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Xu YW, Peng YH, Liu CT, Chen H, Chu LY, Chen HL, Wu ZY, Wei WQ, Xu LY, Wu FC, Li EM. Machine learning technique-based four-autoantibody test for early detection of esophageal squamous cell carcinoma: a multicenter, retrospective study with a nested case-control study. BMC Med 2025; 23:235. [PMID: 40264204 PMCID: PMC12016149 DOI: 10.1186/s12916-025-04066-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 04/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Autoantibodies represent promising diagnostic blood-based biomarkers that may be generated prior to the first clinically detectable signs of cancers. In present study, we aimed to identify a novel optimized autoantibody panel with high diagnostic accuracy for clinical and preclinical esophageal squamous cell carcinoma (ESCC) using machine learning (ML) algorithms. METHODS We identified potential autoantibodies against tumor-associated antigens with serological proteome analysis. Serum autoantibody levels were measured by ELISA. Using a training set (n = 531), 102 models based on ML algorithms were constructed, and Partial Least Squares Generalized Linear Models (plsRglm) was selected out using receiver operating characteristics (ROC), Kolmogorov-Smirnov (K-S) test, and Population Stability Index (PSI), and further validated through an internal validation set (n = 413), external validation set 1 (n = 371), and external validation set 2 (n = 202). Then, we validated the ability of plsRglm model in predicting preclinical ESCC by a nested case-control study (24 preclinical ESCCs and 112 matched controls) within a population-based prospective cohort study. RESULTS ROC analysis, K-S test, and PSI showed that plsRglm model based on four autoantibodies (ALDOA, ENO1, p53, and NY-ESO-1) exhibited the better diagnostic performance and robustness, which provided a high diagnostic accuracy in diagnosing ESCC with the respective AUCs (sensitivities and specificities) of 0.860 (68.8% and 90.4%) in the training set, 0.826 (65.3% and 89.1%) in the internal validation set, and 0.851 (69.2% and 87.3%) in the external validation set 1. For early-stage ESCC, this signature also maintained diagnostic performance [0.817 (62.3% and 90.4%) in the training set; 0.842 (62.5% and 89.1%) in the internal validation set; 0.854 (63.2% and 87.3%) in the external validation set 1; and 0.850 (67.3% and 90.1%) in the external validation set 2]. In the nested case-control study, this plsRglm model could detect the presence of preclinical ESCC with the AUC of 0.723, sensitivity of 54.2%, and specificity of 86.6%. CONCLUSIONS Our findings indicated that the plsRglm model based on four autoantibodies might help identify preclinical and early-stage ESCC.
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Affiliation(s)
- Yi-Wei Xu
- Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China.
- Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China.
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China
| | - Can-Tong Liu
- Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
- Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China
| | - Hao Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Ling-Yu Chu
- Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Hai-Lu Chen
- Department of Surgical Oncology, Shantou Central Hospital, Shantou, 515031, China
| | - Zhi-Yong Wu
- Department of Surgical Oncology, Shantou Central Hospital, Shantou, 515031, China
| | - Wen-Qiang Wei
- Department of Cancer Epidemiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Li-Yan Xu
- Institute of Oncological Pathology, Shantou University Medical College, Shantou, 515041, China.
| | - Fang-Cai Wu
- Department of Radiation Oncology, Esophageal Cancer Prevention and Control Research Center, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China.
| | - En-Min Li
- Esophageal Cancer Prevention and Control Research Center, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China.
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, China.
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Mo M, Hou C, Yuan H, Zhao R, Chen M, Jiang Y, Xu K, Zhang T, Chen X, Suo C. Shared genetic factors and the interactions with fresh fruit intake contributes to four types squamous cell carcinomas. PLoS One 2024; 19:e0316087. [PMID: 39739889 DOI: 10.1371/journal.pone.0316087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 12/05/2024] [Indexed: 01/02/2025] Open
Abstract
Studies have reported risk factors for a single-squamous cell carcinoma(Single-SCCs). However, the shared common germline genetic factors and environmental factors have not been well elucidated with respect to augmented risk of pan-squamous cell carcinoma(Pan-SCCs). By integrating a large-scale genotype data of 1,928 Pan-SCCs cases and 7,712 age- and sex-matched controls in the UK Biobank cohort, as well as multiple transcriptome and protein databases, we conducted a multi-omics analysis. Genome-wide association analysis (GWAS) was used to identify genetic susceptibility loci of SCCs. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA and tested for association with SCCs. Credible risk variants (CRVs) were combined risk SNPs reported in GWAS Catalog and our study, followed by comprehensive bioinformatics analyses. We identified six novel index SNPs in the progression of SCCs, which were also strongly interacted with fresh fruit intake. Moreover, our study systematically characterize the HLA variants and their relationship to SCCs susceptibility. We identified HLA-A*01 and six HLA-A amino acid position were associated independently with SCCs. Credible risk variants were annotated to 469 target genes, further GO and KEGG Pathway Enrichment Analysis showed that SCCs genes were primarily involved in immune-related pathways, espechially regulated by HLA region. The transcriptome analysis showed that there were 270 differentially expressed genes(DEGs), with the upregulated genes were enriched in the regulation of stem cell differentiation, proliferation, development, and maintenance. The PPI Network and Modular Analysis uncovered the Keratin(KRT) genes may serve as a potential marker in SCCs. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of SCCs, providing not only novel insights into the genetic commonality among SCCs but also a set of plausible gene targets for post-GWAS functional experiments.
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Affiliation(s)
- Mengqing Mo
- Department of Epidemiology & Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Department of Outpatient Office, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Can Hou
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Huangbo Yuan
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Renjia Zhao
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Mingyang Chen
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
| | - Yanfeng Jiang
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Kelin Xu
- Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Tiejun Zhang
- Department of Epidemiology & Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
- Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China
| | - Chen Suo
- Department of Epidemiology & Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China
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Di Giuseppe F, Ricci-Vitiani L, Pallini R, Di Pietro R, Di Iorio P, Ascani G, Ciccarelli R, Angelucci S. Changes Induced by P2X7 Receptor Stimulation of Human Glioblastoma Stem Cells in the Proteome of Extracellular Vesicles Isolated from Their Secretome. Cells 2024; 13:571. [PMID: 38607010 PMCID: PMC11011151 DOI: 10.3390/cells13070571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/13/2024] Open
Abstract
Extracellular vesicles (EVs) are secreted from many tumors, including glioblastoma multiforme (GBM), the most common and lethal brain tumor in adults, which shows high resistance to current therapies and poor patient prognosis. Given the high relevance of the information provided by cancer cell secretome, we performed a proteomic analysis of microvesicles (MVs) and exosomes (EXOs) released from GBM-derived stem cells (GSCs). The latter, obtained from the brain of GBM patients, expressed P2X7 receptors (P2X7Rs), which positively correlate with GBM growth and invasiveness. P2X7R stimulation of GSCs caused significant changes in the EV content, mostly ex novo inducing or upregulating the expression of proteins related to cytoskeleton reorganization, cell motility/spreading, energy supply, protection against oxidative stress, chromatin remodeling, and transcriptional regulation. Most of the induced/upregulated proteins have already been identified as GBM diagnostic/prognostic factors, while others have only been reported in peripheral tumors. Our findings indicate that P2X7R stimulation enhances the transport and, therefore, possible intercellular exchange of GBM aggressiveness-increasing proteins by GSC-derived EVs. Thus, P2X7Rs could be considered a new druggable target of human GBM, although these data need to be confirmed in larger experimental sets.
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Affiliation(s)
- Fabrizio Di Giuseppe
- Department of Innovative Technologies in Medicine and Dentistry, ‘G. d’Annunzio’ University of Chieti-Pescara, Via Vestini 31, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), ‘G d’Annunzio’ University of Chieti-Pescara, Via L Polacchi 13, 66100 Chieti, Italy;
- Stem TeCh Group, Via L Polacchi 13, 66100 Chieti, Italy
| | - Lucia Ricci-Vitiani
- Department of Medical, Oral and Biotechnological Sciences, ‘G d’Annunzio’ University of Chieti-Pescara, Via Vestini 31, 66100 Chieti, Italy;
| | - Roberto Pallini
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Via Regina Elena 299, 00161 Rome, Italy;
| | - Roberta Di Pietro
- Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy;
| | - Patrizia Di Iorio
- Department of Medicine and Aging Sciences, ‘G. d’Annunzio’ University of Chieti-Pescara, Via Vestini 31, 66100 Chieti, Italy;
| | - Giuliano Ascani
- UOSD Maxillofacial Surgery, Azienda Sanitaria Locale di Pescara, Via Renato Paolini 47, 65124 Pescara, Italy;
| | - Renata Ciccarelli
- Center for Advanced Studies and Technology (CAST), ‘G d’Annunzio’ University of Chieti-Pescara, Via L Polacchi 13, 66100 Chieti, Italy;
| | - Stefania Angelucci
- Department of Innovative Technologies in Medicine and Dentistry, ‘G. d’Annunzio’ University of Chieti-Pescara, Via Vestini 31, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), ‘G d’Annunzio’ University of Chieti-Pescara, Via L Polacchi 13, 66100 Chieti, Italy;
- Stem TeCh Group, Via L Polacchi 13, 66100 Chieti, Italy
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Zhou X, Li Z, Chen H, Jiao M, Zhou C, Li H. Relevance Analysis of TPM2 and Clinicopathological Characteristics in Breast Cancer. Int J Gen Med 2024; 17:59-74. [PMID: 38221941 PMCID: PMC10788065 DOI: 10.2147/ijgm.s442004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 12/28/2023] [Indexed: 01/16/2024] Open
Abstract
Background The function of tropomyosin 2 (TPM2) in breast cancer is still far understudied. In this study, we aim to explore the roles of TPM2 in breast cancer progression. Methods This research included 155 breast cancer tissues. The expression of TPM2 was analyzed by immunohistochemical staining and grading. The mRNA expression of TPM2 in pan-cancer was analyzed with The Cancer Genome Atlas (TCGA) data plate form. The differential expression of TPM2 protein and the differential promoter methylation level of TPM2 between breast cancer tissues and normal breast tissues were analyzed by the UALCAN online database. The relationship between TPM2 and signaling pathways was interpreted by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) pathway enrichment analyses. The survival curve of TPM2 was analyzed across the Kaplan-Meier plotter online database. Furthermore, the relationship between TPM2 expression and infiltrating macrophages was validated through in vitro co-culture experiments. Results TPM2 expression was significantly down-regulated in breast cancer samples. In addition, TPM2 expression was correlated with lymph node metastasis and high-grade histopathological morphology. The receiver operating characteristic (ROC) curve indicated that TPM2 expression could well distinguish between normal breast tissue and breast cancer tissue. TPM2 may have potential value in breast cancer diagnosis. Bioinformatics analysis illustrated that TPM2 was mainly involved in extracellular matrix organization, collagen fibril organization, cell junction assembly, focal adhesion, cAMP signaling pathway, estrogen signaling pathway, Wnt signaling pathway, and adaptive immune system. TPM2 expression was correlated with immune infiltrating cells and immune checkpoint molecules. Our in vitro co-culture experiments showed that the M2 macrophages could upregulate the expression of TPM2. Conclusion TPM2 may play key roles in breast cancer occurrence and development, especially in cancer metastasis. TPM2 may be a potential biomarker for breast cancer diagnosis.
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Affiliation(s)
- Xingchen Zhou
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Zhishuang Li
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Huan Chen
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Meng Jiao
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Hui Li
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
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Zhang Z, Zhou P, Liu M, Pei B. Expression And Prognostic Role of PRDX1 In Gastrointestinal Cancers. J Cancer 2023; 14:2895-2907. [PMID: 37781072 PMCID: PMC10539570 DOI: 10.7150/jca.86568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/23/2023] [Indexed: 10/03/2023] Open
Abstract
Esophageal, gastric, liver, and colorectal cancers represent four prevalent gastrointestinal cancers that pose substantial threats to global health due to their high morbidity and mortality rates. Peroxiredoxin 1 (PRDX1), a significant component of the PRDXs family, primarily functions to counteract the peroxides produced by metabolic activities in the body, thereby maintaining the dynamic equilibrium of peroxides in vivo. Intriguingly, PRDX1 expression correlates strongly with cancer's onset, progression, and prognosis. This study mainly applied bioinformatics methods to analyze PRDX1's expression, diagnosis, and prognosis in gastrointestinal cancers and to summarize current research advancements. Evidence from the bioinformatics database suggested that the high expression of PRDX1 was a prominent characteristic of these four gastrointestinal cancers, with this observation reaching statistical significance. The high expression of PRDX1 in gastrointestinal cancer cells also confirms this result. Notably, the primary alteration in PRDX1 within these cancers is the presence of genetic mutations. PRDX1 demonstrated the highest diagnostic efficacy for colorectal cancer. Nevertheless, elevated PRDX1 levels only significantly diminished the survival time of liver cancer patients, exerting no statistically significant impact on the survival duration of patients afflicted by the other three types of gastrointestinal cancers. Recent research has indicated variability in PRDX1 expression across different cancer types, with high expression being predominantly observed in these four gastrointestinal cancers and, in most instances, unfavorable prognosis. These findings broadly align with the results derived from bioinformatics. This research underscores the high expression of PRDX1 in gastrointestinal cancers, its relevance to the diagnosis and prognosis monitoring of these cancers, and its potential to guide clinical treatment for these cancers.
