{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DIRAS1, a member of the DIRAS family of small Ras‐related GTPases, has emerged in multiple studies as a potent tumor suppressor whose loss or downregulation is associated with aggressive disease. In esophageal squamous cell carcinoma, for example, reduced DIRAS1 expression—mediated in part by loss of heterozygosity and promoter methylation—correlates with advanced clinical stage, lymph node metastasis, and poorer overall survival. Re‐expression of DIRAS1 in these tumors suppresses cell proliferation, motility, and tumor formation by modulating mitogen‐activated protein kinase (MAPK) signaling (specifically ERK1/2 and p38) to promote apoptotic cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Similar tumor‐suppressive roles have been described in osteosarcoma, where nuclear DIRAS1 curtails malignant behaviors—its silencing enhances proliferation, invasion, migration and impedes apoptosis—while its overexpression inactivates the ERK pathway. In renal cell carcinoma, epigenetically driven loss of DIRAS1 expression is again linked to increased proliferation and invasion, with restoration of DIRAS1 resulting in growth inhibition, enhanced apoptosis, and reduced tumorigenicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In gliomas, DIRAS1 is markedly downregulated relative to non‐neoplastic brain tissue, underscoring its putative tumor‐suppressive role in the central nervous system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In ovarian cancer, along with its paralogues, DIRAS1 contributes to growth suppression by inducing autophagy; this is achieved through concurrent inhibition of the AKT1–mTOR and RAS–MAPK pathways, ultimately leading to autophagy‐mediated cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the molecular level, DIRAS1 can interact directly with the chaperone SmgGDS and act in a dominant‐negative manner to competitively block the binding of other small oncogenic GTPases, thereby restraining their activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in tumor suppression, a genetic alteration (a recessive 4‐bp deletion) in the DIRAS family has been implicated in canine generalized myoclonic epilepsy with photosensitivity, hinting at broader physiological functions for DIRAS1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these data indicate that DIRAS1 functions as a critical tumor suppressor across a spectrum of malignancies—exerting its effects via modulation of key signaling pathways, promotion of apoptosis or autophagy, and interference with oncogenic small GTPase activation. Restoration or therapeutic modulation of DIRAS1 therefore presents a promising strategy for cancers characterized by its loss.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ying-Hui Zhu, Li Fu, Leilei Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of the novel tumor suppressor DIRAS1 predicts poor prognosis in esophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-2663"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-2663"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23436800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23436800"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Huan Liu, Weibin Shu, Tianyue Liu, et al. 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