Dataset Information

NFATC2 is a novel therapeutic target for colorectal cancer stem cells.

ABSTRACT:

Background

Colorectal cancer stem cells (CRC-SCs) contribute to the initiation and progression of colorectal cancer (CRC). However, the underlying mechanisms for the propagation of CRC-SCs have remained elusive.

Purpose

The objective of this study was to study the role of NFATC2 in maintenance of the stemness in CRC-SCs.

Method

The expression levels of mRNA and protein were determined by qRT-PCR and western-blot, respectively. CRC-SCs were isolated by spheroid formation assay and flowcytometry. The sphere-forming and self-renewal abilities of CRC-SCs were determined by spheroid formation assay. The tumorigenicity of CRC-SCs was determined by cell-derived xenograft model. Gene manipulation was performed by lentivirus-mediated delivery system.

Results

We first found that NFATC2 is upregulated in primary CRC-SCs. Overexpression of NFATC2 promotes self-renewal and the expression of stem cell markers of CRC-SCs. Conversely, knockdown of NFATC2 attenuates stem cell-like properties of CRC-SCs. Mechanistic analysis indicated that NFATC2 upregulates the expression of AJUBA, downregulates the phosphorylation level of YAP, and therefore activates the transcriptional activities of YAP and promotes the stemness of CRC-SCs.

Conclusion

Our findings demonstrate NFATC2 as an oncogene that can promote the stemness of CRC-SCs. This work suggests a novel therapeutic strategy against CRC caused by aberrant expression of NFATC2.

SUBMITTER: Lang T

PROVIDER: S-EPMC6199214 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

NFATC2 is a novel therapeutic target for colorectal cancer stem cells.

Lang Tingyuan T Ding Xiaojuan X Kong Liangsheng L Zhou Xiaoyan X Zhang Zhiqi Z Ju Huangxian H Ding Shijia S

OncoTargets and therapy 20181015

<h4>Background</h4>Colorectal cancer stem cells (CRC-SCs) contribute to the initiation and progression of colorectal cancer (CRC). However, the underlying mechanisms for the propagation of CRC-SCs have remained elusive.<h4>Purpose</h4>The objective of this study was to study the role of NFATC2 in maintenance of the stemness in CRC-SCs.<h4>Method</h4>The expression levels of mRNA and protein were determined by qRT-PCR and western-blot, respectively. CRC-SCs were isolated by spheroid formation ass ...[more]

PMID: 30410349

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Project description:BackgroundAs a novel class of noncoding RNAs, circRNAs have been recently identified to regulate tumorigenesis and aggressiveness. However, the function of circRNAs in colorectal cancer (CRC) metastasis remains unclear. We aimed to identify circRNAs that are upregulated in CRC tissues from patients and study their function in CRC metastasis.MethodsWe compared six pairs of CRC tissues and their matched adjacent non-tumor tissues by using circRNA microarray. We first evaluated the expression of circPTK2 (hsa_circ_0005273) in fresh tissues from CRC tumors and corresponding adjacent tissues by qPCR analysis. CircPTK2 expression levels in the tissue microarray with 5 years of survival information were determined by RNA-ISH analysis. Meanwhile, the expression levels of circulating circPTK2 were further analyzed according to the patients' clinical features. We analyzed cell apoptosis, colony formation, migration, and invasion in CRC cells. To further elucidate the effect of circPTK2 in CRC metastasis, we also conducted a colon cancer hepatic and pulmonary metastasis experiment. We used RNA biotin-labeled pull down and mass spectrometry to identify the target of circPTK2. We established a PDTX model to evaluate the effect of shRNA specifically targeting circPTK2 on tumor metastasis.ResultsWe identified a novel circRNA, circPTK2, which is back-spliced of three exons (exons 27, 28 and 29) of PTK2 by using circRNA microarray, bioinformatics and functional studies. CircPTK2 was elevated in CRC tissues and positively associated with tumor growth and metastasis. CRC patients with increased circPTK2 expression were positively correlated with poorer survival rates. Furthermore, our studies showed that circPTK2 could promote EMT of CRC cells in vitro and in vivo by binding to vimentin protein on sites Ser38, Ser55 and Ser82. We further demonstrated the interaction of circPTK2 and vimentin mediated the regulation of CRC by knockdown or overexpression of vimentin. In addition, we revealed that tail vein injection of shRNA specifically targeting circPTK2 blunt tumor metastasis in a patient-derived CRC xenograft model.ConclusionsCollectively, these results demonstrate that circPTK2 exerts critical roles in CRC growth and metastasis and may serve as a potential therapeutic target for CRC metastasis, and also a promising biomarker for early diagnosis of metastasis.

Dataset Information

NFATC2 is a novel therapeutic target for colorectal cancer stem cells.

Background

Purpose

Method

Results

Conclusion

Publications

NFATC2 is a novel therapeutic target for colorectal cancer stem cells.

Similar Datasets

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