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Affiliation(s)
- Zhou Zhang
- Department of Clinical Laboratory, Wuxi Huishan District People's Hospital, Wuxi, Jiangsu Province, 214000, China
| | - Pengli Zhou
- College of Basic Medicine, China Medical University, Shenyang, Liaoning province 110000, China
| | - Mingyue Liu
- Department of Ultrasound, Wuxi No.2 People's Hospital; Jiangnan University Medical Center, Affiliated Wuxi Clinical College of Nantong University, Wuxi, Jiangsu province 214002, China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, Jiangsu, 223800, China
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Duan P, Cui J, Li H, Yuan L. Tropomyosin 2 exerts anti-tumor effects in lung adenocarcinoma and is a novel prognostic biomarker. Histol Histopathol 2023; 38:669-680. [PMID: 36102257 DOI: 10.14670/hh-18-514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
BACKGROUND Tropomyosin 2 (TPM2), a member of the actin filament binding protein family, plays distinct roles in the progression of different cancer types. Until now, there has been no study reporting TPM2 expression nor its function in lung adenocarcinoma (LUAD). METHODS In the present study, we examined the expression profile of TPM2 by immunohistochemistry (IHC). The clinical significance of TPM2 was assessed by univariate and multivariate analyses. Function of TPM2 in LUAD was evaluated by knockdown and overexpression strategies in three LUAD cell lines, followed by proliferation and invasion assays. Xenografts were conducted in nude mice to further validate the tumor-related role of TPM2. RESULTS Our results showed that TPM2 was downregulated in LUAD specimens and the low expression of TPM2 was associated with poor outcomes of LUAD patients. Overexpressing TPM2 inhibited cell proliferation and invasion of LUAD cell lines, while silencing TPM2 exerted the opposite effects. The effects of TPM2 in LUAD were further confirmed by xenograft assays. CONCLUSIONS Our results indicated that TPM2 exerted an anti-oncogenic role in LUAD via inhibiting tumor progression, thus providing a novel direction for the prognostic prediction and disease treatment.
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Affiliation(s)
- Peng Duan
- Department of Oncology, The Third People's Hospital of Qingdao, Qingdao, China
| | - Jing Cui
- Department of Emergency, The Third People's Hospital of Qingdao, Qingdao, China
| | - Hongyan Li
- Department of Oncology, The Third People's Hospital of Qingdao, Qingdao, China
| | - Lei Yuan
- Department of Respiratory, The Third People's Hospital of Qingdao, Qingdao, China.
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Liao W, Du J, Li L, Wu X, Chen X, Feng Q, Xu L, Chen X, Liao M, Huang J, Yuan K, Zeng Y. CircZNF215 promotes tumor growth and metastasis through inactivation of the PTEN/AKT pathway in intrahepatic cholangiocarcinoma. J Exp Clin Cancer Res 2023; 42:125. [PMID: 37198696 PMCID: PMC10193609 DOI: 10.1186/s13046-023-02699-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/05/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Increasing evidence shows that circular RNAs (circRNAs), a novel class of noncoding RNAs, play a crucial role in the development of cancers, including intrahepatic cholangiocarcinoma (iCCA). Nevertheless, their functions and exact mechanisms in iCCA progression and metastasis are still unclear. Ipatasertib is a highly selective inhibitor of AKT that inhibits tumor growth by blocking the PI3K/AKT pathway. In addition, phosphatase and tensin homolog (PTEN) can also inhibit the activation of the PI3K/AKT pathway, but it is not clear whether the cZNF215-PRDX-PTEN axis plays a role in the antitumor activity of ipatasertib. METHODS We identified a new circRNA (circZNF215, termed cZNF215) through high-throughput circRNA sequencing (circRNA-seq). In addition, RT‒qPCR, immunoblot assay, RNA pull-down assay, RNA immunoprecipitation (RIP) assay, and fluorescence in situ hybridization assay (FISH) were used to investigate the interaction of cZNF215 with peroxiredoxin 1 (PRDX1). Coimmunoprecipitation (Co-IP) assays and duolink in situ proximity ligation assays (PLAs) were conducted to analyze the effects of cZNF215 on the interaction between PRDX1 and PTEN. Finally, we tested the potential effects of cZNF215 on the antitumor activity of ipatasertib with in vivo experiments. RESULTS We found that cZNF215 expression was obviously upregulated in iCCA tissues with postoperative metastases and was correlated with iCCA metastasis and poor outcome in patients with iCCA. We further revealed that overexpression of cZNF215 promoted iCCA cell growth and metastasis in vitro and in vivo, while cZNF215 knockdown had the opposite effect. Mechanistic studies suggested that cZNF215 competitively interacted with PRDX1, which blocked the association between PRDX1 and PTEN, subsequently leading to oxidation-induced inactivation of the PTEN/AKT pathway and finally contributing to iCCA progression and metastasis. Additionally, we also revealed that silencing cZNF215 in iCCA cells had the potential to enhance the antitumor effect of ipatasertib. CONCLUSIONS Our study demonstrates that cZNF215 facilitates iCCA progression and metastasis by regulating the PTEN/AKT pathway and may serve as a novel prognostic predictor in patients with iCCA.
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Affiliation(s)
- Wenwei Liao
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Jinpeng Du
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Lian Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Xianquan Wu
- Department of General Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, Guangdong, China
| | - Xing Chen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Qingbo Feng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Lin Xu
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
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Bahou WF, Marchenko N, Nesbitt NM. Metabolic Functions of Biliverdin IXβ Reductase in Redox-Regulated Hematopoietic Cell Fate. Antioxidants (Basel) 2023; 12:antiox12051058. [PMID: 37237924 DOI: 10.3390/antiox12051058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/19/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Cytoprotective heme oxygenases derivatize heme to generate carbon monoxide, ferrous iron, and isomeric biliverdins, followed by rapid NAD(P)H-dependent biliverdin reduction to the antioxidant bilirubin. Recent studies have implicated biliverdin IXβ reductase (BLVRB) in a redox-regulated mechanism of hematopoietic lineage fate restricted to megakaryocyte and erythroid development, a function distinct and non-overlapping from the BLVRA (biliverdin IXα reductase) homologue. In this review, we focus on recent progress in BLVRB biochemistry and genetics, highlighting human, murine, and cell-based studies that position BLVRB-regulated redox function (or ROS accumulation) as a developmentally tuned trigger that governs megakaryocyte/erythroid lineage fate arising from hematopoietic stem cells. BLVRB crystallographic and thermodynamic studies have elucidated critical determinants of substrate utilization, redox coupling and cytoprotection, and have established that inhibitors and substrates bind within the single-Rossmann fold. These advances provide unique opportunities for the development of BLVRB-selective redox inhibitors as novel cellular targets that retain potential for therapeutic applicability in hematopoietic (and other) disorders.
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Affiliation(s)
- Wadie F Bahou
- Department of Medicine, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Natalia Marchenko
- Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Natasha M Nesbitt
- Blood Cell Technologies, 25 Health Sciences Drive, Stony Brook, NY 11790, USA
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Sun C, Zhang K, Ni C, Wan J, Duan X, Lou X, Yao X, Li X, Wang M, Gu Z, Yang P, Li Z, Qin Z. Transgelin promotes lung cancer progression via activation of cancer-associated fibroblasts with enhanced IL-6 release. Oncogenesis 2023; 12:18. [PMID: 36990991 DOI: 10.1038/s41389-023-00463-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/31/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs), the principal constituent of the heterogenous tumor microenvironment, have been shown to promote tumor progression; however, the underlying mechanism is still less clear. Here, we find that transgelin (TAGLN) protein levels increased in primary CAFs isolated from human lung cancer, compared with those in paired normal fibroblasts. Tumor microarrays (TMAs) revealed that increased stromal TAGLN levels correlates with more lymphatic metastasis of tumor cells. In a subcutaneous tumor transplantation model, overexpression of Tagln in fibroblasts also increased tumor cell spread in mice. Further experiments show that Tagln overexpression promoted fibroblast activation and mobility in vitro. And TAGLN facilitates p-p65 entry into the nucleus, thereby activating the NF-κB signaling pathway in fibroblasts. Activated fibroblasts promote lung cancer progression via enhancing the release of pro-inflammatory cytokines, especially interleukine-6 (IL-6). Our study revealed that the high levels of stromal TAGLN is a predictive risk factor for patients with lung cancer. Targeting stromal TAGLN may present an alternative therapeutic strategy against lung cancer progression.
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Affiliation(s)
- Chanjun Sun
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Kaishang Zhang
- Thoracic Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chen Ni
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jiajia Wan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xixi Duan
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaohan Lou
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaohan Yao
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiangnan Li
- Thoracic Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ming Wang
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhuoyu Gu
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Pengyuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 100101, Beijing, China
| | - Zhenzhen Li
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Zhihai Qin
- Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, No. 15 Datun Road, Chaoyang Area, 100101, Beijing, China.
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10
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Wu Z, Ge L, Ma L, Lu M, Song Y, Deng S, Duan P, Du T, Wu Y, Zhang Z, Zhang S. TPM2 attenuates progression of prostate cancer by blocking PDLIM7-mediated nuclear translocation of YAP1. Cell Biosci 2023; 13:39. [PMID: 36823643 PMCID: PMC9948342 DOI: 10.1186/s13578-023-00993-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 02/18/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a common malignant tumor of the genitourinary system. Clinical intervention in advanced PCa remains challenging. Tropomyosins 2 (TPM2) are actin-binding proteins and have been found as a biomarker candidate for certain cancers. However, no studies have explored the role of TPM2 in PCa and its regulatory mechanism. METHODS TPM2 expression was assessed in Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) PCa patient dataset. The effect of TPM2 on PCa progression was assessed in vitro and in vivo by quantifying proliferation, migration, invasion and tumor growth assays, and the mechanism of TPM2 in PCa progression was gradually revealed by Western blotting, immunoprecipitation, and immunofluorescence staining arrays. RESULTS TPM2 was found to be severely downregulated in tumor tissues of PCa patients compared with tumor-adjacent normal tissues. In vitro experiments revealed that TPM2 overexpression inhibited PCa cell proliferation, invasion and androgen-independent proliferation. Moreover, TPM2 overexpression inhibited the growth of subcutaneous xenograft tumors in vivo. Mechanistically, this effect was noted to be dependent on PDZ-binding motif of TPM2. TPM2 competed with YAP1 for binding to PDLIM7 through the PDZ-binding motif. The binding of TPM2 to PDLIM7 subsequently inhibited the nuclear transport function of PDLIM7 for YAP1. YAP1 sequestered in the cytoplasm phosphorylated at S127, resulting in its inactivation or degradation which in turn inhibited the expression of YAP1 downstream target genes. CONCLUSIONS This study investigated the role of TPM2, PDLIM7, and YAP1 in PCa progression and castration resistance. TPM2 attenuates progression of PCa by blocking PDLIM7-mediated nuclear translocation of YAP1. Accordingly, targeting the expression or functional modulation of TPM2, PDLIM7, or YAP1 has the potential to be an effective therapeutic approach to reduce PCa proliferation and prevent the progression of castration-resistant prostate cancer (CRPC).
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Affiliation(s)
- Zonglong Wu
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Liyuan Ge
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Lulin Ma
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Min Lu
- grid.11135.370000 0001 2256 9319Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China
| | - Yimeng Song
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Shaohui Deng
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Peichen Duan
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Tan Du
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Yaqian Wu
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Zhanyi Zhang
- grid.411642.40000 0004 0605 3760Department of Urology, Peking University Third Hospital, Beijing, 100191 People’s Republic of China
| | - Shudong Zhang
- Department of Urology, Peking University Third Hospital, Beijing, 100191, People's Republic of China.
