Western Medicine, The First People's Hospital of Wenling, Wenling, Zhejiang, China
| | - Huan Yu
- The Department of Traditional Chinese Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Lei Pan
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Zhaoran S, Linnebacher CS, Linnebacher M. Increased SEC23A Expression Correlates with Poor Prognosis and Immune Infiltration in Stomach Adenocarcinoma. Cancers (Basel) 2023; 15:2065. [PMID: 37046730 PMCID: PMC10093042 DOI: 10.3390/cancers15072065] [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: 02/22/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND Previous studies have described that the SEC23A gene is involved in the occurrence and development of various tumor entities. However, little is known about its expression and relevance in stomach adenocarcinoma (STAD). The aim of this study was to bioinformatically analyze the role of SEC23A in STAD, followed by patient tissue sample analyses. MATERIALS AND METHODS SEC23A expression levels in STAD and normal gastric tissues were analyzed in the Cancer Genome Atlas and Gene Expression Omnibus databases; results were verified in fresh clinical STAD specimens on both gene and protein expression levels. SEC23A expression correlated with survival parameters by Kaplan-Meier and multivariate Cox regression analyses. The top genes co-expressed with SEC23A were identified by gene set enrichment analysis (GSEA) using the clusterProfiler package in R. Furthermore, the R package (immunedeconv), integrating the CIBERSORT algorithm, was used to estimate immune cell infiltration levels in STAD. RESULTS SEC23A gene and sec23a protein expression were both significantly upregulated in STAD, and this correlated with the pT stage. Moreover, high SEC23A expression was associated with poor disease-free and overall survival of STAD patients. Cox analyses revealed that besides age and pathologic stage, SEC23A expression is an independent risk factor for STAD. GSEA indicated that SEC23A was positively associated with ECM-related pathways. In the CIBERSORT analysis, the level of SEC23A negatively correlated with various infiltrating immune cell subsets, including follicular helper T cells, Tregs, activated NK cells and myeloid dendritic cells. Finally, the expression levels of immune checkpoint-related genes, including HAVCR2 and PDCD1LG2, were significantly increased in the high SEC23A expression group. CONCLUSIONS We observed the significantly upregulated expression of SEC23A in STAD, an association with disease progression, patients' prognosis and infiltrating immune cell subsets. Thus, we propose SEC23A as an independent prognostic factor with a putative role in immune response regulation in STAD.
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Affiliation(s)
- Su Zhaoran
- Departments of Gastrointestinal Surgery, People’s Hospital of Tongling City, Tongling 244000, China
- College of Mathematics and Computer Science, Tongling University, Tongling 244000, China
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057 Rostock, Germany
| | - Christina Susanne Linnebacher
- Patient Models for Precision Medicine, Clinic of General Surgery, University Medical Center Rostock, 18057 Rostock, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057 Rostock, Germany
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Ma T, Wang D, Wu J, Xiao Y, Fan A, Cao X, Cao J, Ren K. KCTD10 functions as a tumor suppressor in hepatocellular carcinoma by triggering the Notch signaling pathway. Am J Transl Res 2023; 15:125-137. [PMID: 36777839 PMCID: PMC9908486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/01/2022] [Indexed: 02/14/2023]
Abstract
OBJECTIVE Our previous study found KCTD10 negatively regulates Notch signaling, but whether KCTD10 regulates human hepatocellular carcinoma (HCC) carcinogenicity was uncertain. METHODS We used lentivirus infection to regulate KCTD10 expression in HCC cell lines, then monitored tumor sphere formation rate, cell migration, in vitro and in vivo tumorigenicity, cancer stem cell (CSC) biomarkers and Notch signaling variation. RESULTS Down-regulation of KCTD10 in HCC cell lines (Hep3B and MHCC97H) enhanced the expression of CSC marker genes, promoted self-renewal and tumorigenic ability, and increased the CD133+ cell population. Further molecular studies showed that the transmembrane/intracellular region (NTM) of Notch1 decreased when KCTD10 was knocked down in HCC cell lines, and that the balance between P53 and Notch activity was regulated. CONCLUSIONS The results demonstrated that KCTD10 can act as a tumor suppressor in HCC cells through Notch signaling.
