Journal Article

Transduced caudal‐type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX‐deficient gastric cancer by rapid intestinal differentiation

Tsuji, Yosuke, Tomida, Shuta, Inada, Ken‐ichi, Shiogama, Kazuya, Nakayama, Chiemi, Nagae, Genta, Takahashi, Yu, Fujishiro, Mitsuhiro, Koike, Kazuhiko, Sakurai, Kouhei, Takeuchi, Chihiro, Yamamichi, Nobutake, Tsutsumi, Yutaka, Niimi, Keiko, Aburatani, Hiroyuki, Ono, Satoshi, Kageyama‐Yahara, Natsuko

2018

Overview

Intestinal metaplasia induced by ectopic expression of caudal‐type homeobox (CDX)2 and/or CDX1 (CDX) is frequently observed around gastric cancer (GC). Abnormal expression of CDX is also observed in GC and suggests that inappropriate gastrointestinal differentiation plays essential roles in gastric tumorigenesis, but their roles on tumorigenesis remain unelucidated. Publicly available databases show that GC patients with higher CDX expression have significantly better clinical outcomes. We introduced CDX2 and CDX1 genes separately into GC‐originated MKN7 and TMK1 cells deficient in CDX. Marked suppression of cell growth and dramatic morphological change into spindle‐shaped flat form were observed along with induction of intestinal marker genes. G0‐G1 growth arrest was accompanied by changed expression of cell cycle‐related genes but not with apoptosis or senescence. Microarray analyses additionally showed decreased expression of gastric marker genes and increased expression of stemness‐associated genes. Hierarchical clustering of 111 GC tissues and 21 non‐cancerous gastric tissues by selected 18 signature genes based on our transcriptome analyses clearly categorized the 132 tissues into non‐cancer, “CDX signature”‐positive GC, and “CDX signature”‐negative GC. Gene set enrichment analysis indicated that “CDX signature”‐positive GC has lower malignant features. Immunohistochemistry of 89 GC specimens showed that 50.6% were CDX2‐deficient, 66.3% were CDX1‐deficient, and 44.9% were concomitant CDX2/CDX1‐deficient, suggesting that potentially targetable GC cases by induced intestinal differentiation are quite common. In conclusion, exogenous expression of CDX2/CDX1 can lead to efficient growth inhibition of CDX‐deficient GC cells. It is based on rapidly induced intestinal differentiation, which may be a future therapeutic strategy. Exogenous expression of CDX2/CDX1 can lead to G0‐G1 growth arrest in CDX‐deficient gastric cancer cells, accompanied by induction of intestinal genes and decreased expression of gastric genes. Publicly available databases and hierarchical clustering of gastric tissue showed that gastric cancer with CDX expression has significantly better clinical outcomes. A novel therapy against gastric cancer based on induced intestinal differentiation may be possible in the future.

• Publisher: John Wiley and Sons Inc
• Subject: CDX / CDX2 Transcription Factor - genetics / CDX2 Transcription Factor - metabolism / Cell Differentiation / Cell Line, Tumor / Cell Proliferation / gastric cancer / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Gene Regulatory Networks / hierarchical clustering / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humans / intestinal differentiation / Oligonucleotide Array Sequence Analysis / Original / Stomach Neoplasms - genetics / Stomach Neoplasms - therapy / Survival Analysis / transcriptome / Transduction, Genetic