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11
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Jayathirtha M, Whitham D, Alwine S, Donnelly M, Neagu AN, Darie CC. Investigating the Function of Human Jumping Translocation Breakpoint Protein (hJTB) and Its Interacting Partners through In-Solution Proteomics of MCF7 Cells. Molecules 2022; 27:8301. [PMID: 36500393 PMCID: PMC9740069 DOI: 10.3390/molecules27238301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 11/30/2022] Open
Abstract
Human jumping translocation breakpoint (hJTB) gene is located on chromosome 1q21 and is involved in unbalanced translocation in many types of cancer. JTB protein is ubiquitously present in normal cells but it is found to be overexpressed or downregulated in various types of cancer cells, where this protein and its isoforms promote mitochondrial dysfunction, resistance to apoptosis, genomic instability, proliferation, invasion and metastasis. Hence, JTB could be a tumor biomarker for different types of cancer, such as breast cancer (BC), and could be used as a drug target for therapy. However, the functions of the protein or the pathways through which it increases cell proliferation and invasiveness of cancer cells are not well-known. Therefore, we aim to investigate the functions of JTB by using in-solution digestion-based cellular proteomics of control and upregulated and downregulated JTB protein in MCF7 breast cancer cell line, taking account that in-solution digestion-based proteomics experiments are complementary to the initial in-gel based ones. Proteomics analysis allows investigation of protein dysregulation patterns that indicate the function of the protein and its interacting partners, as well as the pathways and biological processes through which it functions. We concluded that JTB dysregulation increases the epithelial-mesenchymal transition (EMT) potential and cell proliferation, harnessing cytoskeleton organization, apical junctional complex, metabolic reprogramming, and cellular proteostasis. Deregulated JTB expression was found to be associated with several proteins involved in mitochondrial organization and function, oxidative stress (OS), apoptosis, and interferon alpha and gamma signaling. Consistent and complementary to our previous results emerged by using in-gel based proteomics of transfected MCF7 cells, JTB-related proteins that are overexpressed in this experiment suggest the development of a more aggressive phenotype and behavior for this luminal type A non-invasive/poor-invasive human BC cell line that does not usually migrate or invade compared with the highly metastatic MDA-MB-231 cells. This more aggressive phenotype of MCF7 cells related to JTB dysregulation and detected by both in-gel and in-solution proteomics could be promoted by synergistic upregulation of EMT, Mitotic spindle and Fatty acid metabolism pathways. However, in both JTB dysregulated conditions, several downregulated JTB-interacting proteins predominantly sustain antitumor activities, attenuating some of the aggressive phenotypical and behavioral traits promoted by the overexpressed JTB-related partners.
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Affiliation(s)
- Madhuri Jayathirtha
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY 13699-5810, USA
| | - Danielle Whitham
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY 13699-5810, USA
| | - Shelby Alwine
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY 13699-5810, USA
| | - Mary Donnelly
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY 13699-5810, USA
| | - Anca-Narcisa Neagu
- Laboratory of Animal Histology, Faculty of Biology, “AlexandruIoanCuza” University of Iasi, Carol I bvd. No. 20A, 700505 Iasi, Romania
| | - Costel C. Darie
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY 13699-5810, USA
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12
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Wu K, Liu F, Zhang T, Zhou Z, Yu S, Quan Y, Zhu S. miR-375 suppresses the growth and metastasis of esophageal squamous cell carcinoma by targeting PRDX1. J Gastrointest Oncol 2022; 13:2154-2168. [PMID: 36388649 PMCID: PMC9660039 DOI: 10.21037/jgo-22-929] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/17/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Esophageal cancer (EC) is one of the most lethal cancers. Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype in Asian people. Diverse microRNAs, such as miR-375, have been confirmed to be involved in the process of tumorigenesis and metastasis. However, the underlying mechanism through which miR-375 acts in ESCC patients remains unknown. METHODS We used The Cancer Genome Atlas (TCGA) database to analyze the association between miR-375 and the survival rate in patients with esophageal squamous cell carcinoma. Real Time quantitative PCR (RT-qPCR) analysis was performed to evaluate the level of miR-375 in EC tissues and cells. A luciferase reporter assay was used to confirm the target gene of miR-375. A colony formation assay as well as flow cytometric and transwell invasion experiments were employed to examine the effects of miR-375 and peroxiredoxin 1 (PRDX1) on ESCC cells. A tumor xenograft mouse model was then used to investigate the role of miR-375 on tumor growth in vivo. Moreover, we performed rescue experiments to evaluate the effect of PRDX1 on ESCC progression. RESULTS miR-375 expression was significantly downregulated in both ESCC clinical tissues and serum, and the reduction of miR-375 was remarkably linked to a poor prognosis in ESCC. Further investigation illustrated that aberrant expression of miR-375 dampened the growth and infiltration of ESCC cells both in vitro and in vivo. Bioinformatics and luciferase reporter analysis verified that the transcript of PRDX1 is a direct target of miR-375 and its expression in ESCC cells was found to be inversely modulated by miR-375. Moreover, the tumor formation experiment in nude mice confirmed that miR-375 can effectively dampen tumor growth in xenograft tumor mice models. Notably, over-expression of PRDX1 effectively counteracted the tumor-suppressing capabilities of miR-375. CONCLUSIONS We demonstrated the antitumor effect of miR-375 on ESCC by targeting PRDX1 both in vitro and in vivo.
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Affiliation(s)
- Kunpeng Wu
- Department of Thoracic Surgery, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Feng Liu
- Department of Thoracic Surgery, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Tingting Zhang
- Department of Gastroenterology, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Zhiliang Zhou
- Department of Thoracic Surgery, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Shouqiang Yu
- Department of Thoracic Surgery, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Yonghui Quan
- Department of Thoracic Surgery, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Shaojin Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
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Bisht D, Singh R, Sharma D, Sharma D, Gupta MK. Analysis of Membrane Proteins of Streptomycin-Resistant Mycobacterium
tuberculosis Isolates. CURR PROTEOMICS 2022; 19:388-399. [DOI: 10.2174/1570164619666220428082752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/11/2022] [Accepted: 03/14/2022] [Indexed: 11/22/2022]
Abstract
Background:
Drug-resistant tuberculosis remains a health security threat and resistance
to second-line drugs limits the options for treatment. Consequently, there is an utmost need for identifying
and characterizing new biomarkers/drug targets of prime importance. Membrane proteins
have an anticipated role in biological processes and could qualify as biomarkers/drug targets. Streptomycin
(SM) is recommended as a second-line treatment regimen only when amikacin resistance
has been confirmed. As extensively drug-resistant (XDR) isolates are frequently cross-resistant to
second-line injectable drugs, an untapped potential for the continued use of SM has been suggested.
Objective:
The study aimed to analyze the membrane proteins overexpressed in SM resistant isolates
of Mycobacterium tuberculosis using proteomics approaches.
Methods:
Membrane proteins were extracted employing sonication and ultracentrifugation. Twodimensional
gel electrophoresis (2DGE) of membrane proteins was performed and identification of
proteins was done by liquid chromatography-mass spectrometry (LCMS) and bioinformatics tools.
Results:
On analyzing the two-dimensional (2D) gels, five protein spots were found overexpressed
in the membrane of SM resistant isolates. Docking analysis revealed that SM might bind to the conserved
domain of overexpressed proteins and Group-based prediction system-prokaryotic ubiquitinlike
protein (GPS-PUP) predicted potential pupylation sites within them.
Conclusion:
These proteins might be of diagnostic importance for detecting the cases early and for
exploring effective control strategies against drug-resistant tuberculosis, particularly SM.
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Affiliation(s)
- Deepa Bisht
- Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra (UP)-282004, India
| | - Rananjay Singh
- Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra (UP)-282004, India
| | - Devesh Sharma
- Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra (UP)-282004, India
| | - Divakar Sharma
- Department of Microbiology, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi-110002, India
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Zhang J, Guo X, Jin B, Zhu Q. Editorial: Tumor-associated antigens and their autoantibodies, from discovering to clinical utilization. Front Oncol 2022; 12:970623. [PMID: 35936692 PMCID: PMC9346231 DOI: 10.3389/fonc.2022.970623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/07/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- Jianying Zhang
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, United States
- *Correspondence: Jianying Zhang, ; Xiangqian Guo,
| | - Xiangqian Guo
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Academy for Advanced Interdisciplinary Studies, Henan University, Kaifeng, China
- *Correspondence: Jianying Zhang, ; Xiangqian Guo,
| | - Bilian Jin
- Cancer Center, Dalian Medical University, Dalian, China
| | - Qing Zhu
- West China Hospital, Sichuan University, Chengdu, China
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Kitsiranuwat S, Suratanee A, Plaimas K. Integration of various protein similarities using random forest technique to infer augmented drug-protein matrix for enhancing drug-disease association prediction. Sci Prog 2022; 105:368504221109215. [PMID: 35801312 PMCID: PMC10358641 DOI: 10.1177/00368504221109215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Identifying new therapeutic indications for existing drugs is a major challenge in drug repositioning. Most computational drug repositioning methods focus on known targets. Analyzing multiple aspects of various protein associations provides an opportunity to discover underlying drug-associated proteins that can be used to improve the performance of the drug repositioning approaches. In this study, machine learning models were developed based on the similarities of diversified biological features, including protein interaction, topological network, sequence alignment, and biological function to predict protein pairs associating with the same drugs. The crucial set of features was identified, and the high performances of protein pair predictions were achieved with an area under the curve (AUC) value of more than 93%. Based on drug chemical structures, the drug similarity levels of the promising protein pairs were used to quantify the inferred drug-associated proteins. Furthermore, these proteins were employed to establish an augmented drug-protein matrix to enhance the efficiency of three existing drug repositioning techniques: a similarity constrained matrix factorization for the drug-disease associations (SCMFDD), an ensemble meta-paths and singular value decomposition (EMP-SVD) model, and a topology similarity and singular value decomposition (TS-SVD) technique. The results showed that the augmented matrix helped to improve the performance up to 4% more in comparison to the original matrix for SCMFDD and EMP-SVD, and about 1% more for TS-SVD. In summary, inferring new protein pairs related to the same drugs increase the opportunity to reveal missing drug-associated proteins that are important for drug development via the drug repositioning technique.
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Affiliation(s)
- Satanat Kitsiranuwat
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
- Advanced Virtual and Intelligent Computing (AVIC) center, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut's University of Technology North Bangkok, Bangkok, Thailand
- Intelligent and Nonlinear Dynamic Innovations Research Center, Science and Technology Research Institute, King Mongkut's University of Technology North Bangkok, Bangkok, Thailand
| | - Kitiporn Plaimas
- Advanced Virtual and Intelligent Computing (AVIC) center, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Omics Sciences and Bioinformatics Center, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
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Revealing therapeutic targets and mechanism of baicalin for anti-chronic gastritis using proteomic analysis of the gastric tissue. J Chromatogr B Analyt Technol Biomed Life Sci 2022; 1196:123214. [DOI: 10.1016/j.jchromb.2022.123214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/19/2022] [Accepted: 03/04/2022] [Indexed: 11/24/2022]
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Zhang H, Zhang Y, Xia T, Lu L, Luo M, Chen Y, Liu Y, Li Y. The Role of Keratin17 in Human Tumours. Front Cell Dev Biol 2022; 10:818416. [PMID: 35281081 PMCID: PMC8912659 DOI: 10.3389/fcell.2022.818416] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/03/2022] [Indexed: 12/24/2022] Open
Abstract
Keratins are a group of proteins that can constitute intermediate fibers. It is a component of the cytoskeleton and plays an important role in cell protection and structural support. Keratin 17, a Type I keratin, is a multifunctional protein that regulates a variety of biological processes, including cell growth, proliferation, migration, apoptosis and signal transduction. Abnormal expression of KRT17 is associated with a variety of diseases, such as skin diseases. In recent years, studies have shown that KRT17 is abnormally expressed in a variety of malignant tumours, such as lung cancer, cervical cancer, oral squamous cell carcinoma and sarcoma. These abnormal expressions are related to the occurrence, development and prognosis of malignant tumors. In this review, we summarized the expression patterns of KRT17 in a variety of malignant tumours, the role of KRT17 in the development and prognosis of different malignant tumors and its molecular mechanisms. We also discuss the potential clinical application of KRT17 as a valuable therapeutic target.
