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1
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Yang MJ, Lee H, Kang D, Park CJ. Biophysical investigation of the molecular interaction between minichromosome maintenance protein 6 and Bloom syndrome helicase. FEBS J 2025. [PMID: 40007132 DOI: 10.1111/febs.70047] [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: 10/02/2024] [Revised: 01/14/2025] [Accepted: 02/17/2025] [Indexed: 02/27/2025]
Abstract
The minichromosome maintenance protein (MCM) complex and Bloom syndrome helicase (BLM) are crucial components in DNA replication and cell division. MCM, a hexameric helicase that unwinds double-stranded DNA, serves as an important diagnostic and prognostic biomarker for cancer cells and a target for anticancer drug development. BLM, associated with G-quadruplex structures, is another key helicase in maintaining genomic stability. In this study, we investigate the interaction between MCM6 and BLM at the atomic level, as their expression levels are highly correlated in various cancer types, with elevated levels indicating poor prognosis. To elucidate the molecular basis of MCM6/BLM interaction, we employed fluorescence polarization anisotropy analysis, NMR chemical shifts perturbation analysis (CSP), and paramagnetic relaxation enhancement (PRE) experiments. MCM6 binding domain (MBD) C and D exhibit similar binding affinities to MCM6 winged-helix domain (WHD). However, significant CSPs with MBD-D and PRE experiments suggested that MBD-D is closer to MCM6 WHD than MBD-C. Despite both proteins containing numerous negatively charged residues, hydrophobic interactions govern the association between MCM6 WHD and BLM MBD-D. This biophysical characterization of the MCM6/BLM interaction provides new insights into their functional relationship and challenges existing models. Our findings reveal that MCM6 binds BLM at a different site than its other known partner chromatin licensing and DNA replication factor. Understanding these protein-protein interactions at the molecular level may contribute to the development of novel anticancer therapies targeting the MCM6/BLM interaction.
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Affiliation(s)
- Min June Yang
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Haeun Lee
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Donguk Kang
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Chin-Ju Park
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Korea
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2
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Li J, Qi C, Shao S, Chen Y, Peng Z, Shen Q, Zhang Z. SP1 transcriptionally regulates UBE2N expression to promote lung adenocarcinoma progression. MOLECULAR BIOMEDICINE 2023; 4:7. [PMID: 36964266 PMCID: PMC10039148 DOI: 10.1186/s43556-023-00118-2] [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: 12/12/2022] [Accepted: 02/05/2023] [Indexed: 03/26/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is the main cause of cancer-related death worldwide. Understanding the mechanisms of LUAD progression may provide insights into targeted therapy approaches for this malignancy. Ubiquitin-conjugating enzyme 2 N (UBE2N) has been demonstrated to play key roles in the progression of various cancers. However, the functions and mechanisms underlying UBE2N expression in LUAD are still unclear. In this study, we found that UBE2N is highly expressed in LUAD and patients with high UBE2N expression in their tumors have poor clinical outcomes. Moreover, we showed that UBE2N interference significantly inhibited LUAD progression in vitro and in vivo. At the molecular level, we demonstrated that the UBE2N is a bona fide target of transcription factor SP1. SP1 directly bound to the promoter of UBE2N and upregulated its expression in LUAD cells, which in turn contributed to the progression of LUAD. Furthermore, we found that there is a strong positive correlation between the expression of SP1 and UBE2N in LUAD samples. Importantly, LUAD patients with concomitantly high expression of SP1 and UBE2N were significantly associated with poor clinical outcomes. In conclusion, our study demonstrated that the SP1-UBE2N signaling axis might play a key role in the malignant progression of LUAD, which provides new targets and strategies for the treatment of LUAD.
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Affiliation(s)
- Jianjun Li
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
- Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China
| | - Chunchun Qi
- Medical College of Nankai University, Tianjin, 300071, China
| | - Shanshan Shao
- Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yanru Chen
- Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, 152 Aiguo Road, Nanchang, Jiangxi, 330006, China
| | - Zimei Peng
- Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, 152 Aiguo Road, Nanchang, Jiangxi, 330006, China
| | - Qinglin Shen
- Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, 152 Aiguo Road, Nanchang, Jiangxi, 330006, China.
- Department of Oncology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Jiangxi, Nanchang, 330006, China.
| | - Zhen Zhang
- Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, 152 Aiguo Road, Nanchang, Jiangxi, 330006, China.
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3
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Zhang S, You X, Zheng Y, Shen Y, Xiong X, Sun Y. The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells. J Clin Invest 2023; 133:162434. [PMID: 36548081 PMCID: PMC9927933 DOI: 10.1172/jci162434] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Ubiquitin-conjugating enzyme E2C (UBE2C) mediates ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo. Here we report that UBE2C was indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C was required for KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibited tumor formation and extended the lifespan of mice. Mechanistically, KrasG12D induced expression of UBE2C, which coupled with APC/CCDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of mTORC signaling. Importantly, DEPTOR levels fluctuated during cell cycle progression in a manner dependent on UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescued the tumor inhibitory effect of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene and tumor suppressor cascade that regulates cell cycle progression and autophagy and validates UBE2C an attractive target for lung cancer associated with Kras mutations.
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Affiliation(s)
- Shizhen Zhang
- Cancer Institute and.,Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, the Second Affiliated Hospital, and
| | - Xiahong You
- Cancer Institute and.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yawen Zheng
- Cancer Institute and.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanwen Shen
- Cancer Institute and.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiufang Xiong
- Cancer Institute and.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Sun
- Cancer Institute and.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University Cancer Center, Hangzhou, China.,Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, China
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4
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Song H, Shen R, Mahasin H, Guo Y, Wang D. DNA replication: Mechanisms and therapeutic interventions for diseases. MedComm (Beijing) 2023; 4:e210. [PMID: 36776764 PMCID: PMC9899494 DOI: 10.1002/mco2.210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 01/08/2023] [Accepted: 01/09/2023] [Indexed: 02/09/2023] Open
Abstract
Accurate and integral cellular DNA replication is modulated by multiple replication-associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication-target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.
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Affiliation(s)
- Hao‐Yun Song
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - Rong Shen
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - Hamid Mahasin
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - Ya‐Nan Guo
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
| | - De‐Gui Wang
- School of Basic Medical SciencesLanzhou UniversityLanzhouGansuChina
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5
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Wang H, Chu F, Zhang XF, Zhang P, Li LX, Zhuang YL, Niu XF, He X, Li ZJ, Bai Y, Mao D, Liu ZW, Zhang DL, Li BA. TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs. Cell Death Dis 2023; 14:64. [PMID: 36707511 PMCID: PMC9883482 DOI: 10.1038/s41419-022-05537-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 12/17/2022] [Accepted: 12/21/2022] [Indexed: 01/29/2023]
Abstract
The pregnane X receptor (PXR) is an important regulator of hepatocellular carcinoma cellular resistance to antitumor drugs. Activation of PXR was modulated by the co-regulators. The target protein for the Xenopus plus end-directed kinesin-like protein (Xklp2) known as TPX2 that was previously considered as a tubulin regulator, also functions as the regulator of some transcription factors and pro-oncogenes in human malignances. However, the actions of TPX2 on PXR and HCC cells are still unclear. In the present study, our results demonstrate that the high expression of endogenous mRNA level of TPX2 not only correlated with the poor prognosis of advanced HCC patients who received sorafenib treatment but also with expression of PXR's downstream genes, cyp3a4 and/or mdr-1. Results from luciferase and real-time polymerase chain reaction (qPCR) showed that TPX2 leads to enhancement of the transcription factor activation of PXR. Protein-protein interactions between PXR and TPX2 were identified using co-immunoprecipitation. Mechanically, overexpression of TPX2 led to enhancement of PXR recruitment to its downstream gene cyp3a4's promoter region (the PXRE region) or enhancer region (the XREM region). Treatment of HCC cells with paclitaxel, a microtubule promoter, led to enhancement of the effects of TPX2, whereas vincristine, a microtubule depolymerizing agent caused a decrease in TPX2-associated effects. TPX2 was found to cause acceleration of the metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI) in HCC cells and in turn led to the resistance to sorafenib by HCC cells. By establishing novel actions of TXP2 on PXR in HCC cells, the results indicate that TPX2 could be considered a promising therapeutic target to enhance HCC cells sensitivity to antitumor drugs.
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Affiliation(s)
- Hongbo Wang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Fang Chu
- Department of Emergency, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Xiao-Feng Zhang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Peng Zhang
- Department of Urology, Chinese People's Liberation Army (PLA) General Hospital/Chinese PLA Medical Academy, Beijing, 100853, China
| | - Li-Xin Li
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Yun-Long Zhuang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Xiao-Feng Niu
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Xi He
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Zhi-Jie Li
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Ying Bai
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China
| | - Da Mao
- Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, 100191, China
- Division of Chemical Metrology and Analytical Science, National Institute of Metrology, Beijing, 100029, China
| | - Zhen-Wen Liu
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China.
| | - Da-Li Zhang
- Senior Department of Hepatology, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China.
| | - Bo-An Li
- Clinical Laboratory, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100039, China.
