{"type": "root", "children": [{"type": "t", "text": "<div>\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Long non‐coding RNA HOTTIP acts as a central oncogenic regulator in diverse cancers by re‐programming chromatin states and modulating key transcriptional networks. In hepatocellular carcinoma and gastric cancer, HOTTIP is significantly up‐regulated and forms a bidirectional regulatory loop with 5′ HOXA genes (especially HOXA13), via recruitment of the WDR5/MLL complex to induce H3K4 trimethylation, thereby enhancing proliferation, invasion, metastasis, and correlating with poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In pancreatic ductal adenocarcinoma, HOTTIP overexpression drives tumor progression and chemoresistance—mediated at least in part through activation of HOXA13 transcription and engagement of the Wnt/β-catenin pathway—with a further role in maintaining cancer stem cell properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In esophageal squamous cell carcinoma and papillary thyroid carcinoma, HOTTIP contributes to epithelial-mesenchymal transition and promotes invasion and migration by functioning as a competing endogenous RNA that sequesters microRNAs (e.g., miR-30b and miR-637), thereby alleviating repression of downstream oncogenic targets."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, in small cell lung cancer HOTTIP exerts oncogenic effects by binding miR-216a to relieve its suppression of anti-apoptotic factors such as BCL-2, which enhances chemoresistance and tumor growth"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and in ovarian cancer, HOTTIP promotes immune evasion by interacting with c-jun to upregulate IL-6 production and, in turn, PD-L1 expression on neutrophils."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, additional layers of regulation are apparent in hepatocellular carcinoma, where miRNAs such as miR-192 and miR-204 help control HOTTIP expression, highlighting its integration into broader oncogenic networks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings demonstrate that HOTTIP is a multifaceted oncogenic lncRNA whose aberrant expression facilitates tumor aggressiveness, metastasis, chemoresistance, and immune escape across multiple malignancies. Its pivotal function in reactivating HOXA loci and co-opting microRNA‐mediated repression underscores its promise as a prognostic biomarker and potential therapeutic target.\n "}]}, {"type": "t", "text": "\n</div>"}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Luca Quagliata, Matthias S Matter, Salvatore Piscuoglio, et al. 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