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Affiliation(s)
- Hanqun Zhang
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Yun Zhang
- Department of Pathology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Tingting Xia
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Liang Lu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Min Luo
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Yanping Chen
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Yuncong Liu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
- *Correspondence: Yuncong Liu, ; Yong Li,
| | - Yong Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
- *Correspondence: Yuncong Liu, ; Yong Li,
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18
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Zhang F, Attarilar S, Xie K, Han C, Qingyang Liang, Huang K, Lan C, Wang C, Yang C, Wang L, Mozafari M, Li K, Liu J, Tang Y. Carfilzomib alleviated osteoporosis by targeting PSME1/2 to activate Wnt/β-catenin signaling. Mol Cell Endocrinol 2022; 540:111520. [PMID: 34838695 DOI: 10.1016/j.mce.2021.111520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 11/21/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022]
Abstract
Osteoporosis (OP) is characterized by decreased bone mineral density and impaired bone strength. Carfilzomib (CFZ) is a new-generation proteasome inhibitor and has been found to affect bone metabolism. However, the effect and mechanism of CFZ on OP has not been investigated systematically. In this study, we found that protein levels of proteasome activator subunit 1/2 (PSME1/2) increased in OP, and accumulated mostly in osteoblasts and osteoclasts. Treatment with PSME1/2 recombinant protein inhibited osteogenesis and promoted osteoclast formation in vitro. Also, PSME1/2 inhibited the expression of β-catenin protein, resulting in limitation of Wnt/β-catenin signaling. CFZ inhibited PSME1 and PSME2 proteasome activities and increased β-catenin protein level, resulting in the translocation of β-catenin to the nucleus and activation of canonical Wnt/β-catenin signaling, further promoting osteogenesis and inhibiting osteoclastic differentiation. In vivo, we conducted ovariectomy (OVX) to create a model of OVX-induced postmenopausal OP in mice. When analyzed by micro-CT scanning, enhancement of bone mineral density, bone volume, trabecular number, and thickness was seen in the CFZ-treated mice. Also, we noticed increased osteogenesis and decreased osteoclastogenesis, diminished expression of PSME1 and PSME2 and activated Wnt/β-catenin signaling in bone sections from OP mice treated with CFZ. Overall, our data indicated that PSME1/2 may serve as new targets for the treatment of OP, and targeting PSME1/2 with CFZ provides a candidate therapeutic molecule for postmenopausal OP.
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Affiliation(s)
- Fan Zhang
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Shokouh Attarilar
- State Key Laboratory of Metal Matrix Composites, School of Material Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Kegong Xie
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Chao Han
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Qingyang Liang
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Ke Huang
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Changgong Lan
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Chong Wang
- School of Mechanical Engineering, Dongguan University of Technology, Dongguan, Guangdong, 523808, China
| | - Chengliang Yang
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Liqiang Wang
- State Key Laboratory of Metal Matrix Composites, School of Material Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Masoud Mozafari
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Kai Li
- Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China.
| | - Jia Liu
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
| | - Yujin Tang
- Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, 533000, Guangxi, China; Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
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Tian Z, Zhao J, Wang Y. The prognostic value of TPM1-4 in hepatocellular carcinoma. Cancer Med 2021; 11:433-446. [PMID: 34850589 PMCID: PMC8729055 DOI: 10.1002/cam4.4453] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022] Open
Abstract
Background Despite advances in multiple disciplinary diagnoses and treatments, the prognosis of hepatocellular carcinoma (HCC) remains poor. Some evidence has identified that the aberrant expression of tropomyosins (TPMs) is involved with some cancers development. However, prognostic values of TPMs in HCC have not been thoroughly investigated. Methods Original TPM1–4 mRNA expression of TCGA HCC data and GTEx was downloaded from UCSC XENA. Oncomine database and GSE46408 were used for verification. Clinical stages and survival analysis of TPM1–4 in HCC were performed by GEPIA2. cBioPortal was utilized to assess TPM1–4 gene alteration in HCC. TIMER2.0 was used for investigating the relevance of TPM1–4 to tumor‐infiltrating immune cells in HCC. Additionally, we constructed a TPM1–4 prognostic model to explore the value of TPM1–4 for prognostic evaluation in HCC. LinkedOmics was applied to elucidate TPM3 co‐expression networks in HCC. Results This present study showed that TPM1–4 was upregulated in all HCC tissues, and TPM3 overexpression was correlated with poor survival outcomes in patients with HCC. Besides, TPM3 amplification was the main altered type in TPM1–4 genetic alteration, which affected the prognosis of HCC patients. The risk model revealed that TPM1, TPM2, and TPM3 were applied to risk assessment of HCC prognosis, among which TPM3 expression was significantly higher in the high‐risk group than that in the low‐risk group. Univariate and multivariate cox regression analyses indicated that TPM3 may be an independent prognostic factor of HCC prognosis. In addition, TPM3 co‐expression genes mainly participated in the cell cycle by maintaining microtubule cytoskeleton in HCC progression. TPM1–4 was associated with some tumor‐infiltrating immune cells in HCC. Conclusion Our study detected that the expression level of TPM1–4 was all remarkably elevated in HCC, suggesting that TPM1–4 may serve an important role in HCC development. High TPM3 expression was found to be correlated with poor overall survival, and TPM3 may be an independent prognostic factor for HCC.
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Affiliation(s)
- Zhihui Tian
- Gastroenterology Ward One, Shanxi Province Cancer Hospital, Taiyuan, Shanxi, China
| | - Jian Zhao
- Gastroenterology Ward One, Shanxi Province Cancer Hospital, Taiyuan, Shanxi, China
| | - Yusheng Wang
- Gastroenterology Ward One, Shanxi Province Cancer Hospital, Taiyuan, Shanxi, China
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20
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Ashenova A, Daniyarov A, Molkenov A, Sharip A, Zinovyev A, Kairov U. Meta-Analysis of Esophageal Cancer Transcriptomes Using Independent Component Analysis. Front Genet 2021; 12:683632. [PMID: 34795689 PMCID: PMC8594933 DOI: 10.3389/fgene.2021.683632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 10/05/2021] [Indexed: 11/17/2022] Open
Abstract
Independent Component Analysis is a matrix factorization method for data dimension reduction. ICA has been widely applied for the analysis of transcriptomic data for blind separation of biological, environmental, and technical factors affecting gene expression. The study aimed to analyze the publicly available esophageal cancer data using the ICA for identification and comprehensive analysis of reproducible signaling pathways and molecular signatures involved in this cancer type. In this study, four independent esophageal cancer transcriptomic datasets from GEO databases were used. A bioinformatics tool « BiODICA-Independent Component Analysis of Big Omics Data» was applied to compute independent components (ICs). Gene Set Enrichment Analysis (GSEA) and ToppGene uncovered the most significantly enriched pathways. Construction and visualization of gene networks and graphs were performed using the Cytoscape, and HPRD database. The correlation graph between decompositions into 30 ICs was built with absolute correlation values exceeding 0.3. Clusters of components-pseudocliques were observed in the structure of the correlation graph. The top 1,000 most contributing genes of each ICs in the pseudocliques were mapped to the PPI network to construct associated signaling pathways. Some cliques were composed of densely interconnected nodes and included components common to most cancer types (such as cell cycle and extracellular matrix signals), while others were specific to EC. The results of this investigation may reveal potential biomarkers of esophageal carcinogenesis, functional subsystems dysregulated in the tumor cells, and be helpful in predicting the early development of a tumor.
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Affiliation(s)
- Ainur Ashenova
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Center for Life Sciences, Nazarbayev University, Nur-Sultan, Kazakhstan
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Asset Daniyarov
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Center for Life Sciences, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Askhat Molkenov
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Center for Life Sciences, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Aigul Sharip
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Center for Life Sciences, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Andrei Zinovyev
- Institut Curie, PSL Research University, INSERM U900, Paris, France
- Laboratory of Advanced Methods for High-dimensional Data Analysis, Lobachevsky University, Nizhny Novgorod, Russia
| | - Ulykbek Kairov
- Laboratory of Bioinformatics and Systems Biology, National Laboratory Astana, Center for Life Sciences, Nazarbayev University, Nur-Sultan, Kazakhstan
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21
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Guo Y, Dong X, Jin J, He Y. The Expression Patterns and Prognostic Value of the Proteasome Activator Subunit Gene Family in Gastric Cancer Based on Integrated Analysis. Front Cell Dev Biol 2021; 9:663001. [PMID: 34650966 PMCID: PMC8505534 DOI: 10.3389/fcell.2021.663001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence supports that proteasome activator subunit (PSME) genes play an indispensable role in multiple tumors. The diverse expression patterns, prognostic value, underlying mechanism, and the role in the immunotherapy of PSME genes in gastric cancer (GC) have yet to be fully elucidated. We systematically demonstrated the functions of these genes in GC using various large databases, unbiased in silico approaches, and experimental validation. We found that the median expression levels of all PSME genes were significantly higher in GC tissues than in normal tissues. Our findings showed that up-regulated PSME1 and PSME2 expression significantly correlated with favorable overall survival, post-progression survival, and first progression survival in GC patients. The expression of PSME1 and PSME2 was positively correlated with the infiltration of most immune cells and the activation of anti-cancer immunity cycle steps. Moreover, GC patients with high PSME1 and PSME2 expression have higher immunophenoscore and tumor mutational burden. In addition, a receiver operating characteristic analysis suggested that PSME3 and PSME4 had high diagnostic performance for distinguishing GC patients from healthy individuals. Moreover, our further analysis indicated that PSME genes exert an essential role in GC, and the present study indicated that PSME1 and PSME2 may be potential prognostic markers for enhancing survival and prognostic accuracy in GC patients and may even act as potential biomarkers for GC patients indicating a response to immunotherapy. PSME3 may serve as an oncogene in tumorigenesis and may be a promising therapeutic target for GC. PSME4 had excellent diagnostic performance and could serve as a good diagnostic indicator for GC.
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Affiliation(s)
- Yongdong Guo
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoping Dong
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jing Jin
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yutong He
- Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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22
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Xu TT, Zeng XW, Wang XH, Yang LX, Luo G, Yu T. Cystatin-B Negatively Regulates the Malignant Characteristics of Oral Squamous Cell Carcinoma Possibly Via the Epithelium Proliferation/Differentiation Program. Front Oncol 2021; 11:707066. [PMID: 34504787 PMCID: PMC8421684 DOI: 10.3389/fonc.2021.707066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/30/2021] [Indexed: 12/24/2022] Open
Abstract
Disturbance in the proteolytic process is one of the malignant signs of tumors. Proteolysis is highly orchestrated by cysteine cathepsin and its inhibitors. Cystatin-B (CSTB) is a general cysteine cathepsin inhibitor that prevents cysteine cathepsin from leaking from lysosomes and causing inappropriate proteolysis. Our study found that CSTB was downregulated in both oral squamous cell carcinoma (OSCC) tissues and cells compared with normal controls. Immunohistochemical analysis showed that CSTB was mainly distributed in the epithelial structure of OSCC tissues, and its expression intensity was related to the grade classification. A correlation analysis between CSTB and clinical prognosis was performed using gene expression data and clinical information acquired from The Cancer Genome Atlas (TCGA) database. Patients with lower expression levels of CSTB had shorter disease-free survival times and poorer clinicopathological features (e.g., lymph node metastases, perineural invasion, low degree of differentiation, and advanced tumor stage). OSCC cell models overexpressing CSTB were constructed to assess the effects of CSTB on malignant biological behaviors and upregulation of CSTB inhibited cell proliferation, migration, and invasion in vitro. Weighted gene correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) were performed based on the TCGA data to explore potential mechanisms, and CSTB appeared to correlate with squamous epithelial proliferation-differentiation processes, such as epidermal cell differentiation and keratinization. Moreover, in WGCNA, the gene module most associated with CSTB expression (i.e., the brown module) was also the one most associated with grade classification. Upregulation of CSTB promoted the expression levels of markers (LOR, IVL, KRT5/14, and KRT1/10), reflecting a tendency for differentiation and keratinization in vitro. Gene expression profile data of the overexpressed CSTB cell line were obtained by RNA sequencing (RNA-seq) technology. By comparing the GSEA enrichment results of RNA-seq data (from the OSCC models overexpressing CSTB) and existing public database data, three gene sets (i.e., apical junction, G2/M checkpoint, etc.) and six pathways (e.g., NOTCH signaling pathway, glycosaminoglycan degradation, mismatch repair, etc.) were enriched in the data from both sources. Overall, our study shows that CSTB is downregulated in OSCC and might regulate the malignant characteristics of OSCC via the epithelial proliferation/differentiation program.
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Affiliation(s)
- Tian-Tian Xu
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Xiao-Wen Zeng
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Xin-Hong Wang
- Department of Oral Pathology and Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Lu-Xi Yang
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Gang Luo
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Ting Yu
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
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Mancuso C. Biliverdin reductase as a target in drug research and development: Facts and hypotheses. Free Radic Biol Med 2021; 172:521-529. [PMID: 34224815 DOI: 10.1016/j.freeradbiomed.2021.06.034] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/14/2021] [Accepted: 06/30/2021] [Indexed: 12/26/2022]
Abstract
Biliverdin reductase-A (BVR) catalyzes the reduction of heme-derived biliverdin into bilirubin, this latter being a powerful endogenous free radical scavenger. Furthermore, BVR is also endowed with both serine/threonine/tyrosine kinase and scaffold activities, through which it interacts with the insulin receptor kinase, conventional and atypical protein kinase C isoforms, mitogen-activated protein kinases as well as the phosphatidylinositol-3 kinase/Akt system. By regulating this complex array of signal transduction pathways, BVR is involved in the pathogenesis of neurodegenerative, metabolic, cardiovascular and immune-inflammatory diseases as well as in cancer. In addition, both BVR and BVR-B, this latter being an alternate isozyme predominant during fetal development but sometimes detectable through adulthood, have been studied as peripheral biomarkers for an early detection of Alzheimer's disease, atherosclerosis and some types of cancer. However, despite these interesting lines of evidence, to date BVR has not been considered as an appealing drug target. Only limited evidence supports the neuroprotective effects of atorvastatin and ferulic acid through BVR regulation in the aged canine brain and human neuroblastoma cells, whereas interesting results have been reported regarding the use of BVR-based peptides in preclinical models of cardiac diseases and cancer.
