**5.1 Biomolecular and signal pathways activated by DEN**

Activation of β-catenin is the central effector of canonical Wnt pathway. DEN-induced tumorigenesis was examined in hepatic β-catenin conditional knockout (β-cat KO) mice. βcat KO mice show a paradoxical increase in susceptibility to DEN-induced tumorigenesis. This accelerated tumorigenesis is due to increased injury and inflammation, unrestricted oxidative stress, fibrosis, and a compensatory increase in hepatocyte proliferation secondary to PDGFRα/phosphoinositide 3-kinase (PIK3CA)/Akt activation and c-Myc overexpression. Loss of β-catenin impairs the ability of liver to counteract DEN-induced oxidative stress and enhances tumorigenesis through PDGFRα/PIK3CA/Akt signaling. [66].

C/EBPα is a transcription factor that regulates liver quiescence. Phosphorylation of C/EBPα at serine 193 (S193-ph) is upregulated in older mice and is thought to contribute to ageassociated liver dysfunction. DEN treatment of knock-in mice expressing a phosphomimetic aspartic acid residue in place of serine at position 193 (S193D) of C/EBPα induces the formation of liver cancer, and actually results in earlier development of liver tumors. DEN/phenobarbital treatment is associated with specific degradation of both the S193-ph and S193D isoforms of C/EBPα through activation of the ubiquitin-proteasome system (UPS) [66].

The role of PBP/MED1 [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] in DEN-induced hepatocarcinogenesis was also examined. The carcinogenic process of PBP/MED1D mice was initiated by injection of DEN and initiated cells were promoted with phenobarbital. These mice revealed a striking proliferative response in the few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of the PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1DLiv mouse livers. Multiple hepatocellular carcinomas developed in the DEN-initiated PBP/MED1fl/fl and PBP/MED1DLiv mice [67].

DEN may activate PDGFRα/PIK3CA/Akt signaling through β-Catenin, and mediate C/EBPα phosphorylation through the ubiquitin-proteasome system (UPS), and regulate PBP/MED1, and involve nasopharyngeal carcinogenesis.

#### **5.2 Biomolecular and signal pathways activated by DMAB**

When K5-protein kinase C-alpha (PKCA) mice (transgenic mice that overexpress PKCA in the epidermis) were initiated with DMBA and promoted with a low dose of 12-Otetradecanoylphorbol-13-acetate (TPA), 58% of the mice developed skin papillomas that progressed to carcinoma. CXCR2 is expressed by keratinocytes and transformation by

increased in hyperplasia but was decreased in dysplasia and neoplasia, and sometimes even totally disappeared. Similarly, the esterase activity of human NPC was markedly decreased compared with the surrounding epithelia of the cancer foci and the squamous or ciliated columnar epithelia of the nasopharynx in the control cases, and decreased to varying extents in different cancer cells of various cases or in different foci of the same case. The reactivity remained in well-differentiated cancer cells, but entirely disappeared in poorly

**5. Molecular and signal transduction activated by chemical carcinogens** 

Activation of β-catenin is the central effector of canonical Wnt pathway. DEN-induced tumorigenesis was examined in hepatic β-catenin conditional knockout (β-cat KO) mice. βcat KO mice show a paradoxical increase in susceptibility to DEN-induced tumorigenesis. This accelerated tumorigenesis is due to increased injury and inflammation, unrestricted oxidative stress, fibrosis, and a compensatory increase in hepatocyte proliferation secondary to PDGFRα/phosphoinositide 3-kinase (PIK3CA)/Akt activation and c-Myc overexpression. Loss of β-catenin impairs the ability of liver to counteract DEN-induced oxidative stress and

C/EBPα is a transcription factor that regulates liver quiescence. Phosphorylation of C/EBPα at serine 193 (S193-ph) is upregulated in older mice and is thought to contribute to ageassociated liver dysfunction. DEN treatment of knock-in mice expressing a phosphomimetic aspartic acid residue in place of serine at position 193 (S193D) of C/EBPα induces the formation of liver cancer, and actually results in earlier development of liver tumors. DEN/phenobarbital treatment is associated with specific degradation of both the S193-ph and S193D isoforms of C/EBPα through activation of the ubiquitin-proteasome system

