{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMIGD3 encodes multiple isoforms, of which isoform1 (i1) acts as a suppressor of osteosarcoma (OS) progression by inhibiting anchorage‐ and serum‐independent growth. Mechanistically, overexpression of TMIGD3 i1—but not isoform3 (i3) sharing a common C-terminal region—reduces malignant properties such as increased cell proliferation, tumor formation, and metastasis through inhibition of NF‑κB activity. This suppression of NF‑κB activity is achieved in part by downregulating the PKA-Akt-NF‑κB signaling axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\nDisrupting TMIGD3 expression by knockdown experiments results in enhanced tumorigenic properties, underscoring its role as a protective factor in OS. Notably, the study identifies that the adenosine A3 receptor (A3AR), which shares an identical N-terminal region with TMIGD3 i1 and exhibits similar biological profiles, also acts to inhibit this signaling axis. However, TMIGD3 i1 only partially rescues the phenotype induced by A3AR knockdown, suggesting that while their inhibitory pathways converge on the PKA-Akt-NF‑κB route, TMIGD3 i1 might also operate through additional, distinct mechanisms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\nFurthemore, reduced protein expression levels of both TMIGD3 and A3AR are observed in human OS tissues compared to normal tissues, reinforcing the notion that diminished TMIGD3 expression contributes to OS aggressiveness. These findings collectively reveal an unappreciated tumor suppressor role for TMIGD3 i1, positioning it as a potential diagnostic marker and therapeutic target in osteosarcoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Swathi V Iyer, Atul Ranjan, Harold K Elias, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide RNAi screening identifies TMIGD3 isoform1 as a suppressor of NF-κB and osteosarcoma progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms13561"}], "href": "https://doi.org/10.1038/ncomms13561"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27886186"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27886186"}]}]}]}