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6
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Xu Q, Cha Q, Qin H, Liu B, Wu X, Shi J. Identification of Master Regulators Driving Disease Progression, Relapse, and Drug Resistance in Lung Adenocarcinoma. FRONTIERS IN BIOINFORMATICS 2022; 2:813960. [PMID: 36304306 PMCID: PMC9580914 DOI: 10.3389/fbinf.2022.813960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/04/2022] [Indexed: 11/13/2022] Open
Abstract
Backgrounds: Lung cancer is the leading cause of cancer related death worldwide. Current treatment strategies primarily involve surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, determined by TNM stages, histologic types, and genetic profiles. Plenty of studies have been trying to identify robust prognostic gene expression signatures. Even for high performance signatures, they usually have few shared genes. This is not totally unexpected, since a prognostic signature is associated with patient survival and may contain no upstream regulators. Identification of master regulators driving disease progression is a vital step to understand underlying molecular mechanisms and develop new treatments. Methods: In this study, we have utilized a robust workflow to identify potential master regulators that drive poor prognosis in patients with lung adenocarcinoma. This workflow takes gene expression signatures that are associated with poor survival of early-stage lung adenocarcinoma, EGFR-TKI resistance, and responses to immune checkpoint inhibitors, respectively, and identifies recurrent master regulators from seven public gene expression datasets by a regulatory network-based approach. Results: We have found that majority of the master regulators driving poor prognosis in early stage LUAD are cell-cycle related according to Gene Ontology annotation. However, they were demonstrated experimentally to promote a spectrum of processes such as tumor cell proliferation, invasion, metastasis, and drug resistance. Master regulators predicted from EGFR-TKI resistance signature and the EMT pathway signature are largely shared, which suggests that EMT pathway functions as a hub and interact with other pathways such as hypoxia, angiogenesis, TNF-α signaling, inflammation, TNF-β signaling, Wnt, and Notch signaling pathways. Master regulators that repress immunotherapy are enriched with MYC targets, E2F targets, oxidative phosphorylation, and mTOR signaling. Conclusion: Our study uncovered possible mechanisms underlying recurrence, resistance to targeted therapy, and immunotherapy. The predicted master regulators may serve as potential therapeutic targets in patients with lung adenocarcinoma.
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Affiliation(s)
- Qiong Xu
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiongfang Cha
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Qin
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Liu
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueling Wu
- Department of Respiratory Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Xueling Wu, ; Jiantao Shi,
| | - Jiantao Shi
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- *Correspondence: Xueling Wu, ; Jiantao Shi,
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7
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Jiang X, Yuan Y, Tang L, Wang J, Liu Q, Zou X, Duan L. Comprehensive Pan-Cancer Analysis of the Prognostic and Immunological Roles of the METTL3/lncRNA-SNHG1/miRNA-140-3p/UBE2C Axis. Front Cell Dev Biol 2021; 9:765772. [PMID: 34858987 PMCID: PMC8631498 DOI: 10.3389/fcell.2021.765772] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 10/15/2021] [Indexed: 01/01/2023] Open
Abstract
Growing evidence has demonstrated that UBE2C plays a critical role in cancer progression, but there is no study focusing on the prognosis, upstream regulation mechanism, and immunological roles of UBE2C across diverse tumor types. In this study, we found that UBE2C was elevated in this human pan-cancer analysis, and high expression of UBE2C was correlated with poor prognosis. In addition, UBE2C expression was markedly associated with tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and diverse drug sensitivities. Finally, we showed that the METTL3/SNHG1/miRNA-140-3p axis could potentially regulate UBE2C expression. N(6)-Methyladenosine (m6A) modifications improved the stability of methylated SNHG1 transcripts by decreasing the rate of RNA degradation, which lead to upregulation of SNHG1 in non-small cell lung cancer (NSCLC). In vitro functional experiments showed that SNHG1, as a competing endogenous RNA, sponges miR-140-3p to increase UBE2C expression in NSCLC cell lines. Our study elucidates the clinical importance and regulatory mechanism of the METTL3/SNHG1/miRNA-140-3p/UBE2C axis in NSCLC and provides a prognostic indicator, as well as a promising therapeutic target for patients with NSCLC.
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Affiliation(s)
- Xiulin Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China
| | - Yixiao Yuan
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lin Tang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Juan Wang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qianqian Liu
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiaolan Zou
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lincan Duan
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
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8
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Huang S, Pang L, Wei C. Identification of a Four-Gene Signature With Prognostic Significance in Endometrial Cancer Using Weighted-Gene Correlation Network Analysis. Front Genet 2021; 12:678780. [PMID: 34616422 PMCID: PMC8488359 DOI: 10.3389/fgene.2021.678780] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 08/30/2021] [Indexed: 01/01/2023] Open
Abstract
Endometrial hyperplasia (EH) is a precursor for endometrial cancer (EC). However, biomarkers for the progression from EH to EC and standard prognostic biomarkers for EC have not been identified. In this study, we aimed to identify key genes with prognostic significance for the progression from EH to EC. Weighted-gene correlation network analysis (WGCNA) was used to identify hub genes utilizing microarray data (GSE106191) downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified from the Uterine Corpus Endometrial Carcinoma (UCEC) dataset of The Cancer Genome Atlas database. The Limma-Voom R package was applied to detect differentially expressed genes (DEGs; mRNAs) between cancer and normal samples. Genes with |log2 (fold change [FC])| > 1.0 and p < 0.05 were considered as DEGs. Univariate and multivariate Cox regression and survival analyses were performed to identify potential prognostic genes using hub genes overlapping in the two datasets. All analyses were conducted using R Bioconductor and related packages. Through WGCNA and overlapping genes in hub modules with DEGs in the UCEC dataset, we identified 42 hub genes. The results of the univariate and multivariate Cox regression analyses revealed that four hub genes, BUB1B, NDC80, TPX2, and TTK, were independently associated with the prognosis of EC (Hazard ratio [95% confidence interval]: 0.591 [0.382–0.912], p = 0.017; 0.605 [0.371–0.986], p = 0.044; 1.678 [1.132–2.488], p = 0.01; 2.428 [1.372–4.29], p = 0.02, respectively). A nomogram was established with a risk score calculated using the four genes’ coefficients in the multivariate analysis, and tumor grade and stage had a favorable predictive value for the prognosis of EC. The survival analysis showed that the high-risk group had an unfavorable prognosis compared with the low-risk group (p < 0.0001). The receiver operating characteristic curves also indicated that the risk model had a potential predictive value of prognosis with area under the curve 0.807 at 2 years, 0.783 at 3 years, and 0.786 at 5 years. We established a four-gene signature with prognostic significance in EC using WGCNA and established a nomogram to predict the prognosis of EC.
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Affiliation(s)
- Shijin Huang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lihong Pang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Changqiang Wei
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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9
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Ubiquitin-Conjugating Enzymes in Cancer. Cells 2021; 10:cells10061383. [PMID: 34199813 PMCID: PMC8227520 DOI: 10.3390/cells10061383] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/28/2021] [Accepted: 05/30/2021] [Indexed: 12/22/2022] Open
Abstract
The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.
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10
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Huang C, Lei C, Pan B, Fang S, Chen Y, Cao W, Liu L. Potential Prospective Biomarkers for Non-small Cell Lung Cancer: Mini-Chromosome Maintenance Proteins. Front Genet 2021; 12:587017. [PMID: 33936158 PMCID: PMC8079985 DOI: 10.3389/fgene.2021.587017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 03/18/2021] [Indexed: 11/13/2022] Open
Abstract
Minichromosome maintenance proteins (MCMs) are considered to be essential factors coupling DNA replication to both cell cycle progression and checkpoint regulation. Previous studies have shown that dysregulation of MCMs are implicated in tumorigenesis of lung cancer. However, the distinct expression/mutation patterns and prognostic values of MCMs in lung cancer have yet to be systematically elucidated. In the present study, we analyzed the transcriptional levels, mutations, and prognostic value of MCM1-10 in non-small cell lung cancer (NSCLC) patients using multiple bioinformatics tools, including ONCOMINE, GEPIA, Kaplan-Meier Plotter, cBioPortal, and GESA. The analysis results from GEPIA dataset showed that MCM2/4/10 was significantly high expressed in both lung adenocarcinoma (LUAD) and squamous cell lung carcinomas (LUSCs). Meanwhile, the expression levels of MCM2/4/6/7/8 were associated with advanced tumor stages. Subsequent survival analysis using the Kaplan-Meier Plotter indicated that high expression levels of MCM1/2/3/4/5/6/7/8/10 were associated with worse overall survival (OS), while high expression level of MCM9 predicted better OS in these patients. Furthermore, we experimentally validated overexpression of MCM2 and MCM4 in NSCLC, thus the results from this study support a view that they may serve as potential prospective biomarkers to identify high-risk subgroups of NSCLC patients.
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Affiliation(s)
- Chen Huang
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy-Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chuqi Lei
- Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, China
| | - Boyu Pan
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy-Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Senbiao Fang
- Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, China
| | - Yubao Chen
- Department of Computational Biology, Beijing Computing Center, Beijing, China
| | - Wenfeng Cao
- Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy-Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Liren Liu
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy-Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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11
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Cheng Y, Wang M, Zhou J, Dong H, Wang S, Xu H. The Important Role of N6-methyladenosine RNA Modification in Non-Small Cell Lung Cancer. Genes (Basel) 2021; 12:genes12030440. [PMID: 33808751 PMCID: PMC8003501 DOI: 10.3390/genes12030440] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications of eukaryotic RNA. The m6A modification is a dynamic and reversible process, regulated by three kinds of regulator, including m6A methyltransferases, demethylases and m6A-binding proteins, and this modification plays a vital role in many diseases, especially in cancers. Accumulated evidence has proven that this modification has a significant effect on cellular biological functions and cancer progression; however, little is known about the effects of the m6A modification in non-small cell lung cancer (NSCLC). In this review, we summarized how various m6A regulators modulate m6A RNA metabolism and demonstrated the effect of m6A modification on the progression and cellular biological functions of NSCLC. We also discussed how m6A modification affects the treatment, drug resistance, diagnosis and prognosis of NSCLC patients.