The role of PBP/MED1 [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] in DEN-induced hepatocarcinogenesis was also examined. The carcinogenic process of PBP/MED1D mice was initiated by injection of DEN and initiated cells were promoted with phenobarbital. These mice revealed a striking proliferative response in the few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of the PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1DLiv mouse livers. Multiple hepatocellular carcinomas developed in the DEN-initiated PBP/MED1fl/fl and PBP/MED1DLiv mice [67]. DEN may activate PDGFRα/PIK3CA/Akt signaling through β-Catenin, and mediate C/EBPα phosphorylation through the ubiquitin-proteasome system (UPS), and regulate

When K5-protein kinase C-alpha (PKCA) mice (transgenic mice that overexpress PKCA in the epidermis) were initiated with DMBA and promoted with a low dose of 12-Otetradecanoylphorbol-13-acetate (TPA), 58% of the mice developed skin papillomas that progressed to carcinoma. CXCR2 is expressed by keratinocytes and transformation by

**5.1 Biomolecular and signal pathways activated by DEN** 

PBP/MED1, and involve nasopharyngeal carcinogenesis.

**5.2 Biomolecular and signal pathways activated by DMAB** 

enhances tumorigenesis through PDGFRα/PIK3CA/Akt signaling. [66].

differentiated cancer cells.

(UPS) [66].

oncogenic ras (a hallmark of DMBA initiation) or TPA exposure induced all CXCR2 ligands. Ras induction of CXCR2 ligands was mediated by autocrine activation of epidermal growth factor receptor and nuclear factor-KB, and potentiated by PKCA. Oncogenic ras also induced CXCR2 ligands in keratinocytes that were genetically ablated for CXCR2. *In vitro*, CXCR2 was found to be essential for CXCR2 ligand-stimulated migration of ras-transformed keratinocytes and for ligand activation of the extracellular signal-regulated kinase (ERK) and Akt pathways. Both cell migration and activation of ERK and Akt were restored by CXCR2 reconstitution of CXCR2 null keratinocytes [68].

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been described in a variety of human malignancies and has been suggested to play an important role in carcinogenesis. The epidermis of inducible Stat3-deficient mice treated with 4 hytroxytamoxifen (TM) showed a significant increase in apoptosis induced by DMBA and reduced proliferation following exposure to TPA. In two-stage skin carcinogenesis assays, inducible Stat3-deficient mice treated with TM during the promotion stage showed a significant delay in tumor development and a significantly reduced number of tumors compared with control groups. Inducible Stat3-deficient mice treated with TM before initiation with DMBA also showed a significant delay in tumor development and a significantly reduced number of tumors compared with control groups [69]

#### **5.3 Biomolecular and signal transduction targeted by DNP**

DNP displays some degree of organ specificity for nasopharyngeal epithelium in inducing rat NPC. To clarify the mechanism underlying this DNP organotropic action, a rat NPC model was constructed using DNP, and atypical hyperplasic nasopharyngeal and NPC tissue was obtained from rats at different stages of tumorigenesis. Differential protein expression was screened using proteome analysis and further confirmed by immunoblotting. Expression of heat shock protein 70 (HSP70) and Mucin was increased in the atypical hyperplasia and NPC cells, and we therefore postulated that DNP might upregulate these genes. In further studies to determine whether DNP does regulate HSP70 and Mucin, we treated HENE cells (cultured from biopsies of normal nasopharyngeal tissue) with 2M and 4M DNP and showed that expression of HSP70 and Mucin increased in dose-dependent manner. To confirm the specificity of DNP, we used arsenite as a control because its carcinogenicity has previously been proven [70]. Expression of HSP70 and Mucin was not induced by arsenite. We therefore think that HSP70 and Mucin might be specific and important targets of DNP [57].

DNP induced expression of phosphorylated ezrin at threonine 567 (phos-ezrin Thr567) in a dose- and time-dependent manner in 6-10B nasopharyngeal carcinoma cells (Fig.5 Effects of DNP on ezrin phosphorylation at Thr 567**.** 6-10B cells were treated with 2 or 4 M DNP for 24 h (A), and treated with 4M DNP for 12 or 24 h (B), and ezrin and phos-ezrin expression were assayed with immunoblotting). Furthermore, DNP-induced expression of phos-ezrin Thr567 was dependent on increased Rho kinase and PKC activity. The activation of Rho kinase and PKC occurred through binding to Rho kinase pleckstrin-homology (PH) and promotion of PKC translocation to the plasma membrane. Ezrin is associated with induction of filopodia growth in 6-10B cells, and further studies showed that DNP induces filopodia formation in 6-10B NPC cells and also increases invasion and motility of these cells. This indicated that DNP is involved in NPC metastasis, and DNP-mediated NPC metastasis was

Chemical Carcinogenesis and Nasopharyngeal Carcinoma 79

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indeed confirmed in nude mice. However, DNP did not effectively induce motility and invasion of DNP-treated NPC cells containing ezrin mutated at Thr 567. Similarly, motility and invasion were not induced in DNP-treated NPC cells transfected with si-RNAs against Rho or PKC. These findings indicate that DNP induces ezrin phosphorylation at Thr567, increases motility and invasion of cells, and promotes tumor metastasis. DNP may therefore be involved in NPC metastasis through regulation of ezrin phosphorylation at Thr567 [71].