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Affiliation(s)
- Tao Ma
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Hunan Aerospace HospitalNo. 139 Fenglin Third Road, Yuelu District, Changsha 410205, Hunan, China
| | - Daoyuan Wang
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
| | - Jiajun Wu
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
| | - Yihui Xiao
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
| | - Anfang Fan
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
| | - Xiaocheng Cao
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
| | - Jianguo Cao
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
| | - Kaiqun Ren
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal UniversityChangsha 410013, Hunan, China,Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan ProvinceChangsha 410013, Hunan, China
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Angrisani A, Di Fiore A, De Smaele E, Moretti M. The emerging role of the KCTD proteins in cancer. Cell Commun Signal 2021; 19:56. [PMID: 34001146 PMCID: PMC8127222 DOI: 10.1186/s12964-021-00737-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/05/2021] [Indexed: 12/24/2022] Open
Abstract
The human family of Potassium (K+) Channel Tetramerization Domain (KCTD) proteins counts 25 members, and a significant number of them are still only partially characterized. While some of the KCTDs have been linked to neurological disorders or obesity, a growing tally of KCTDs are being associated with cancer hallmarks or involved in the modulation of specific oncogenic pathways. Indeed, the potential relevance of the variegate KCTD family in cancer warrants an updated picture of the current knowledge and highlights the need for further research on KCTD members as either putative therapeutic targets, or diagnostic/prognostic markers. Homology between family members, capability to participate in ubiquitination and degradation of different protein targets, ability to heterodimerize between members, role played in the main signalling pathways involved in development and cancer, are all factors that need to be considered in the search for new key players in tumorigenesis. In this review we summarize the recent published evidence on KCTD members' involvement in cancer. Furthermore, by integrating this information with data extrapolated from public databases that suggest new potential associations with cancers, we hypothesize that the number of KCTD family members involved in tumorigenesis (either as positive or negative modulator) may be bigger than so far demonstrated. Video abstract.
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Affiliation(s)
| | - Annamaria Di Fiore
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
| | - Marta Moretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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K + Channel Tetramerization Domain 5 (KCTD5) Protein Regulates Cell Migration, Focal Adhesion Dynamics and Spreading through Modulation of Ca 2+ Signaling and Rac1 Activity. Cells 2020; 9:cells9102273. [PMID: 33053687 PMCID: PMC7600296 DOI: 10.3390/cells9102273] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/03/2020] [Accepted: 10/05/2020] [Indexed: 01/08/2023] Open
Abstract
Cell migration is critical for several physiological and pathophysiological processes. It depends on the coordinated action of kinases, phosphatases, Rho-GTPases proteins, and Ca2+ signaling. Interestingly, ubiquitination events have emerged as regulatory elements of migration. Thus, the role of proteins involved in ubiquitination processes could be relevant to a complete understanding of pro-migratory mechanisms. KCTD5 is a member of Potassium Channel Tetramerization Domain (KCTD) proteins that have been proposed as a putative adaptor for Cullin3-E3 ubiquitin ligase and a novel regulatory protein of TRPM4 channels. Here, we study whether KCTD5 participates in cell migration-associated mechanisms, such as focal adhesion dynamics and cellular spreading. Our results show that KCTD5 CRISPR/Cas9- and shRNA-based depletion in B16-F10 cells promoted an increase in cell migration and cell spreading, and a decrease in the focal adhesion area, consistent with an increased focal adhesion disassembly rate. The expression of a dominant-negative mutant of Rho-GTPases Rac1 precluded the KCTD5 depletion-induced increase in cell spreading. Additionally, KCTD5 silencing decreased the serum-induced Ca2+ response, and the reversion of this with ionomycin abolished the KCTD5 knockdown-induced decrease in focal adhesion size. Together, these data suggest that KCTD5 acts as a regulator of cell migration by modulating cell spreading and focal adhesion dynamics through Rac1 activity and Ca2+ signaling, respectively.
