|
1
|
Luo Z, Dong X, Yu J, Xia Y, Berry KP, Rao R, Xu L, Xue P, Chen T, Lin Y, Yu J, Huang G, Li H, Zhou W, Lu QR. Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas. Front Cell Dev Biol 2021; 9:634056. [PMID: 33681213 PMCID: PMC7930499 DOI: 10.3389/fcell.2021.634056] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/28/2021] [Indexed: 12/21/2022] Open
Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, however, the mechanisms underlying tumorigenesis in different MB subgroups remain incompletely understood. Although previous studies of MB predisposition have been conducted in tertiary referral centers primarily in Caucasian cohorts, it is not unclear clear whether there exist population-specific genetic alterations in MBs. In this study, we investigated the contribution of genomic and transcriptomic alterations to the risk of malignant MB in the Chinese population (designated as the Asian cohort). We analyze the genomic and transcriptomic alterations of the Asian MB cohort by using a combination of whole-exome sequencing (WES) and RNA-deep-sequencing. In addition, we integrate publicly available data with the Asian MB cohort and identify a subset of potential MB-driving genes specifically enriched in each of the MB subgroups. We further characterize a newly identified group-3-enriched transcriptional regulator, ZNF124, and demonstrate that ZNF124 is critical for the growth of the most aggressive group-3 MB cells. Together, our analyses indicate conserved yet distinct genetic alterations and gene expression patterns of MBs between different ethnic groups. Our studies further provide an important resource for identifying potential tumor-driving factors in MBs, enhancing our understanding of the disease process for developing ethnically targeted therapies in patients with MB.
Collapse
Affiliation(s)
- Zaili Luo
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xinran Dong
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jianzhong Yu
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yong Xia
- Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Kalen P Berry
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Rohit Rao
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Lingli Xu
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Ping Xue
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Tong Chen
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yifeng Lin
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jiyang Yu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Guoying Huang
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hao Li
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Wenhao Zhou
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Q Richard Lu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| |
Collapse
|
|
2
|
Peng K, Chen E, Li W, Cheng X, Yu Y, Cui Y, Li Q, Wang Y, Xu X, Tang C, Gan L, Yu S, Liu T. A 16-mRNA signature optimizes recurrence-free survival prediction of Stages II and III gastric cancer. J Cell Physiol 2020; 235:5777-5786. [PMID: 32048287 DOI: 10.1002/jcp.29511] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 01/06/2020] [Indexed: 12/11/2022]
Abstract
High-throughput messenger RNA (mRNA) analysis has become a powerful tool for exploring tumor recurrence or metastasis mechanisms. Here, we constructed a signature to predict the recurrence risk of Stages II and III gastric cancer (GC) patients. A least absolute shrinkage and selection operator method Cox regression model was utilized to construct the signature. Using this method, a 16-mRNA signature was identified to be associated with the relapse-free survival of Stages II and III GCs in training dataset GSE62254 (n = 194). Then this signature was validated in an independent Gene Expression Omnibus cohort GSE26253 (n = 297) and a dataset of The Cancer Genome Atlas (TCGA; n = 235). This classifier could successfully screen out the high-risk Stages II and III GCs in the training cohort (hazard ratio [HR] = 40.91; 95% confidence interval [CI] = 5.58-299.7; p < .0001). Analysis in two independent validation cohorts yielded consistent results (GSE26253: HR = 1.69, 95% CI = 1.17-2.43,; p = .0045; TCGA: HR = 2.01, 95% CI = 1.13-3.56, p = .0146). Cox regression analyses revealed that the risk score derived from this signature was an independent risk factor in Stages II and III GCs. Besides, a nomogram was constructed to serve clinical practice. Through gene set variation analysis, we found several gene sets associated with chemotherapeutic drug resistance and tumor metastasis significantly enriched in high-risk patients. In summary, this 16-mRNA signature can be used as a powerful tool for prognostic evaluation and help clinicians identify high-risk patients.