Fig. 5. Effects of DNP on ezrin phosphorylation at Thr 567**.** 6-10B cells were treated with 2 or 4 M DNP for 24 h (A), and treated with 4M DNP for 12 or 24 h (B), and ezrin and phos-ezrin expression were assayed with immunoblotting.

#### **6. Acknowledgment**

This work was in part supported by National Natural Science Foundation of China (81071718, 81000881), Program for New Century Excellent Talents in University, NCET (NCET-06-0685), the Fundamental Research Funds for the Central Universities

### **7. References**


indeed confirmed in nude mice. However, DNP did not effectively induce motility and invasion of DNP-treated NPC cells containing ezrin mutated at Thr 567. Similarly, motility and invasion were not induced in DNP-treated NPC cells transfected with si-RNAs against Rho or PKC. These findings indicate that DNP induces ezrin phosphorylation at Thr567, increases motility and invasion of cells, and promotes tumor metastasis. DNP may therefore be involved in NPC metastasis through regulation of ezrin phosphorylation at Thr567 [71].

Fig. 5. Effects of DNP on ezrin phosphorylation at Thr 567**.** 6-10B cells were treated with 2 or 4 M DNP for 24 h (A), and treated with 4M DNP for 12 or 24 h (B), and ezrin and

This work was in part supported by National Natural Science Foundation of China (81071718, 81000881), Program for New Century Excellent Talents in University, NCET

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**5** 

*Taiwan* 

Li-Jen Liao1,2 and Mei-Shu Lai2

*National Taiwan University, Taipei,* 

**Epstein-Barr Virus Serology in the Detection** 

*1Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City, 2Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health,* 

Nasopharyngeal carcinoma (NPC) is a common cancer among Southern Chinese with a male dominance of about 3:1. The age-adjusted incidence for both sexes is less than one per 100, 000 population worldwide. The reported incidence of NPC among men and women in Hong Kong is 20–30 per 100, 000 and 15–20 per 100, 000.(Wei and Sham, 2005) The reported incidence of NPC among men and women in Taiwan is 8.3 per 100 000 and 2.8 per 100 000, respectively.(Bureau of health promotion, Taiwan, 2010) It mainly afflicts people in mid-life. There is now compelling evidences to suggest that Epstein-Barr virus (EBV) is associated with the development of NPC and is most likely to be involved in the multi-step and multifactorial carcinogenesis of NPC. In this chapter, the role of EBV in pathogenesis of NPC is reviewed briefly, and principle applications of EBV antibodies and circulating EBV DNA as markers of NPC are outlined. Based on current knowledge of EBV antibody responses by NPC and taking available testing technologies into account, serologic screening strategy to

The pathogenesis of NPC includes multi-stepped process that leads to the development of NPC **(Fig. 1.).** EBV infection alone cannot drive normal cells towards carcinoma development. It is thought that loss of heterozygosity (LOH on chromosome 3p and 9p, which are the location of some tumor suppressor genes), possibly as a result of inherited traits (Chinese ethnicity) as well as exposure to dietary factors (salted fish) and other environmental cofactors (Formaldehyde), is an early stage event in the pathogenesis of this disease. EBV is infected within these low-grade pre-invasive lesions, subsequent to further

EBV was first suspected to be linked with NPC on the basis of the serological observations by Old and colleagues (Old et al., 1966) in 1966. This link was formally demonstrated later by in situ hybridization of the viral DNA in the nuclei of epithelial cells (zur Hausen et al., 1970). The full length EBV genome is contained in all malignant epithelial cells, but not in most infiltrating lymphocytes. The association with EBV is constant, regardless of the

facilitate efficient early detection of NPC is formulated.

**2. EBV related pathogenesis of NPC** 

genetic and epigenetic alterations.

**1. Introduction** 

**and Screening of Nasopharyngeal Carcinoma** 