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Sakamaki K, Funasaka K, Miyahara R, Furukawa K, Yamamura T, Ohno E, Nakamura M, Kawashima H, Hirooka Y, Fujishiro M, Goto H. Low ETV1 mRNA expression is associated with recurrence in gastrointestinal stromal tumors. Sci Rep 2020; 10:14767. [PMID: 32901065 PMCID: PMC7478956 DOI: 10.1038/s41598-020-71719-y] [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: 01/15/2020] [Accepted: 07/22/2020] [Indexed: 12/28/2022] Open
Abstract
Although the majority of gastrointestinal stromal tumors (GISTs) possess KIT mutations that induce constitutive signal transduction, the clinical outcomes are variable. The ETS translocation variant 1 (ETV1) gene encodes a transcription factor that is reported to cooperate with KIT in GISTs. However, the clinical role of ETV1 is largely unknown. The aim of this study was to examine ETV1 expression and its associations with clinical features in GISTs. We conducted a cohort study involving 64 patients with GISTs who underwent surgical resection between October 2008 and February 2015. ETV1 mRNA expression was compared with that in non-GISTs and was analyzed among risk classifications or clinical outcomes. The GIST samples exhibited significantly higher ETV1 mRNA expression than the non-GIST samples (P < 0.0001). Sixty-four GISTs were stratified into high or low ETV1 mRNA expression groups based on the median relative abundance of ETV1 mRNA. The multivariate analysis showed that low ETV1 expression, as well as tumor size and mitotic index, was an independent factor of recurrence (hazard ratio: 8.1). Patients with high ETV1 expression achieved significantly longer recurrence-free survival (RFS) times than those with low ETV1 expression (P = 0.025). Our study revealed that low ETV1 expression is an independent factor of recurrence after surgery in patients with GISTs, and thus, low ETV1 expression might be a marker of more aggressive malignant GISTs.
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Affiliation(s)
- Keiichi Sakamaki
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Kohei Funasaka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
- Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
| | - Ryoji Miyahara
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Takeshi Yamamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Eizaburo Ohno
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
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Liutkeviciene R, Vilkeviciute A, Gedvilaite G, Kaikaryte K, Kriauciuniene L. Haplotypes of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 Gene Polymorphisms in Age-Related Macular Degeneration. DISEASE MARKERS 2019; 2019:9602949. [PMID: 31583032 PMCID: PMC6754896 DOI: 10.1155/2019/9602949] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/30/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND To determine the impact of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 genotypes on the development of age-related macular degeneration (AMD) in the Lithuanian population. METHODS A total of 916 subjects were examined: 309 patients with early AMD, 301 patients with exudative AMD, and 306 healthy controls. The genotyping of HTRA1 rs11200638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 was carried out using the RT-PCR method. RESULTS Our study showed that single-nucleotide polymorphisms rs3793784 and rs11200638 were associated with increased odds of early and exudative AMD, and the variant in KCTD10 (rs56209061) was found to be associated with decreased odds of early and exudative AMD development after adjustments for age and gender in early AMD analysis and after adjustments only for age in exudative AMD. The haplotype containing two minor alleles C-A and the G-A haplotype in rs3793784-rs11200638 were statistically significantly associated with an increased risk of exudative AMD development after adjustment for age, while the G-G haplotype showed a protective role against early and exudative AMD and the haplotype C-G in rs3793784-rs11200638 was associated with a decreased risk only of exudative AMD development. CONCLUSIONS Our study identified two markers, rs11200638 and rs3793784, as risk factors for early and exudative AMD, and one marker, rs56209061, as a protective factor for early and exudative AMD development. The haplotypes constructed of rs3793784-rs11200638 were found to be associated with AMD development, as well.
