Epigenetic Inactivation of Inositol polyphosphate 4-phosphatase B INPP4B, a Regulator of PI3K-AKT Signaling Pathway in EBV-Associated Nasopharyngeal CarcinomaReport as inadecuate




Epigenetic Inactivation of Inositol polyphosphate 4-phosphatase B INPP4B, a Regulator of PI3K-AKT Signaling Pathway in EBV-Associated Nasopharyngeal Carcinoma - Download this document for free, or read online. Document in PDF available to download.

Nasopharyngeal carcinoma NPC is a common viral-associated neoplasm in which multiple signaling cascades are interfered with by Epstein-Bar virus EBV latent proteins and various genetic alterations. Aside from the previously reported PIK3CA amplification, we examined the role of INPP4B, a negative regulator of the PI3K-AKT signaling pathway in the development of NPC. By RT-PCR and Western blotting, we revealed that the expression of INPP4B was down-regulated in all five established EBV-positive tumor lines. While INPP4B was consistently expressed in normal nasopharyngeal epithelial cells, downregulation of INPP4B was found in 32-65 49.2% of primary tumors by immunohistochemistry. Furthermore, our study also demonstrated the hypermethylation of the 5′CpG island of INPP4B in the tumors in which INPP4B transcription was downregulated. Notably, the re-expression of INPP4B was detected in the NPC cells treated with the demethylation agent 5-aza-2′deoxycytidine. Our study showed that promoter hypermethylation was the major mechanism for transcriptional silencing of INPP4B in NPC. Furthermore, restoration of INPP4B expression significantly suppressed PI3K-AKT downstream signals in the NPC C666-1 cells. In vivo growth inhibition was clearly demonstrated in the tumor cells stably expressing INPP4B. The findings indicate that epigenetic inactivation of INPP4B is one of the key mechanisms in activating PI3K-AKT signaling cascade and playing a role in the tumorigenesis of NPC.



Author: Jessie Wai-Fong Yuen, Grace Tin-Yun Chung, Samantha Wei-Man Lun, Chartia Ching-Mei Cheung, Ka-Fai To, Kwok-Wai Lo

Source: http://plos.srce.hr/



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