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12
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Jiang Y, Huang Y, Du Y, Zhao Y, Ren J, Ma S, Wu C. Identification of Prognostic Genes and Pathways in Lung Adenocarcinoma Using a Bayesian Approach. Cancer Inform 2020; 16:1176935116684825. [PMID: 33354107 PMCID: PMC7736146 DOI: 10.1177/1176935116684825] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 11/24/2016] [Indexed: 01/02/2023] Open
Abstract
Lung cancer is the leading cause of cancer-associated mortality in the United States and the world. Adenocarcinoma, the most common subtype of lung cancer, is generally diagnosed at the late stage with poor prognosis. In the past, extensive effort has been devoted to elucidating lung cancer pathogenesis and pinpointing genes associated with survival outcomes. As the progression of lung cancer is a complex process that involves coordinated actions of functionally associated genes from cancer-related pathways, there is a growing interest in simultaneous identification of both prognostic pathways and important genes within those pathways. In this study, we analyse The Cancer Genome Atlas lung adenocarcinoma data using a Bayesian approach incorporating the pathway information as well as the interconnections among genes. The top 11 pathways have been found to play significant roles in lung adenocarcinoma prognosis, including pathways in mitogen-activated protein kinase signalling, cytokine-cytokine receptor interaction, and ubiquitin-mediated proteolysis. We have also located key gene signatures such as RELB, MAP4K1, and UBE2C. These results indicate that the Bayesian approach may facilitate discovery of important genes and pathways that are tightly associated with the survival of patients with lung adenocarcinoma.
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Affiliation(s)
- Yu Jiang
- Division of Epidemiology, Biostatistics
and Environmental Health, School of Public Health, University of Memphis, Memphis,
TN, USA
- Cooperative Studies Program, VA
Connecticut Healthcare System, West Haven, CT, USA
| | - Yuan Huang
- Cooperative Studies Program, VA
Connecticut Healthcare System, West Haven, CT, USA
- Department of Biostatistics, Yale
University, New Haven, CT, USA
| | - Yinhao Du
- Department of Statistics, Kansas State
University, Manhattan, KS, USA
| | - Yinjun Zhao
- Department of Biostatistics, Yale
University, New Haven, CT, USA
| | - Jie Ren
- Department of Statistics, Kansas State
University, Manhattan, KS, USA
| | - Shuangge Ma
- Cooperative Studies Program, VA
Connecticut Healthcare System, West Haven, CT, USA
- Department of Biostatistics, Yale
University, New Haven, CT, USA
| | - Cen Wu
- Department of Statistics, Kansas State
University, Manhattan, KS, USA
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13
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Zhang Y, Zhao X, Zhou Y, Wang M, Zhou G. Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer. Front Med 2019; 14:318-326. [DOI: 10.1007/s11684-019-0708-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/25/2019] [Indexed: 01/05/2023]
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14
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Li S, Jiang Z, Li Y, Xu Y. Prognostic significance of minichromosome maintenance mRNA expression in human lung adenocarcinoma. Oncol Rep 2019; 42:2279-2292. [PMID: 31545501 PMCID: PMC6826304 DOI: 10.3892/or.2019.7330] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 08/09/2019] [Indexed: 12/21/2022] Open
Abstract
The minichromosome maintenance (MCM) gene family plays an essential role in DNA replication and cell cycle progression. However, MCM gene expression has not been well-studied in lung adenocarcinoma (LUAD). In the present study, the expression, prognostic value and functions of MCMs in LUAD were investigated using several databases and bioinformatic tools, including Oncomine, GEPIA, cBioPortal, CancerSEA and Kaplan-Meier plotter. It was demonstrated that the mRNA expression of MCM2, MCM4 and MCM10 were significantly increased in patients with LUAD. High mRNA expression of MCM2-5, MCM8 and MCM10 were associated with poor overall survival and progression-free survival. High MCM4 expression was associated with adverse post-progression survival. In addition, the Human Protein Atlas database showed that MCM protein expression was consistent with the mRNA expression. These results demonstrate that MCM2, MCM4 and MCM10 are potential prognostic markers and therapeutic targets for LUAD.
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Affiliation(s)
- Shu Li
- Department of Hematology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Zhou Jiang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, P.R. China
| | - Yang Xu
- Department of Hematology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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15
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He SY, Xi WJ, Wang X, Xu CH, Cheng L, Liu SY, Meng QQ, Li B, Wang Y, Shi HB, Wang HJ, Wang ZZ. Identification of a Combined RNA Prognostic Signature in Adenocarcinoma of the Lung. Med Sci Monit 2019; 25:3941-3956. [PMID: 31132294 PMCID: PMC6556069 DOI: 10.12659/msm.913727] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Adenocarcinoma of the lung is a type of non-small cell lung cancer (NSCLC). Clinical outcome is associated with tumor grade, stage, and subtype. This study aimed to identify RNA expression profiles, including long noncoding RNA (lncRNA), microRNA (miRNA), and mRNA, associated with clinical outcome in adenocarcinoma of the lung using bioinformatics data. Material/Methods The miRNA and mRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database, and lncRNA expression profiles were downloaded from The Atlas of Noncoding RNAs in Cancer (TANRIC) database. The independent dataset, the Gene Expression Omnibus (GEO) accession dataset, GSE81089, was used. RNA expression profiles were used to identify comprehensive prognostic RNA signatures based on patient survival time. Results From 7,704 lncRNAs, 787 miRNAs, and 28,937 mRNAs of 449 patients, four joint RNA molecular signatures were identified, including RP11-909N17.2, RP11-14N7.2 (lncRNAs), MIR139 (miRNA), KLHDC8B (mRNA). The random forest (RF) classifier was used to test the prediction ability of patient survival risk and showed a good predictive accuracy of 71% and also showed a significant difference in overall survival (log-rank P=0.0002; HR, 3.54; 95% CI, 1.74–7.19). The combined RNA signature also showed good performance in the identification of patient survival in the validation and independent datasets. Conclusions This study identified four RNA sequences as a prognostic molecular signature in adenocarcinoma of the lung, which may also provide an increased understanding of the molecular mechanisms underlying the pathogenesis of this malignancy.
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Affiliation(s)
- Si-Yu He
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Wen-Jing Xi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Xin Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Chao-Han Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Liang Cheng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Si-Yao Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Qian-Qian Meng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Boyan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Yahui Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Hong-Bo Shi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
| | - Hong-Jiu Wang
- College of Science, Heilongjiang University of Science and Technology, Harbin, Heilongjiang, China (mainland)
| | - Zhen-Zhen Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China (mainland)
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16
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Ni M, Liu X, Wu J, Zhang D, Tian J, Wang T, Liu S, Meng Z, Wang K, Duan X, Zhou W, Zhang X. Identification of Candidate Biomarkers Correlated With the Pathogenesis and Prognosis of Non-small Cell Lung Cancer via Integrated Bioinformatics Analysis. Front Genet 2018; 9:469. [PMID: 30369945 PMCID: PMC6194157 DOI: 10.3389/fgene.2018.00469] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 09/24/2018] [Indexed: 01/10/2023] Open
Abstract
Background and Objective: Non-small cell lung cancer (NSCLC) accounts for 80-85% of all patients with lung cancer and 5-year relative overall survival (OS) rate is less than 20%, so that identifying novel diagnostic and prognostic biomarkers is urgently demanded. The present study attempted to identify potential key genes associated with the pathogenesis and prognosis of NSCLC. Methods: Four GEO datasets (GSE18842, GSE19804, GSE43458, and GSE62113) were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between NSCLC samples and normal ones were analyzed using limma package, and RobustRankAggreg (RRA) package was used to conduct gene integration. Moreover, Search Tool for the Retrieval of Interacting Genes database (STRING), Cytoscape, and Molecular Complex Detection (MCODE) were utilized to establish protein-protein interaction (PPI) network of these DEGs. Furthermore, functional enrichment and pathway enrichment analyses for DEGs were performed by Funrich and OmicShare. While the expressions and prognostic values of top genes were carried out through Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan Meier-plotter (KM) online dataset. Results: A total of 249 DEGs (113 upregulated and 136 downregulated) were identified after gene integration. Moreover, the PPI network was established with 166 nodes and 1784 protein pairs. Topoisomerase II alpha (TOP2A), a top gene and hub node with higher node degrees in module 1, was significantly enriched in mitotic cell cycle pathway. In addition, Interleukin-6 (IL-6) was enriched in amb2 integrin signaling pathway. The mitotic cell cycle was the most significant pathway in module 1 with the highest P-value. Besides, five hub genes with high degree of connectivity were selected, including TOP2A, CCNB1, CCNA2, UBE2C, and KIF20A, and they were all correlated with worse OS in NSCLC. Conclusion: The results showed that TOP2A, CCNB1, CCNA2, UBE2C, KIF20A, and IL-6 may be potential key genes, while the mitotic cell cycle pathway may be a potential pathway contribute to progression in NSCLC. Further, it could be used as a new biomarker for diagnosis and to direct the synthesis medicine of NSCLC.
