{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nmiR‐376c (including its 3′‐isoform) is emerging as a multifaceted regulator whose expression is dynamically altered in several human pathologies. In certain contexts, its decreased expression in tumor tissues—such as metastatic prostate cancer—has been linked to more aggressive disease (for example, see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", whereas its elevation in blood has been explored as a minimally invasive biomarker in early breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the oncological arena, miR‐376c plays context‐dependent roles. In ovarian cancer cells, ectopic expression of miR‐376c targets ALK7 and enhances cell proliferation, survival, and resistance to cisplatin"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "; similarly, in gastric carcinoma its upregulation and suppression of ARID4A promote oncogenic features."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Conversely, in osteosarcoma, miR‐376c is downregulated so that its restoration suppresses tumorigenicity by targeting transforming growth factor‐α (TGFA)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in intrahepatic cholangiocarcinoma its overexpression reduces epidermal growth factor–dependent migration via direct inhibition of GRB2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In head and neck squamous cell carcinoma, downregulation of the 3′‑variant miR‐376c‑3p contributes to metastasis by de‐repressing a RUNX2/INHBA axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In prostate cancer, miR‐376c directly targets the 3′‑untranslated regions of the androgen‑inactivating enzymes UGT2B15/17, thereby interfering with dihydrotestosterone glucuronidation and modulating androgen receptor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Additional studies in ovarian and lung cancer further demonstrate that miR‐376c, when delivered either in a cell‐autonomous context or via extracellular vesicles, can suppress tumor growth by targeting key regulators such as FOXO3 (modulated via sponging by circEXOC6B;"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and liver receptor homolog‑1 (LRH‑1)"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", while its restoration in cervical cancer impairs proliferation and invasion through direct inhibition of BMI1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer, miR‐376c modulates diverse physiological processes. In platelets, it inversely regulates levels of phosphatidylcholine transfer protein (PC‐TP) and correlates with PAR4 reactivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In the placental trophoblasts, its interaction with the long noncoding RNA DLX6‑AS1 and consequent targeting of GADD45A impacts cell proliferation, migration, and invasion—mechanisms relevant to preeclampsia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Moreover, in bone precursor cells, miR‐376c‑3p is regulated by TWIST‑1 and acts to inhibit osteogenic differentiation by downregulating IGF1R/Akt signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Its reduced expression has also been observed in neonatal hypoxic‑ischemic encephalopathy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and in liver, miR‑376c‑3p limits the translation of glutathione transferase zeta 1 (GSTZ1), thereby influencing metabolic functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Collectively, these studies underscore the context‑dependent functions of miR‑376c as both a potential oncogene and tumor suppressor, as well as its broader regulatory roles in cell metabolism, differentiation, and response to injury.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A Formosa, E K Markert, A M Lena, et al. 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