Inflammation-caused abnormalities in gastric differentiation and molecular epidemiologic analysis of gastric cancer

1. 转录因子SOX2上调胃蛋白酶原A基因表达SOX2在正常胃黏膜中表达，而在正常结肠中不表达。为了明确SOX2的作用，我们分析了10株胃癌（GC）和10株结直肠癌（CRC）细胞株中SOX2和胃蛋白酶原（胃分化标志物）的表达情况。6株GC和5株CRC细胞株RT-PCR显示SOX2表达。8株GC和7株CRC细胞株中均检测到胃蛋白酶原A的表达，而大多数细胞株均表达胃蛋白酶原C。过表达SOX2可上调内源性胃蛋白酶原A的表达，但在GC和CRC细胞株中不上调胃蛋白酶原C的表达。SOX2 RNA干扰可显著降低胃癌细胞株胃蛋白酶原A的表达。这些数据提示SOX2在调节胃蛋白酶原A中发挥重要作用，SOX2的异位表达可能与结直肠癌细胞的异常分化有关。在胃细胞中，Notch信号通路介导细胞分化。我们研究了7个notch相关基因的mRNA表达，并与8株胃癌细胞系中胃黏液蛋白基因MUC5AC和MUC6的表达进行了比较。Notch1/2/3和Hes1在大多数胃癌细胞系和正常胃粘膜中均有表达，而Hes2/3在这些细胞系和正常胃中均不表达。5株GC细胞株未检测到Hath1，而正常胃黏膜表达Hath1。在大多数胃癌细胞系中，Hath1和MUC6的表达模式密切相关。许多muc5ac阳性病例也倾向于显示Hath1表达。GC细胞中过表达Math1可提高MUC6和MUC5AC mRNA水平。RNA干扰敲低Hath1可显著降低两种粘蛋白基因的表达。这些数据表明，Hath1是GC细胞中MUC6和MUC5AC的转录调节因子之一。Hath1表达的缺失也可能在胃癌发生中起作用。少

1. Transcription factor SOX2 up-regulates stomach- specific pepsinogen A gene expressionSOX2 is expressed in normal gastric mucosae but not in the normal colon. To clarify the role of SOX2, we analyzed expression of SOX2 and pepsinogens, differentiation markers of the stomach, in 10 gastric cancer (GC) and 10 colorectal cancer (CRC) cell lines. Six GC and five CRC cell lines showed SOX2 expression on RT-PCR. Expression of pepsinogen A was detectable in 8 GC and 7 CRC cell lines, whereas the majority of the cell lines expressed pepsinogen C. Over-expression of SOX2 up-regulated expression of endogenous pepsinogen A but not that of pepsinogen C in GC and CRC cell lines. Moreover, pepsinogen A expression was significantly reduced by SOX2 RNA interference in GC cell lines. These data suggest that SOX2 plays an important role in regulation of pepsinogen A, and ectopic expression of SOX2 may be associated with abnormal differentiation of colorectal cancer cells.2. Hath1 up-regulates gastric … More mucin gene expression in gastric cellsThe Notch signaling pathway is known to mediate cell differentiation. We investigated mRNA expression of seven Notch-related genes, and compared it with expression of gastric mucin genes, MUC5AC and MUC6, in 8 gastric cancer (GC) cell lines. Notch1/2/3 and Hes1 were expressed in most GC cell lines as well as normal gastric mucosae, while Hes2/3 were expressed in neither these cell lines nor the normal stomach. As for Hath1, 5 GC cell lines exhibited undetectable levels, while normal gastric mucosa expressed Hath1. The expression patterns of Hath1 and MUC6 were closely related in most GC cell lines. Many MUC5AC-positive cases also tended to show Hath1 expression. Over-expression of Math1 in the GC cells enhanced both the MUC6 and MUC5AC mRNA levels. Knockdown of Hath1 by RNA interference significantly decreased expression of both mucin genes. These data indicate that Hath1 is one of the transcriptional regulators for MUC6 and MUC5AC in GC cells. It is also possible that loss of Hath1 expression may play a role in gastric carcinogenesis. Less