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Affiliation(s)
- Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Dan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jinhui Tian
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Ting Wang
- Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Kaihuan Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaojiao Duan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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17
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Wang S, Chen Y, Chai Y. Prognostic role of targeting protein for Xklp2 in solid tumors: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e13018. [PMID: 30412141 PMCID: PMC6221728 DOI: 10.1097/md.0000000000013018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The prognostic role of targeting protein for Xklp2 (TPX2) in solid tumors has been investigated in several researches, but the results remain controversial. Here we present a meta-analysis to systematically review the association between TPX2 expression levels and prognosis of human solid tumors. METHODS Studies published until December 2017 were searched in PubMed, Web of Science, and EBSCO, 13 studies (2134 patients) were collected for analysis. Odds ratios (ORs) for overall survival (OS) and disease-free survival (DFS) from individual studies were calculated by the application of Mantel-Haenszel random effect model. Pooled ORs were estimated by Z test. Publication bias and interstudy heterogeneity analyses were also performed. RESULTS TPX2 overexpression was associated with poor OS at 3 and 5 years [OR = 4.63, 95% confidence interval (CI): 3.27-6.56, P < .00001; OR = 4.05, 95% CI: 2.32-7.07, P < .00001, respectively] of solid tumors. Similar results were observed with DFS at 3 and 5 years (OR = 3.35, 95% CI: 1.83-6.14, P < .0001; OR = 2.94, 95% CI: 1.74-4.98, P < .0001, respectively). Subgroup analysis revealed that increased TPX2 expression was related to worse prognosis of gastric cancer and hepatocellular cancer, while irrelevant to esophageal squamous cell cancer at 5-year survival rate. CONCLUSIONS Overexpression of TPX2 is related to poor survival rate in most solid tumors, which indicates that the expression level of TPX2 is a significant prognostic parameter and potential therapeutic target in various solid tumors.
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18
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Wu W, Wang X, Shan C, Li Y, Li F. Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma. Onco Targets Ther 2018; 11:5025-5034. [PMID: 30174440 PMCID: PMC6109654 DOI: 10.2147/ott.s169002] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Minichromosome maintenance protein 2 (MCM2), which is a member of MCM family, has been found to be a relevant marker for progression and prognosis in a variety of human cancers. Due to lack of effective therapeutic target in lung squamous cell carcinoma (LUSC) patients, the aim of our study was to screen and identify biomarkers which are associated to clinicopathological characteristics including prognosis in LUSC patients. Methods The expression status of MCM2 in lung cancer was analyzed using the publicly available Gene Expression Omnibus databases (GSE3268 and GSE10245). The mRNA and protein expression of MCM2 in lung cancer tissues and cell lines was detected by quantitative real-time PCR and Western blot, and the association between MCM2 expression and clinicopathological factors was analyzed by immunohistochemistry. The loss-of-function study of MCM2 was conducted in LUSC cell lines. Results In our study, we found MCM2 expression was increased in LUSC tissues compared with paired adjacent normal lung tissues or lung adenocarcinoma tissues through analyzing microarray data sets (GSE3268 and GSE10245), which confirmed that MCM2 mRNA and protein were overexpressed in LUSC tissues and cell lines. Meanwhile, we analyzed the association between MCM2 protein expression and clinicopathological characteristics of LUSC patients, and found high expression of MCM2 protein was obviously associated with malign differentiated degree, advanced clinical stage, large tumor size, more lymph node metastasis and present distant metastasis. The survival analysis showed MCM2 overexpression was an independent unfavorable prognostic factor for LUSC patients. Conclusion MCM2 is involved in the development and progression of LUSC as an oncogene, and thereby may act as a potential therapeutic target for LUSC patients.
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Affiliation(s)
- Wei Wu
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China,
| | - Xianwei Wang
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China,
| | - Changting Shan
- Department of Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China,
| | - Yong Li
- Department of Emergency, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, People's Republic of China
| | - Fengzhu Li
- Department of Paediatric Surgery, Jining No 1 People's Hospital, Jining, Shandong 272011, People's Republic of China
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19
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Guo J, Wu Y, Du J, Yang L, Chen W, Gong K, Dai J, Miao S, Jin D, Xi S. Deregulation of UBE2C-mediated autophagy repression aggravates NSCLC progression. Oncogenesis 2018; 7:49. [PMID: 29904125 PMCID: PMC6002383 DOI: 10.1038/s41389-018-0054-6] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/12/2018] [Accepted: 04/23/2018] [Indexed: 02/07/2023] Open
Abstract
The roles of aberrantly regulated autophagy in human malignancy and the mechanisms that initiate and sustain the repression of autophagy in carcinogenesis are less well defined. Activation of the oncogene UBE2C and repression of autophagy are concurrently underlying the initiation, progression, and metastasis of lung cancer and exploration of essential association of UBE2C with autophagy will confer more options in searching novel molecular therapeutic targets in lung cancer. Here we report that aberrant activation of UBE2C in lung tumors from patients associates with adverse prognosis and enhances cell proliferation, clonogenicity, and invasive growth of NSCLC. UBE2C selectively represses autophagy in NSCLC and disruption of UBE2C-mediated autophagy repression attenuates cell proliferation, clonogenicity, and invasive growth of NSCLC. Autophagy repression is essentially involved in UBE2C-induced cell proliferation, clonogenicity, and invasive growth of NSCLC. Interference of UBE2C-autophagy repression axis by Norcantharidin arrests NSCLC progression. UBE2C is repressed post-transcriptionally via tumor suppressor miR-381 and epitranscriptionally stabilized with maintenance of lower m6A level within its mature RNAs due to the upregulation of m6A demethylase ALKBH5 in NSCLC. Collectively, our results indicated that deregulated UBE2C-autophagy repression axis drives NSCLC progression which renders varieties of potential molecular targets in cancer therapy of NSCLC.
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Affiliation(s)
- Jiwei Guo
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Yan Wu
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Jing Du
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Lijuan Yang
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Weiwei Chen
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Kaikai Gong
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Juanjuan Dai
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Shuang Miao
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Dan Jin
- Department of Pain Ward, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China
| | - Sichuan Xi
- Cancer Research Institute, Binzhou Medical University Hospital, 256603, Binzhou, P.R. China.
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20
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UBE2C is overexpressed in ESCC tissues and its abrogation attenuates the malignant phenotype of ESCC cell lines. Oncotarget 2018; 7:65876-65887. [PMID: 27588470 PMCID: PMC5323199 DOI: 10.18632/oncotarget.11674] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 08/13/2016] [Indexed: 11/25/2022] Open
Abstract
The esophageal squamous cell carcinoma (ESCC) is widely known as a highly lethal and poor understood cancer, then requiring the search for novel molecular markers to improve its management and patients survival. Recently, ubiquitin-conjugating enzyme E2C (UBE2C) has been figuring as a prominent tumor biomarker candidate, once it has been recognized as a key player in cell cycle progression. In this way, the aim of this study was to evaluate the expression profile of UBE2C gene and protein in ESCC samples, as well as its diagnostic and prognostic marker potential, and its contribution to ESSC genesis and/or progression by performing in vitro functional assays. The analysis of UBE2C gene expression in 52 paired ESCC samples (tumor and respective histologically normal surrounding tissue), by qRT-PCR, revealed that this gene is overexpressed in 73% of ESCC samples. Subsequently, immunohistochemical analysis confirmed that UBE2C protein expression was upregulated in all ESCC cases, but absent in the histologically normal tumor surrounding tissues. Moreover, we showed that UBE2C mRNA expression was able to accurately discriminate ESCC tissue from both healthy esophageal and histologically normal tumor surrounding tissues, pointing out its role as a diagnostic marker for this cancer. Finally, we report that UBE2C affects proliferation rates and cell cycle profile of ESCC cell lines, by directly interfering with cyclin B1 protein levels, suggesting its involvement in crucial steps of ESCC carcinogenesis.
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21
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Sivakumar S, Lucas FAS, McDowell TL, Lang W, Xu L, Fujimoto J, Zhang J, Futreal PA, Fukuoka J, Yatabe Y, Dubinett SM, Spira AE, Fowler J, Hawk ET, Wistuba II, Scheet P, Kadara H. Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma. Cancer Res 2017; 77:6119-6130. [PMID: 28951454 DOI: 10.1158/0008-5472.can-17-1605] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 08/25/2017] [Accepted: 09/22/2017] [Indexed: 01/02/2023]
Abstract
There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR.
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Affiliation(s)
- Smruthy Sivakumar
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas
| | - F Anthony San Lucas
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina L McDowell
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wenhua Lang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Li Xu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Junya Fujimoto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianjun Zhang
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - P Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Junya Fukuoka
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Steven M Dubinett
- Division of Pulmonology and Critical Care Medicine, University of California Los Angeles, Los Angeles, California
| | - Avrum E Spira
- School of Medicine, Boston University, Boston, Massachusetts
| | - Jerry Fowler
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ernest T Hawk
- Division of Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paul Scheet
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas
| | - Humam Kadara
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Department of Biochemistry and Molecular Genetics, The American University of Beirut, Beirut, Lebanon
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22
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Qin T, Huang G, Chi L, Sui S, Song C, Li N, Sun S, Li N, Zhang M, Zhao Z, Li L, Li M. Exceptionally high UBE2C expression is a unique phenomenon in basal-like type breast cancer and is regulated by BRCA1. Biomed Pharmacother 2017; 95:649-655. [PMID: 28881292 DOI: 10.1016/j.biopha.2017.08.095] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/21/2017] [Accepted: 08/23/2017] [Indexed: 12/20/2022] Open
Abstract
Ubiquitin-conjugating enzyme 2C (UBE2C) is overexpressed in various types of cancer, leading to poor outcomes and drug resistance. UBE2C may also have a critical role in phenotypes associated with poor prognosis in breast cancer; however, the relationship between UBE2C expression and clinical outcome in breast cancer subtypes has not previously been investigated. We firstly analyzed breast cancer patient data and immunohistochemistry of breast cancer patient samples. We demonstrated that UBE2C was associated with poor prognosis in breast cancer, particularly basal-like breast cancer, a subtype with aggressive clinical features. Interestingly, we found that there was a close relationship between the expression of BRCA1 and UBE2C in the MCF-7 and MDA-MB-231 breast cancer cell lines. Upregulation of BRCA1 could inhibit the expression of UBE2C. In cells with BRCA1 silenced down, expression of UBE2C was obviously increased, with a concurrent decrease in cellular sensitivity to doxorubicin. Suppression of UBE2C expression by RNA interference led to decrease the mRNA expressions of BCRP, MRP1 and P-gp in doxorubicin-treated MDA-MB-231 cells. Moreover, treatment with 1μg/ml doxorubicin led to increased expression of UBE2C. The results show high expression of UBE2C is a potential prognostic factor of poor outcome in basal-like breast cancer. Moreover, loss of BRCA1 function results in an increase in UBE2C expression and chemical resistance to doxorubicin in breast cancer cells.