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Affiliation(s)
- Cesare Mancuso
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168, Rome, Italy.
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24
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Yu WW, Fu XL, Cai XW, Sun MH, Guo YM. Identification of differentially expressed proteins in the locoregional recurrent esophageal squamous cell carcinoma by quantitative proteomics. J Gastrointest Oncol 2021; 12:991-1006. [PMID: 34295551 DOI: 10.21037/jgo-21-278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/15/2021] [Indexed: 11/06/2022] Open
Abstract
Background This study aimed to identify potential biomarkers associated with locoregional recurrence in patients with esophageal squamous cell carcinoma (ESCC) after radical resection. Methods We performed a quantitative proteomics analysis using isobaric tags for relative and absolute quantification (iTRAQ) with reversed-phase liquid chromatography-mass spectrometry (RPLC-MS) to identify differential expression proteins (DEPs) between a locoregional recurrence group and good prognosis group of ESCC after radical esophagectomy. The bioinformatics analysis was performed with ingenuity pathway analysis software (IPA) and Gene Ontology (GO) database using the software of MAS 3.0. Kaplan-Meier (KM) Plotter Online Tool (http://www.kmplot.com) was used to evaluate the relationship between the differential expression of proteins and survival in patients with ESCC. Results More than 400 proteins were quantitated of which 27 proteins had upregulated expression and 55 proteins had downregulated expression in the locoregional recurrence group compared to the good prognosis group. These 82 DEPs were associated with biological procession of cancer development including cellular movement, cellular assembly and organization, cellular function and maintenance, cellular growth and proliferation, cell death and survival, DNA replication recombination and repair, and so on. Of these DEPs, SPTAN1 and AGT proteins were identified to be associated with RFS in ESCC. SPTAN1 was positively associated with RFS and AGT was negatively associated with RFS. Expression of SPTAN1 tended to have favorable OS while expression of AGT tended to have poor OS. Conclusions Our results demonstrated that quantitative proteomics is an effective discovery tool to identify biomarkers for prognosis prediction in ESCC. However, it needs more studies with large populations of ESCC to validate these potential biomarkers.
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Affiliation(s)
- Wei-Wei Yu
- Department of Radiation Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiao-Long Fu
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xu-Wei Cai
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Meng-Hong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yan-Mei Guo
- Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai, China
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25
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Li J, Qin B, Huang M, Ma Y, Li D, Li W, Guo Z. Tumor-Associated Antigens (TAAs) for the Serological Diagnosis of Osteosarcoma. Front Immunol 2021; 12:665106. [PMID: 33995397 PMCID: PMC8119874 DOI: 10.3389/fimmu.2021.665106] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/08/2021] [Indexed: 01/07/2023] Open
Abstract
Osteosarcoma (OS) is the most common form of malignant bone tumor found in childhood and adolescence. Although its incidence rate is low among cancers, the prognosis of OS is usually poor. Although some biomarkers, such as p53, have been identified in OS, the association between the biomarkers and clinical outcome is not well understood. Thus, it is necessary to establish a method to identify patients diagnosed with OS at an early stage. It is becoming obvious that anti-tumor-associated antigens (TAAs) autoantibodies (TAAbs) in sera could be used as serological biomarkers in the detection of many different types of cancers. This notion indicates that TAAbs are considered as immunological “sentinels” associated with tumorigenesis underlying molecular events. It provides new insights into the molecular and cellular biology of the differential diagnosis of cancers. What’s more, it is reported that a customized TAA array could significantly increase the sensitivity/specificity. TAA arrays also have great application prospects in detecting cancer at an early stage, monitoring cancer progression, discovering new therapeutic targets, and designing personalized treatment. In this review, we provide an overview of the TAAs identified in OS as well as the possibility that TAAs and TAAbs system be used as biomarkers in the immunodiagnosis and prognosis of OS.
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Affiliation(s)
- Jitian Li
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital)/Henan Institute of Orthopedic and Traumatology, Luoyang, China
| | - Bo Qin
- Transitional Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Manyu Huang
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital)/Henan Institute of Orthopedic and Traumatology, Luoyang, China
| | - Yan Ma
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital)/Henan Institute of Orthopedic and Traumatology, Luoyang, China
| | - Dongsheng Li
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital)/Henan Institute of Orthopedic and Traumatology, Luoyang, China
| | - Wuyin Li
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital)/Henan Institute of Orthopedic and Traumatology, Luoyang, China
| | - Zhiping Guo
- Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital)/Henan Institute of Orthopedic and Traumatology, Luoyang, China
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26
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Yang X, Suo C, Zhang T, Yin X, Man J, Yuan Z, Yu J, Jin L, Chen X, Lu M, Ye W. Targeted proteomics-derived biomarker profile develops a multi-protein classifier in liquid biopsies for early detection of esophageal squamous cell carcinoma from a population-based case-control study. Biomark Res 2021; 9:12. [PMID: 33597040 PMCID: PMC7890600 DOI: 10.1186/s40364-021-00266-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/04/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Early diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC. METHODS We selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay. RESULTS We found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation. CONCLUSIONS Our study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.
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Affiliation(s)
- Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, China.,Clinical Research Center of Shandong University, Qilu Hospital of Shandong University, Jinan, China
| | - Chen Suo
- Department of Epidemiology and Health Statistics, School of Public Health, Fudan University, Shanghai, China
| | - Tongchao Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, China
| | - Xiaolin Yin
- Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, China
| | - Jinyu Man
- Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, China
| | - Ziyu Yuan
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Jingru Yu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Li Jin
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China
| | - Xingdong Chen
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China. .,State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China.
| | - Ming Lu
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, China. .,Clinical Research Center of Shandong University, Qilu Hospital of Shandong University, Jinan, China. .,Fudan University Taizhou Institute of Health Sciences, Taizhou, China.
| | - Weimin Ye
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Epidemiology and Health Statistics & Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
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27
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Yuan X, Yi M, Dong B, Chu Q, Wu K. Prognostic significance of KRT19 in Lung Squamous Cancer. J Cancer 2021; 12:1240-1248. [PMID: 33442422 PMCID: PMC7797641 DOI: 10.7150/jca.51179] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022] Open
Abstract
Backgroud: Keratin 19 (KRT19) is the intermediate filament that constitutes the cytoskeleton and regulates cell-cycle and cell death. Objective: We aimed to assess whether KRT19 was involved in lung cancer development. Methods: The expression of KRT19 in lung cancer was evaluated from mRNA expression on open databse and protein abundance on tumor tissue array. Results: Using open microarray gene expression datasets and differential expression analysis, we found that KRT19 was upregulated in lung cancer compared with normal tissue. Further analysis suggested that KRT19 mRNA expression was correlated with tumor progression and overall survival in lung cancer patients. As KRT19 was overexpressed in adenocarcinoma (AC) and squamous cell carcinoma (SCC), we examined the prognostic value of KRT19 protein abundance by tissue microarray (TMA). The results suggested that protein expression of KRT19 was significantly associated with overall survival of SCC. Conclusions: Giving the prognostic role of KRT19 in lung cancer, KRT19 could be considered as an potential molecular marker in lung cancer, especially in SCC.
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Affiliation(s)
- Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China
| | - Bing Dong
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.,Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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Keratin 17 Expression Predicts Poor Clinical Outcome in Patients With Advanced Esophageal Squamous Cell Carcinoma. Appl Immunohistochem Mol Morphol 2020; 29:144-151. [PMID: 32554975 DOI: 10.1097/pai.0000000000000862] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 04/23/2020] [Indexed: 12/14/2022]
Abstract
The major roles of keratin 17 (K17) as a prognostic biomarker have been highlighted in a range of human malignancies. However, its relevance to esophageal squamous cell carcinoma (ESCC) remains unexplored. In this study, the relationship between K17 expression and clinicopathologic parameters and survival were determined by RNA sequencing (RNA-Seq) in 90 ESCCs and by immunohistochemistry (IHC) in 68 ESCCs. K17 expression was significantly higher in ESCC than in paired normal tissues at both the messenger RNA and protein levels. K17 messenger RNA and staining by IHC were significantly correlated with aggressive characteristics, including advanced clinical stage, invasion depth, and lymph node metastases; and were predictive of poor prognosis in advanced disease patients. Furthermore, K17 expression was detected by IHC in high-grade premalignant lesions of the esophageal mucosa, suggesting that K17 could also be a biomarker of dysplasia of the esophageal mucosa. Overall, this study established that K17 is a negative prognostic biomarker for the most common subtype of esophageal cancer.
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29
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Fu Z, Zhang S, Wang B, Huang W, Zheng L, Cheng A. Annexin A1: A double-edged sword as novel cancer biomarker. Clin Chim Acta 2020; 504:36-42. [DOI: 10.1016/j.cca.2020.01.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/22/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023]
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30
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Mao H, Xu Y, Zhang Z, Sun G, Wang Z, Qiao D, Yin X, Liu S, Bo P. Biliverdin Reductase A (BLVRA) Promotes Colorectal Cancer Cell Progression by Activating the Wnt/β-Catenin Signaling Pathway. Cancer Manag Res 2020; 12:2697-2709. [PMID: 32425592 PMCID: PMC7187560 DOI: 10.2147/cmar.s242531] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 03/06/2020] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Biliverdin reductase A (BLVRA) is a pleiotropic enzyme that converts biliverdin-IX-alpha into the antioxidant and anti-nitrosative compound, bilirubin-IX-alpha. It is related to various diseases, including cancer. It is overexpressed in many types of cancers and promotes cancer development and metastasis, but the effects of BLVRA in colorectal cancer have not been researched at present. This study was aimed to investigate the effects of biliverdin reductase A (BLVRA) in vivo and vitro experiments and its possible mechanism. METHODS The clinical samples of CRC patients and CRC cell lines HT-29 and SW620 were chosen to perform the experiments. ELISA and Immunohistochemistry (IHC) were applied to test the level of BLVRA in patients. HT-29 knockdown of BLVRA and SW620 overexpression of BLVRA was established by the lentiviral vector transfection. Reverse transcription-quantitative real-time polymerase chain reaction and Western blotting were performed to examine the expression of BLVRA. MTT was used to detect the proliferation of CRC cells. Flow cytometry was applied to assess the rate of apoptosis. Transwell assay was performed to examine the capacity of migration and invasion. Immunofluorescence staining was adopted to assess the expression of E-cadherin and vimentin. Western blotting was utilized to detect the expression of apoptosis-related proteins, EMT-related proteins and target proteins of Wnt/β-catenin signaling pathway. RESULTS Analysis of the clinical samples revealed that BLVRA was overexpressed in CRC patients and implied poor prognosis. BLVRA overexpression in the in vitro studies revealed that it increased the potential of CRC cells for proliferation, migration and invasion; augmented EMT; and hindered apoptosis. In addition, BLVRA overexpression was found to upregulate positive target genes and downregulate negative target genes of the Wnt/β-catenin signaling pathway, which implied that the biological effects of BLVRA in CRC were mediated by this pathway. In contrast, knockdown of BLVRA manifested the opposite effects. CONCLUSION Our results suggested that BLVRA might be a promising prognostic marker and a potential therapeutic target in CRC.
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Affiliation(s)
- Haiyan Mao
- Oncology Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province225000, People’s Republic of China
- Department of Integrative Chinese and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu Province225009, People’s Republic of China
| | - Yuan Xu
- Oncology Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province225000, People’s Republic of China
| | - Zhengrong Zhang
- Oncology Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province225000, People’s Republic of China
| | - Guozhuang Sun
- Laboratory Department, Xuyi People’s Hospital, Huai’an, Jiangsu Province211700, People’s Republic of China
| | - Zhu Wang
- Oncology Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province225000, People’s Republic of China
| | - Dawei Qiao
- Department of Integrative Chinese and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu Province225009, People’s Republic of China
| | - Xudong Yin
- Oncology Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu Province225000, People’s Republic of China
| | - Siping Liu
- Imaging Department, Yangzhou Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Yangzhou225000, People’s Republic of China
| | - Ping Bo
- Department of Integrative Chinese and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu Province225009, People’s Republic of China
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Chu LY, Peng YH, Weng XF, Xie JJ, Xu YW. Blood-based biomarkers for early detection of esophageal squamous cell carcinoma. World J Gastroenterol 2020; 26:1708-1725. [PMID: 32351288 PMCID: PMC7183865 DOI: 10.3748/wjg.v26.i15.1708] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 03/13/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive system worldwide, especially in China. Due to the lack of effective early detection methods, ESCC patients often present at an advanced stage at the time of diagnosis, which seriously affects the prognosis of patients. At present, early detection of ESCC mainly depends on invasive and expensive endoscopy and histopathological biopsy. Therefore, there is an unmet need for a non-invasive method to detect ESCC in the early stages. With the emergence of a large class of non-invasive diagnostic tools, serum tumor markers have attracted much attention because of their potential for detection of early tumors. Therefore, the identification of serum tumor markers for early detection of ESCC is undoubtedly one of the most effective ways to achieve early diagnosis and treatment of ESCC. This article reviews the recent advances in the discovery of blood-based ESCC biomarkers, and discusses the origins, clinical applications, and technical challenges of clinical validation of various types of biomarkers.
