BackgroundOct4 is a major transcription factor related to stem cell self-renewal and differentiation. To fulfill its functions, it must be able to enter the nucleus and remain there to affect transcription. KPNA2, a member of the karyopherin family, plays a central role in nucleocytoplasmic transport. The objective of the current study was to examine the association between Oct4 and KPNA2 expression levels with regard to both the clinicopathological characteristics and prognoses of patients with non-small-cell lung cancer (NSCLC).MethodsImmunohistochemistry was used to detect the expression profile of Oct4 and KPNA2 in NSCLC tissues and adjacent noncancerous lung tissues. Real-time polymerase chain reaction and western blotting were used to detect the mRNA and protein expression profiles of Oct4 and KPNA2 in lung cancer cell lines. Small interfering RNAs were used to deplete Oct4 and KPNA2 expressions. Double immunofluorescence was used to detect Oct4 expression in KPNA2 knockdown cells. Co-immunoprecipitation was used to detect the interaction of Oct4 and KPNA2.ResultsOct4 was overexpressed in 29 of 102 (28.4%) human lung cancer samples and correlated with differentiation (P = 0.002) and TNM stage (P = 0.003). KPNA2 was overexpressed in 56 of 102 (54.9%) human lung cancer samples and correlated with histology (P = 0.001) and differentiation (P = 0.045). Importantly, Oct4 and KPNA2 expression levels correlated significantly (P < 0.01). Expression of Oct4 and KPNA2 was associated with short overall survival. In addition, depleting Oct4 and KPNA2 expression using small interfering RNAs inhibited proliferation in lung cancer cell lines. Real-time polymerase chain reaction and western blotting analysis indicated that reduction of KPNA2 expression significantly reduced mRNA and nucleoprotein levels of Oct4. Double immunofluorescence analysis revealed that nuclear Oct4 signals were reduced significantly in KPNA2 knockdown cells. Co-immunoprecipitation experiments revealed that KPNA2 interacts with Oct4 in lung cancer cell lines.ConclusionOct4 and KPNA2 play an important role in NSCLC progression. Oct4 nuclear localization may be mediated by its interaction with KPNA2.

This study examined the relationship between external environmental factors and Epstein-Barr virus (EBV) infection in nasal natural killer (NK)/T-cell lymphomagenesis. Archival paraffin sections from 134 cases of nasopharyngeal lymphomas in the northeast of China were investigated by in situ hybridization of EBV-encoded small RNA-1 (EBER-1) and by immunohistochemistry of the status of programmed cell death (PCD). The cases examined included 74 (55.2%) cases of NK/T-cell lymphomas (NKTCL) in T-cell and NK-cell neoplasms as well as 32 (23.9%) cases of B-cell neoplasms (B-MLs) and 9 (6.7%) cases of carcinomas. These cases indicated a significant dominant occurrence of NKTCL in the nasal cavity and of B-MLs in the pharynx. Many EBV-associated NKTCLs were seen in the nasopharynx, all three cases of EBV-associated B-MLs were in the nasal cavity and all three cases of EBV-associated carcinomas were only seen in the pharynx. The low number of NKTCL cases showing little or no EBV association, together with the existence of EBER-1-free lymphoma cells in EBV-associated NKTCLs, suggested EBV-related lymphoma cell expansion during lymphomagenesis. Peculiar necrosis, frequently observed in NKTCLs, was due to accelerated PCD. This PCD was autophagic cell death as judged by labeling of Beclin-1 and LC3, which possibly occurred due to EBV infection, when apoptosis was suppressed by survivin. Very minute squamous carcinomas, observed in 10 of 23 cases of NKTCLs with residual epithelia that were survivin-positive but not EBV-associated suggested that carcinogenesis occurred before lymphomagenesis. These data suggest that external environmental oncogenic factors initiate nasopharyngeal carcinomas and lymphomas whereas EBV infection promotes them.

Recently we reported the different frequencies of p53 and c-kit gene mutations among sinonasal NK/T cell lymphoma (NKTCL) in Korea, north China (Beijing), and Japan, suggesting some racial, environmental, or life-style differences as a possible cause of nasal tumorigenesis. In this study, gene mutations in p53, c-kit, Kras, and β β β β-catenin gene were analyzed by polymerase chain reaction (

This study investigated autophagy in 37 cases of nasopharyngeal lymphomas including 23 nasal natural killer (NK)/T-cell lymphomas (NKTCL), 3 cytotoxic T-cell lymphomas (cytotoxic-TML) and 9 B-cell lymphomas (BML) by means of antigen-retrieval immunohistochemistry of beclin-1, LC3, mitochondria (AE-1) and cathepsin D. Peculiar necrosis was noted in EBV+ lymphomas comprising 21 NKTCL, 2 cytotoxic-TML and 1 BML. Lymphomas without peculiar necrosis showed high expression of beclin-1, macrogranular cytoplasmal stain of LC3 with sporadic nuclear stain, a hallmark of autophagic cell death (ACD), some aggregated mitochondria and high expression of cathepsin D, suggesting a state of growth with enhanced autophagy with sporadic ACD. EBV+ NKTCL with the peculiar necrosis, showed significantly low level of macrogranular staining of LC3, aggregated mitochondria and low expression of cathepsin D in the cellular areas when degenerative lymphoma cells showed decreased beclin-1, significantly advanced LC3-labeled autophagy, residual aggregated mitochondria and significantly reduced expression of cathepsin D, suggesting advanced autophagy with regional ACD. Consequently it was suggested that enhanced autophagy and reduced expression of lysosomal enzymes induced regional ACD under EBV infection in NKTCL.

Cases of nasal NK/T-cell lymphoma (NKTCL) occur occasionally in Asian and Latin American countries but rarely in Western countries. The etiological role of life-style and environmental factors in nasal NKTCL was investigated. Five university hospitals in Japan and one each in Korea and China participated in this study; a total of 88 cases and 305 hospital controls were accrued during 2000-2005. The odds ratio (OR) of NKTCL obtained after adjustments of age, sex and country was 4.15 (95% confidence interval (CI), 1.74-9.87) for farmers, 2.81 (CI, 1.49-5.29) for producers of crops, 4.01 (CI, 1.99-8.09) for pesticide users, 11.65 (CI, 1.17-115.82) for residents near garbage burning plants, 2.95 (CI, 1.25-6.95) for former drinkers, and 0.49 (CI, 0.23-1.04) for current smokers. The ORs for crop producers, who minimized their exposure to pesticides by using gloves and glasses, and sprinkling downwind at the time of pesticide use, were 3.30 (95% CI, 1.28-8.54), 1.18 (95% CI, 0.11-12.13) and 2.20 (95% CI, 0.88-5.53), respectively, which were lower than those for producers who did not take these precautions. Exposure to pesticides and chemical solvents could be causative of NKTCL. Taken together, life-style and environmental factors might be risk factors for NKTCL. ' 2006 Wiley-Liss, Inc.