Gastric chief cells differentiate from mucous neck cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal cell loss, chief cells transdifferentiate into mucous cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in chief cells and identified miRNAs involved in chief cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in chief cells and significantly decreased during the process of chief cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized chief cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM cells as well as in chief cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of chief cell transdifferentiation into SPEM.

胃主细胞从粘液颈细胞分化，并在泌酸腺基部发育成熟状态，表达分泌酶原颗粒。壁细胞丢失后，主细胞转分化为粘液细胞化生，称为表达解痉多肽的化生（SPEM），被认为是胃癌的候选前体。我们检查了主细胞中 microRNA (miRNA) 的表达范围，并鉴定了参与主细胞转分化为 SPEM 的 miRNA。其中，miR-148a在主细胞中强特异性表达，并在主细胞转分化过程中显着下降。有趣的是，在条件永生化主细胞系中抑制 miR-148a 会诱导 CD44 变体 9 (CD44v9)（SPEM 发育早期表达的转录本之一）和 DNA 甲基转移酶 1 (Dnmt1)（已确定的靶标）上调。 miR-148a。免疫染色分析表明，在使用 DMP-777 或 L635 的急性泌酸萎缩小鼠模型中，在出现 SPEM 之前，Dnmt1 在 SPEM 细胞以及主细胞中上调。在导致转分化的级联事件中，在 xCT 敲除小鼠中急性泌酸萎缩后或在柳氮磺吡啶抑制 xCT 后，miR-148a 下调。这些发现表明，miR-148a 表达的改变是主细胞转分化为 SPEM 过程中的早期事件。