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  • br SUMMARY br Sal like protein and

    2020-08-28

    
    36 SUMMARY
    38 Sal-like protein 4 and Krüppel-like factor 5 expression is
    39 strongly up-regulated in capping UNC-1999 protein of muscle Z-
    40 line a subunit 1 (CAPZA1)-overexpressing cells after Heli-
    41 cobacter pylori infection. High epithelial splicing regulatory
    42 protein 1 expression in CAPZA1-overexpressing cells infec-
    43 ted with H pylori induces CD44 variant 9 expression. CD44
    44 variant 9–positive gastric cancer stem-like cells are devel-
    45 oped from CAPZA1-overexpressing cells infected with H
    50 cancer stem-like cells strongly contribute to the development
    52 CD44v9-positive cells is uncertain. 53 54 METHODS: CD44v9, b-catenin, and epithelial splicing regula-
    55 tory protein 1 signals were assessed by real-time reverse-
    56 transcription polymerase chain reaction, immunoblot analysis,
    57 or immunofluorescence microscopy. Capping actin protein of
    58 muscle Z-line a 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 malon-dialdehyde 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 AGS cells.
    RESULTS: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of b-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 b-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  75
    2 Tsugawa et al Cellular and Molecular Gastroenterology and Hepatology Vol. -, No. -
    117 into the mechanisms underlying the development of CD44v9-
    125Q7 Q8 ancer stem cells are found in several cancer tissues
    126Q9 Cand are considered to facilitate tumorigenesis
    127 because of their abilities to self-renew and transform into
    128 multiple cell types.1 CD44 is a cell-surface marker impli-
    129 cated in the development of cancer stem cells. Several iso-
    130 forms of CD44 are generated by alternative splicing of its
    131 variant exons.2 CD44 variant 9 (CD44v9)-positive cancer 132 stem-like cells show enhanced metastasis and treatment
    133 resistance.3,4 These cells strongly contribute to the devel-
    134 opment and recurrence of gastric cancer.5–7 However, the 135 origin of CD44v9-positive cells is uncertain.
    136 Large-scale prospective cohort studies have shown a
    137 close relationship between chronic Helicobacter pylori
    138 infection and gastric carcinogenesis.8,9 The H pylori–derived
    139 virulence factor cytotoxin-associated gene A (CagA) trans-
    140 locates into host epithelial cells via the bacterial type IV
    141 secretion system and functions as an oncogenic driver in
    142 gastric epithelial cells.10–12 CagA causes reprogramming and
    143 de-differentiation of fully differentiated cells into tissue
    144 stem-like precursor cells with cancer stem cell proper-
    145 ties.13–15 However, translocated CagA usually is degraded by
    146 autophagy.16 Therefore, CagA must evade autophagic 147 degradation and accumulate in host epithelial cells to pro-
    148 mote their reprogramming and differentiation into tissue
    149 stem-like precursor cells with cancer stem cell properties.
    150 Indeed, our previous report showed that translocated CagA
    151 accumulates in CD44v9-positive cancer stem-like cells in
    152 human gastric cancer tissues by evading autophagic
    153 degradation.16 154 Capping actin protein of muscle Z-line a subunit 1
    155 (CAPZA1) plays an important role in the regulation of actin
    156 polymerization and cell motility by binding to the barbed