{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMicroRNAs of the miR‐664 family have emerged as versatile regulators in a variety of biological and pathological contexts. In infectious and vascular settings, miR‐664 dysregulation was noted in influenza patients, where its altered expression, together with other microRNAs, distinguished infected from healthy individuals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similarly, in patients with obstructive sleep apnea and subclinical atherosclerosis, decreased circulating miR‑664a‑3p levels correlated with carotid intima–media thickness, suggesting its promise as a noninvasive biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of cancer, miR‑664 displays context‐dependent functions. In cutaneous malignant melanoma, miR‑664 was markedly downregulated relative to benign lesions; its ectopic expression inhibited cell proliferation, modulated cell‐cycle regulators, and directly targeted proteins such as PLP2, thereby acting as a tumor suppressor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In contrast, studies in osteosarcoma have reported its upregulation: one investigation demonstrated that heightened miR‑664 levels enhanced migration and invasion through suppression of the tumor suppressor SOX7"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while another analysis also observed upregulated miR‑664a associated with increased migratory behavior and altered interactions with the MEG3 long noncoding RNA."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In metastatic colorectal cancer, expression of miR‑664‑3p was evaluated as part of a multi‐marker signature, although its individual prognostic impact appears modest."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In breast cancer, reduced miR‑664 levels accompanied aggressive tumor features, with functional studies demonstrating that restoration of miR‑664 expression suppressed proliferation and invasion via direct targeting of IRS1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, in hepatocellular carcinoma, two distinct regulatory axes have been proposed: one study found that the lncRNA OTUD6B‑AS1 sequesters miR‑664b‑3p to enhance GSKIP/Wnt/β‑catenin signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and another predicted a MEG3/miR‑664a‑3p/ADH4 network in which MEG3 downregulation leads to miR‑664a‑3p overexpression and concomitant ADH4 suppression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, preliminary work in cutaneous squamous cell carcinoma has implicated aberrant miR‑664 expression in tumor growth and metastasis, although its specific role in this cancer type remains to be fully elucidated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond oncogenesis, miR‑664 isoforms significantly influence cellular differentiation and tissue homeostasis. In human bone marrow–derived mesenchymal stem cells, miR‑664a‑5p is upregulated during osteogenic differentiation and acts by directly targeting HMGA2, thereby promoting osteoblast formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In a neuronal differentiation model using SH‑SY5Y cells, upregulation of miR‑664a‑5p likewise enhances neurogenesis, suggesting an important role in neuronal development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In the context of kidney disease, miR‑664a‑5p levels increase in response to albumin exposure, leading to modulation of the HIPK2/Calpain1 pathway, inhibition of autophagy, and acceleration of apoptosis in renal tubular epithelial cells and podocytes—a mechanism that may contribute to the progression of idiopathic membranous nephropathy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paul A Tambyah, Sugunavathi Sepramaniam, Jaminah Mohamed Ali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "microRNAs in circulation are altered in response to influenza A virus infection in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0076811"}], "href": "https://doi.org/10.1371/journal.pone.0076811"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24116168"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24116168"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kun Li, Zhiting Chen, Yanwen Qin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-664a-3p expression in patients with obstructive sleep apnea: A potential marker of atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000009813"}], "href": "https://doi.org/10.1097/MD.0000000000009813"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29419680"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29419680"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Zhenhua Ding, Sun Jian, Xuebiao Peng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of MiR-664 Expression Enhances Cutaneous Malignant Melanoma Proliferation by Upregulating PLP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000001327"}], "href": "https://doi.org/10.1097/MD.0000000000001327"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26287415"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26287415"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yongzheng Bao, Bin Chen, Qiang Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of miR-664 is associated with enhanced osteosarcoma cell migration and invasion ability via targeting SOX7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Exp Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10238-015-0398-6"}], "href": "https://doi.org/10.1007/s10238-015-0398-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26515813"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26515813"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yunus Sahin, Zekiye Altan, Kaifee Arman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of miR-664a interferes with the migration of osteosarcoma cells via modulation of MEG3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2017.06.174"}], "href": "https://doi.org/10.1016/j.bbrc.2017.06.174"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28669734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28669734"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ondrej Fiala, Pavel Pitule, Petr Hosek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The association of miR-126-3p, miR-126-5p and miR-664-3p expression profiles with outcomes of patients with metastatic colorectal cancer treated with bevacizumab."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1010428317709283"}], "href": "https://doi.org/10.1177/1010428317709283"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28714375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28714375"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Liang Wu, Yuefeng Li, Jingye Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-664 Targets Insulin Receptor Substrate 1 to Suppress Cell Proliferation and Invasion in Breast Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504018X15193500663936"}], "href": "https://doi.org/10.3727/096504018X15193500663936"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29495974"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29495974"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Shuzhen Kong, Hui Xue, Yingchao Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The long noncoding RNA OTUD6B-AS1 enhances cell proliferation and the invasion of hepatocellular carcinoma cells through modulating GSKIP/Wnt/β-catenin signalling via the sequestration of miR-664b-3p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2020.112180"}], "href": "https://doi.org/10.1016/j.yexcr.2020.112180"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32682012"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32682012"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Shreyas H Karunakara, Lakshana D Puttahanumantharayappa, Nirmala G Sannappa Gowda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel Insights into MEG3/miR664a-3p/ADH4 Axis and Its Possible Role in Hepatocellular Carcinoma from an in Silico Perspective."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes (Basel) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/genes13122254"}], "href": "https://doi.org/10.3390/genes13122254"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36553522"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36553522"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiangzhi Li, Cheng Zhou, Chen Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-664 functions as an oncogene in cutaneous squamous cell carcinomas (cSCC) via suppressing interferon regulatory factor 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Dermatol Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jdermsci.2019.05.004"}], "href": "https://doi.org/10.1016/j.jdermsci.2019.05.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31138473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31138473"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yan Zhang, Yue Liu, Ming Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-664a-5p promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by directly downregulating HMGA2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2019.09.122"}], "href": "https://doi.org/10.1016/j.bbrc.2019.09.122"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31630797"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31630797"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Kazunori Watanabe, Ryuhei Yamaji, Takashi Ohtsuki "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-664a-5p promotes neuronal differentiation of SH-SY5Y cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Cells (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/gtc.12559"}], "href": "https://doi.org/10.1111/gtc.12559"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29341475"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29341475"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Zhiming Shan, Zhenchao Zhuang, Peiyao Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-664a-5p promotes experimental membranous nephropathy progression through HIPK2/Calpain1/GSα-mediated autophagy inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.18074"}], "href": "https://doi.org/10.1111/jcmm.18074"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38186203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38186203"}]}]}]}