{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIn breast cancers, miR-665 is frequently upregulated and functions as an oncomiR by promoting epithelial‐mesenchymal transition (EMT), proliferation, migration, and invasion. Elevated miR-665 levels are associated with increased metastatic dissemination and poorer patient outcomes, largely through the downregulation of targets such as nuclear receptor NR4A3 that leads to activation of the MEK signaling cascade."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of intestinal injury and inflammation, miR-665 (or its isoform miR-665-3p) plays a notable role in modulating autophagy and apoptotic pathways. In models of intestinal ischemia/reperfusion, its high expression impairs autophagic flux by directly targeting ATG4B, thereby exacerbating inflammation and cell death. Similarly, in inflammatory bowel disease, upregulation of miR-665 correlates with enhanced apoptosis under inflammatory stimuli through direct repression of key endoplasmic reticulum stress regulators, such as XBP1 and ORMDL3."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nConversely, in cervical cancer cells, miR-665 is downregulated and acts as a tumor-suppressing factor. Restoration of its levels inhibits cell proliferation, migration, and invasion, in part by directly repressing transforming growth factor beta receptor 1 (TGFBR1) and modulating the downstream ERK/SMAD signaling pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic studies in other malignancies have revealed that miR-665 is subject to upstream regulation by transcription factors. For example, in a metastasis model, ΔNp63α represses miR-665 (along with miR-527), which results in the de-repression of TGFβ effectors, including SMAD4 and TGFBR2, thereby facilitating metastatic spread."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn gastric cancers, miR-665 expression appears to be context dependent. In gastric signet ring cell carcinoma, miR-665 is downregulated, whereas in intestinal-type gastric adenocarcinoma its upregulation is linked to aggressive tumor behavior. In the latter, miR-665 promotes tumor progression by targeting suppressor of cytokine signaling 3 (SOCS3) and thereby activating downstream signaling via the FAK/Src pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn ovarian cancer, miR-665 appears to serve a tumor-suppressive role. Its overexpression leads to the inhibition of cell proliferation, migration, and invasion by directly targeting oncogenic factors such as HOXA10, and low miR-665 expression in ovarian tumors is associated with more aggressive disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCardiovascular studies also implicate miR-665 in disease modulation. In chronic heart failure, a significant decrease in miR-665 is observed; under normal conditions, miR-665 mediates the regulation of cannabinoid receptor signaling by targeting CB2 receptors, implicating its role in protecting myocardial tissue through modulating the endocannabinoid system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hematologic malignancies, particularly acute lymphoblastic leukemia (ALL), high miR-665 expression contributes to disease progression by promoting cell growth and inhibiting apoptosis. This oncogenic activity is mediated through the direct targeting of EXT1, which leads to the activation of the ERK1/2 signaling pathway, correlating with poor patient survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn osteosarcoma, a competing endogenous RNA (ceRNA) mechanism has been elucidated wherein the long noncoding RNA SND1-IT1 sequesters miR-665. This sequestration relieves miR-665-mediated repression of the transcription factor POU2F1, suggesting that under normal circumstances, miR-665 may act to restrain oncogenic signaling pathways in osteosarcoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, in neuroinflammatory and infectious contexts, miR-665-3p plays a protective role. In microglial cells subjected to oxygen-glucose deprivation (a stroke model), overexpression of miR-665-3p attenuates apoptosis and inflammatory responses by targeting TRIM8 and thereby inhibiting NF-κB signaling. Similarly, during Mycobacterium tuberculosis infection, a MIAT-mediated downregulation of miR-665 leads to altered autophagy via ULK1, influencing antimicrobial responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xin-Ge Zhao, Jing-Ye Hu, Jun Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-665 expression predicts poor survival and promotes tumor metastasis by targeting NR4A3 in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-1705-z"}], "href": "https://doi.org/10.1038/s41419-019-1705-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31209222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31209222"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jing Li, Weichao Wang, Yajia Zhang, et al. 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