{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMIR4435‐2HG is a long non‑coding RNA that is consistently overexpressed in a wide variety of human cancers and is closely associated with advanced stage, metastasis and poor clinical prognosis. Its upregulation has been reported in lung, ovarian, gastric, prostate and several other carcinomas where it modulates major oncogenic signaling pathways—including Wnt/β‑catenin, TGF‑β, PI3K/AKT, MDM2/p53, Hippo and MAPK/ERK—to promote cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT) and the maintenance of cancer stem cell traits."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA common mechanistic theme is that MIR4435‑2HG functions as a competitive endogenous RNA (ceRNA), sequestering specific microRNAs and thereby derepressing their target messenger RNAs. For example, in oral squamous cell carcinoma it sponges miR‑296‑5p to modulate Akt2‐mediated upregulation of the EMT transcription factor SNAI1; in glioma it acts as a sponge for miR‑125a‑5p and miR‑125b‑5p to enhance CD44 expression; in glioblastoma cells it binds and downregulates miR‑1224‑5p to promote TGF‑β receptor 2 (TGFBR2) expression; in head and neck squamous cell carcinoma it interacts with miR‑383‑5p to upregulate RBM3; and in liver cancer, its interaction with miR‑136‑5p leads to increased expression of B3GNT5."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several tumor models, MIR4435‑2HG also promotes EMT and metastatic behavior by positively regulating TGF‑β signaling. In oral squamous cell carcinoma, for instance, its overexpression is associated with increased levels of TGF‑β1 and enhanced cell migration, proliferation and invasion—a process that can be interrupted by TGF‑β inhibitors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as a ceRNA and signal modulator, unique structural features of MIR4435‑2HG appear critical for its function. A nearly identical hairpin structure—also found in its homolog LINC00152—has been shown to be essential for promoting cellular invasion. Moreover, MIR4435‑2HG can influence cellular metabolism and immune responses; for example, in primary myeloid dendritic cells from HIV‑1 elite controllers, its upregulation is linked to enhanced immunometabolic activity via epigenetic modification of the mTORC1 component RPTOR, while in fumarate hydratase–deficient renal cell carcinoma it is induced by fumarate, binds to STAT1 and activates glutaminase (GLS1) to reprogram tumor metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, the expression of MIR4435‑2HG has emerged as an important biomarker not only for tumor aggressiveness across malignancies such as colorectal, bladder, melanoma and head and neck cancers but also in non‑malignant conditions. Its differential expression in pre‑malignant colon polyps, osteoarthritis and in exosomes derived from M2‑polarized macrophages in infantile hemangiomas underscores its potential utility for early diagnosis, prognostication and as a predictor of therapeutic response (for example, in Bacillus Calmette–Guérin–treated non‑muscle invasive bladder cancer)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Haiyun Qian, Li Chen, Jiangping Huang, et al. 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