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Affiliation(s)
- Ling-Yu Chu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xue-Fen Weng
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Zhang X, Gao F, Li N, Zhang J, Dai L, Yang H. Peroxiredoxins and Immune Infiltrations in Colon Adenocarcinoma: Their Negative Correlations and Clinical Significances, an In Silico Analysis. J Cancer 2020; 11:3124-3143. [PMID: 32231717 PMCID: PMC7097948 DOI: 10.7150/jca.38057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 01/04/2020] [Indexed: 01/05/2023] Open
Abstract
Background: Peroxiredoxins (PRDXs) were reported to be associated with inflammation response in previous studies. In colon adenocarcinoma (COAD), however, their correlations and clinical significance were unclear. Methods: The RNA-seq data of 452 COAD patients with clinical information was downloaded from The Cancer Genome Atlas (TCGA) and transcripts per million (TPM) normalized. Comparisons of relative expressions of PRDXs between COAD tumor and normal controls were applied. PRDXs dy-regulations in COAD were validated via Oncomine, Human Protein Atlas (HPA) and Gene Expression Omnibus (GEO) repository. Through Tumor Immune Estimation Resource (TIMER), the immune estimation of TCGA-COAD patients was downloaded and the dy-regulated PRDXs were analyzed for their correlations with immune infiltrations in COAD. The TCGA-COAD patients were divided into younger group (age≤65 years) and older group (age>65 years) to investigate the prognostic roles of age, TNM stage, dy-regulated PRDXs and the immune infiltrations in different age groups through Kaplan-Meier survival and Cox regression analyses. Results: Three of the PRDX members showed their expressional differences both at protein and mRNA level. PRDX2 was consistently up-regulated while PRDX6 down-regulated in COAD. PRDX1 was overexpressed (mRNA) while nuclear absent (protein) in the tumor tissues. PRDX1 overexpression and PRDX6 under-expression were also shown in the stem-like colonospheres from colon cancer cells. Via TIMER, PRDX1, PRDX2, and PRDX6 were found to be negatively correlated with the immune infiltrations in COAD. Both in the younger and older patients, TNM stage had prognostic effects on their overall survival (OS) and recurrence-free survival (RFS). CD4+ T cell had independent unfavorable effects on OS of the younger patients while age had similar effects on RFS of the older ones. CD8+ T cell was independently prognostic for RFS in the two groups. Conclusions: Late diagnosis indicated poor prognosis in COAD and dy-regulated PRDXs w might be new markers for its early diagnosis. Age was prognostic and should be considered in the treatments of the older patients. Dy-regulated PRDXs were negatively correlated with immune infiltration levels. CD4+ T cell and CD8+ T cell infiltrations were prognostic in COAD and their potential as immune targets needed further investigation.
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Affiliation(s)
- Xiuzhi Zhang
- Department of Pathology, Henan Medical College, Zhengzhou, Henan Province, China.,Medical Laboratory Center, Henan Medical College, Zhengzhou, Henan Province, China.,Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Fenglan Gao
- Department of Pathology, Henan Medical College, Zhengzhou, Henan Province, China
| | - Ningning Li
- Department of Pathology, Henan Medical College, Zhengzhou, Henan Province, China
| | - Jinzhong Zhang
- Medical Laboratory Center, Henan Medical College, Zhengzhou, Henan Province, China
| | - Liping Dai
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Hongmei Yang
- Department of Pathology, Henan Medical College, Zhengzhou, Henan Province, China.,Medical Laboratory Center, Henan Medical College, Zhengzhou, Henan Province, China
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Canesin G, Hejazi SM, Swanson KD, Wegiel B. Heme-Derived Metabolic Signals Dictate Immune Responses. Front Immunol 2020; 11:66. [PMID: 32082323 PMCID: PMC7005208 DOI: 10.3389/fimmu.2020.00066] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/10/2020] [Indexed: 12/21/2022] Open
Abstract
Heme is one of the most abundant molecules in the body acting as the functional core of hemoglobin/myoglobin involved in the O2/CO2 carrying in the blood and tissues, redox enzymes and cytochromes in mitochondria. However, free heme is toxic and therefore its removal is a significant priority for the host. Heme is a well-established danger-associated molecular pattern (DAMP), which binds to toll-like receptor 4 (TLR4) to induce immune responses. Heme-derived metabolites including the bile pigments, biliverdin (BV) and bilirubin (BR), were first identified as toxic drivers of neonatal jaundice in 1800 but have only recently been appreciated as endogenous drivers of multiple signaling pathways involved in protection from oxidative stress and regulators of immune responses. The tissue concentration of heme, BV and BR is tightly controlled. Heme oxygenase-1 (HO-1, encoded by HMOX1) produces BV by heme degradation, while biliverdin reductase-A (BLVR-A) generates BR by the subsequent conversion of BV. BLVR-A is a fascinating protein that possesses a classical protein kinase domain, which is activated in response to BV binding to its enzymatic site and initiates the downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. This links BLVR-A activity to cell growth and survival pathways. BLVR-A also contains a bZip DNA binding domain and a nuclear export sequence (NES) and acts as a transcription factor to regulate the expression of immune modulatory genes. Here we will discuss the role of heme-related immune response and the potential for targeting the heme system for therapies directed toward hepatitis and cancer.
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Affiliation(s)
- Giacomo Canesin
- Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Seyed M. Hejazi
- Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Kenneth D. Swanson
- Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Barbara Wegiel
- Department of Surgery, Cancer Research Institute and Transplant Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
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Liu Z, Yu S, Ye S, Shen Z, Gao L, Han Z, Zhang P, Luo F, Chen S, Kang M. Keratin 17 activates AKT signalling and induces epithelial-mesenchymal transition in oesophageal squamous cell carcinoma. J Proteomics 2019; 211:103557. [PMID: 31669361 DOI: 10.1016/j.jprot.2019.103557] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/18/2019] [Accepted: 10/17/2019] [Indexed: 12/24/2022]
Abstract
Oesophageal squamous cell carcinoma (ESCC) is an aggressive malignancy and a leading cause of cancer-related death worldwide. Lack of effective early diagnosis strategies and ensuing complications from tumour metastasis account for the majority of ESCC death. Thus, identification of key molecular targets involved in ESCC carcinogenesis and progression is crucial for ESCC prognosis. In this study, four pairs of ESCC tissues were used for mRNA sequencing to determine differentially expressed genes (DEGs). 347 genes were found to be upregulated whereas 255 genes downregulated. By screening DEGs plus bioinformatics analyses such as KEGG, PPI and IPA, we found that there were independent interactions between KRT family members. KRT17 upregulation was confirmed in ESCC and its relationship with clinicopathological features were analysed. KRT17 was significantly associated with ESCC histological grade, lymph node and distant metastasis, TNM stage and five-year survival rate. Upregulation of KRT17 promoted ESCC cell growth, migration, and lung metastasis. Mechanistically, we found that KRT17-promoted ESCC cell growth and migration was accompanied by activation of AKT signalling and induction of EMT. These findings suggested that KRT17 is significantly related to malignant progression and poor prognosis of ESCC patients, and it may serve as a new biological target for ESCC therapy. SIGNIFICANCE: Oesophageal cancer is one of the leading causes of cancer mortality worldwide and oesophageal squamous cell carcinoma (ESCC) is the major histological type of oesophageal cancer in Eastern Asia. However, the molecular basis for the development and progression of ESCC remains largely unknown. In this study, RNA sequencing was used to establish the whole-transcriptome profile in ESCC tissues versus the adjacent non-cancer tissues and the results were bioinformatically analysed to predict the roles of the identified differentially expressed genes. We found that upregulation of KRT17 was significantly associated with advanced clinical stage, lymph node and distant metastasis, TNM stage and poor clinical outcome. Keratin 17 (KRT17) upregulation in ESCC cells not only promoted cell proliferation but also increased invasion and metastasis accompanied with AKT activation and epithelial-mesenchymal transition (EMT). These data suggested that KRT17 played an important role in ESCC development and progression and may serve as a prognostic biomarker and therapeutic target in ESCC.
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Affiliation(s)
- Zhun Liu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Shaobin Yu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Shuting Ye
- Key Laboratory of Gastrointestinal Cancer, Fujian Medical University, Ministry of Education, Fuzhou 350122, China
| | - Zhimin Shen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Lei Gao
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Ziyang Han
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Peipei Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Fei Luo
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Sui Chen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China.
| | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China; Key Laboratory of Gastrointestinal Cancer, Fujian Medical University, Ministry of Education, Fuzhou 350122, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350122, China.
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Yu N, Gao YL, Liu JX, Wang J, Shang J. Robust hypergraph regularized non-negative matrix factorization for sample clustering and feature selection in multi-view gene expression data. Hum Genomics 2019; 13:46. [PMID: 31639067 PMCID: PMC6805321 DOI: 10.1186/s40246-019-0222-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background As one of the most popular data representation methods, non-negative matrix decomposition (NMF) has been widely concerned in the tasks of clustering and feature selection. However, most of the previously proposed NMF-based methods do not adequately explore the hidden geometrical structure in the data. At the same time, noise and outliers are inevitably present in the data. Results To alleviate these problems, we present a novel NMF framework named robust hypergraph regularized non-negative matrix factorization (RHNMF). In particular, the hypergraph Laplacian regularization is imposed to capture the geometric information of original data. Unlike graph Laplacian regularization which captures the relationship between pairwise sample points, it captures the high-order relationship among more sample points. Moreover, the robustness of the RHNMF is enhanced by using the L2,1-norm constraint when estimating the residual. This is because the L2,1-norm is insensitive to noise and outliers. Conclusions Clustering and common abnormal expression gene (com-abnormal expression gene) selection are conducted to test the validity of the RHNMF model. Extensive experimental results on multi-view datasets reveal that our proposed model outperforms other state-of-the-art methods.
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Affiliation(s)
- Na Yu
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
| | - Ying-Lian Gao
- Library of Qufu Normal University, Qufu Normal University, Rizhao, 276826, China
| | - Jin-Xing Liu
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China.
| | - Juan Wang
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China.
| | - Junliang Shang
- School of Information Science and Engineering, Qufu Normal University, Rizhao, 276826, China
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Transgelin, a p53 and PTEN-Upregulated Gene, Inhibits the Cell Proliferation and Invasion of Human Bladder Carcinoma Cells in Vitro and in Vivo. Int J Mol Sci 2019; 20:ijms20194946. [PMID: 31591355 PMCID: PMC6801752 DOI: 10.3390/ijms20194946] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/14/2019] [Accepted: 10/03/2019] [Indexed: 12/26/2022] Open
Abstract
Transgelin (TAGLN/SM22-α) is a regulator of the actin cytoskeleton, affecting the survival, migration, and apoptosis of various cancer cells divergently; however, the roles of TAGLN in bladder carcinoma cells remain inconclusive. We compared expressions of TAGLN in human bladder carcinoma cells to the normal human bladder tissues to determine the potential biological functions and regulatory mechanisms of TAGLN in bladder carcinoma cells. Results of RT-qPCR and immunoblot assays indicated that TAGLN expressions were higher in bladder smooth muscle cells, fibroblast cells, and normal epithelial cells than in carcinoma cells (RT-4, HT1376, TSGH-8301, and T24) in vitro. Besides, the results of RT-qPCR revealed that TAGLN expressions were higher in normal tissues than the paired tumor tissues. In vitro, TAGLN knockdown enhanced cell proliferation and invasion, while overexpression of TAGLN had the inverse effects in bladder carcinoma cells. Meanwhile, ectopic overexpression of TAGLN attenuated tumorigenesis in vivo. Immunofluorescence and immunoblot assays showed that TAGLN was predominantly in the cytosol and colocalized with F-actin. Ectopic overexpression of either p53 or PTEN induced TAGLN expression, while p53 knockdown downregulated TAGLN expression in bladder carcinoma cells. Our results indicate that TAGLN is a p53 and PTEN-upregulated gene, expressing higher levels in normal bladder epithelial cells than carcinoma cells. Further, TAGLN inhibited cell proliferation and invasion in vitro and blocked tumorigenesis in vivo. Collectively, it can be concluded that TAGLN is an antitumor gene in the human bladder.
