{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAX8 is a paired‐box transcription factor that plays a central role in embryogenesis and tissue‐specific differentiation. It is crucial for the development and maintenance of the thyroid gland, kidney, and Müllerian system, where its nuclear expression is exquisitely restricted. In normal tissues, PAX8 cooperates with factors such as thyroid transcription factor‑1 (TTF‑1) to regulate thyroid‐specific genes, and its restricted distribution makes it an excellent diagnostic immunomarker for neoplasms derived from thyroid, renal, and Müllerian tissues. This conserved expression pattern is illustrated by studies that have characterized its role in thyroid organogenesis, its synergy with TTF‑1 for target gene activation, and its selective diagnostic utility in diverse benign and malignant tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in PAX8 function contribute to neoplastic processes through several molecular mechanisms. In thyroid neoplasia, chromosomal rearrangements leading to PAX8‑PPARγ fusion proteins and dominant‐negative mutations disrupt normal transcriptional regulation and impair coactivator recruitment. Moreover, PAX8 has been shown to directly regulate target promoters such as that of E2F1, thereby influencing cell cycle progression. Its expression can be modulated by noncoding RNAs—for example, miR‑146b targets the PAX8 3′‑UTR to impair iodide uptake—highlighting a regulatory network that links differentiation, proliferation, and treatment responsiveness. Such findings underscore the dual role of PAX8 as both a lineage marker and an active participant in oncogenic transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental and regulatory functions, PAX8 is widely applied as a diagnostic tool in surgical pathology. Its strong and diffuse nuclear immunoreactivity is exploited to distinguish primary tumors from metastases in the thyroid, kidney, Müllerian tract, and even in the male genital system. In addition, recent investigations have linked aberrant PAX8 expression to ovarian cancer progression and renal cell carcinoma oncogenic networks via enhancer activation and long noncoding RNA interactions, thus identifying PAX8 as a candidate oncogene and therapeutic target. Its diagnostic utility is further enhanced when used in immunohistochemical panels to differentiate mesothelial from serous neoplasms and to clarify the lineage of challenging metastatic lesions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stefania Miccadei, Rossana De Leo, Enrico Zammarchi, et al. 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