{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMembers of the MIRLET7A2/let‑7a family are emerging as key tumor suppressors in a range of malignancies. In acute myeloid leukemia, for example, high let‑7a‑2‑3p expression is linked to significantly improved overall and event‑free survival, while in osteosarcoma and Ewing sarcoma, reduced let‑7a expression is associated with upregulation of oncogenic targets such as E2F2, RAS, HIF‑1α, and EWS‑FLI‑1, collectively contributing to increased tumor aggressiveness. In breast cancer, particularly in cases harboring BRCA mutations, diminished let‑7a levels have been observed, and exosomal transfer of let‑7a in triple‑negative breast cancer appears to modulate oncogenes like c‑Myc. In pancreatic ductal adenocarcinoma, although TGF‑β induces a long non‑coding RNA that encodes several miRNAs, let‑7a levels remain unchanged—underscoring its inherent anti‑tumorigenic role—whereas in hepatitis B virus‑associated hepatocellular carcinoma, viral mRNAs sequester let‑7a, thereby de‑repressing oncogenes. Additionally, let‑7a has been shown to positively regulate USP35 expression, which in turn stabilizes ABIN‑2 and restrains NF‑κB signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in oncogenesis, MIRLET7A2 functions significantly in cardiovascular and metabolic contexts as well as in diagnostic applications. In endothelial cells, let‑7a (along with let‑7b) targets the 3′‑UTR of LOX‑1, thereby mitigating oxLDL‑induced apoptosis and dysfunction—a mechanism that may help protect against atherosclerosis. In diabetic nephropathy, down‑expression of let‑7a accompanied by certain SNPs in the regulatory region of the let‑7a‑2 gene has been associated with an increased risk of developing kidney complications in diabetic patients. Moreover, altered let‑7a expression levels have also been investigated in esophageal squamous cell carcinoma for their potential diagnostic value."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMIRLET7A2 expression is subject to diverse layers of regulation that affect both developmental processes and signal transduction responses. Detailed analysis of the let‑7a‑2 promoter in lung cancer cells has revealed that its transcription is modulated by factors such as retinoic acid and lithium chloride. In pluripotent cells, let‑7 operates antagonistically to the embryonic stem cell cycle‐promoting miR‑372, thereby influencing primordial germ cell specification. Furthermore, a unique cis‑element in the AGO1 mRNA directs translational readthrough—a process promoted by let‑7a binding—which generates an extended AGO1 isoform that acts as a competitive inhibitor of the miRNA pathway. In lens epithelial cells, upregulation of let‑7a‑5p suppresses TGF‑β‑induced proliferation, migration, invasion, and epithelial‑to‑mesenchymal transition by directly targeting Smad2, while in the context of cardiovascular signaling, intracellular binding of pre‑let‑7a‑2 to the angiotensin II type 2 receptor’s third intracellular loop attenuates receptor‑mediated antiproliferative and proapoptotic signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "17"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elif Erturk, Gulsah Cecener, Unal Egeli, et al. 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