Collapse
Affiliation(s)
- Ke Peng
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Erbao Chen
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Wei Li
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Xi Cheng
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Yuehong Cui
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Qian Li
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Xiaojing Xu
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Cheng Tang
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Lu Gan
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China
| |
Collapse
|
|
3
|
Dey KK, Pal I, Bharti R, Dey G, Kumar BNP, Rajput S, Parekh A, Parida S, Halder P, Kulavi I, Mandal M. Identification of RAB2A and PRDX1 as the potential biomarkers for oral squamous cell carcinoma using mass spectrometry-based comparative proteomic approach. Tumour Biol 2015; 36:9829-37. [PMID: 26159854 DOI: 10.1007/s13277-015-3758-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Accepted: 07/02/2015] [Indexed: 10/23/2022] Open
Abstract
Despite the recent advances in diagnostic and therapeutic strategies, oral squamous cell carcinoma (OSCC) remains a major health burden. Protein biomarker discovery for early detection will help to improve patient survival rate in OSCC. Mass spectrometry-based proteomics has emerged as an excellent approach for detection of protein biomarkers in various types of cancers. In the current study, we have used 4-Plex isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun quantitative proteomic approach to identify proteins that are differentially expressed in cancerous tissues compared to normal tissues. The high-resolution mass spectrometric analysis resulted in identifying 2,074 proteins, among which 288 proteins were differentially expressed. Further, it was noticed that 162 proteins were upregulated, while 125 proteins were downregulated in OSCC-derived cancer tissue samples as compared to the adjacent normal tissues. We identified some of the known molecules which were reported earlier in OSCC such as MMP-9 (8.4-fold), ZNF142 (5.6-fold), and S100A7 (3.5-fold). Apart from this, we have also identified some novel signature proteins which have not been reported earlier in OSCC including ras-related protein Rab-2A isoform, RAB2A (4.6-fold), and peroxiredoxin-1, PRDX1 (2.2-fold). The immunohistochemistry-based validation using tissue microarray slides in OSCC revealed overexpression of the RAB2A and PRDX1 gene in 80 and 68 % of the tested clinical cases, respectively. This study will not only serve as a resource of candidate biomarkers but will contribute towards the existing knowledge on the role of the candidate molecules towards disease progression and therapeutic potential.
Collapse
Affiliation(s)
- Kaushik Kumar Dey
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Ipsita Pal
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Rashmi Bharti
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Goutam Dey
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - B N Prashanth Kumar
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Shashi Rajput
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Aditya Parekh
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Sheetal Parida
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Priyanka Halder
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| | - Indranil Kulavi
- Bankura Sammilani Medical College, Bankura, West Bengal, 722101, India.
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
| |
Collapse
|
|
4
|
Li Y, Zhao Q, Fan LQ, Wang LL, Tan BB, Leng YL, Liu Y, Wang D. Zinc finger protein 139 expression in gastric cancer and its clinical significance. World J Gastroenterol 2014; 20:18346-18353. [PMID: 25561801 PMCID: PMC4277971 DOI: 10.3748/wjg.v20.i48.18346] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 05/30/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of zinc finger protein 139 (ZNF139) in gastric cancer (GC), and to analyze its clinical significance.
METHODS: A total of 108 patients who were diagnosed with GC and underwent surgery between January 2005 and March 2007 were enrolled in this study. Gastric tumor specimens and paired tumor-adjacent tissues were collected and paraffin-embedded, and the clinicopathologic characteristics and prognosis were recorded. The expression of ZNF139, Bcl-2, Bax, and caspase-3 were determined by immunohistochemistry, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. SPSS 13.0 software was used for data processing and analyses, and significance was determined at P < 0.05.
RESULTS: The expression of ZNF139 was stronger in tumors than in tumor-adjacent tissues (66.67% vs 44.44%; P < 0.01). Overexpression of ZNF139 correlated with tumor differentiation, invasion depth, clinical stage, lymphatic metastasis, and blood vessel invasion (all Ps < 0.05). Patients with overexpression of ZNF139 had a poorer prognosis (P < 0.01), and overexpression of ZNF139 was an independent factor for the prognosis of GC patients by a Cox survival analysis (P = 0.02). A negative relationship between ZNF139 and the apoptosis index was observed (r = -0.686; P < 0.01). The expression of Bcl-2 in GC was stronger than in tumor-adjacent tissues (66.67% vs 41.67%), whereas the expression levels of Bax and caspase-3 were lower in primary tumors (54.63% and 47.22%, respectively) than in tumor-adjacent tissues (73.15% and 73.15%, respectively) (all Ps < 0.05). The expression of ZNF139 negatively correlated with caspase-3 (r = -0.370; P < 0.01). The expressions of Bcl-2 and Bax were also negatively correlated (r = -0.231; P = 0.02). The expressions of caspase-3 and Bax protein were positively correlated (r = 0.217; P = 0.024).
CONCLUSION: ZNF139 is related to clinicopathologic characteristics and prognosis of GC. Furthermore, it is overexpressed and involved in apoptosis in GC tissues by regulating caspase-3.
Collapse
|