title: Epigenetic inactivation of inositol polyphosphate 4-phosphatase B (INPP4B), a regulator of PI3K/AKT signaling pathway in EBV-associated nasopharyngeal carcinoma.
abstract: 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.
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Jessie Wai-Fong
authors.initials: JW
authors.lastname: Yuen
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Grace Tin-Yun
authors.initials: GT
authors.lastname: Chung
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Samantha Wei-Man
authors.initials: SW
authors.lastname: Lun
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Chartia Ching-Mei
authors.initials: CC
authors.lastname: Cheung
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020031:Epstein-Barr Virus Infections / Q000201:enzymology* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase