{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNKX2-8, a homeobox transcription factor originally involved in lung development, has been implicated in diverse roles in cancer. In non‐small cell lung cancer (NSCLC), NKX2-8 is frequently coactivated with TTF-1 through gene amplification at chromosome 14q13, defining a subset of early stage tumors with poor prognosis and cisplatin resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, loss of NKX2-8 increases lung cancer development, as demonstrated in both murine models and human studies"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", and its deletion has been shown to reprogram fatty acid metabolism, thereby contributing to chemoresistance in epithelial ovarian cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn other malignancies, NKX2-8 appears to function in a tumor suppressor role. In esophageal squamous cell carcinoma, downregulation of NKX2-8 is associated with enhanced angiogenesis via VEGF-C upregulation and NF-κB activation mediated by reduction of AKIP1, correlating with disease progression and poor overall survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Similarly, in invasive bladder cancer, reduced NKX2-8 expression correlates with advanced tumor stage, higher proliferation indices, and unfavorable survival outcomes; enforced NKX2-8 expression in these cells induces G₁/S cell cycle arrest and impairs proliferative signaling through the MEK/ERK pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional evidence for the multifaceted nature of NKX2-8 comes from its role in developmental gene regulation and modulation of the oncogenic phenotype. Initially identified via its binding to the promoter-coupling element of the alpha-fetoprotein gene, NKX2-8 is critical in mediating developmental silencing and neoplastic reactivation of target genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In bladder urothelial carcinoma, enforced expression of NKX2-8 directly represses the EMT inducer Twist1, thereby inhibiting epithelial-to-mesenchymal transition, invasiveness, and metastatic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In conjunction, NKX2-8 also enhances chemosensitivity by transcriptionally downregulating MDR1/P-glycoprotein expression, with positive NKX2-8 correlating with improved responses to chemotherapy and better patient outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "David S Hsu, Chaitanya R Acharya, Bala S Balakumaran, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Both gene amplification and allelic loss occur at 14q13.3 in lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-10-1892"}], "href": "https://doi.org/10.1158/1078-0432.CCR-10-1892"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21148747"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21148747"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jinrong Zhu, Geyan Wu, Libing Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EBioMedicine (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ebiom.2019.04.041"}], "href": "https://doi.org/10.1016/j.ebiom.2019.04.041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31047858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31047858"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chuyong Lin, Libing Song, Hui Gong, et al. 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