Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells

Hitoshi Tsugawa, Chihiro Kato, Hideki Mori, Juntaro Matsuzaki, Kaori Kameyama, Hideyuki Saya, Masanori Hatakeyama, Makoto Suematsu, Hidekazu Suzuki

Research output: Contribution to journalArticle

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Abstract

Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

Original languageEnglish
Pages (from-to)319-334
Number of pages16
JournalCMGH
Volume8
Issue number3
DOIs
Publication statusPublished - 2019 Jan 1

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Helicobacter
Neoplastic Stem Cells
Catenins
Protein Splicing
Histones
Oxidative Stress
Cytotoxins
Acetylation
Gastric Mucosa
Stomach Neoplasms
Protein Carbonylation
Gerbillinae
Chromatin Immunoprecipitation
Alternative Splicing
Malondialdehyde
Fluorescence Microscopy
Genetic Promoter Regions
Genes
Reverse Transcription
Actins

Keywords

  • Autophagy
  • CagA
  • Cancer Stem Cells
  • CD44v9
  • Eradication Therapy

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells. / Tsugawa, Hitoshi; Kato, Chihiro; Mori, Hideki; Matsuzaki, Juntaro; Kameyama, Kaori; Saya, Hideyuki; Hatakeyama, Masanori; Suematsu, Makoto; Suzuki, Hidekazu.

In: CMGH, Vol. 8, No. 3, 01.01.2019, p. 319-334.

Research output: Contribution to journalArticle

Tsugawa, Hitoshi ; Kato, Chihiro ; Mori, Hideki ; Matsuzaki, Juntaro ; Kameyama, Kaori ; Saya, Hideyuki ; Hatakeyama, Masanori ; Suematsu, Makoto ; Suzuki, Hidekazu. / Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells. In: CMGH. 2019 ; Vol. 8, No. 3. pp. 319-334.
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AU - Kato, Chihiro

AU - Mori, Hideki

AU - Matsuzaki, Juntaro

AU - Kameyama, Kaori

AU - Saya, Hideyuki

AU - Hatakeyama, Masanori

AU - Suematsu, Makoto

AU - Suzuki, Hidekazu

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N2 - Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

AB - Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

KW - Autophagy

KW - CagA

KW - Cancer Stem Cells

KW - CD44v9

KW - Eradication Therapy

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