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Xu YW, Peng YH, Xu LY, Xie JJ, Li EM. Autoantibodies: Potential clinical applications in early detection of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma. World J Gastroenterol 2019; 25:5049-5068. [PMID: 31558856 PMCID: PMC6747294 DOI: 10.3748/wjg.v25.i34.5049] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/28/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EGJA) are the two main types of gastrointestinal cancers that pose a huge threat to human health. ESCC remains one of the most common malignant diseases around the world. In contrast to the decreasing prevalence of ESCC, the incidence of EGJA is rising rapidly. Early detection represents one of the most promising ways to improve the prognosis and reduce the mortality of these cancers. Current approaches for early diagnosis mainly depend on invasive and costly endoscopy. Non-invasive biomarkers are in great need to facilitate earlier detection for better clinical management of patients. Tumor-associated autoantibodies can be detected at an early stage before manifestations of clinical signs of tumorigenesis, making them promising biomarkers for early detection and monitoring of ESCC and EGJA. In this review, we summarize recent insights into the iden-tification and validation of tumor-associated autoantibodies for the early detection of ESCC and EGJA and discuss the challenges remaining for clinical validation.
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Affiliation(s)
- Yi-Wei Xu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Chen Z, He S, Zhan Y, He A, Fang D, Gong Y, Li X, Zhou L. TGF-β-induced transgelin promotes bladder cancer metastasis by regulating epithelial-mesenchymal transition and invadopodia formation. EBioMedicine 2019; 47:208-220. [PMID: 31420300 PMCID: PMC6796540 DOI: 10.1016/j.ebiom.2019.08.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/29/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022] Open
Abstract
Background Metastatic bladder cancer (BLCA) is a lethal disease with an unmet need for study. Transgelin (TAGLN) is an actin-binding protein that affects the dynamics of the actin cytoskeleton indicating its robust potential as a metastasis initiator. Here, we sought to explore the expression pattern of TAGLN and elucidate its specific functioning and mechanisms in BLCA. Methods A comprehensive assessment of TAGLN expression in BLCA was performed in three cohorts with a total of 847 patients. The potential effects of TAGLN on BLCA were further determined using clinical genomic analyses that guided the subsequent functional and mechanistic studies. In vitro migration, invasion assays and in vivo metastatic mouse model were performed to explore the biological functions of TAGLN in BLCA cells. Immunofluorescence, western blot and correlation analysis were used to investigate the molecular mechanisms of TAGLN. Findings TAGLN was highly expressed in BLCA and correlated with advanced prognostic features. TAGLN promoted cell colony formation and cell migration and invasion both in vitro and in vivo by inducing invadopodia formation and epithelial-mesenchymal transition, during which a significant correlation between TAGLN and Slug was observed. The progression-dependent correlation between TGF-β and TAGLN was analysed at both the cellular and tissue levels, while TGF-β-mediated migration was abolished by the suppression of TAGLN. Interpretation Overall, TAGLN is a promising novel prognosis biomarker of BLCA, and its metastatic mechanisms indicate that TAGLN may represent a novel target agent that can be utilized for the clinical management of invasive and metastatic BLCA. Fund This work was supported by the National Natural Science Foundation of China [81772703, 81672546, 81602253]; the Natural Science Foundation of Beijing [71772219, 7152146]. and Innovative Fund for Doctoral Students of Peking University Health Science Center (BUM2018BSS002). Funders had no role in the design of the study, data collection, data analysis, interpretation, or the writing of this report.
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Affiliation(s)
- Zhicong Chen
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China
| | - Yonghao Zhan
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China; Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 45000, China
| | - Anbang He
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China
| | - Dong Fang
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China
| | - Yanqing Gong
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China.
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China.
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China.
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Zu X, Xie X, Zhang Y, Liu K, Bode AM, Dong Z, Kim DJ. Lapachol is a novel ribosomal protein S6 kinase 2 inhibitor that suppresses growth and induces intrinsic apoptosis in esophageal squamous cell carcinoma cells. Phytother Res 2019; 33:2337-2346. [PMID: 31225674 DOI: 10.1002/ptr.6415] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/13/2019] [Accepted: 05/26/2019] [Indexed: 12/18/2022]
Abstract
Lapachol is a 1,4-naphthoquinone that is isolated from the Bignoniaceae family. It has been reported to exert anti-inflammatory, antibacterial, and anticancer activities. However, the anticancer activity of lapachol and its molecular mechanisms against esophageal squamous cell carcinoma (ESCC) cells have not been fully investigated. Herein, we report that lapachol is a novel ribosomal protein S6 kinase 2 (RSK2) inhibitor that suppresses growth and induces intrinsic apoptosis in ESCC cells. We found that lapachol strongly attenuates downstream signaling molecules of RSK2 in ESCC cells and also directly inhibits RSK2 activity in vitro. The RSK protein is highly activated in ESCC cells and knockdown of RSK2 significantly suppresses anchorage-dependent and anchorage-independent growth of ESCC cells. Additionally, lapachol inhibits anchorage-dependent and anchorage-independent growth of ESCC cells, and the inhibition of cell growth by lapachol is dependent on the expression of RSK2. We also found that lapachol induces mitochondria-mediated cellular apoptosis by activating caspases-3, -7, and PARP, inducing the expression of cytochrome c and BAX by inhibiting downstream molecules of RSK2. Overall, lapachol is a potent RSK2 inhibitor that might be used for chemotherapy against ESCC.
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Affiliation(s)
- Xueyin Zu
- Department of Molecular and Cellular Biology, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiaomeng Xie
- Department of Molecular and Cellular Biology, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuanyuan Zhang
- Department of Molecular and Cellular Biology, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Kangdong Liu
- Department of Molecular and Cellular Biology, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, China.,The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Zigang Dong
- Department of Molecular and Cellular Biology, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China.,The Hormel Institute, University of Minnesota, Austin, Minnesota.,International Joint Research Center Of Cancer Chemoprevention, Zhengzhou, China
| | - Dong Joon Kim
- Department of Molecular and Cellular Biology, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
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Wang Q, Wang F, Lv J, Xin J, Xie L, Zhu W, Tang Y, Li Y, Zhao X, Wang Y, Li X, Guo X. Interactive online consensus survival tool for esophageal squamous cell carcinoma prognosis analysis. Oncol Lett 2019; 18:1199-1206. [PMID: 31423180 PMCID: PMC6607102 DOI: 10.3892/ol.2019.10440] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 05/15/2019] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common types of cancer worldwide. However, operative diagnostic and prognostic systems for ESCC remain to be established. To improve assessment of the prognosis for patients with ESCC, the present study developed an online consensus survival tool for ESCC, termed OSescc. OSescc was built using 264 ESCC cases with gene expression data and relevant clinical information obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Kaplan-Meier survival plots with hazard ratios and P-values were generated by OSescc to predict the association between potential biomarkers and relapse free survival and overall survival. In addition, the current study integrated a function by which one could assess the prognosis based on an individual probe or the mean value of multiple probes for each gene, which helped improve the evaluation of the validity and reliability of the potential prognosis biomarkers. OSescc can be accessed at bioinfo.henu.edu.cn/DBList.jsp.
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Affiliation(s)
- Qiang Wang
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Fengling Wang
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Jiajia Lv
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China.,Department of Thoracic Surgery, The Affiliated Nanshi Hospital of Henan University, Nanyang, Henan 473003, P.R. China
| | - Junfang Xin
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Longxiang Xie
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Wan Zhu
- Department of Anesthesia, Stanford University, Stanford, CA 94305, USA
| | - Yitai Tang
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Yongqiang Li
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Xiaofang Zhao
- Jiangsu SuperBio Co., Ltd., Nanjing, Jiangsu 210061, P.R. China
| | - Yunlong Wang
- Henan Bioengineering Research Center, Zhengzhou, Henan 450046, P.R. China
| | - Xianzhe Li
- Department of Thoracic Surgery, The Affiliated Nanshi Hospital of Henan University, Nanyang, Henan 473003, P.R. China
| | - Xiangqian Guo
- Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Cell Signal Transduction Laboratory, School of Software, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, P.R. China
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41
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Etiology, cancer stem cells and potential diagnostic biomarkers for esophageal cancer. Cancer Lett 2019; 458:21-28. [PMID: 31125642 DOI: 10.1016/j.canlet.2019.05.018] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/10/2019] [Accepted: 05/15/2019] [Indexed: 12/19/2022]
Abstract
Esophageal cancer (EC) has been a leading cause of cancer death worldwide in part due to late detection and lack of precision treatment. EC includes two major malignancies, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Recent studies reveal that ESCC and EAC have distinct cell of origin and contain cancer stem cells (also known as tumor initiating cells) expressing different cell surface markers. These biomarkers have potentially important values for both early detection and finding effective therapy. In this review we summarize the updated findings for cell of origin and provide an overview of cancer cell biomarkers that have been tested for ESCC and EAC. In addition, we also discuss recent progress in the study of molecular mechanisms leading to these malignancies.
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Cystatins in cancer progression: More than just cathepsin inhibitors. Biochimie 2019; 166:233-250. [PMID: 31071357 DOI: 10.1016/j.biochi.2019.05.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 05/03/2019] [Indexed: 12/20/2022]
Abstract
Cystatins are endogenous and reversible inhibitors of cysteine peptidases that are important players in cancer progression. Besides their primary role as regulators of cysteine peptidase activity, cystatins are involved in cancer development and progression through proteolysis-independent mechanisms. Mechanistic studies of cystatin function revealed that they affect all stages of cancer progression including tumor growth, apoptosis, invasion, metastasis and angiogenesis. Recently, the involvement of cystatins in the antitumor immune responses was reported. In this review, we discuss molecular mechanisms and clinical aspects of cystatins in cancer. Altered expression of cystatins in cancer resulting in harmful excessive cysteine peptidase activity has been a subject of several studies in order to find correlations with clinical outcome and therapy response. However, involvement in anti-tumor immune response and signaling cascades leading to cancer progression designates cystatins as possible targets for development of new anti-tumor drugs.
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Belczacka I, Latosinska A, Metzger J, Marx D, Vlahou A, Mischak H, Frantzi M. Proteomics biomarkers for solid tumors: Current status and future prospects. MASS SPECTROMETRY REVIEWS 2019; 38:49-78. [PMID: 29889308 DOI: 10.1002/mas.21572] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/08/2018] [Indexed: 06/08/2023]
Abstract
Cancer is a heterogeneous multifactorial disease, which continues to be one of the main causes of death worldwide. Despite the extensive efforts for establishing accurate diagnostic assays and efficient therapeutic schemes, disease prevalence is on the rise, in part, however, also due to improved early detection. For years, studies were focused on genomics and transcriptomics, aiming at the discovery of new tests with diagnostic or prognostic potential. However, cancer phenotypic characteristics seem most likely to be a direct reflection of changes in protein metabolism and function, which are also the targets of most drugs. Investigations at the protein level are therefore advantageous particularly in the case of in-depth characterization of tumor progression and invasiveness. Innovative high-throughput proteomic technologies are available to accurately evaluate cancer formation and progression and to investigate the functional role of key proteins in cancer. Employing these new highly sensitive proteomic technologies, cancer biomarkers may be detectable that contribute to diagnosis and guide curative treatment when still possible. In this review, the recent advances in proteomic biomarker research in cancer are outlined, with special emphasis placed on the identification of diagnostic and prognostic biomarkers for solid tumors. In view of the increasing number of screening programs and clinical trials investigating new treatment options, we discuss the molecular connections of the biomarkers as well as their potential as clinically useful tools for diagnosis, risk stratification and therapy monitoring of solid tumors.
