Abstract
PurposeDistinct subgroup of the Ras family member 3 (DIRAS3), also called Aplasia Ras homolog member I, is a tumor suppressor gene that induces autophagy in several cancer cell lines.MethodsThis study analyzed DIRAS3, and markers of autophagy (p62, and LC3B-II) in surgically resected GC samples from 420 patients. The promotion of autophagy by DIRAS3 in gastric cancer (GC) cells was explored, which might explain its inhibitory role in gastric cancer cells.ResultsDIRAS3 expression in GC was positively correlated with LC3B-II amount, and negatively with metastasis; DIRAS3 and p62 levels were independent prognostic factors in GC. Overexpression of DIRAS3 in BGC-823 cells induced autophagy, led to decreased proliferation, cell cycle arrest in G0/G1 phase, increased apoptosis, and impaired migration and invasion. While knockdown of DIRAS3 promoted proliferation and migration in MKN-45 cells. Overexpression of DIRAS3 in BGC-823 cells elevated autophagy levels in subcutaneous xenograft and inhibited tumor growth in mice; the hematogenous liver and lung metastasis of cancer cells were also suppressed.ConclusionsIn conclusion, the results suggest DIRAS3 may play a role in affecting proliferation and metastatic potential of GC cells, which may be associated with its involvement in autophagy regulation.
Highlights
Basal autophagy eliminates damaged cellular components and the resulting breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways (White et al 2015)
The relationship between DIRAS3 expression in clinical specimens and metastasis is still unclear, and as far as we know there have been no studies relating to DIRAS3 and its role in autophagy in gastric cancer (GC)
This study found that DIRAS3, as a tumor suppressor gene, is an independent prognostic factor in GC and that this may be related to increased levels of autophagy when DIRAS3 is expressed
Summary
Basal autophagy eliminates damaged cellular components and the resulting breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways (White et al 2015). Some cancers use autophagy-mediated recycling to meet their high metabolic demand for growth and proliferation. Autophagy prevents the buildup of toxins and so limits oxidative stress, chronic tissue damage, and oncogenic signaling (White et al 2015). Consider autophagy to impede early cancer development while facilitating advanced tumor progression and metastasis (Kenific 2015). LC3B-II is a marker for autophagic structures, and its turnover is widely used as an indicator to monitor autophagy flux (Klionsky et al 2016; Mizushima et al 2010). P62, an oncogene, acts as a signal hub between autophagy and Journal of Cancer Research and Clinical Oncology (2018) 144:1869–1886 proteasome degradation pathways (Moscat and Diaz-Meco 2009). LC3B-II is a marker for autophagic structures, and its turnover is widely used as an indicator to monitor autophagy flux (Klionsky et al 2016; Mizushima et al 2010). p62, an oncogene, acts as a signal hub between autophagy and Journal of Cancer Research and Clinical Oncology (2018) 144:1869–1886 proteasome degradation pathways (Moscat and Diaz-Meco 2009). p62 accumulates due to the lack of effective degradation in autophagy-deficient conditions, suggesting that the increase in p62 expression may indicate autophagy deficiency (Ichimura et al 2008)
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