Distinct subgroup of the Ras family member 3 (DIRAS3) expression impairs metastasis and induces autophagy of gastric cancer cells in mice.

PURPOSE:Distinct 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. METHODS:This 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. RESULTS:DIRAS3 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. CONCLUSIONS:In 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.

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