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Affiliation(s)
- Rasa Liutkeviciene
- Neuroscience Institute, Lithuanian University of Health Sciences, Medical Academy, Eiveniu 2, Kaunas LT-50161, Lithuania
| | - Alvita Vilkeviciute
- Neuroscience Institute, Lithuanian University of Health Sciences, Medical Academy, Eiveniu 2, Kaunas LT-50161, Lithuania
| | - Greta Gedvilaite
- Neuroscience Institute, Lithuanian University of Health Sciences, Medical Academy, Eiveniu 2, Kaunas LT-50161, Lithuania
| | - Kriste Kaikaryte
- Neuroscience Institute, Lithuanian University of Health Sciences, Medical Academy, Eiveniu 2, Kaunas LT-50161, Lithuania
| | - Loresa Kriauciuniene
- Neuroscience Institute, Lithuanian University of Health Sciences, Medical Academy, Eiveniu 2, Kaunas LT-50161, Lithuania
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Teng X, Aouacheria A, Lionnard L, Metz KA, Soane L, Kamiya A, Hardwick JM. KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders. CNS Neurosci Ther 2019; 25:887-902. [PMID: 31197948 PMCID: PMC6566181 DOI: 10.1111/cns.13156] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/02/2019] [Accepted: 05/13/2019] [Indexed: 12/12/2022] Open
Abstract
The underlying molecular basis for neurodevelopmental or neuropsychiatric disorders is not known. In contrast, mechanistic understanding of other brain disorders including neurodegeneration has advanced considerably. Yet, these do not approach the knowledge accrued for many cancers with precision therapeutics acting on well-characterized targets. Although the identification of genes responsible for neurodevelopmental and neuropsychiatric disorders remains a major obstacle, the few causally associated genes are ripe for discovery by focusing efforts to dissect their mechanisms. Here, we make a case for delving into mechanisms of the poorly characterized human KCTD gene family. Varying levels of evidence support their roles in neurocognitive disorders (KCTD3), neurodevelopmental disease (KCTD7), bipolar disorder (KCTD12), autism and schizophrenia (KCTD13), movement disorders (KCTD17), cancer (KCTD11), and obesity (KCTD15). Collective knowledge about these genes adds enhanced value, and critical insights into potential disease mechanisms have come from unexpected sources. Translation of basic research on the KCTD-related yeast protein Whi2 has revealed roles in nutrient signaling to mTORC1 (KCTD11) and an autophagy-lysosome pathway affecting mitochondria (KCTD7). Recent biochemical and structure-based studies (KCTD12, KCTD13, KCTD16) reveal mechanisms of regulating membrane channel activities through modulation of distinct GTPases. We explore how these seemingly varied functions may be disease related.
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Affiliation(s)
- Xinchen Teng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical SciencesSoochow UniversitySuzhouChina
- W. Harry Feinstone Department of Molecular Microbiology and ImmunologyJohns Hopkins University Bloomberg School of Public HealthBaltimoreMaryland
| | - Abdel Aouacheria
- ISEM, Institut des Sciences de l'Evolution de Montpellier, CNRS, EPHE, IRDUniversité de MontpellierMontpellierFrance
| | - Loïc Lionnard
- ISEM, Institut des Sciences de l'Evolution de Montpellier, CNRS, EPHE, IRDUniversité de MontpellierMontpellierFrance
| | - Kyle A. Metz
- W. Harry Feinstone Department of Molecular Microbiology and ImmunologyJohns Hopkins University Bloomberg School of Public HealthBaltimoreMaryland
- Present address:
Feinberg School of MedicineNorthwestern UniversityChicagoUSA
| | - Lucian Soane
- W. Harry Feinstone Department of Molecular Microbiology and ImmunologyJohns Hopkins University Bloomberg School of Public HealthBaltimoreMaryland
| | - Atsushi Kamiya
- Department of Psychiatry and Behavioral SciencesJohns Hopkins School of MedicineBaltimoreMaryland
| | - J. Marie Hardwick
- W. Harry Feinstone Department of Molecular Microbiology and ImmunologyJohns Hopkins University Bloomberg School of Public HealthBaltimoreMaryland
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10
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Liu X, Chu KM. Molecular biomarkers for prognosis of gastrointestinal stromal tumor. Clin Transl Oncol 2018; 21:145-151. [PMID: 30003531 DOI: 10.1007/s12094-018-1914-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. However, the development of molecular markers, especially circulating biomarkers, remains largely undone for the prognosis of GIST. We discussed the clinical-pathological characteristics of GIST and identified potential biomarkers for guidance of therapy and prognosis of GIST. Around 90% of GISTs contain mutations in KIT or PDGFRA and the remaining 10% of GISTs are wild-type. Recent studies have indicated that various DNAs and miRNAs could serve as potential biomarkers for prognosis of GIST, including KIT, PDGFRA, other DNAs (such as BRAF, SDH, SETD2 and ROR2), and microRNAs (miRNAs). The pressing need and challenges in the development of circulating prognostic biomarkers for GIST are also discussed. Although challenges remain, DNAs and miRNAs are promising circulating biomarkers for surveillance and prognosis of GIST. Advances in clarification of aberrant molecular alterations may open new avenues for exploration of reliable and robust biomarkers to improve the management of GIST.
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Affiliation(s)
- X Liu
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
| | - K-M Chu
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong. .,Department of Surgery, Queen Mary Hospital, Pokfulam, Hong Kong.
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Functional analysis of Cullin 3 E3 ligases in tumorigenesis. Biochim Biophys Acta Rev Cancer 2017; 1869:11-28. [PMID: 29128526 DOI: 10.1016/j.bbcan.2017.11.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 11/06/2017] [Accepted: 11/06/2017] [Indexed: 12/14/2022]
Abstract
Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.
