Original research articleClinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues
Introduction
The incidence of thyroid cancer (TC) has increased dramatically worldwide in recent decades [[1], [2], [3]]. On the basis of the cell type of origin and growth patterns, four types of TCs have been identified: differentiated papillary, follicular, medullary, and undifferentiated anaplastic carcinomas [4]. With developments in modern medicine, TC is usually curable. Nevertheless, an effective diagnostic approach with high accuracy and a risk evaluation method is needed. A recent study demonstrated that TC could exhibit divergent clinical behavior, with some cases exceeding expectations [5]. Ultrasound-guided fine needle aspiration biopsy, which is widely used in the diagnosis of TC, has limitations, especially in terms of the follicular lesions labeled “indeterminate” or “nondiagnostic” and those suspicious for malignancy according to the Bethesda system of thyroid cytology classification [5,6]. The surgical strategies and prognosis evaluations in TC depend on the diagnosis and risk estimations. An understanding of the molecular mechanisms of TC would facilitate improvements in diagnosis and therapy [7].
The cyclin E2 (CCNE2) gene, located at 8q22.1, encodes CCNE2 in humans and regulates the G1/S transition [[8], [9], [10]]. In addition to playing a role in cell division, CCNE2 promotes DNA replication and activates cyclin-dependent kinase 2 (CDK2), which has important functions in cellular biological processes [[8], [9], [10]]. The accumulating evidence suggests that CCNE2 can act as a proto-oncogene in cancers. For example, in castration-resistant prostate cancer, CCNE2 expression is downregulated, leading to cancer suppression [11]. Aberrant CCNE2 expression has been found in a variety of cancers [[11], [12], [13]]. However, the specific roles and underlying mechanisms of CCNE2 in the development and progression of TC remain elusive.
Therefore, to verify the changes in CCNE2 expression in TC and to investigate the underlying molecular mechanisms, immunohistochemical (IHC), RNA-sequencing (RNA-seq), and microarray data were analyzed to determine the clinical value of CCNE2 expression in TC. The co-expressed genes of CCNE2 were also identified. The enrichment pathway of the CCNE2 co-expressed and hub genes was assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, as well as protein–protein interaction (PPI) network analysis. The discoveries of this study could increase the understanding of the role of CCNE2 in the development and progression of TC.
Section snippets
Immunohistochemical detection of cyclin E2 protein levels
Two tissue microarrays, THC961 and THC1021, were obtained from Fanpu, Inc. (Guilin, China). They consisted of 23 non-cancerous thyroid tissues and 125 TC tissues. The TC tissues included papillary carcinoma (PTC), follicular carcinoma (FTC), and anaplastic carcinoma (ATC)/undifferentiated thyroid carcinoma (UTC) tissues. In addition, 64 non-cancerous thyroid tissues and 46 TC tissues from patients who came to the Department of Pathology at the First Affiliated Hospital of Guangxi Medical
Immunohistochemical investigation of cyclin E2 protein levels
A total of 171 TC and 87 non-cancerous tissue samples were obtained from the First Affiliated Hospital of Guangxi Medical University and the Human Protein Atlas (Table 1; Fig. 1, Fig. 2). The CCNE2 expression levels in the 171 TC samples (7.21 ± 1.631) were statistically significantly higher than those in the 87 non-cancerous tissue samples (1.22 ± 1.497; p < 0.001; Fig. 3a). The AUC, which reflected the capacity of CCNE2 expression to make a distinction between the TC and non-cancerous
Discussion
This study had two goals: (1) the exploration and verification of the changes in CCNE2 expression in TC and (2) the preliminary investigation of the possible underlying mechanisms of CCNE2 in TC by means of the CCNE2 co-expression genes. The 1157 TC and 366 non-cancerous thyroid samples, which were combined from the IHC experiment, and the RNA-seq and microarray data were considered. The expression level of CCNE2 in the TC tissues was significantly higher than that in the non-cancerous tissues.
Conclusion
In summary, the over-expression of CCNE2 in TC was demonstrated through the analysis of TC and normal samples from all possible sources, including immunohistochemistry, TCGA, microarrays, and the literature. CCNE2 was found to be highly correlated with the cell cycle. Nevertheless, the specific molecular mechanisms in CCNE2, which promotes the biological aggressiveness of TC, need further study.
Data statement
Data used for meta-analysis and gene expression analysis was extracted from previously published papers and publicly available databases.
Financial disclosure
The current study was supported by Funds of Guangxi Zhuang Autonomous Region Health and Family Planning Commission Self-Financed Scientific Research Project (Z2012053), National Natural Science Foundation of China (NSFC81960329), Natural Science Foundation of Guangxi, China (2017GXNSFAA198253) and the Guangxi Zhuang Autonomous Region University Student Innovative Plan (201910598148).
The Author Contribution
Study Design: Cui-Zhen Liu, Jin-Bo Peng, Gang Chen, Peng Lin, Hong Yang, Yun He, Yu-Yan Pang, Wei Ma.
