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CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance.

ABSTRACT: Radiotherapy is a mainstay for treatment of many human cancer types, including head and neck squamous cell carcinoma (HNSCC). Thereby, it is clinically very relevant to understand the mechanisms determining radioresistance. Here, we identify CIP2A as an Oct4 target gene and provide evidence that they co-operate in radioresistance. Oct4 positively regulates CIP2A expression both in testicular cancer cell lines as well as in embryonic stem cells. To expand the relevance of these findings we show that Oct4 and CIP2A are co-expressed in CD24 positive side-population of patient-derived HNSCC cell lines. Most importantly, all Oct4 positive HNSCC patient samples were CIP2A positive and this double positivity was linked to poor differentiation level, and predicted for decreased patient survival among radiotherapy treated HNSCC patients. Oct4 and CIP2A expression was also linked with increased aggressiveness and radioresistancy in HNSCC cell lines. Together we demonstrate that CIP2A is a novel Oct4 target gene in stem cells and in human cancer cell lines. Clinically these results suggest that diagnostic evaluation of HNSCC tumors for Oct4 or Oct4/CIP2A positivity might help to predict HNSCC tumor radioresistancy. These results also identify both Oct4 and CIP2A as potential targets for radiosensitation.

SUBMITTER: Ventela S

PROVIDER: S-EPMC4381584 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance.

Ventelä Sami S Sittig Eleonora E Mannermaa Leni L Mäkelä Juho-Antti JA Kulmala Jarmo J Löyttyniemi Eliisa E Strauss Leena L Cárpen Olli O Toppari Jorma J Grénman Reidar R Westermarck Jukka J

Oncotarget 20150101 1

Radiotherapy is a mainstay for treatment of many human cancer types, including head and neck squamous cell carcinoma (HNSCC). Thereby, it is clinically very relevant to understand the mechanisms determining radioresistance. Here, we identify CIP2A as an Oct4 target gene and provide evidence that they co-operate in radioresistance. Oct4 positively regulates CIP2A expression both in testicular cancer cell lines as well as in embryonic stem cells. To expand the relevance of these findings we show t ...[more]

PMID: 25474139

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Project description:PurposeHead and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer globally, and radiotherapy plays a crucial part in its treatment. This study was designed to identify potential genes related to radiation resistance in HNSCC.MethodWe first used text mining to obtain common genes related to radiotherapy resistance and HNSCC in published articles. Functional enrichment analyses were conducted to identify the significantly enriched pathways and genes. Protein and protein interactions were performed, and the most significant gene modules were determined; then, genes in the gene modules were validated at transcriptional levels and overall survival. Gene set variation analysis (GSVA) score was calculated, and the association between GSVA score and survival/pathway was estimated. Immune cell infiltration, methylation, and genetic alteration analysis of these genes was conducted in HNSCC patients. Finally, potential sensitive anticancer drugs related to target genes were obtained.ResultWe identified 583 common genes through text mining. After further validation, a four-gene signature (EPHB2, SPP1, SERPINE1, and VEGFC) was constructed. The patients with higher GSVA scores have a worse prognosis than those with lower GSVA scores. Differences in methylation of these four genes in HNSCC tumor tissue and normal tissue were compared, with higher methylation levels of EBPH2 and SPP1 in normal tissue and higher methylation levels of SERPINE1 in the tumor. Immune cell infiltration revealed that the increased expression of these genes was closely related to the infiltration level of CD4+ T cell, neutrophil, macrophage, and dendritic cell. Thirty drugs, including 22 positively and eight negatively correlated drugs that most correlated with related genes, were available for treating HNSCC.ConclusionIn this study, we identified four potential genes as well as corresponding drugs that might be related to radioresistance in HNSCC patients. These candidate genes may provide a promising avenue to further elevate radiotherapy efficacy.

Dataset Information

CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance.

Publications

CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance.

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