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Affiliation(s)
- Tao Qin
- Department of Pathology, Dalian Medical University, Dalian 116044, Liaoning Province, China.
| | - Gena Huang
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China.
| | - Liyuan Chi
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Silei Sui
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Chen Song
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Na Li
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Siwen Sun
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Ning Li
- Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Min Zhang
- Department of Oncology, Pulandian Central Hospital, Dalian 116200, Liaoning Province, China
| | - Zuowei Zhao
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China; Breast Disease and Reconstruction Center, Breast Cancer Key Lab of Dalian, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China.
| | - Lianhong Li
- Department of Pathology, Dalian Medical University, Dalian 116044, Liaoning Province, China.
| | - Man Li
- Department of Oncology, Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China.
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Garrido G, Vernos I. Non-centrosomal TPX2-Dependent Regulation of the Aurora A Kinase: Functional Implications for Healthy and Pathological Cell Division. Front Oncol 2016; 6:88. [PMID: 27148480 PMCID: PMC4831974 DOI: 10.3389/fonc.2016.00088] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 03/29/2016] [Indexed: 01/09/2023] Open
Abstract
Aurora A has been extensively characterized as a centrosomal kinase with essential functions during cell division including centrosome maturation and separation and spindle assembly. However, Aurora A localization is not restricted to the centrosomes and compelling evidence support the existence of specific mechanisms of activation and functions for non-centrosomal Aurora A in the dividing cell. It has been now well established that spindle assembly involves an acentrosomal RanGTP-dependent pathway that triggers microtubule assembly and organization in the proximity of the chromosomes whether centrosomes are present or not. The mechanism involves the regulation of a number of NLS-containing proteins, generically called SAFS (Spindle Assembly Factors) that exert their functions upon release from karyopherins by RanGTP. One of them, the nuclear protein TPX2 interacts with and activates Aurora A upon release from importins by RanGTP. This basic mechanism triggers the activation of Aurora A in the proximity of the chromosomes potentially translating the RanGTP signaling gradient centered on the chromosome into an Aurora A phosphorylation network. Here, we will review our current knowledge on the RanGTP-dependent TPX2 activation of Aurora A away from centrosomes: from the mechanism of activation and its functional consequences on the kinase stability and regulation to its roles in spindle assembly and cell division. We will then focus on the substrates of the TPX2-activated Aurora A having a role in microtubule nucleation, stabilization, and organization. Finally, we will briefly discuss the implications of the use of Aurora A inhibitors in anti-tumor therapies in the light of its functional interaction with TPX2.
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Affiliation(s)
- Georgina Garrido
- Cell and Developmental Biology Programme, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Isabelle Vernos
- Cell and Developmental Biology Programme, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain
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Zhang Z, Liu P, Wang J, Gong T, Zhang F, Ma J, Han N. Ubiquitin-conjugating enzyme E2C regulates apoptosis-dependent tumor progression of non-small cell lung cancer via ERK pathway. Med Oncol 2015; 32:149. [PMID: 25832867 DOI: 10.1007/s12032-015-0609-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 11/29/2022]
Abstract
The oncogenic role of ubiquitin-conjugating enzyme E2C (UBE2C) had been identified in some types of human tumors, while the clinical and biological role of UBE2C in non-small cell lung cancer (NSCLC) is still elusive. Here, we have determined the specific role of UBE2C in NSCLC. Western blot and qRT-PCR were used for detecting the mRNA level and protein level of UBE2C in NSCLC samples and cell lines, respectively. Lentivirus product was used to conduct loss of function assay. qRT-PCR array was employed to detect potential downstream genes regulated by UBE2C. As the result, UBE2C mRNA level was approximately threefold overexpression in NSCLC tissues compared with normal tissues, while a sharp change was detected at protein level. Overexpression of UBE2C in lung cancer samples was correlated with advanced pathological stage. UBE2C regulated cell growth in an apoptosis-dependent way. PCR Array analysis revealed that UBE2C regulated the expression of genes associated with tumor growth, apoptosis, and angiogenesis. Furthermore, UBE2C could regulate phospho-ERK1/2 level but not STAT3, YAP, or AKT pathway, which was accompanied with the classic function of ERK pathway in cell growth and apoptosis. In conclusion, our results indicated UBE2C might be a novel therapeutic target in NSCLC.
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Affiliation(s)
- Zhongmian Zhang
- Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University School of Medicine, Central Laboratory, No. 2, Jingba Rd, Zhengzhou, 450000, Henan, China
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25
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Li SZ, Song Y, Zhang HH, Jin BX, Liu Y, Liu WB, Zhang XD, Du RL. UbcH10 overexpression increases carcinogenesis and blocks ALLN susceptibility in colorectal cancer. Sci Rep 2014; 4:6910. [PMID: 25376843 PMCID: PMC4223683 DOI: 10.1038/srep06910] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 10/15/2014] [Indexed: 12/18/2022] Open
Abstract
Cyclins are essential for cell proliferation, the cell cycle and tumorigenesis in all eukaryotes. UbcH10 regulates the degradation of cyclins in a ubiquitin-dependent manner. Here, we report that UbcH10 is likely involved in tumorigenesis. We found that cancer cells exposed to n-acetyl-leu-leu-norleucinal (ALLN) treatment and UbcH10 depletion exhibit a synergistic therapeutic effect. Abundant expression of UbcH10 drives resistance to ALLN-induced cell death, while cells deficient in UbcH10 were susceptible to ALLN-induced cell death. The depletion of UbcH10 hindered tumorigenesis both in vitro and in vivo, as assessed by colony formation, growth curve, soft agar and xenograft assays. These phenotypes were efficiently rescued through the introduction of recombinant UbcH10. In the UbcH10-deficient cells, alterations in the expression of cyclins led to cell cycle changes and subsequently decreases in tumorigenesis. The tumorigenesis of xenograft tumors from UbcH10-deficient cells treated with ALLN was decreased relative to wild-type cells treated with ALLN in nude mice. On the molecular level, we observed that UbcH10 deficiency enhances the activation of caspase 8 and caspase 3 but not caspase 9 to impair cell viability upon ALLN treatment. Collectively, our results suggest that, as an oncogene, UbcH10 is a potential drug target for the treatment of colorectal cancer.
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Affiliation(s)
- Shang-Ze Li
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Yang Song
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Hui-Hui Zhang
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Bing-Xue Jin
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Yi Liu
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Wen-Bin Liu
- College of Health Science and Nursing, Wuhan Polytechnic University, Wuhan 430023, China
| | - Xiao-Dong Zhang
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Run-Lei Du
- College of Life Sciences, Wuhan University, Wuhan 430072, China
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Neumayer G, Belzil C, Gruss OJ, Nguyen MD. TPX2: of spindle assembly, DNA damage response, and cancer. Cell Mol Life Sci 2014; 71:3027-47. [PMID: 24556998 PMCID: PMC11114040 DOI: 10.1007/s00018-014-1582-7] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 01/28/2014] [Accepted: 01/30/2014] [Indexed: 10/25/2022]
Abstract
For more than 15 years, TPX2 has been studied as a factor critical for mitosis and spindle assembly. These functions of TPX2 are attributed to its Ran-regulated microtubule-associated protein properties and to its control of the Aurora A kinase. Overexpressed in cancers, TPX2 is being established as marker for the diagnosis and prognosis of malignancies. During interphase, TPX2 resides preferentially in the nucleus where its function had remained elusive until recently. The latest finding that TPX2 plays a role in amplification of the DNA damage response, combined with the characterization of TPX2 knockout mice, open new perspectives to understand the biology of this protein. This review provides an historic overview of the discovery of TPX2 and summarizes its cytoskeletal and signaling roles with relevance to cancer therapies. Finally, the review aims to reconcile discrepancies between the experimental and pathological effects of TPX2 overexpression and advances new roles for compartmentalized TPX2.
