Dynamic alteration of Dclk1 isoform expression in gastric carcinogenesis

Abstract

Dclk1 was proposed as a putative quiescent stem cell marker in the intestine, but also identified as a marker of tuft cells in the stomach. Dclk1 has multiple transcript variants that encode different isoforms, long form (LF, full-length), short form (SF, kinase domain only), and 363 isoform (doublecortin domain only). Prior studies have noted the expression of Dclk1 in association with various cancers. However, no investigations have studied the expression of Dclk1 isoforms in association with metaplasia and gastric cancer. Here, using DMP-777 treated mouse SPEM model, altered expression of Dclk1 isoforms in association with gastric carcinogenesis was analyzed by western blotting and qPCR analysis. Both LF and SF of Dclk1 expression intensity increased in all regions of the gastric mucosa as metaplasia was induced. In contrast to translational level, gene expression patterns of each isoforms varied regionally. In addition, immunohistochemistry and in situ hybridization(ISH) analyses confirmed different distribution of Dclk1 isoforms as well as altered expression of Dclk1 isoforms involved in the course of gastric carcinogenesis. Especially, strong SF-expressing cells appeared in the neck-isthmus region as metaplasia was induced compared to normal gastric mucosa. Moreover, examination of Dclk1 isoforms in resected specimens of gastric cancer patients revealed loss of LF in cancer while it existed in normal and intestinal metaplasia (IM). These results provide possibility of Dclk1 LF as a new cellular and molecular marker in gastric cancer progression.