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Hu B, Shi C, Jiang HX, Qin SY. Identification of novel therapeutic target genes and pathway in pancreatic cancer by integrative analysis. Medicine (Baltimore) 2017; 96:e8261. [PMID: 29049217 PMCID: PMC5662383 DOI: 10.1097/md.0000000000008261] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Gene alterations are crucial to the molecular pathogenesis of pancreatic cancer. The present study was designed to identify the potential candidate genes in the pancreatic carcinogenesis. METHODS Gene Expression Omnibus database (GEO) datasets of pancreatic cancer tissue were retrieval and the differentially expressed genes (DEGs) from individual microarray data were merged. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) networks, and gene coexpression analysis were performed. RESULTS Three GEO datasets, including 74 pancreatic cancer samples and 55 controls samples were selected. A total of 2325 DEGs were identified, including 1383 upregulated and 942 downregulated genes. The GO terms for molecular functions, biological processes, and cellular component were protein binding, small molecule metabolic process, and integral to membrane, respectively. The most significant pathway in KEGG analysis was metabolic pathways. PPI network analysis indicated that the significant hub genes including cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1), mitogen-activated protein kinase 3 (MAPK3), and phospholipase C, gamma 1 (PLCG1). Gene coexpression network analysis identified 4 major modules, and the potassium channel tetramerization domain containing 10 (KCTD10), kin of IRRE like (KIRREL), dipeptidyl-peptidase 10 (DPP10), and unc-80 homolog (UNC80) were the hub gene of each modules, respectively. CONCLUSION Our integrative analysis provides a comprehensive view of gene expression patterns associated with the pancreatic carcinogenesis.
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姚 思, 罗 庆. 野生型胃肠间质瘤分子机制研究进展. Shijie Huaren Xiaohua Zazhi 2017; 25:1166-1172. [DOI: 10.11569/wcjd.v25.i13.1166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是消化系最常见的间叶源性肿瘤, 80%-95%GIST存在KIT或PDGFRA基因突变, 未突变者称为野生型GIST(WT-GIST). 目前证实, 突变型GIST对酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)分子靶向治疗有效. 但WT-GIST通常对TKI类药物不敏感, 其分子理论基础、发生机制需明确阐述.
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Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling. Cell Signal 2017; 29:138-149. [DOI: 10.1016/j.cellsig.2016.10.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 10/14/2016] [Accepted: 10/18/2016] [Indexed: 01/24/2023]
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Sun J, Qian Y, Jiang Y, Chen J, Dai J, Jin G, Wang J, Hu Z, Liu S, Shen C, Shen H. Association of KCTD10, MVK, and MMAB polymorphisms with dyslipidemia and coronary heart disease in Han Chinese population. Lipids Health Dis 2016; 15:171. [PMID: 27716295 PMCID: PMC5050677 DOI: 10.1186/s12944-016-0348-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 09/30/2016] [Indexed: 12/31/2022] Open
Abstract
Background Several genome-wide association studies have discovered novel loci at chromosome 12q24, which includes mevalonate kinase (MVK), methylmalonic aciduria (cobalamin deficiency) cbIB type (MMAB), and potassium channel tetramerization domain-containing 10 (KCTD10), all of which influence HDL-cholesterol concentrations. However, there are few reports on the associations between these polymorphisms and HDL-C concentrations in Chinese population. This study aimed to evaluate the associations between functional polymorphisms in three genes (MVK, MMAB and KCTD10) and HDL-C concentrations, as well as coronary heart disease (CHD) susceptibility in Chinese individuals. Methods We systematically selected and genotyped 18 potentially functional polymorphisms in MVK, MMAB and KCTD10 by using the TaqMan OpenArray Genotyping System in a Chinese population including 399 dyslipidemia cases, 697 CHD cases and 465 controls. Multivariate logistic regression analyses were performed to estimate the relationship between the genotypes and dyslipidemia, CHD risk with adjustment of relevant confounders. Results Among six polymorphisms showing significant associations with dyslipidemia, the minor alleles of rs11066782 in KCTD10, rs11613718 in KCTD10 and rs11067233 in MMAB were significantly associated with a decreased risk of CHD (additive model: OR = 0.71, 95 % CI = 0.53–0.97, P = 0.029 for rs11066782; OR = 0.73, 95 % CI = 0.54–0.99, P = 0.044 for rs11613718 and OR = 0.57, 95 % CI = 0.40–0.80, P = 0.001 for rs11067233). Further combined analysis showed that individuals carrying “3-4” favorable alleles presented a 62 % (OR = 0.38, 95 % CI = 0.21–0.66) decreased risk of CHD compared with those carrying “0–2” favorable alleles. Conclusions These findings suggest that rs11066782 in KCTD10, rs11613718 in KCTD10 and rs11067233 in MMAB may contribute to the susceptibility of CHD by altering plasma HDL-C levels in Han Chinese. Electronic supplementary material The online version of this article (doi:10.1186/s12944-016-0348-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jie Sun
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Yun Qian
- Department of Chronic Non-communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, 214023, China
| | - Yue Jiang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Jiaping Chen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Juncheng Dai
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Guangfu Jin
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Jianming Wang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China.,Department of Social Medicine and Health Education, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Zhibin Hu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
| | - Sijun Liu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China. .,Department of Social Medicine and Health Education, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China.
