{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‐22 is a multifunctional regulator whose effects depend on cellular context. In breast cancer models, for example, miR‐22 promotes epithelial–mesenchymal transition, enhances invasiveness and expands the cancer stem cell compartment via targeting TET‐family dioxygenases and thereby silencing antimetastatic miR‐200."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " By contrast, in hematopoietic malignancies its upregulation fosters aberrant stem cell self‐renewal and contributes to malignant transformation through repression of TET2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", whereas in other settings miR‐22 triggers cellular senescence through downregulation of key cell cycle and survival regulators including CDK6, SIRT1 and Sp1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hormone‐dependent cancers, miR‐22 directly represses estrogen receptor α by targeting its extended 3′ untranslated region (UTR)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and further diminishes oncogenic signals by reducing CD147 expression through both direct targeting of its 3′UTR and indirect modulation via Sp1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, miR‐22 regulates mesenchymal lineage choices by attenuating adipogenic differentiation while promoting osteogenesis through suppression of HDAC6"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and it also participates in the control of vascular cell phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMiR‐22 further modulates critical oncogenic signaling pathways and stress responses. In colon cancer, its overexpression reduces hypoxia‐induced HIF‐1α and VEGF production, thereby exerting an anti‐angiogenic effect."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In response to genotoxic stress, miR‐22 is induced as a p53 target and functions to repress p21, favoring apoptosis over cell cycle arrest."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Notably, in p53‐mutant colon cancer cells, enforced miR‐22 expression can enhance chemosensitivity through upregulation of PTEN and subsequent attenuation of the AKT pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA broad spectrum of miR‐22 targets further underscores its role in curbing oncogenic signals. MiR‐22 downregulates MYCBP, an essential coactivator of c-Myc, thereby dampening proliferative cascades"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and in acute myeloid leukemia its restoration inhibits leukaemic cell viability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In diverse tumor types—including gastric, breast, bladder and melanoma—miR‐22 suppresses epithelial–mesenchymal transition and invasion by targeting key regulators such as MMP14, Snail and MAPK1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "20"}]}, {"type": "t", "text": " Moreover, in Ewing sarcoma, reduced miR‐22 levels permit overexpression of the histone demethylase KDM3A, while in osteosarcoma it targets HMGB1 to block autophagy and mitigate chemoresistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMiR‐22 is also embedded within a complex regulatory network that integrates diverse extracellular and intracellular signals. Long noncoding RNAs and circular RNAs—such as DGCR5 and MALAT1—can sequester miR‐22, thereby modulating its availability and impacting pathways including NF‐κB signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "26"}]}, {"type": "t", "text": " In addition, regulatory inputs from agents like diallyl disulfide lead to miR‐22 upregulation and cooperate with other miRNAs (e.g. miR‐200b) to target oncogenic factors, including Wnt‐1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " The modulation of endothelial function by MALAT1 via miR‐22, which affects CXCR2 expression and the AKT pathway, further illustrates its role in vascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Circulating miR‐22 levels have been proposed as non‐invasive biomarkers in settings such as prostate cancer, premature ovarian failure and endometriosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "32"}]}, {"type": "t", "text": " Moreover, miR‐22 can temper NF‐κB activity by targeting coactivators"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": ", and it controls glucocerebrosidase expression via interactions with its pseudogene GBAP1, a mechanism relevant to Parkinson’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Finally, its transcriptional induction by bile acid–activated FXR, which leads to cyclin A2 suppression, and its upregulation by TPA to modulate the Myc–Max axis, underscore additional layers of regulation that link miR‐22 to differentiation and growth arrest."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Su Jung Song, Laura Poliseno, Min Sup Song, et al. 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