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.
Highlights
The PI3K/AKT pathway regulates a number of cellular processes, such as cell growth, proliferation, apoptosis, migration, angiogenesis, and glucose metabolism [1,2,3]
We proved that the restoration of Inositol polyphosphate 4-phosphatase B (INPP4B) expression inhibited the phosphorylation of AKT and mTOR in the Nasopharyngeal carcinoma (NPC) C666-1 cells
In agreement with observations in melanoma, our functional study revealed no obvious effect of INPP4B expression on the proliferation and survival of NPC cells in vitro [35]
Summary
The PI3K/AKT pathway regulates a number of cellular processes, such as cell growth, proliferation, apoptosis, migration, angiogenesis, and glucose metabolism [1,2,3]. PI3K is a major signaling component that transduces signals from various growth factors and cytokines into intracellular messages by generating the second messenger phosphatidylinositol 3,4,5-trisphosphate (Ptdlns(3,4,5)P3) from phosphatidylinositol 4,5-bisphosphate (Ptdlns(4,5)P2) [4,5] This recruits AKT to the plasma membrane where it is subsequently phosphorylated at Threonine 308 and Serine 473 by PDK1 and PDK2 (mTOR2) respectively [6]. Multiple studies have revealed altered expression or mutation of many components (e.g. PIK3CA, PTEN, AKT) of the PI3K/ AKT pathway in a broad range of human cancers [1,2,3,10,11,12] These genetic and epigenetic changes promote proliferation and survival of tumor cells by activating AKT kinase activity
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