| | - Chong Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China.
| | - Hongbing Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, 101 Longmian AV., Nanjing, Jiangsu, 211166, China
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Akaike K, Toda-Ishii M, Suehara Y, Mukaihara K, Kubota D, Mitani K, Takagi T, Kaneko K, Yao T, Saito T. TERT promoter mutations are a rare event in gastrointestinal stromal tumors. SPRINGERPLUS 2015; 4:836. [PMID: 26753123 PMCID: PMC4695492 DOI: 10.1186/s40064-015-1606-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 12/11/2015] [Indexed: 12/14/2022]
Abstract
Recently, the impact of telomere dysregulation on malignant progression has been reported in many cancers. A few studies have examined TERT promoter mutations in gastrointestinal stromal tumors (GISTs). Irregular telomerase activation can be maintained by TERT hot spot alterations and alternative lengthening of telomeres (ALT) characterized by inactivation of either the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX). To elucidate the clinicopathological impact of telomere dysregulation in GISTs, we examined 92 cases of GISTs for TERT promoter hot spot mutations along with immunohistochemical analysis of ATRX and DAXX expression, and compared these findings with the clinicopathological features. Univariate clinicopathological analysis revealed that tumor site, smaller tumor size, presence of necrosis, higher mitotic rate (>5/50 high-power fields) and risk classification were prognostic factors for either disease-free survival or overall survival. Two of 92 informative cases (2.2 %) were found to have heterozygous TERT promoter mutations (C228T), and these mutations occurred in a low-risk and a high-risk tumor, respectively. On immunohistochemical analysis for ATRX and DAXX, 16 (17.4 %) and 3 (3.3 %) of 92 cases showed loss of expression of ATRX and DAXX, respectively. Loss of expression of ATRX and DAXX were mutually exclusive except for one case. TERT promoter mutations were also mutually exclusive of the ALT phenotype. Telomere dysregulation was not associated with patient survival; however, telomere dysregulation was frequently observed in tumors of extra-gastric origin, which have an adverse outcome compared to those of gastric origin.
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Affiliation(s)
- Keisuke Akaike
- Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan ; Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Midori Toda-Ishii
- Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan ; Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Yoshiyuki Suehara
- Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Kenta Mukaihara
- Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan ; Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Daisuke Kubota
- Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Keiko Mitani
- Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Tatsuya Takagi
- Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Kazuo Kaneko
- Department of Orthopedic Surgery, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo, 113-8421 Japan
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High APRIL expression correlates with unfavourable survival of gastrointestinal stromal tumour. Pathology 2015; 46:617-22. [PMID: 25393252 DOI: 10.1097/pat.0000000000000162] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A proliferation inducing ligand (APRIL) is a member of the tumour necrosis factor superfamily. High APRIL expression has been found to correlate with tumour development, suggesting that APRIL participates in oncogenesis. However, little is known about APRIL expression in gastrointestinal stromal tumours (GISTs) or the relationship between APRIL expression and the clinical characteristics of GIST. Therefore, we assessed the expression of APRIL immunohistochemically using a tissue microarray from 178 patients with GIST and evaluated the relationship between APRIL expression and patient prognosis. Strong APRIL expression was observed in 42.7% of GISTs, with APRIL expression significantly associated with tumour diameter, gross classification and tumour grade (p < 0.05 each). Kaplan-Meier analysis suggested that low APRIL expression and tumour size <5 cm were associated with longer overall survival. These findings indicate that APRIL expression is correlated with malignant GIST phenotypes and it may serve as an unfavourable prognostic marker in patients with GIST.
