{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe HER2 locus is now recognized as a bi‐functional unit that encodes both the well‐known membrane receptor and the intronic microRNA miR-4728, which functions as a versatile regulator in various disease contexts. In rheumatoid arthritis, for instance, miR-4728-5p downregulates PADI2—a newly identified risk gene—thereby emerging as a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In cancer, miR-4728 assumes complex roles. In breast cancer, one study demonstrated that miR-4728 acts as a negative regulator of MAPK signaling by directly targeting the ERK upstream kinase MST4, thus exerting tumor-suppressive effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Meanwhile, alternative targeting mechanisms have been identified: miR-4728-3p can use either a canonical seed (nucleotides 2–8) or a shifted internal seed (nucleotides 6–12) to regulate expression of estrogen receptor α, linking two major biomarkers in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, in HER2-amplified breast cancers, miR-4728 targets ESR1 mRNA, leading to reduced NOXA expression and contributing to resistance against HER2 inhibitors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional research has further elucidated the multifaceted regulatory roles of miR-4728. Its co-expression with HER2 has been confirmed in several cell lines and tissue samples, underlining its close relationship with its host oncogene."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Interestingly, miR-4728-3p also exerts oncogenic influence by stabilizing miR-21-5p via inhibition of the non-canonical poly(A) polymerase PAPD5, thereby reinforcing HER2-driven oncogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond its role in cancer, miR-4728-5p has been implicated in non-neoplastic processes; for example, in age-related cataract, overexpression of this miRNA leads to downregulation of the DNA repair gene OGG1 through a regulatory axis involving a long noncoding RNA, which may exacerbate oxidative DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In colorectal cancer, reduced levels of miR-4728-5p were observed alongside perturbations in transcription factor networks, suggesting its involvement in tumor development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, in breast cancer, a feedback loop in which miR-4728-5p directly targets EBP1 to increase HER2 expression has been shown to promote cell proliferation and migration, further highlighting its role in oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yukinori Okada, Tomoki Muramatsu, Naomasa Suita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Significant impact of miRNA-target gene networks on genetics of human complex traits."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep22223"}], "href": "https://doi.org/10.1038/srep22223"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26927695"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26927695"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "D C Schmitt, L Madeira da Silva, W Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2015.116"}], "href": "https://doi.org/10.1038/cddis.2015.116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25950472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25950472"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Inga Newie, Rolf Søkilde, Helena Persson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The HER2-encoded miR-4728-3p regulates ESR1 through a non-canonical internal seed interaction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0097200"}], "href": "https://doi.org/10.1371/journal.pone.0097200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24828673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24828673"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Konstantinos V Floros, Timothy L Lochmann, Bin Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Coamplification of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "miR-4728"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " protects "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "HER2"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": "-amplified breast cancers from targeted therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1717820115"}], "href": "https://doi.org/10.1073/pnas.1717820115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29476008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29476008"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Hai Li, Xin Zhou, Jun Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-4728-3p could act as a marker of HER2 status."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biomark (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/CBM-150524"}], "href": "https://doi.org/10.3233/CBM-150524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26406406"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26406406"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Inga Newie, Rolf Søkilde, Helena Persson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep35664"}], "href": "https://doi.org/10.1038/srep35664"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27752128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27752128"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Tianqiu Zhou, Junfang Zhang, Bai Qin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long non‑coding RNA NONHSAT143692.2 is involved in oxidative DNA damage repair in the lens by regulating the miR‑4728‑5p/OGG1 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2020.4707"}], "href": "https://doi.org/10.3892/ijmm.2020.4707"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33000245"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33000245"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "T Gurer, A Aytekin, E Caki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[miR-485-3p and miR-4728-5p as Tumor Suppressors in Pathogenesis of Colorectal Cancer]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol (Mosk) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.31857/S0026898422030077"}], "href": "https://doi.org/10.31857/S0026898422030077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35621109"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35621109"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yu Zhou, Yuan Yuan, Liuyi Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HER2-intronic miR-4728-5p facilitates HER2 expression and accelerates cell proliferation and migration by targeting EBP1 in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0245832"}], "href": "https://doi.org/10.1371/journal.pone.0245832"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33529238"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33529238"}]}]}]}