Familial Nasopharyngeal Carcinoma 6

Molecular Signaling Pathways in Nasopharyngeal Cancer 37cell proliferation, differentiation, and viability(Bartel 2004; Stefani and Slack, 2008). MiRNAare 22–24 nucleotide noncoding RNAs that are processedfrom a primary transcript, or pri-miRNA,usually found in introns or other noncoding regions.Pri-RNA are cleaved in the nucleus by an enzymecalled Drosha to yield hairpin pre-miRNA, which aretransported to the cytoplasm where it is cleaved furtherby Dicer to yield the final miRNA. These RNAfragments perform their regulatory role as a componentof the RISC complex, which either inhibits proteintranslation or promote mRNA degradation(Ambros, 2004; Bartel, 2004). Close to 40 miRNAhave been found to be expressed in the differentregions of the EBV genome (Cosmopoulos et al.2009) and the expression pattern of these miRNA isdependent on cell type and the overall pattern ofEBV gene expression. For example, while one clusterof miRNA from BamHI-A regions (BART miRNAs)is robustly expressed in NPC, a second clusterencoded in the HamHI-H region known as BHRFImiRNA is not detected in these cells at all. Thereverse, on the other hand, is true for EBV-relatedlymphoma (Swaminathan 2008). One of the majortargets of EBV-encoded BART miRNA is LMP1,which is a major EBV-derived oncogene (Lo et al.2007). Although LMP1 has transforming properties,overexpression of this protein may inhibit cell proliferationand increased susceptibility to apoptoticstress (Kaykas and Sugden 2000). There fore, suppressionof excessive LMP1 production on NPC byBART miRNA appeared to protect LMP1 expressingNPC cells from apoptotic stimuli and enhance cisplatinresistance (Lo et al. 2007). BART miRNA regulationof LMP1 protein synthesis also explains forthe observed discrepancies between LMP1 transcriptsand protein expression that are often notedin NPC tumor tissues (Lo et al. 2007).In addition to EBV-derived miRNA, several cellularmiRNAs, which are encoded in the host cells, arealso found to be aberrantly expressed in NPC andsuch aberrant expression can promote aggressivetumor phenotype through changes in the expressionof their downstream targets. For examples, miR-29cis consistently downregulated in primary NPC tumorswhen compared with normal nasopharyngeal mucosa.On further investigation, most of miR-29c’s targetgenes encodes for extracellular matrix proteins suchas laminin-g1, which are associated with tumor cellinvasiveness and metastatic protential (Senguptaet al. 2008,). Another large-scale miRNA profilingstudy of 13 NPC tumor samples and 9 adjacentnormal tissues yielded 35 cellular miRNA with alteredexpression in the tumor. Changes included upregulationof oncogenic miRNA such as miR-155 and downregulationof tumor suppressive miRNA such asmiR-34 and miR-143. Computational analysis of the22 downregulated miRNAs showed that these potentiallytarget several signaling pathways that areknown to play an important role in NPC developmentand progression. These include the previously discussedWnt and VEGF pathways, cell cycle regulators,and survival pathways (Chen et al. 2009).These data together indicate that the miRNA fromboth the virus and the host cells play a critical role inmediating NPC development and spread. However,our understanding of the function of these miRNAsand their dowstream targets is still at the infancylevel. A better knowledge of the complex networkinvolving miRNAs and their targets leading to a coordinatedpattern of gene expression in NPC willundoubtedly provide important tools to develop noveltherapeutic strategies for these tumors. In addition,selective regulation of particular miRNAs targetingtumor cell survival, invasion, and angiogenesis is apromising prospect for future antitumor therapy.3.6SummaryThe highly integrated and complex circuitry of cellularmolecular signaling in NPC remains only partiallyunderstood. However, it is certain that molecularsignaling pathways such as EGFR, VEGF, the Wntpathway, and miRNA regulation are vitally importantin the understanding of the biological behavior of thedisease and its treatment. Expression of EGFR andVEGF appear to be predictive for the prognosis ofNPC. Although still in early phases of investigation,therapeutic strategies directed against EGFR and angiogenesissignaling pathways, using existing drugs, representpromising advances in the management ofNPC. Preclinical and clinical data indicate that boththe Wnt signaling pathways and miRNA play a majorrole in NPC development and progression. Activeresearch is ongoing in several laboratories to identifythe best approaches to mediate the function of thesemolecules. Better understanding of the Wnt signalingnetwork, their protein structural function, miRNAregulation, and the function of their respective targetswill offer new therapeutic strategies in the managementof nasopharyngeal cancer.