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

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

  • Virchows Arch. 2021 Mar;478(3):401-411. doi: 10.1007/s00428-020-02899-1.
Takuji Sakuratani 1 Tamotsu Takeuchi 2 Itaru Yasufuku 1 Yoshinori Iwata 1 Chiemi Saigo 3 Yusuke Kito 3 Kazuhiro Yoshida 1
Affiliations

Affiliations

  • 1 Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
  • 2 Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, 501-1193, Japan. takeutit08@gmail.com.
  • 3 Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, 501-1193, Japan.
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.

Keywords

ARID1A; Apoptosis; Devimistat; Gastric cancer; Harakiri.

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