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Affiliation(s)
- Gernot Neumayer
- Department of Clinical Neurosciences, Department of Cell Biology and Anatomy, Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Canada,
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27
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Zhao Y, Ai Y, Li L, Jane JL, Hendrich S, Birt DF. Inhibition of azoxymethane-induced preneoplastic lesions in the rat colon by a stearic acid complexed high-amylose cornstarch using different cooking methods and assessing potential gene targets. J Funct Foods 2014. [DOI: 10.1016/j.jff.2013.11.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Gold KA, Kim ES, Liu DD, Yuan P, Behrens C, Solis LM, Kadara H, Rice DC, Wistuba II, Swisher SG, Hofstetter WL, Lee JJ, Hong WK. Prediction of survival in resected non-small cell lung cancer using a protein expression-based risk model: implications for personalized chemoprevention and therapy. Clin Cancer Res 2013; 20:1946-54. [PMID: 24366692 DOI: 10.1158/1078-0432.ccr-13-1959] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Patients with resected non-small cell lung cancer (NSCLC) are at risk for recurrence of disease, but we do not have tools to predict which patients are at highest risk. We set out to create a risk model incorporating both clinical data and biomarkers. EXPERIMENTAL DESIGN We assembled a comprehensive database with archival tissues and clinical follow-up from patients with NSCLC resected between 2002 and 2005. Twenty-one proteins identified from our preclinical studies as related to lung carcinogenesis were investigated, including pathways related to metabolism, DNA repair, inflammation, and growth factors. Expression of proteins was quantified using immunohistochemistry. Immunohistochemistry was chosen because it is widely available and can be performed on formalin-fixed paraffin-embedded specimens. Cox models were fitted to estimate effects of clinical factors and biomarkers on recurrence-free survival (RFS) and overall survival (OS). RESULTS A total of 370 patients are included in our analysis. With median follow-up of 5.3 years, median OS is 6.4 years. A total of 209 cases with recurrence or death were observed. Multicovariate risk models for RFS and OS were developed including relevant biomarkers, age, and stage. Increased expression of phospho-adenosine monophosphate-activated protein kinase (pAMPK), phospho-mTOR (pmTOR), epithelial cell adhesion molecule (EpCAM), and calcium/calmodulin-dependent serine protein kinase were significant (P < 0.05) predictors for favorable RFS; insulin receptor, chemokine (C-X-C motif) receptor 2 (CXCR2), and insulin-like growth factor-1 receptor predicted for unfavorable RFS. Significant (P < 0.05) predictors for favorable OS include pAMPK, pmTOR, and EpCAM; CXCR2 and flap structure-specific endonuclease-1 predicted unfavorable OS. CONCLUSION We have developed a comprehensive risk model predictive for recurrence in our large retrospective database, which is one of the largest reported series of resected NSCLC.
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Affiliation(s)
- Kathryn A Gold
- Authors' Affiliations: Departments of Thoracic/Head and Neck Medical Oncology, Biostatistics, Pathology, and Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Levine Cancer Center; Philips Digital Pathology; and Department of Pathology, University of San Francisco Xavier de Chuquisaca Sucre-Bolivia, San Francisco, California
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Wei P, Zhang N, Xu Y, Li X, Shi D, Wang Y, Li D, Cai S. TPX2 is a novel prognostic marker for the growth and metastasis of colon cancer. J Transl Med 2013; 11:313. [PMID: 24341487 PMCID: PMC3878622 DOI: 10.1186/1479-5876-11-313] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 12/11/2013] [Indexed: 01/30/2023] Open
Abstract
Background We have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer. Methods TPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. Results TPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity. Conclusions These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease.
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Affiliation(s)
| | | | | | | | | | | | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
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Snoek BC, Wilt LHAMD, Jansen G, Peters GJ. Role of E3 ubiquitin ligases in lung cancer. World J Clin Oncol 2013; 4:58-69. [PMID: 23936758 PMCID: PMC3708064 DOI: 10.5306/wjco.v4.i3.58] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/10/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023] Open
Abstract
E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome. Therefore, E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation, proliferation and apoptosis. E3 ubiquitin ligases are often found overexpressed in human cancers, including lung cancer, and their deregulation has been shown to contribute to cancer development. However, the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting. In this review, we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer. Furthermore, we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets. By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis, we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.
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Target protein for Xklp2 (TPX2), a microtubule-related protein, contributes to malignant phenotype in bladder carcinoma. Tumour Biol 2013; 34:4089-100. [PMID: 23873098 DOI: 10.1007/s13277-013-1000-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 07/04/2013] [Indexed: 01/05/2023] Open
Abstract
Increasing evidence demonstrated that TPX2 was highly expressed and tightly associated with human tumor development and progression. However, its precise role in bladder carcinoma remains to be delineated. In the present study, we revealed the high expression of TPX2 at both mRNA and protein levels in bladder carcinoma tissues and cells, and TPX2 levels in pN1-3 and pT2-4 status were significantly higher than those in pN0 and pTa-T1 status, respectively. Additionally, high TPX2 level was strongly associated with pT status (P = 0.001), higher histological grade (P = 0.001), lymph node metastasis (P = 0.022), and shorter survival time (P = 0.0279). Further investigation showed that TPX2 level in T24 cells was markedly higher than those in 5637, J82 and RT4 cells, in which RT4, a well-differentiated cell line derived from bladder carcinoma with low-grade non-invasive T0, displayed the lowest TPX2 mRNA and protein levels. Besides, TPX2 overexpression promoted proliferation and tumorigenicity, shortened cell cycle in G0/G1 phase, and suppressed cell apoptosis in T24 cells; conversely, TPX2 depletion exhibited opposite effects. Furthermore, TPX2 overexpression evoked the elevation of cyclin D1 and cdk2 levels as well as reduction of p21 level and caspase-3 activity, whereas reversed effects were observed in TPX2-depleted T24 cells. Taken altogether, TPX2 may play a central role in the development and progression of bladder carcinoma, and thus inhibition of TPX2 level may be a novel strategy for therapy of the patients with bladder carcinoma.
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Morikawa T, Kawai T, Abe H, Kume H, Homma Y, Fukayama M. UBE2C is a marker of unfavorable prognosis in bladder cancer after radical cystectomy. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2013; 6:1367-1374. [PMID: 23826418 PMCID: PMC3693202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 05/28/2013] [Indexed: 06/02/2023]
Abstract
It has been suggested that ubiquitin-conjugating enzyme E2C (UBE2C, also known as UBCH10) represents a promising cancer biomarker. However, the clinicopathological or prognostic significance as well as the functions of UBE2C in bladder cancer are largely unknown. To investigate the significance of UBE2C expression in bladder cancer, immunohistochemical analysis was performed using a tissue microarray. UBE2C positivity was observed in 51 of 82 (62%) bladder urothelial carcinoma cases treated with radical cystectomy. In contrast, UBE2C was negative in all of the non-neoplastic urothelium examined. UBE2C positivity was significantly associated with higher tumor stage (p=0.0061) and presence of lymphovascular invasion (p=0.0045). In addition, UBE2C positivity was significantly associated with shorter cancer-specific survival after cystectomy (log rank p=0.0017; multivariate hazard ratio, 2.49; 95% confidence interval, 1.09-5.71). Small interfering RNA-mediated suppression of UBE2C in UM-UC-3 bladder cancer cells inhibited cell proliferation in vitro. Taken together, our results suggest that UBE2C is a novel prognostic biomarker as well as a potential therapeutic target in bladder cancer.
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Affiliation(s)
- Teppei Morikawa
- Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
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Pérez de Castro I, Malumbres M. Mitotic Stress and Chromosomal Instability in Cancer: The Case for TPX2. Genes Cancer 2013; 3:721-30. [PMID: 23634259 DOI: 10.1177/1947601912473306] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cell cycle deregulation is a common motif in human cancer, and multiple therapeutic strategies are aimed to prevent tumor cell proliferation. Whereas most current therapies are designed to arrest cell cycle progression either in G1/S or in mitosis, new proposals include targeting the intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) or aneuploidy (a genomic composition that differs from diploid) that many tumor cells display. Why tumors cells are chromosomally unstable or aneuploid and what are the consequences of these alterations are not completely clear at present. Several mitotic regulators are overexpressed as a consequence of oncogenic alterations, and they are likely to alter the proper regulation of chromosome segregation in cancer cells. In this review, we propose the relevance of TPX2, a mitotic regulator involved in the formation of the mitotic spindle, in oncogene-induced mitotic stress. This protein, as well as its partner Aurora-A, is frequently overexpressed in human cancer, and its deregulation may participate not only in chromosome numeric aberrations but also in other forms of genomic instability in cancer cells.
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Affiliation(s)
- Ignacio Pérez de Castro
- Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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Li Y, Tang H, Sun Z, Bungum AO, Edell ES, Lingle WL, Stoddard SM, Zhang M, Jen J, Yang P, Wang L. Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients. Lung Cancer 2013; 80:91-8. [PMID: 23357462 PMCID: PMC3595338 DOI: 10.1016/j.lungcan.2012.12.022] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Revised: 12/18/2012] [Accepted: 12/31/2012] [Indexed: 11/23/2022]
Abstract
Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.