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Wang CJ, Zhang ZZ, Xu J, Wang M, Zhao WY, Tu L, Zhuang C, Liu Q, Shen YY, Cao H, Zhang ZG. SLITRK3 expression correlation to gastrointestinal stromal tumor risk rating and prognosis. World J Gastroenterol 2015; 21:8398-8407. [PMID: 26217092 PMCID: PMC4507110 DOI: 10.3748/wjg.v21.i27.8398] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/13/2015] [Accepted: 04/28/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the influence of SLIT and NTRK-like family member 3 (SLITRK3) on the prognosis of gastrointestinal stromal tumor (GIST) and determine whether SLITRK3 can help improve current risk stratification systems.
METHODS: We hypothesized that SLITRK3 could be used as a prognostic molecular biomarker for GIST. 35 fresh tumor samples and 417 paraffin-embedded specimens from GIST patients were utilized. SLITRK3 mRNA expression in GIST tumor tissue was detected by real-time polymerase chain reaction, and SLITRK3 protein levels were estimated by immunohistochemistry. The correlation of SLITRK3 expression with various tumor clinicopathological characteristics and follow-up data were analyzed.
RESULTS: GIST tumors had high expression of SLITRK3 compared with adjacent normal tissues and the expression level gradually increased with risk grade. SLITRK3 protein expression was closely associated with gastrointestinal bleeding, tumor site, tumor size, mitotic index, and National Institutes of Health (NIH) classification. Survival analysis showed that SLITRK3 expression was closely correlated with overall survival and disease-free survival of GIST patients. Multivariate analysis also identified SLITRK3 expression, mitotic index, and NIH stage as significant risk factors of GIST recurrence.
CONCLUSION: SLITRK3 expression is a highly significant predictor of GIST recurrence and metastasis. Combinations of SLITRK3 and NIH stage have strong predictive and prognostic value, and are feasible markers for clinical practice in gastrointestinal stromal tumor.
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Zhu JQ, Ou WB. Therapeutic targets in gastrointestinal stromal tumors. World J Transl Med 2015; 4:25-37. [DOI: 10.5528/wjtm.v4.i1.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 09/14/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The tumorigenesis of GISTs is driven by gain-of-function mutations in KIT or platelet-derived growth factor receptor α (PDGFRA), resulting in constitutive activation of the tyrosine kinase and its downstream signaling pathways. Oncogenic KIT or PDGFRA mutations are compelling therapeutic targets for the treatment of GISTs, and the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GISTs. However, most GIST patients develop clinical resistance to imatinib and other tyrosine kinase inhibitors. Five mechanisms of resistance have been characterized: (1) acquisition of a secondary point mutation in KIT or PDGFRA; (2) genomic amplification of KIT; (3) activation of an alternative receptor tyrosine kinase; (4) loss of KIT oncoprotein expression; and (5) wild-type GIST. Currently, sunitinib is used as a second-line treatment for patients after imatinib failure, and regorafenib has been approved for patients whose disease is progressing on both imatinib and sunitinib. Phase II/III trials are currently in progress to evaluate novel inhibitors and immunotherapies targeting KIT, its downstream effectors such as phosphatidylinositol 3-kinase, protein kinase B and mammalian target of rapamycin, heat shock protein 90, and histone deacetylase inhibitor. Other candidate targets have been identified, including ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A. These candidates warrant clinical evaluation as novel therapeutic targets in GIST.
