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ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth.

ABSTRACT: Islet-1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is specifically expressed in certain tissue types only. Previously, we reported that ISL1 is aberrantly overexpressed in gastric cancer (GC). However, its role in GC is not clear. Here, we report that ISL1 is aberrantly upregulated not only in human gastric carcinoma tissues but also in some GC cell lines. Upregulated ISL1 expression enhanced xenografted gastric carcinoma development, while ISL1 knockdown inhibited GC growth in nude mice. ISL1 overexpression promoted GC cell proliferation, colony formation, and cell growth in soft agar, and facilitated cell cycle transition in GC cells, demonstrated an increase in the proportion of cells in the G2/M and S phases and a decrease in the proportion of cells in the G1 phase. Furthermore, we provide evidence that ISL1 is a novel regulator of the cyclin B1 (CCNB1), cyclin B2 (CCNB2) and c-myc (c-MYC) genes. ISL1 activated the expression of these genes in GC cells by binding to the conserved binding sites on their promoters or enhancers. The expression levels of the genes were decreased in response to ISL1 knockdown. Therefore, ISL1 may serve as a potential therapeutic target in GC.

SUBMITTER: Shi Q

PROVIDER: S-EPMC5095015 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth.

Shi Qiong Q Wang Weiping W Jia Zhuqing Z Chen Ping P Ma Kangtao K Zhou Chunyan C

Oncotarget 20160601 24

Islet-1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is specifically expressed in certain tissue types only. Previously, we reported that ISL1 is aberrantly overexpressed in gastric cancer (GC). However, its role in GC is not clear. Here, we report that ISL1 is aberrantly upregulated not only in human gastric carcinoma tissues but also in some GC cell lines. Upregulated ISL1 expression enhanced xenografted gastric carcinoma development, while ISL1 knockdown inhibited ...[more]

PMID: 27183908

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Project description:BackgroundWilms tumour (WT) is a mixed type of embryonal tumour that usually occurs in early childhood. However, our knowledge of the pathogenesis or progression mechanism of WT is inadequate, and there is a scarcity of beneficial therapeutic strategies.MethodsHigh-throughput RNA sequencing was employed in this study to identify differentially expressed genes (DEGs) in clinical tumor samples and matching normal tissues. The STRING database was utilized to build a protein-protein interaction (PPI) network, and the Cytohubba method was used to identify the top 10 highly related HUB genes. Then, the key genes were further screened by univariate COX survival analysis. Subsequently, the XCELL algorithm was used to evaluate the tumour immune infiltration. RT-PCR, WB, and IF were used to verify the expression level of key genes in clinical tissues and tumour cell lines. Finally, the function of the key gene was further verified by loss-of-function experiments.ResultsWe initially screened 1612 DEGs, of which 1030 were up-regulated and 582 were down-regulated. The GO and KEGG enrichment analysis suggested these genes were associated with 'cell cycle', 'DNA replication'. Subsequently, we identified 10 key HUB genes, among them CCNB1 was strongly related to WT patients' overall survival. Multiple survival analyses showed that CCNB1 was an independent indicator of WT prognosis. Thus, we constructed a nomogram of CCNB1 combined with other clinical indicators. Single gene GSEA and immune infiltration analysis revealed that CCNB1 was associated with the degree of infiltration or activation status of multiple immune cells. TIDE analysis indicated that this gene was correlated with multiple key immune checkpoint molecules and TIDE scores. Finally, we validated the differential expression level of CCNB1 in an external gene set, the pan-cancer, clinical samples, and cell lines. CCNB1 silencing significantly inhibited the proliferation, migration, and invasive capabilities of WIT-49 cells, also, promoted apoptosis, and in turn induced G2 phase cell cycle arrest in loss-of-function assays.ConclusionOur study suggests that CCNB1 is closely related to WT progression and prognosis, and serves as a potential target.

Dataset Information

ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth.

Publications

ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth.

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