{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTFAP2E is emerging as a multifaceted regulator of chemotherapeutic response in gastrointestinal malignancies. In colorectal and gastric cancers, epigenetic modification (hypermethylation) of TFAP2E has been proposed to diminish its expression and contribute to chemotherapy resistance, particularly against 5‑fluorouracil. In colorectal cancer, early studies suggested a potential role for TFAP2E alterations and its downstream mediator DKK4 in predicting therapeutic response, although subsequent larger analyses report that hypermethylation does not uniformly result in loss of protein expression nor affect survival. Similarly, in gastric cancer, hypermethylation of TFAP2E is associated with lower expression, with evidence indicating that exosomal microRNAs may further influence chemoresistance by targeting key regulatory genes such as E2F1, MTOR, and STAT3."}, {"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": "\nBeyond its role in tumor cell drug responsiveness, TFAP2E contributes to developmental processes. In zebrafish and human melanocytes, TFAP2E functions redundantly with TFAP2A to maintain the expression of the receptor tyrosine kinase Kit, thereby promoting melanocyte differentiation. In addition, during chondrocyte hypertrophy, TFAP2E (AP‑2ε) directly downregulates the promoter activity of the type II collagen (COL2A1) gene, implicating it as a modulator of the cartilage developmental program."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn other tumor contexts, TFAP2E appears to play contrasting roles. In neuroblastoma, low TFAP2E expression is significantly associated with a poorer prognosis; TFAP2E functions as a tumor suppressor by modulating DNA damage responses—possibly through the upregulation of p21WAF1—thus sensitizing cells to genotoxic stress. Conversely, in malignant melanoma, high levels of TFAP2E act as potent inducers of metastasis by promoting cell plasticity and migration, which contribute to a more aggressive disease phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Matthias P A Ebert, Marc Tänzer, Benjamin Balluff, et al. 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"}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "TFAP2E"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-17-2940"}], "href": "https://doi.org/10.1158/1078-0432.CCR-17-2940"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29535127"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29535127"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sun Jingyue, Wang Xiao, Zha Juanmin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2E methylation promotes 5‑fluorouracil resistance via exosomal miR‑106a‑5p and miR‑421 in gastric cancer MGC‑803 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2019.10237"}], "href": "https://doi.org/10.3892/mmr.2019.10237"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31115533"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31115533"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Eric Van Otterloo, Wei Li, Gregory Bonde, et al. 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