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Downregulation of ARID1A in gastric cancer cells: a putative protective molecular mechanism against the Harakiri-mediated apoptosis pathway

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Abstract

This study was designed to unravel the pathobiological role of impaired ARID1A expression in gastric carcinogenesis. We examined ARID1A expression immunohistochemically in 98 gastric cancer tissue specimens with regard to the clinicopathological features. Based on the proportion and intensity of ARID1A immunoreactivity at the cancer invasion front, we subdivided the specimens into low- and high-expression ARID1A groups. Notably, low ARID1A expression was significantly correlated with overall survival of the patients. Subsequently, we determined the molecular signature that distinguished ARID1A low/poor prognosis from ARID1A high/good prognosis gastric cancers. A comprehensive gene profiling analysis followed by immunoblotting revealed that a mitochondrial apoptosis mediator, Harakiri, was less expressed in ARID1A low/poor prognosis than ARID1A high/good prognosis gastric cancers. siRNA-mediated ARID1A downregulation significantly reduced expression of the Harakiri molecule in cultured gastric cancer cells. Interestingly, downregulation of ARID1A conferred resistance to apoptosis induced by the mitochondrial metabolism inhibitor, devimistat. In contrast, enforced Harakiri expression restored sensitivity to devimistat-induced apoptosis in ARID1A downregulated gastric cancer cells. The present findings indicate that impaired ARID1A expression might lead to gastric carcinogenesis, putatively through gaining resistance to the Harakiri-mediated apoptosis pathway.

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Data availability

The microarray data have been deposited to the GEO database with accession number GSE110078.

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Acknowledgments

We thank Dr. Hayao Nakanishi at the Division of Oncological Pathology, Aichi Cancer Center Research Institute, for the kind gift of GPM-2 gastric cancer cells.

Contributions

TS: analyzing data, collecting data, preparing manuscript

YI, IY: analyzing data, technical support, preparing manuscript

CS, YK: technical support

TT and KY: study design, collecting data, analyzing data, preparing manuscript

Funding

This study was supported by grants from the Ministry of Education of Japan (grant nos. 20K07406, KAKEN 15K08361, 15K19051).

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Authors and Affiliations

  1. Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan

    Takuji Sakuratani, Itaru Yasufuku, Yoshinori Iwata & Kazuhiro Yoshida

  2. Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, 501-1193, Japan

    Tamotsu Takeuchi, Chiemi Saigo & Yusuke Kito

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  1. Takuji Sakuratani
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  2. Tamotsu Takeuchi
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  3. Itaru Yasufuku
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  4. Yoshinori Iwata
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Correspondence to Tamotsu Takeuchi.

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This study was approval of the Institutional Review Board of the Gifu University Graduate School of Medicine (specific approval numbers: 28-482 and 28-523). Informed consent was obtained from all participants or authorized representatives. The present study was conducted in accordance with the ethical standards of the 1975 Helsinki Declaration.

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Sakuratani, T., Takeuchi, T., Yasufuku, I. et al. Downregulation of ARID1A in gastric cancer cells: a putative protective molecular mechanism against the Harakiri-mediated apoptosis pathway. Virchows Arch 478, 401–411 (2021). https://doi.org/10.1007/s00428-020-02899-1

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