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20
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Sekine M, Imaoka H, Mizuno N, Hara K, Hijioka S, Niwa Y, Tajika M, Tanaka T, Ishihara M, Ito S, Misawa K, Ito Y, Shimizu Y, Yatabe Y, Ohnishi H, Yamao K. Clinical course of gastrointestinal stromal tumor diagnosed by endoscopic ultrasound-guided fine-needle aspiration. Dig Endosc 2015; 27:44-52. [PMID: 25059428 DOI: 10.1111/den.12333] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 07/14/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract. However, little is known about the clinical presentation of GIST, especially small lesions. The purpose of the present study was to clarify the efficacy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of GIST and to determine its clinical course. METHODS Pathological and clinical records of GIST extracted from our institutional database between 1996 and 2012 were reviewed. All GIST cases were diagnosed pathologically by surgical specimen or EUS-FNA. To examine the efficacy of EUS-FNA for the diagnosis of GIST, the pathological findings of EUS-FNA were compared with the surgical findings from resected cases. Next, to clarify the clinical presentation of GIST, imaging findings and changes in tumor size over time were evaluated in follow up. RESULTS Of 84 cases of GIST, 67 were resected surgically after EUS-FNA; tumor size was <20 mm in 19 patients, and ≥20 mm in 48 patients. For the diagnosis of small GIST<20 mm, sensitivity and positive predictive value of EUS-FNA were 81.3% and 100%, respectively. A total of 27 patients with GIST was follow up for more than 1 year. Tumor size increased significantly during follow up. However, generalized linear analysis showed that there was no significant relationship between tumor size and follow up period. CONCLUSIONS The present results showed that even small GIST can be correctly identified by EUS-FNA. Moreover, size of small GIST increased significantly during follow up.
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Affiliation(s)
- Masanari Sekine
- Division of Gastroenterology and Neurology, Akita University School of Medicine, Akita
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Ren K, Yuan J, Yang M, Gao X, Ding X, Zhou J, Hu X, Cao J, Deng X, Xiang S, Zhang J. KCTD10 is involved in the cardiovascular system and Notch signaling during early embryonic development. PLoS One 2014; 9:e112275. [PMID: 25401743 PMCID: PMC4234411 DOI: 10.1371/journal.pone.0112275] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 10/09/2014] [Indexed: 02/06/2023] Open
Abstract
As a member of the polymerase delta-interacting protein 1 (PDIP1) gene family, potassium channel tetramerisation domain-containing 10 (KCTD10) interacts with proliferating cell nuclear antigen (PCNA) and polymerase δ, participates in DNA repair, DNA replication and cell-cycle control. In order to further investigate the physiological functions of KCTD10, we generated the KCTD10 knockout mice. The heterozygous KCTD10+/− mice were viable and fertile, while the homozygous KCTD10−/− mice showed delayed growth from E9.0, and died at approximately E10.5, which displayed severe defects in angiogenesis and heart development. Further study showed that VEGF induced the expression of KCTD10 in a time- and dose-dependent manner. Quantitative real-time PCR and western blotting results revealed that several key members in Notch signaling were up-regulated either in KCTD10-deficient embryos or in KCTD10-silenced HUVECs. Meanwhile, the endogenous immunoprecipitation (IP) analysis showed that KCTD10 interacted with Cullin3 and Notch1 simultaneously, by which mediating Notch1 proteolytic degradation. Our studies suggest that KCTD10 plays crucial roles in embryonic angiogenesis and heart development in mammalians by negatively regulating the Notch signaling pathway.
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Affiliation(s)
- Kaiqun Ren
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
- Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Research, Medical School, Nanjing University, Nanjing, P.R. China
- College of Medicine, Hunan Normal University, Changsha, P. R. China
| | - Jing Yuan
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
| | - Manjun Yang
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
| | - Xiang Gao
- Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Research, Medical School, Nanjing University, Nanjing, P.R. China
| | - Xiaofeng Ding
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
| | - Jianlin Zhou
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
| | - Xingwang Hu
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
| | - Jianguo Cao
- College of Medicine, Hunan Normal University, Changsha, P. R. China
| | - Xiyun Deng
- College of Medicine, Hunan Normal University, Changsha, P. R. China
| | - Shuanglin Xiang
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
- * E-mail: (SX); (JZ)
| | - Jian Zhang
- Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China
- * E-mail: (SX); (JZ)
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ZHANG YAN, GU MENGLI, ZHOU XINXIN, MA HAN, YAO HANGPING, JI FENG. Altered expression of ETV1 and its contribution to tumorigenic phenotypes in gastrointestinal stromal tumors. Oncol Rep 2014; 32:927-34. [DOI: 10.3892/or.2014.3281] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 02/24/2014] [Indexed: 11/05/2022] Open
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CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling. Neoplasia 2014; 16:265-78, 278.e1-13. [PMID: 24726140 DOI: 10.1016/j.neo.2014.03.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 02/26/2014] [Accepted: 03/03/2014] [Indexed: 01/15/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.
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