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Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells.

ABSTRACT: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. Recent studies have stated that NOTCH signaling plays an important role in the development and progression of CRC. However, the role of Jagged-2 (JAG2), one of the NOTCH ligands, has not been delineated in colorectal tumorigenesis and drug resistance. In the present study, we have examined the impact of targeting JAG2 on CRC cells. Among all the members of NOTCH ligands, only the expression of JAG2 was found up-regulated in the intestinal tumors of Apc Min /+ mice as compared to the nearby normal mucosa. JAG2 expression was also observed in a panel of human CRC cell lines. Pharmacological inhibition or genetic knockdown of ?-catenin in CRC cell lines suppressed JAG2 expression, suggesting Wnt/?-catenin regulation of JAG2 expression. In addition, deletion of Apc gene in the intestinal cells of Apc conditional knockout mice resulted in up-regulation of JAG2 expression. Modulation of JAG2 expression significantly affected in vivo tumorigenicity of CRC cell lines. Moreover, knockdown of JAG2 sensitized CRC cells to chemotherapeutic agents, while ectopic expression of JAG2 increased chemoresistance of the CRC cells. Significant down-regulation of p21 was observed in JAG2-knockdown cells. Forced expression of p21 rescued the sensitivity of JAG2-knockdown cells to doxorubicin. In addition, the chemosensitivity of p21-null cells was not affected by JAG2 knockdown. These results suggest that JAG2 modulates the sensitivity of CRC cells to chemotherapeutic agents through p21. Our study identifies JAG2 as a novel target for therapeutic intervention of CRC.

SUBMITTER: Vaish V

PROVIDER: S-EPMC5581108 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells.

Vaish Vivek V Kim Joohwee J Shim Minsub M

Oncotarget 20170607 32

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. Recent studies have stated that NOTCH signaling plays an important role in the development and progression of CRC. However, the role of Jagged-2 (JAG2), one of the NOTCH ligands, has not been delineated in colorectal tumorigenesis and drug resistance. In the present study, we have examined the impact of targeting JAG2 on CRC cells. Among all the members of NOTCH ligands, only the expression of JAG2 was found up-reg ...[more]

PMID: 28881809

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Project description:BackgroundOur previous studies revealed that Jagged 2 (JAG2) is involved in the regulation of migration and invasion of colon cancer cells without affecting cell proliferation. This study further explored the specific mechanism by which JAG2 promotes migration and invasion of colorectal cancer cells.MethodsJAG2 mRNA expression in different clinical stages of colorectal cancer and normal intestinal tissues was detected by quantitative PCR (QPCR). QPCR and Western Blot were used to analyze the differential expression of JAG2 mRNA and protein between normal human colon tissue cells and various colorectal cancer cells. Co-expression status of JAG2 and epithelial-mesenchymal transition (EMT) markers in colon cancer tissues and cells was analyzed. The difference between TGF-β-induced EMT model and the JAG2 overexpression model were compared in promoting migration and invasion of HT29 cells. HT29 cells were treated with EMT pathway inhibitors (LY2157299 and Slug siRNA) to identify a cross-talk between the JAG2 effect and the Notch pathway. Co-expressed genes of JAG2 in colorectal cancer cells were identified using siRNA and transcriptome microarray technology. The mutual regulation of JAG2 and the co-expressed gene PRAF2 and the regulation of the paracrine effect of exosomes were analyzed.ResultsJAG2 was abnormally expressed in colorectal cancer tissues and directly related to clinical stages. Similar to the findings in tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. It was shown in our cell model that JAG2 was involved in the regulation of migration and invasion independent of the canonical Notch signaling pathway. More interestingly, JAG2 also promoted the migration and invasion of colon cancer cells in a non-EMT pathway. Further analysis revealed the co-expression of JAG2 with PRAF2 in colorectal cancer cells. JAG2-rich exosomes were released from colorectal cancer cells in a PRAF2-dependent way, while these exosomes regulated the metastasis of colorectal cancer cells in a paracrine manner.ConclusionsThis is the evidence supporting the biological function of JAG2 through non-canonical Notch and non-EMT-dependent pathways and also the first demonstration of the functions of PRAF2 in colorectal cancer cells. These findings also provide theoretical basis for the development of small molecules or biological agents for therapeutic intervention targeting JAG2/PRAF2.

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Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells.

Publications

Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells.

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