{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR-646 has emerged as a regulatory microRNA whose dysregulated expression is linked to a variety of human diseases. For example, genetic variations in miR-646 have been associated with hepatocellular carcinoma risk, while aberrant expression of miR-646 has been reported in gastric cancer, suggesting its potential involvement in tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic studies reveal that miR-646 predominantly functions as a tumor suppressor by directly targeting a spectrum of oncogenes and regulatory proteins. In pancreatic cancer, hypoxia-induced HIF‑1α stimulates miR‑646 expression to destabilize MIIP mRNA, thereby promoting tumor cell proliferation and invasion. In endometrial carcinoma, long noncoding RNAs such as HOTAIR and circular RNAs like circWHSC1 act as “sponges” for miR‑646, leading to the derepression of downstream effectors such as nucleophosmin 1 (NPM1). Similarly, in laryngeal squamous cell carcinoma, circ‑CCND1 sequesters miR‑646 to relieve its inhibitory effect on cyclin D1 (CCND1) expression. In prostate cancer, an oncometabolite‐driven increase of circRNA‑51217 sequesters miR‑646 to enhance transforming growth factor‑β1 (TGFβ1) signaling. Additional studies show that miR‑646 directly targets fibroblast growth factor 2 (FGF2) and cyclin D2 (CCND2) in non‑small cell lung cancer, downregulates histone deacetylase 2 (HDAC2) in breast cancer, and suppresses glutathione peroxidase 1 (GPX1) in laryngeal carcinoma. In osteosarcoma, the lncRNA MT1JP upregulates miR‑646 to downregulate FGF2, thereby inhibiting cell migration and invasion. In ocular disorders, circular RNAs such as circ_0041795 and circ_0000527 sponge miR‑646 to modulate the expression of VEGFC and BCL‑2 in diabetic retinopathy and retinoblastoma, respectively, while in primary open‑angle glaucoma, circHBEGF sponges miR‑646 to regulate epidermal growth factor receptor (EGFR) expression. Moreover, in oral squamous cell carcinoma, circ‑PKD2 promotes autophagy and apoptosis through miR‑646 sequestration and subsequent upregulation of Atg13, and in non‑small cell lung cancer, miR‑646 itself directly suppresses proliferation, clonogenicity, invasion, and epithelial-to-mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these observations underscore the multifaceted role of miR‑646 in controlling cell proliferation, migration, invasion, apoptosis, and even autophagy across diverse cellular contexts. The loss or functional attenuation of miR‑646—frequently mediated by its sequestration via circular or long noncoding RNAs—leads to the upregulation of several oncogenic pathways, suggesting that restoring miR‑646 function or disrupting its negative regulatory interactions may offer promising therapeutic avenues in cancer as well as in certain nonmalignant diseases.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rui Wang, Jun Zhang, Weiru Jiang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/bjc.2017.181"}], "href": "https://doi.org/10.1038/bjc.2017.181"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28632723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28632723"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yi Niu, Yan Jin, Shi-Chang Deng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-017-0082-2"}], "href": "https://doi.org/10.1038/s41388-017-0082-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29343850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29343850"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yun-Xiao Zhou, Chuan Wang, Li-Wei Mao, et al. 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