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Affiliation(s)
- Iwona Belczacka
- Mosaiques-Diagnostics GmbH, Hannover, Germany
- University Hospital RWTH Aachen, Institute for Molecular Cardiovascular Research (IMCAR), Aachen, Germany
| | | | | | - David Marx
- Hôpitaux Universitaires de Strasbourg, Service de Transplantation Rénale, Strasbourg, France
- Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), University of Strasbourg, National Center for Scientific Research (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC) UMR 7178, Strasbourg, France
| | - Antonia Vlahou
- Biotechnology Division, Biomedical Research Foundation, Academy of Athens (BRFAA), Athens, Greece
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44
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Sadeghi H, Golalipour M, Yamchi A, Farazmandfar T, Shahbazi M. CDC25A pathway toward tumorigenesis: Molecular targets of CDC25A in cell-cycle regulation. J Cell Biochem 2018; 120:2919-2928. [PMID: 30443958 DOI: 10.1002/jcb.26838] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 10/22/2018] [Indexed: 11/10/2022]
Abstract
The cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell-cycle phases during normal cell division, and in the case of DNA damage, they are key targets of the checkpoint machinery that ensure genetic stability. Little is known about the mechanisms underlying dysregulation and downstream targets of CDC25. To understand these mechanisms, we silenced the CDC25A gene in breast cancer cell line MDA-MB-231 and studied downstream targets of CDC25A gene. MDA-MB-231 breast cancer cells were transfected and silenced by CDC25A small interfering RNA. Total messenger RNA (mRNA) was extracted and analyzed by quantitative real-time polymerase chain reaction. CDC25A phosphatase level was visualized by Western blot analysis and was analyzed by 2D electrophoresis and LC-ESI-MS/MS. After CDC25A silencing, cell proliferation reduced, and the expression of 12 proteins changed. These proteins are involved in cell-cycle regulation, programmed cell death, cell differentiation, regulation of gene expression, mRNA editing, protein folding, and cell signaling pathways. Five of these proteins, including ribosomal protein lateral stalk subunit P0, growth factor receptor bound protein 2, pyruvate kinase muscle 2, eukaryotic translation elongation factor 2, and calpain small subunit 1 increase the activity of cyclin D1. Our results suggest that CDC25A controls the cell proliferation and tumorigenesis by a change in expression of proteins involved in cyclin D1 regulation and G1/S transition.
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Affiliation(s)
- Hossein Sadeghi
- Department of Genetics, Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Masoud Golalipour
- Department of Genetics, Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ahad Yamchi
- Department of Biotechnology, Golestan University, Gorgan, Iran
| | - Touraj Farazmandfar
- Department of Genetics, Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Department of Genetics, Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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The Mitochondrial Genes BAK1, FIS1 and SFN are Linked with Alterations in Mitochondrial Membrane Potential in Barrett's Esophagus. Int J Mol Sci 2018; 19:ijms19113483. [PMID: 30404157 PMCID: PMC6275077 DOI: 10.3390/ijms19113483] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 10/27/2018] [Accepted: 11/03/2018] [Indexed: 01/20/2023] Open
Abstract
Barrett's esophagus and esophageal cancer lack prognostic markers that allow the tailoring of personalized medicine and biomarkers with potential to provide insight into treatment response. This study aims to characterize mitochondrial function across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett's esophagus and examines the functional effect of manipulating mitochondrial genes. Mitochondrial genes of interest were validated in in vitro cell lines across the metaplasia (QH), dysplasia (GO) and adenocarcinoma (OE33) sequence and in in vivo patient tissue samples. These genes were subsequently knocked down in QH and OE33 cells and the functional effect of siRNA-induced knockdown on reactive oxygen species production, mitochondrial mass, mitochondrial membrane potential and cellular metabolism was investigated. Three global mitochondrial genes (BAK1, FIS1 and SFN) were differentially altered across the in vivo Barrett's disease sequence. We also demonstrate that knockdown of BAK1, FIS1 and SFN in vitro resulted in significant alterations in mitochondrial membrane potential; however, no differences in reactive oxygen species or mitochondrial mass were observed. Furthermore, knockdown of these genes in esophageal adenocarcinoma cells significantly altered cellular metabolism. In conclusion, we found that differential expression of BAK1, FIS1, and SFN were altered across the Barrett's disease sequence and manipulation of these genes elicited significant effects on mitochondrial membrane potential.
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Xie X, Liu K, Liu F, Chen H, Wang X, Zu X, Ma X, Wang T, Wu Q, Zheng Y, Bode AM, Dong Z, Kim DJ. Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo. Cancer Lett 2018; 442:126-136. [PMID: 30391783 DOI: 10.1016/j.canlet.2018.10.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 10/11/2018] [Accepted: 10/22/2018] [Indexed: 01/04/2023]
Abstract
Gossypetin as a hexahydroxylated flavonoid found in many flowers and Hibiscus. It exerts various pharmacological activities, including antioxidant, antibacterial and anticancer activities. However, the anticancer capacity of gossypetin has not been fully elucidated. In this study, gossypetin was found to inhibit anchorage-dependent and -independent growth of esophageal cancer cells. To identify the molecular target(s) of gossypetin, various signaling protein kinases were screened and results indicate that gossypetin strongly attenuates the MKK3/6-p38 signaling pathway by directly inhibiting MKK3 and MKK6 protein kinase activity in vitro. Mechanistic investigations showed that arginine-61 in MKK6 is critical for binding with gossypetin. Additionally, the inhibition of cell growth by gossypetin is dependent on the expression of MKK3 and MKK6. Gossypetin caused G2 phase cell cycle arrest and induced intrinsic apoptosis by activating caspases 3 and 7 and increasing the expression of BAX and cytochrome c. Notably, gossypetin suppressed patient-derived esophageal xenograft tumor growth in an in vivo mouse model. Our findings suggest that gossypetin is an MKK3 and MKK6 inhibitor that could be useful for preventing or treating esophageal cancer.
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Affiliation(s)
- Xiaomeng Xie
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Kangdong Liu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450008, China; The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, 450008, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450008, China
| | - Feifei Liu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Hanyong Chen
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Xiangyu Wang
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Xueyin Zu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Xiaoli Ma
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Ting Wang
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Qiong Wu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Yan Zheng
- The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, 450008, China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Zigang Dong
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450008, China; The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
| | - Dong Joon Kim
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China.
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Tong Q, Wang XL, Li SB, Yang GL, Jin S, Gao ZY, Liu XB. Combined detection of IL-6 and IL-8 is beneficial to the diagnosis of early stage esophageal squamous cell cancer: a preliminary study based on the screening of serum markers using protein chips. Onco Targets Ther 2018; 11:5777-5787. [PMID: 30254470 PMCID: PMC6140751 DOI: 10.2147/ott.s171242] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background The diagnosis rate of early stage esophageal squamous cell carcinoma (ESCC) is low due to the lack of specific tumor markers. Seeking for these markers is beneficial to improve the early diagnosis rate and the prognosis of patients. This study profiles the differentially expressed proteins of early stage ESCC patients via the AAH-BLG-507 protein chip, which further consolidates the clinical evidence of ESCC diagnosis. Materials and methods In this study, 20 serum samples were collected from Taihe Hospital between August 2016 and June 2017. Ten of them carried ESCC, while the rest were healthy controls. To profile the proteins’ expression level, the AAH-BLG-507 protein chip was used, and both highly expressed and lowly expressed proteins were fished out. Meanwhile, their biological roles were examined by using Gene Ontology (GO) database and String database, and they were further verified by ELISA. Results Results showed that the expression levels of AXL, ARTN, Ang2, BDNF, BMP7, cripto-1, CCL28, E-selectin, IL-6, IL-8 and SHH in the serum of early ESCC were significantly upregulated (P<0.05), particularly IL-6 and IL-8. The expression levels of TSP1 and MMP-8 were markedly downregulated (P<0.05). Analysis showed that these proteins were mainly involved in angiogenesis, signal transduction, cell proliferation and migration, indicating the close relationship with the development of ESCC. Conclusion It suggested that IL-6 and IL-8 proteins could be considered as the markers for ESCC diagnosis.
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Affiliation(s)
- Qiang Tong
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Xiao-Long Wang
- Department of Gastroenterology, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China
| | - Sheng-Bao Li
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Gong-Li Yang
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Shu Jin
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
| | - Zi-Ye Gao
- Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China
| | - Xiao-Bo Liu
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People's Republic of China,
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48
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Murakami T, Yamamoto CM, Akino T, Tanaka H, Fukuzawa N, Suzuki H, Osawa T, Tsuji T, Seki T, Harada H. Bladder cancer detection by urinary extracellular vesicle mRNA analysis. Oncotarget 2018; 9:32810-32821. [PMID: 30214686 PMCID: PMC6132352 DOI: 10.18632/oncotarget.25998] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 08/04/2018] [Indexed: 01/02/2023] Open
Abstract
Objective Urinary extracellular vesicles (EV) could be promising biomarkers for urological diseases. In this retrospective feasibility study, we conducted biomarker screening for early stage bladder cancer using EV mRNA analysis. Methods Biomarker candidates were identified through RNA-seq analysis of urinary EV from patients with non-muscle invasive bladder cancer (N=3), advanced urothelial cancer (N=3), no residual tumor after TURBT (N=2), and healthy and disease controls (N=4). Diagnostic performance was evaluated by RT-qPCR in a larger patient group including bladder cancer (N=173), renal pelvis and ureter cancer (N=33), no residual tumor and non-cancer disease control (N=36). Results Urinary EV SLC2A1, GPRC5A and KRT17 were overexpressed in pT1 and higher stage bladder cancer by 20.6-fold, 18.2-fold and 29.5-fold, respectively. These genes allowed detection of non-muscle invasive bladder cancer (AUC: 0.56 to 0.64 for pTa, 0.62 to 0.80 for pTis, and 0.82 to 0.86 for pT1) as well as pT2 and higher muscle invasive bladder cancer (AUC: 0.72 to 0.90). Subgroup analysis indicated that these markers could be useful for the detection of cytology-negative/-suspicious and recurrent bladder cancers. Conclusion Three urinary EV mRNA were discovered to be elevated in bladder cancer. Urinary EV mRNA are promising biomarkers of urothelial cancer and worth further investigation.
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Affiliation(s)
| | | | | | | | | | | | - Takahiro Osawa
- Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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49
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Paukovich N, Xue M, Elder JR, Redzic JS, Blue A, Pike H, Miller BG, Pitts TM, Pollock DD, Hansen K, D'Alessandro A, Eisenmesser EZ. Biliverdin Reductase B Dynamics Are Coupled to Coenzyme Binding. J Mol Biol 2018; 430:3234-3250. [PMID: 29932944 DOI: 10.1016/j.jmb.2018.06.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/05/2018] [Accepted: 06/06/2018] [Indexed: 12/28/2022]
Abstract
Biliverdin reductase B (BLVRB) is a newly identified cellular redox regulator that catalyzes the NADPH-dependent reduction of multiple substrates. Through mass spectrometry analysis, we identified high levels of BLVRB in mature red blood cells, highlighting the importance of BLVRB in redox regulation. The BLVRB conformational changes that occur during conezyme/substrate binding and the role of dynamics in BLVRB function, however, remain unknown. Through a combination of NMR, kinetics, and isothermal titration calorimetry studies, we determined that BLVRB binds its coenzyme 500-fold more tightly than its substrate. While the active site of apo BLVRB is highly dynamic on multiple timescales, active site dynamics are largely quenched within holo BLVRB, in which dynamics are redistributed to other regions of the enzyme. We show that a single point mutation of Arg78➔Ala leads to both an increase in active site micro-millisecond motions and an increase in the microscopic rate constants of coenzyme binding. This demonstrates that altering BLVRB active site dynamics can directly cause a change in functional characteristics. Our studies thus address the solution behavior of apo and holo BLVRB and identify a role of enzyme dynamics in coenzyme binding.
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Affiliation(s)
- Natasia Paukovich
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Mengjun Xue
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - James R Elder
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Jasmina S Redzic
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Ashley Blue
- National High Magnetic Field Laboratory, Tallahassee, FL 32310, USA
| | - Hamish Pike
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Brian G Miller
- Department of Chemistry & Biochemistry, Florida State University, Tallahassee, FL 32310, USA
| | - Todd M Pitts
- Division of Medical Oncology, School of Medicine, Aurora, CO 80045, USA
| | - David D Pollock
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Kirk Hansen
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA
| | - Elan Zohar Eisenmesser
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA.
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Cysteine cathepsins as a prospective target for anticancer therapies-current progress and prospects. Biochimie 2018; 151:85-106. [PMID: 29870804 DOI: 10.1016/j.biochi.2018.05.023] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/31/2018] [Indexed: 02/08/2023]
Abstract
Cysteine cathepsins (CTS), being involved in both physiological and pathological processes, play an important role in the human body. During the last 30 years, it has been shown that CTS are highly upregulated in a wide variety of cancer types although they have received a little attention as a potential therapeutic target as compared to serine or metalloproteinases. Studies on the increasing problem of neoplastic progression have revealed that secretion of cell-surface- and intracellular cysteine proteases is aberrant in tumor cells and has an impact on their growth, invasion, and metastasis by taking part in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. Considering the role of CTS in carcinogenesis, inhibition of these enzymes becomes an attractive strategy for cancer therapy. The downregulation of natural CTS inhibitors (CTSsis), such as cystatins, observed in various types of cancer, supports this claim. The intention of this review is to highlight the relationship of CTS with cancer and to present illustrations that explain how some of their inhibitors affect processes related to neoplastic progression.
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