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Affiliation(s)
- Yafei Li
- Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Hui Tang
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Zhifu Sun
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Aaron O. Bungum
- Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Eric S. Edell
- Department of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Wilma L. Lingle
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Shawn M. Stoddard
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Mingrui Zhang
- Department of Computer Science, Winona State University, Winona, Minnesota, U.S.A
| | - Jin Jen
- Department of Advanced Genomics Technology Center, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Ping Yang
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
| | - Liang Wang
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A
- Department of Pathology, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A
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Chronic obstructive pulmonary disease and lung cancer: common pathogenesis, shared clinical challenges. Ann Am Thorac Soc 2012; 9:74-9. [PMID: 22550249 DOI: 10.1513/pats.201107-039ms] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Environmental inhaled noxious particles have been known to play a role in several lung diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer, the deadliest malignancy in the world in both sexes. Of the known noxious agents, tobacco smoking is the leading preventable cause of death worldwide and is a recognized risk for the development of both diseases. The association between COPD and lung cancer has been demonstrated in population-based studies, lung cancer screening programs, epidemiological surveys, and case control and biological mechanistic studies. There is evidence that cumulative smoking history is associated with the risk of developing lung cancer and COPD; however, the majority of smokers do not develop clinical COPD or lung cancer. This suggests the presence of one or several factors that modulate the responses to the offending agents and define the final risk for disease development. The 54th Aspen Lung Conference was convened to provide a forum for a systematic dissection of the potential mechanisms by which persons exposed to the causative agents are able to handle and control the process or, in the case of dysfunctional response, the mechanisms that take off in different directions and result in injury and disease. This summary reviews the themes presented and attempts to integrate them for those clinicians and researchers interested in these topics. The challenges and future directions emanating from the discussions may help frame future conferences and hopefully inspire the interest of young researchers.
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Bose MV, Gopisetty G, Selvaluxmy G, Rajkumar T. Dominant negative Ubiquitin-conjugating enzyme E2C sensitizes cervical cancer cells to radiation. Int J Radiat Biol 2012; 88:629-34. [PMID: 22694363 DOI: 10.3109/09553002.2012.702299] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE To find the radiation sensitivity of human cervical carcinoma cell lines and to investigate the effect of the dominant negative-Ubiquitin-conjugating enzyme E2C (DN-UBE2C) on cell proliferation and radiation response. MATERIALS AND METHODS Radiation sensitivities of human cervical cell lines (SiHa, HeLa, BU25TK, ME 180, and C33A) were analyzed by assessing their cell survival after irradiation by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Soft agar cloning assay, growth curve and radiation response of DN-UBE2C stably transfected SiHa and HeLa cell lines were assessed by MTS assay and Clonogenic assay. RESULTS Difference in sensitivity to radiation was observed among the cervical cancer cell lines studied. SiHa was found to be the most resistant cell line whereas C33A cells were the most sensitive. The growth rate of SiHa and HeLa transfected with DN-UBE2C was significantly reduced compared to vector control. Furthermore, DN-UBE2C-mediated radiosensitivity was correlated with a significant decrease in resistance to radiation by SiHa and HeLa cells after transfection with the DN-UBE2C when compared to control cultures. CONCLUSION These results suggested that the Ubiquitin-conjugating enzyme E2C (UBE2C) gene is a potential therapeutic target for cervical cancer treatment.
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Affiliation(s)
- Mayil Vahanan Bose
- Department of Molecular Oncology, Cancer Institute (WIA), Chennai, India
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High-throughput transcriptomic and RNAi analysis identifies AIM1, ERGIC1, TMED3 and TPX2 as potential drug targets in prostate cancer. PLoS One 2012; 7:e39801. [PMID: 22761906 PMCID: PMC3386189 DOI: 10.1371/journal.pone.0039801] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Accepted: 05/31/2012] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer is a heterogeneous group of diseases and there is a need for more efficient and targeted methods of treatment. In this study, the potential of gene expression data and RNA interference technique were combined to advance future personalized prostate cancer therapeutics. To distinguish the most promising in vivo prevalidated prostate cancer drug targets, a bioinformatic analysis was carried out using genome-wide gene expression data from 9873 human tissue samples. In total, 295 genes were selected for further functional studies in cultured prostate cancer cells due to their high mRNA expression in prostate, prostate cancer or in metastatic prostate cancer samples. Second, RNAi based cell viability assay was performed in VCaP and LNCaP prostate cancer cells. Based on the siRNA results, gene expression patterns in human tissues and novelty, endoplasmic reticulum function associated targets AIM1, ERGIC1 and TMED3, as well as mitosis regulating TPX2 were selected for further validation. AIM1, ERGIC1, and TPX2 were shown to be highly expressed especially in prostate cancer tissues, and high mRNA expression of ERGIC1 and TMED3 associated with AR and ERG oncogene expression. ERGIC1 silencing specifically regulated the proliferation of ERG oncogene positive prostate cancer cells and inhibited ERG mRNA expression in these cells, indicating that it is a potent drug target in ERG positive subgroup of prostate cancers. TPX2 expression associated with PSA failure and TPX2 silencing reduced PSA expression, indicating that TPX2 regulates androgen receptor mediated signaling. In conclusion, the combinatorial usage of microarray and RNAi techniques yielded in a large number of potential novel biomarkers and therapeutic targets, for future development of targeted and personalized approaches for prostate cancer management.
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Poullis M, McShane J, Shaw M, Woolley S, Shackcloth M, Page R, Mediratta N. Lung cancer staging: a physiological update. Interact Cardiovasc Thorac Surg 2012; 14:743-9. [PMID: 22419795 DOI: 10.1093/icvts/ivr164] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The tumour-node metastasis (TNM) classification system is anatomically based. We investigated whether the addition of simple physiological variables, age and body mass index (BMI), would affect survival curves, i.e. a composite anatomical and physiological staging system. We retrospectively analysed a prospectively validated thoracic surgery database (n = 1981). Cox multivariate analysis was performed to determine possible significant factors. Kaplan-Meier survival curves were constructed with combined anatomical and physiological factors. Cox multivariate analysis revealed age (P < 0.001) and BMI (P = 0.01) as significant factors affecting survival. Receiver operating curve analysis determined cut-off levels for age of 67 and BMI of 27.6. A composite anatomical and physiological survival curve based on TNM for BMI > 27.6 and age < 67 was produced. Age and BMI criteria resulted in significantly different survival curves, for stage I (P < 0.0001) and stage II (P = 0.0032), but not for stage III (P = 0.06). Neural network analysis confirmed the importance of BMI and age above cancer stage with regard to long-term survival. Combining age < 67, BMI > 27.6 and TNM anatomical classification results in very different estimated survival curves from the usual TNM system. Patients from stages I, II and III may have survival equivalent to a stage higher or lower depending on their age and BMI.
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Hao Z, Zhang H, Cowell J. Ubiquitin-conjugating enzyme UBE2C: molecular biology, role in tumorigenesis, and potential as a biomarker. Tumour Biol 2011; 33:723-30. [PMID: 22170434 DOI: 10.1007/s13277-011-0291-1] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 12/01/2011] [Indexed: 01/28/2023] Open
Abstract
Ubiquitin-conjugating enzyme 2C (UBE2C) participates in cell cycle progression and checkpoint control by targeted degradation of short-lived proteins. As a conjugating enzyme, it directs polyubiquitination to preferred lysine in the substrates. In addition to its well-known role in cyclin B destruction that is essential for exit from mitosis, UBE2C also plays an important role in mitotic spindle checkpoint control. Cells overexpressing UBE2C ignore the mitotic spindle checkpoint signals and lose genomic stability, which is a hallmark of cancer. UBE2C expression is upregulated upon malignant transformation, and amplification of UBE2C is often seen at the chromosome level in cancers in a manner similar to c-Myc, which is directly upstream of UBE2C. UBE2C levels are upregulated in a wide range of solid tumors and hematological malignancies. The level of expression correlates with the aggressiveness of the tumor. High UBE2C expression is predictive of poor survival and perhaps high risk for relapse. UBE2C immunochemistry may be integrated into the diagnosis of thyroid malignancy and gliomas. This minireview summarizes what is known about the function of UBE2C focusing on its role in the regulation of spindle assembly checkpoint, its part in tumorigenesis, and its potential as a tumor marker for various cancers.
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Affiliation(s)
- Zhonglin Hao
- Georgia Health Sciences University Cancer Center, Georgia Health Sciences University, 1120 15th street, Augusta, GA 30912, USA.
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Chen DT, Hsu YL, Fulp WJ, Coppola D, Haura EB, Yeatman TJ, Cress WD. Prognostic and predictive value of a malignancy-risk gene signature in early-stage non-small cell lung cancer. J Natl Cancer Inst 2011; 103:1859-70. [PMID: 22157961 DOI: 10.1093/jnci/djr420] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The malignancy-risk gene signature is composed of numerous proliferative genes and has been applied to predict breast cancer risk. We hypothesized that the malignancy-risk gene signature has prognostic and predictive value for early-stage non-small cell lung cancer (NSCLC) patients. METHODS The ability of the malignancy-risk gene signature to predict overall survival (OS) of early-stage NSCLC patients was tested using a large NSCLC microarray dataset from the Director's Challenge Consortium (n = 442) and two independent NSCLC microarray datasets (n = 117 and 133, for the GSE13213 and GSE14814 datasets, respectively). An overall malignancy-risk score was generated by principal component analysis to determine the prognostic and predictive value of the signature. An interaction model was used to investigate a statistically significant interaction between adjuvant chemotherapy (ACT) and the gene signature. All statistical tests were two-sided. RESULTS The malignancy-risk gene signature was statistically significantly associated with OS (P < .001) of NSCLC patients. Validation with the two independent datasets demonstrated that the malignancy-risk score had prognostic and predictive values: Of patients who did not receive ACT, those with a low malignancy-risk score had increased OS compared with a high malignancy-risk score (P = .007 and .01 for the GSE13212 and GSE14814 datasets, respectively), indicating a prognostic value; and in the GSE14814 dataset, patients receiving ACT survived longer in the high malignancy-risk score group (P = .03), and a statistically significant interaction between ACT and the signature was observed (P = .02). CONCLUSIONS The malignancy-risk gene signature was associated with OS and was a prognostic and predictive indicator. The malignancy-risk gene signature could be useful to improve prediction of OS and to identify those NSCLC patients who will benefit from ACT.
