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Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma.

ABSTRACT: Background:Minichromosome maintenance protein 2 (MCM2), which is a member of MCM family, has been found to be a relevant marker for progression and prognosis in a variety of human cancers. Due to lack of effective therapeutic target in lung squamous cell carcinoma (LUSC) patients, the aim of our study was to screen and identify biomarkers which are associated to clinicopathological characteristics including prognosis in LUSC patients. Methods:The expression status of MCM2 in lung cancer was analyzed using the publicly available Gene Expression Omnibus databases (GSE3268 and GSE10245). The mRNA and protein expression of MCM2 in lung cancer tissues and cell lines was detected by quantitative real-time PCR and Western blot, and the association between MCM2 expression and clinicopathological factors was analyzed by immunohistochemistry. The loss-of-function study of MCM2 was conducted in LUSC cell lines. Results:In our study, we found MCM2 expression was increased in LUSC tissues compared with paired adjacent normal lung tissues or lung adenocarcinoma tissues through analyzing microarray data sets (GSE3268 and GSE10245), which confirmed that MCM2 mRNA and protein were overexpressed in LUSC tissues and cell lines. Meanwhile, we analyzed the association between MCM2 protein expression and clinicopathological characteristics of LUSC patients, and found high expression of MCM2 protein was obviously associated with malign differentiated degree, advanced clinical stage, large tumor size, more lymph node metastasis and present distant metastasis. The survival analysis showed MCM2 overexpression was an independent unfavorable prognostic factor for LUSC patients. Conclusion:MCM2 is involved in the development and progression of LUSC as an oncogene, and thereby may act as a potential therapeutic target for LUSC patients.

SUBMITTER: Wu W

PROVIDER: S-EPMC6109654 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma.

Wu Wei W Wang Xianwei X Shan Changting C Li Yong Y Li Fengzhu F

OncoTargets and therapy 20180820

<h4>Background</h4>Minichromosome maintenance protein 2 (MCM2), which is a member of MCM family, has been found to be a relevant marker for progression and prognosis in a variety of human cancers. Due to lack of effective therapeutic target in lung squamous cell carcinoma (LUSC) patients, the aim of our study was to screen and identify biomarkers which are associated to clinicopathological characteristics including prognosis in LUSC patients.<h4>Methods</h4>The expression status of MCM2 in lung ...[more]

PMID: 30174440

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Project description:Esophageal squamous cell carcinoma (ESCC), the main subtype of esophageal cancer (EC), is a common lethal type of cancer with a high mortality rate. The aim of the present study was to select key relevant genes and identify potential mechanisms involved in the development of ESCC based on bioinformatics analysis. Minichromosome maintenance 6 complex component (MCM6) has been identified to be upregulated in multiple malignancies; however, its contributions to ESCC remain unclear. For the purposes of the present study, four datasets were downloaded from the Gene Expression Omnibus (GSE63941, GSE26886, GSE17351 and GSE77861), and the intersection of the differentially expressed genes was obtained using a Venn diagram. The protein‑protein interaction was then constructed, and the modules were verified by Cytoscape, in which the key genes have a high connectivity degree with other genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway were subsequently filtered out to analyze the development of ESCC. MCM6, an upregulated gene, was selected and connected with most of the other genes, for further research validation. The expression levels of MCM6 were then assessed using the Oncomine, GEPIA and UALCAN databases and validated in both ESCC tissues samples and cell lines by immunohistochemistry and RT‑qPCR. Cell counting kit‑8 (CCK‑8), flow cytometry, wound healing and Transwell assays were used to determine the proliferation, apoptosis, cell cycle, migration and invasion of ESCC cells. A total of 24 genes were identified by a series of bioinformatics analyses and the results revealed that the genes were associated with DNA replication and cell cycle. Experimental validation revealed that MCM6 expression was significantly elevated in both ESCC tissues and cell lines. The results were consistent with those of bioinformatics analysis. Furthermore, the knockdown of MCM6 inhibited cell proliferation, migration and invasion and promoted cell apoptosis, and made cells arrested in S stage. In summary, the findings of bioinformatics analysis provided a novel hypothesis for ESCC progression. In particular, the aberrantly elevated expression of MCM6 is a potential biomarker for ESCC diagnosis and treatment.

Project description: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.

Dataset Information

Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma.

Publications

Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma.

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