{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMicroRNA‐504 (miR-504) has emerged as a context‐dependent regulator in cancer biology. In certain settings, miR-504 functions oncogenically by directly binding the 3′ untranslated region of p53 mRNA, thereby reducing p53 protein levels and attenuating its transcriptional activity, which leads to decreased apoptosis and impaired cell cycle arrest."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In oral squamous cell carcinoma, miR-504 expression is modulated by connective tissue growth factor such that its ectopic expression enhances migration and invasion via repression of the forkhead transcription factor FOXP1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Conversely, in pancreatic ductal adenocarcinoma, miR-504 levels are elevated and correlate with lower expression of the tumor-suppressive klotho gene and increased phospho-IGF-1R, associating miR-504 with a poorer prognosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn head and neck as well as hypopharyngeal squamous cell carcinomas, miR-504 is found to be downregulated; restoration of miR-504 in these contexts results in inhibited cell proliferation and migration through targeting key cell cycle regulators such as RB1 and CDK6."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In gastric cancer models, reconstitution of TFF1 leads to suppression of miR-504 levels, thereby specifically relieving its inhibitory effect on p53 and promoting p53-dependent tumor suppression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Meanwhile, in nasopharyngeal carcinoma, increased miR-504 expression contributes to radio-resistance by targeting NRF1 and impairing mitochondrial respiratory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies in glioma and hepatocellular carcinoma further support the multifaceted role of miR-504. In glioma, overexpression of miR-504 suppresses tumor proliferation and induces apoptosis through downregulation of FOXP1, acting as a tumor suppressor"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while in hepatocellular carcinoma, miR-504 is frequently downregulated and its enforced expression inhibits cell proliferation and invasion by directly targeting the Wnt receptor FZD7, thereby dampening Wnt/β-catenin signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, in glioblastoma stem cells, decreased miR-504 levels correlate with enhanced self-renewal and invasive capacity; restoring miR-504 levels inhibits these tumorigenic properties by targeting Grb10 and even modulating the tumor microenvironment via extracellular vesicle transfer to microglia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wenwei Hu, Chang S Chan, Rui Wu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Connective tissue growth factor modulates oral squamous cell carcinoma invasion by activating a miR-504/FOXP1 signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2011.423"}], "href": "https://doi.org/10.1038/onc.2011.423"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21927029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21927029"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Diego Sanchez-Martínez, Ewelina Krzywinska, Moeez G Rathore, et al. "}, {"type": "b", "children": [{"type": "t", "text": "All-trans retinoic acid (ATRA) induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biocel.2014.01.003"}], "href": "https://doi.org/10.1016/j.biocel.2014.01.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24440757"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24440757"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Naoko Kikkawa, Takashi Kinoshita, Nijiro Nohata, et al. 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