{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNDRG3, a member of the NDRG gene family originally defined alongside NDRG1, has been characterized through cloning and structural studies that revealed its homology and unique tissue distribution (notably in brain and testis) as well as its regulation during cell differentiation. Early work demonstrated that NDRG3 is a target of oncogenic microRNAs—for example, miR‑122 in HBV‑related hepatocellular carcinoma—highlighting its involvement in malignant transformation. In addition, functional investigations in prostate cancer models showed that overexpression of NDRG3 drives increased cellular proliferation, migration, and tumor growth, while structural analyses suggest that a distinct flexible loop in NDRG3 may be key to its oncogenic activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUnder hypoxic conditions, NDRG3 acts as a critical mediator of lactate-dependent signaling. When lactate accumulates, it binds to NDRG3, protecting it from oxygen‐dependent proteasomal degradation. This stabilization enables NDRG3 to activate downstream pathways such as the Raf‑ERK cascade, promoting angiogenesis and cell growth. Moreover, studies in endothelial and neuronal models indicate that lactate‑induced stabilization of NDRG3 supports cellular adaptation under hypoxia, contributing to processes such as hypoxia postconditioning and neuronal differentiation via regulation of key transcription factors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cancer types, aberrant expression of NDRG3 has been linked to tumor progression, metastasis, and resistance to therapy. Elevated NDRG3 levels have been detected in laryngeal squamous cell carcinoma, hepatocellular carcinoma, and breast cancer, with its overexpression correlating with advanced pathological grade, increased tumor size, and poorer overall survival. In prostate cancer, NDRG3 appears to modulate the hypoxic response by attenuating HIF‑1α signaling, a nuance that suggests context‑dependent effects, including potential anti‑metastatic roles. Furthermore, in chronic myelogenous leukemia, NDRG3 contributes to imatinib resistance via nuclear accumulation of β‑catenin, while studies in gastric cancer and comprehensive reviews have pointed out that, in some settings, reduced or absent expression of NDRG3 may hint at tumor‐suppressive capabilities. Together, these studies underscore the multifaceted and context‑dependent roles of NDRG3 in oncogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xianghu Qu, Yun Zhai, Handong Wei, et al. 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