{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HOXD9 is emerging as a multifunctional gene that plays dual roles in embryonic development and tumorigenesis. On the developmental side, as a member of the 5′ HOXD cluster, HOXD9 contributes to proper limb patterning and skeletal morphogenesis. Genetic alterations—including deletions and single‐nucleotide polymorphisms—in the HOXD9 region have been linked to congenital limb malformations such as synpolydactyly and aberrant digit formation, as well as to developmental dysplasia of the hip, suggesting that precise dosage of HOXD9 is important for normal musculoskeletal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the molecular level, nuclear magnetic resonance analyses of the HOXD9 homeodomain–DNA complex have revealed that the dynamic behavior of lysine side‐chain interactions—mediated by temperature‐dependent rotational motions and hydrogen bond rearrangements—may facilitate efficient DNA binding and target gene regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the oncogenic context, HOXD9 is frequently overexpressed in a variety of malignancies. In melanoma brain metastasis, altered DNA methylation at the HOXD9 promoter correlates with changes in transcript and protein levels and is linked to patient prognosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In mucinous ovarian carcinoma, genetic risk variants associate with deregulated HOXD9 expression that augments the neoplastic phenotype"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while in glioma, HOXD9 promotes cell proliferation and survival, marking a subpopulation of cancer stem-like cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Similarly, in gastric cancer, elevated HOXD9 levels drive tumor growth, invasion, and metastasis via transcriptional activation of downstream targets such as RUFY3"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and in lung squamous cell carcinoma, its upregulation has been identified as part of a distinctive gene expression signature."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " More recently, in colorectal cancer, TGF-β1–dependent upregulation of HOXD9 has been shown to induce epithelial-to-mesenchymal transition and promote invasion and metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings indicate that HOXD9 serves as a critical developmental regulator with a high sensitivity to gene dosage and epigenetic modulation, while its aberrant expression in various cancers contributes to increased cell proliferation, invasion, and metastatic behavior. As such, HOXD9 represents both a potential diagnostic marker and a therapeutic target in oncology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Frances R Goodman, Frank Majewski, Amanda L Collins, et al. 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