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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3853-3864
Number of pages12
JournalCancer science
Volume109
Issue number12
DOIs
Publication statusPublished - 12-2018

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Homeobox Genes
Stomach Neoplasms
Growth
Stomach
Genes
Carcinogenesis
cdc Genes
Metaplasia
Gene Expression Profiling
Microarray Analysis
Cluster Analysis
Immunohistochemistry
Databases
Apoptosis
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Nakayama, Chiemi ; Yamamichi, Nobutake ; Tomida, Shuta ; Takahashi, Yu ; Kageyama-Yahara, Natsuko ; Sakurai, Kouhei ; Takeuchi, Chihiro ; Inada, Ken ichi ; Shiogama, Kazuya ; Nagae, Genta ; Ono, Satoshi ; Tsuji, Yosuke ; Niimi, Keiko ; Fujishiro, Mitsuhiro ; Aburatani, Hiroyuki ; Tsutsumi, Yutaka ; Koike, Kazuhiko. / Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation. In: Cancer science. 2018 ; Vol. 109, No. 12. pp. 3853-3864.
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title = "Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation",
abstract = "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.",
author = "Chiemi Nakayama and Nobutake Yamamichi and Shuta Tomida and Yu Takahashi and Natsuko Kageyama-Yahara and Kouhei Sakurai and Chihiro Takeuchi and Inada, {Ken ichi} and Kazuya Shiogama and Genta Nagae and Satoshi Ono and Yosuke Tsuji and Keiko Niimi and Mitsuhiro Fujishiro and Hiroyuki Aburatani and Yutaka Tsutsumi and Kazuhiko Koike",
year = "2018",
month = "12",
doi = "10.1111/cas.13821",
language = "English",
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Nakayama, C, Yamamichi, N, Tomida, S, Takahashi, Y, Kageyama-Yahara, N, Sakurai, K, Takeuchi, C, Inada, KI, Shiogama, K, Nagae, G, Ono, S, Tsuji, Y, Niimi, K, Fujishiro, M, Aburatani, H, Tsutsumi, Y & Koike, K 2018, 'Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation', Cancer science, vol. 109, no. 12, pp. 3853-3864. https://doi.org/10.1111/cas.13821

Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation. / Nakayama, Chiemi; Yamamichi, Nobutake; Tomida, Shuta; Takahashi, Yu; Kageyama-Yahara, Natsuko; Sakurai, Kouhei; Takeuchi, Chihiro; Inada, Ken ichi; Shiogama, Kazuya; Nagae, Genta; Ono, Satoshi; Tsuji, Yosuke; Niimi, Keiko; Fujishiro, Mitsuhiro; Aburatani, Hiroyuki; Tsutsumi, Yutaka; Koike, Kazuhiko.

In: Cancer science, Vol. 109, No. 12, 12.2018, p. 3853-3864.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation

AU - Nakayama, Chiemi

AU - Yamamichi, Nobutake

AU - Tomida, Shuta

AU - Takahashi, Yu

AU - Kageyama-Yahara, Natsuko

AU - Sakurai, Kouhei

AU - Takeuchi, Chihiro

AU - Inada, Ken ichi

AU - Shiogama, Kazuya

AU - Nagae, Genta

AU - Ono, Satoshi

AU - Tsuji, Yosuke

AU - Niimi, Keiko

AU - Fujishiro, Mitsuhiro

AU - Aburatani, Hiroyuki

AU - Tsutsumi, Yutaka

AU - Koike, Kazuhiko

PY - 2018/12

Y1 - 2018/12

N2 - 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.

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