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Affiliation(s)
- Dung-Tsa Chen
- Department of Biostatistics, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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Solis LM, Behrens C, Raso MG, Lin HY, Kadara H, Yuan P, Galindo H, Tang X, Lee JJ, Kalhor N, Wistuba II, Moran CA. Histologic patterns and molecular characteristics of lung adenocarcinoma associated with clinical outcome. Cancer 2011; 118:2889-99. [PMID: 22020674 DOI: 10.1002/cncr.26584] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 09/02/2011] [Accepted: 09/06/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Lung adenocarcinoma is histologically heterogeneous and has 5 distinct histologic growth patterns: lepidic, acinar, papillary, micropapillary, and solid. To date, there is no consensus regarding the clinical utility of these patterns. METHODS The authors performed a detailed semiquantitative assessment of histologic patterns of 240 lung adenocarcinomas and determined the association with patients' clinicopathologic features, including recurrence-free survival (RFS) and overall survival (OS) rates. In a subset of tumors, expression levels of 2 prognostic molecular markers were evaluated: thyroid transcription factor-1 (TTF-1) (n = 218) and a panel of 5 proteins (referred as the FILM signature index) (n = 185). RESULTS Four mutually exclusive tumor histology pattern groups were identified: 1) any solid (38%), 2) any papillary but no solid (14%), 3) lepidic and acinar but no solid or papillary (30%), and 4) acinar only (18%). Patients in group 3 had a higher RFS rate than patients in group 1 (hazard ratio [HR], 0.4510; P = .0165) and group 2 (HR, 0.4253; P = .0425). Solid pattern tumors (group 1) were associated with a lower OS rate than nonsolid pattern tumors (all stages: HR; 1.665; P = .0144; stages I and II: HR, 2.157; P = .008). In the patients who had tumors with a nonsolid pattern, high TTF-1 expression was associated significantly with higher RFS (HR, 0.994; P = .0017) and OS (HR, 0.996; P = .0276) rates in all stages, and a high FILM signature index score was associated with lower RFS and OS rates in all stages (RFS: HR, 1.343; P = .0192; OS: HR, 1.371; P = .0156) and in stages I and II (RFS: HR, 1.419; P = .0095; OS: HR, 1.315; P = .0422). CONCLUSIONS The presence of a solid histologic pattern was identified as a marker of unfavorable prognosis in patients with primary lung adenocarcinoma. High TTF-1 expression and low FILM signature index scores were associated with a better prognosis for patients who had tumors with a nonsolid pattern.
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Affiliation(s)
- Luisa M Solis
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Kadara H, Behrens C, Yuan P, Solis L, Liu D, Gu X, Minna JD, Lee JJ, Kim E, Hong WK, Wistuba II, Lotan R. A five-gene and corresponding protein signature for stage-I lung adenocarcinoma prognosis. Clin Cancer Res 2011; 17:1490-501. [PMID: 21163870 PMCID: PMC3079395 DOI: 10.1158/1078-0432.ccr-10-2703] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
PURPOSE Identification of effective markers for outcome is expected to improve the clinical management of non-small cell lung cancer (NSCLC). Here, we assessed in NSCLC the prognostic efficacy of genes, which we had previously found to be differentially expressed in an in vitro model of human lung carcinogenesis. EXPERIMENTAL DESIGN Prediction algorithms and risk-score models were applied to the expression of the genes in publicly available NSCLC expression data sets. The prognostic capacity of the immunohistochemical expression of proteins encoded by these genes was also tested using formalin-fixed paraffin-embedded (FFPE) tissue specimens from 156 lung adenocarcinomas and 79 squamous cell carcinomas (SCCs). RESULTS The survival of all-stages (P < 0.001, HR = 2.0) or stage-I (P < 0.001, HR = 2.84) adenocarcinoma patients that expressed the five-gene in vitro lung carcinogenesis model (FILM) signature was significantly poorer than that of patients who did not. No survival differences were observed between SCCs predicted to express or lack FILM signature. Moreover, all stages (P < 0.001, HR = 1.95) or stage-I (P = 0.001, HR = 2.6) adenocarcinoma patients predicted to be at high risk by FILM transcript exhibited significantly worse survival than patients at low risk. Furthermore, the corresponding protein signature was associated with poor survival (all stages, P < 0.001, HR = 3.6; stage-I, P < 0.001, HR = 3.5; stage-IB, P < 0.001, HR = 4.6) and mortality risk (all stages, P = 0.001, HR = 4.0; stage-I, P = 0.01, HR = 3.4; stage-IB, P < 0.001, HR = 7.2) in lung adenocarcinoma patients. CONCLUSIONS Our findings highlight a gene and corresponding protein signature with effective capacity for identification of stage-I lung adenocarcinoma patients with poor prognosis that are likely to benefit from adjuvant therapy.
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Affiliation(s)
- Humam Kadara
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Ping Yuan
- Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Luisa Solis
- Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Diane Liu
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Xuemin Gu
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - John D. Minna
- Hamon Center for Therapeutic Oncology the University of Texas Southwestern, Dallas, TX
| | - J. Jack Lee
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Edward Kim
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Waun-Ki Hong
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Ignacio I. Wistuba
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX
- Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Reuben Lotan
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX
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Fujimoto J, Kadara H, Men T, van Pelt C, Lotan D, Lotan R. Comparative functional genomics analysis of NNK tobacco-carcinogen induced lung adenocarcinoma development in Gprc5a-knockout mice. PLoS One 2010; 5:e11847. [PMID: 20686609 PMCID: PMC2912294 DOI: 10.1371/journal.pone.0011847] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Accepted: 07/07/2010] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Improved understanding of lung cancer development and progression, including insights from studies of animal models, are needed to combat this fatal disease. Previously, we found that mice with a knockout (KO) of G-protein coupled receptor 5A (Gprc5a) develop lung tumors after a long latent period (12 to 24 months). METHODOLOGY/PRINCIPAL FINDINGS To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) i.p. to 2-months old Gprc5a-KO mice and sacrificed groups (n=5) of mice at 6, 9, 12, and 18 months later. Compared to control Gprc5a-KO mice, NNK-treated mice developed lung tumors at least 6 months earlier, exhibited 2- to 4-fold increased tumor incidence and multiplicity, and showed a dramatic increase in lesion size. A gene expression signature, NNK-ADC, of differentially expressed genes derived by transcriptome analysis of epithelial cell lines from normal lungs of Gprc5a-KO mice and from NNK-induced adenocarcinoma was highly similar to differential expression patterns observed between normal and tumorigenic human lung cells. The NNK-ADC expression signature also separated both mouse and human adenocarcinomas from adjacent normal lung tissues based on publicly available microarray datasets. A key feature of the signature, up-regulation of Ube2c, Mcm2, and Fen1, was validated in mouse normal lung and adenocarcinoma tissues and cells by immunohistochemistry and western blotting, respectively. CONCLUSIONS/SIGNIFICANCE Our findings demonstrate that lung tumorigenesis in the Gprc5a-KO mouse model is augmented by NNK and that gene expression changes induced by tobacco carcinogen(s) may be conserved between mouse and human lung epithelial cells. Further experimentation to prove the reliability of the Gprc5a knockout mouse model for the study of tobacco-induced lung carcinogenesis is warranted.
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Affiliation(s)
- Junya Fujimoto
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Humam Kadara
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Taoyan Men
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Carolyn van Pelt
- Department of Veterinary Medicine and Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Dafna Lotan
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Reuben Lotan
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
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Expression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma. Brain Res 2010; 1352:200-7. [PMID: 20599806 DOI: 10.1016/j.brainres.2010.06.060] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Revised: 06/23/2010] [Accepted: 06/23/2010] [Indexed: 12/30/2022]
Abstract
In humans, the targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a cell cycle-associated protein, and altered TPX2 expression has been found in various malignancies. However, the contribution of TPX2 expression to astrocytoma progression is unclear. The aim of this study was to investigate TPX2 expression in human astrocytoma samples and cell lines. TPX2 protein expression was detected in the nucleus of astrocytoma tissues by immunohistochemistry and immunofluorescence staining. Real-time PCR and Western blot analysis showed that the expression levels of TPX2 were higher in high-grade astrocytoma tissues and cell lines than that in low-grade astrocytoma tissues and normal cell lines. Immunohistochemical analysis of tumor tissues from 52 patients with astrocytoma showed that TPX2 over-expression was significantly associated with decreased patient survival. In addition, down-regulation of the TPX2 gene by RNA interference inhibited proliferation of U87 cells. TPX2 gene silencing also increased early-stage apoptosis in U87 cells. Western blotting and real-time PCR showed changes in the protein and mRNA expression of Aurora A, Ran, p53, c-Myc and cyclin B1 in U87 cells that had been transfected with pSUPER/TPX2/siRNA. These data suggest that TPX2 expression is associated with the progression of malignant astrocytoma.
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Abstract
This perspective on Kadara et al. (beginning on p. 702 in this issue of the journal) examines the critical development of genomic and proteomic signatures of lung cancer risk, prognosis, and sensitivity to chemoprevention or chemotherapy. The novel work of Kadara et al. represents the first demonstration that a molecular signature developed in a premalignancy model (in this case, cultured normal human bronchial epithelial cells and increasingly transformed derivative cells) is clinically relevant to invasive lung cancer.
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Affiliation(s)
- David P Carbone
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 685 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA.
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