Data Collection: Wan-ping Guo, Peng Lin, Xiao-Li Huang, Xiao-Fan Liu, Yu-Yan Pang, Wei Ma.
Statistical Analysis: Wan-ping Guo, Peng Lin, Xiao-Li Huang, Xiao-Fan Liu.
Data Interpretation: Wan-ping Guo, Peng Lin, Xiao-Li Huang, Xiao-Fan Liu, Gang Chen, Peng Lin, Hong Yang, Yun He.
Manuscript Preparation: Cui-Zhen Liu, Wan-Ping Guo, Xiao-Li Huang, Xiao-Fan Liu, Peng Lin, Yu-Yan Pang, Wei Ma.
Literature
Declaration of competing interest
The authors declare no conflict of interests.
References (42)
- et al.
Metformin targets a YAP1-TEAD4 complex via AMPKalpha to regulate CCNE1/2 in bladder cancer cells
J Exp Clin Canc Res
(2019) - et al.
Evaluation of multiplex PCR assay for detection of Babesia spp, Ehrlichia canis and Trypanosoma evansi in dogs
Acta Trop
(2018) - et al.
Oncometabolites as biomarkers in thyroid cancer: a systematic review
Canc Manag Res
(2019) - et al.
Development of a prognostic index based on an immunogenomic landscape analysis of papillary thyroid cancer
Aging
(2019) - et al.
The thyroid cancer epidemic, 2017 perspective
Curr Opin Endocrinol Diabetes Obes
(2017) - et al.
MicroRNA-524-5p suppresses the progression of papillary thyroid carcinoma cells via targeting on FOXE1 and ITGA3 in cell autophagy and cycling pathways
J Cell Physiol
(2019) - et al.
Metabolic alterations of thyroid cancer as potential therapeutic targets
BioMed Res Int
(2017) - et al.
BRAF(V600E) mutation analysis in fine-needle aspiration cytology specimens for diagnosis of thyroid nodules: the influence of false-positive and false-negative results
Cancer Med
(2019) - et al.
Identification of differential expressed lncRNAs in human thyroid cancer by a genome-wide analyses
Cancer Med
(2018) - et al.
Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2
J Exp Clin Canc Res
(2018)
Knockdown of long non-coding RNA KCNQ1OT1 restrained glioma cells' malignancy by activating miR-370/CCNE2 Axis
Front Cell Neurosci
Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs
Nat Commun
Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma
Proc Natl Acad Sci U S A
Gene expression profiling of the 8q22-24 position in human breast cancer: TSPYL5, MTDH, ATAD2 and CCNE2 genes are implicated in oncogenesis, while WISP1 and EXT1 genes may predict a risk of metastasis
Oncol Lett
Overexpressed BSG related to the progression of lung adenocarcinoma with high-throughput data-mining, immunohistochemistry, in vitro validation and in silico investigation
Am J Transl Res
Up-regulation of Polo-like Kinase 1 in nasopharyngeal carcinoma tissues: a comprehensive investigation based on RNA-sequencing, gene chips, and in-house tissue arrays
Am J Transl Res
Aberrantly DNA methylated-differentially expressed genes and pathways in hepatocellular carcinoma
J Canc
Comprehensive clinical implications of homeobox A10 in 3,199 cases of non-small cell lung cancer tissue samples combining qRT-PCR, RNA sequencing and microarray data
Am J Transl Res
Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large-scale genomic databases: MUC4/MUC16/MUC20 signature is associated with poor survival in human carcinomas
J Transl Med
Characteristics of the Cancer Genome Atlas cases relative to U.S. general population cancer cases
Br J Canc
Prognosis of clear cell renal cell carcinoma (ccRCC) based on a six-lncRNA-based risk score: an investigation based on RNA-sequencing data
J Transl Med
Cited by (8)
Comprehensive expression analysis reveals upregulated LUZP2 in prostate cancer tissues
2022, Electronic Journal of BiotechnologyCitation Excerpt :In addition, we used DAVID to implement Gene Ontology (GO). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also used to study possible related pathways to predict the obtained intersection genes’ biological functions and potential molecular mechanisms as previously reported [25,26,27,28]. The expression of LUZP2 mRNA in gene chips was collected, and log2 conversion was performed.
RAD21: A Key Transcriptional Regulator in the Development of Residual Liver Cancer
2024, Journal of Hepatocellular CarcinomaInvestigation of common genetic risk factors between thyroid traits and breast cancer
2024, Human Molecular GeneticsTestosterone promotes the migration, invasion and EMT process of papillary thyroid carcinoma by up-regulating Tnnt1
2024, Journal of Endocrinological InvestigationConstructing Integrative ceRNA Networks and Finding Prognostic Biomarkers in Renal Cell Carcinoma
2023, IEEE/ACM Transactions on Computational Biology and Bioinformatics
- 1
Contributed equally as co-first authors.