{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HOXB‐AS3 is a multifunctional long noncoding RNA that exhibits context‐dependent roles in human disease. In colon cancer, HOXB‐AS3 is unique in that its transcript encodes a conserved 53–amino acid micropeptide that suppresses tumor growth by interfering with hnRNP A1–mediated pyruvate kinase M splicing, thereby curtailing metabolic reprogramming."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In contrast, in hematologic malignancies such as acute myeloid leukemia and myelodysplastic syndromes, elevated HOXB‐AS3 expression promotes cell proliferation by engaging with effector proteins (e.g., EBP1) to enhance ribosomal RNA transcription and expedite cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In several solid tumors, including non–small cell lung cancer, epithelial ovarian cancer, hepatocellular carcinoma, endometrial carcinoma, and oral squamous cell carcinoma, HOXB‐AS3 functions predominantly as an oncogene. For example, its upregulation in lung cancer is associated with enhanced proliferation and invasion through modulation of the PI3K/AKT pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while in ovarian and endometrial cancers, HOXB‐AS3 promotes malignant behaviors via mechanisms that include deregulation of glycolytic factors through microRNA sponging"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and upregulation of ADAM9 by sequestering miR‐498‑5p."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In hepatocellular carcinoma, it interacts with DNMT1 to epigenetically repress p53, thereby facilitating cell proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and in oral squamous cell carcinoma, its encoded protein directly binds IGF2BP2 to stabilize c–Myc."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its oncogenic roles, HOXB‐AS3 also exerts protective functions; in doxorubicin–treated cardiomyocytes, it mitigates cytotoxicity by targeting miR–875–3p and restoring proliferative capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Its deep evolutionary conservation further suggests developmental functions; along with its paralog HOXA–AS3, HOXB–AS3 is involved in regulating the expression of HOX genes during embryonic differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Moreover, recent reviews have underscored the broader significance of small open reading frame–derived peptides encoded by HOXB‐AS3 in cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and its role in forming complexes with EZH2 to suppress Dicer expression has been implicated in sorafenib resistance in liver cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Finally, HOXB‐AS3 has emerged as a component of prognostic RNA signatures in prostate cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies reveal that HOXB‐AS3 can function either as a tumor suppressor or as an oncogene depending on the cellular context and cancer type. It achieves its diverse effects through multiple mechanisms—including metabolic regulation, modulation of alternative splicing, promoter and chromatin interactions, and microRNA sponging—highlighting its potential as a diagnostic biomarker and therapeutic target.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jin-Zhou Huang, Min Chen, De Chen, et al. 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