{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe miR‐15/16 family, which includes mature miR‑16 generated from both the MIR16‐1 and MIR16‑2 clusters, is emerging as a key regulator of cell fate. In multiple studies, altered expression of miR‑16 (including that originating from MIR16‑2) has been implicated in the modulation of cell cycle regulators, apoptosis, and differentiation. In contexts such as esophageal cancer and progenitor cell biology, aberrant miR‑16 expression correlates with deregulated tumor‐promoting pathways and impaired regenerative responses, underscoring a critical role in cellular homeostasis and disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn malignant tumors, reduced expression or loss of miR‑16 derived from the MIR16‑2 cluster is frequently associated with enhanced proliferation, invasion, and chemoresistance. For instance, in esophageal carcinomas, transient transfection of miR‑16‑2 suppressed retinoic acid receptor‐β2 expression and paradoxically increased proliferation, while in a mouse model deletion of the miR‑15b/16‑2 cluster precipitated B‑cell malignancy through upregulation of key cell cycle and anti‐apoptotic regulators. Similar tumor‑suppressive properties have been observed in colorectal cancer, gastric cancer, chordoma, and neuroblastoma, where exogenous restoration of miR‑16 (commonly measured as miR‑16‑5p) led to the inhibition of oncogenes such as ITGA2, SMAD3, and MYCN, ultimately reducing tumor cell proliferation and increasing sensitivity to chemotherapy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond direct tumor suppression, miR‑16 (including products from MIR16‑2) has gained attention for its diagnostic and therapeutic potential. Its stable expression in exosomal preparations suggests utility as a circulating biomarker in cancers such as breast and glioma, while its modulation influences cancer cell radiosensitivity and apoptotic responses in cervical, lung, and prostate cancer models by targeting genes like CARM1, MEK1, and AKT3. Such studies demonstrate that restoring miR‑16 expression can curb tumor growth and sensitize malignant cells to cytotoxic stress, highlighting its promise as a strategic target in personalized anticancer therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional layers of regulation have been uncovered through studies showing that miR‑16 (including isoforms emerging from MIR16‑2) is itself regulated by competing endogenous RNAs. In papillary thyroid and osteosarcoma cells, for example, oncogenic long non‑coding RNAs and circular RNAs act as molecular sponges to sequester miR‑16‑5p, thereby de‐repressing targets that promote tumor progression. Moreover, in non‐cancer settings—ranging from cardiomyocyte endoplasmic reticulum and oxidative stress to advancements in biomarker research for community‑acquired pneumonia—miR‑16’s functional modulation is linked to altered cellular stress responses and tissue homeostasis. Collectively, these findings underscore the multifaceted roles of MIR16‑2–derived miR‑16 in controlling cell proliferation, apoptosis, differentiation, and stress adaptation, firmly establishing it as both a critical prognostic biomarker and a promising therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuxin Hu, Arlene M Correa, Ashraful Hoque, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Oncol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/annonc/mdt412"}], "href": "https://doi.org/10.1093/annonc/mdt412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24148817"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24148817"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Abhisek Chatterjee, Dhrubajyoti Chattopadhyay, Gopal Chakrabarti "}, {"type": "b", "children": [{"type": "t", "text": "MiR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2014.11.023"}], "href": "https://doi.org/10.1016/j.cellsig.2014.11.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25435430"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25435430"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Francesca Lovat, Matteo Fassan, Pierluigi Gasparini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-15b/16-2 deletion promotes B-cell malignancies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1514954112"}], "href": "https://doi.org/10.1073/pnas.1514954112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26324892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26324892"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Lisong Li, Jie Jia, Xianzhe Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-16-5p Controls Development of Osteoarthritis by Targeting SMAD3 in Chondrocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Pharm Des (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1381612821666150909094712"}], "href": "https://doi.org/10.2174/1381612821666150909094712"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26350536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26350536"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Chenyu Zhu, Qun Huang, Hongyu Zhu "}, {"type": "b", "children": [{"type": "t", "text": "Melatonin Inhibits the Proliferation of Gastric Cancer Cells Through Regulating the miR-16-5p-Smad3 Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "DNA Cell Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/dna.2017.4040"}], "href": "https://doi.org/10.1089/dna.2017.4040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29359963"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29359963"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Hongliang Zhang, Kang Yang, Tingting Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-16-5p inhibits chordoma cell proliferation, invasion and metastasis by targeting Smad3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-018-0738-z"}], "href": "https://doi.org/10.1038/s41419-018-0738-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29880900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29880900"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Srinivas Chava, C Patrick Reynolds, Anup S Pathania, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-15a-5p, miR-15b-5p, and miR-16-5p inhibit tumor progression by directly targeting MYCN in neuroblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/1878-0261.12588"}], "href": "https://doi.org/10.1002/1878-0261.12588"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31637848"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31637848"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Qingtao Ni, Ines Stevic, Chi Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Different signatures of miR-16, miR-30b and miR-93 in exosomes from breast cancer and DCIS patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-018-31108-y"}], "href": "https://doi.org/10.1038/s41598-018-31108-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30154547"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30154547"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "A Krell, M Wolter, N Stojcheva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-16-5p is frequently down-regulated in astrocytic gliomas and modulates glioma cell proliferation, apoptosis and response to cytotoxic therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuropathol Appl Neurobiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/nan.12532"}], "href": "https://doi.org/10.1111/nan.12532"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30548945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30548945"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Zebo Huang, Wenjiao Chen, Yiping Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum miR-16 as a potential biomarker for human cancer diagnosis: results from a large-scale population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cancer Res Clin Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00432-019-02849-8"}], "href": "https://doi.org/10.1007/s00432-019-02849-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30706130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30706130"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Vadim V Maximov, Rania Akkawi, Saleh Khawaled, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA‑16‑5p regulates cell survival, cell cycle and apoptosis by targeting AKT3 in prostate cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2020.7682"}], "href": "https://doi.org/10.3892/or.2020.7682"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32705237"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32705237"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Qicen Yao, Yixi Xing, Zaiyan Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Long non-coding RNA LINC00649 regulates YES-associated protein 1 (YAP1)/Hippo pathway to accelerate gastric cancer (GC) progression via sequestering miR-16-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2021.1924554"}], "href": "https://doi.org/10.1080/21655979.2021.1924554"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33975517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33975517"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Jingbing Lou, Hongliang Zhang, Jiuhui Xu, et al. 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