{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSOX8, a member of the SRY‐related HMG‐box transcription factor family, plays multifaceted roles in normal tissue physiology. In the human enteric nervous system, nuclear expression of SOX8 (together with SOX9/10) facilitates the identification and quantification of enteric glial cells, a finding that may be exploited for the pathological assessment of gastrointestinal disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, SOX8 is specifically expressed in microfold (M) cells of the gut‐associated lymphoid tissue where it directly binds and activates the Gp2 promoter, a critical step in the maturation of M cells necessary for antigen uptake and effective mucosal immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, aberrant expression and activity of SOX8 have been linked to tumor progression, chemoresistance, and poor prognosis across a variety of malignancies. Genetic association studies have identified a SOX8 variant as a susceptibility locus for multiple sclerosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", and in hepatocellular carcinoma, overexpression of SOX8 correlates with elevated β‐catenin signaling and enhanced cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In non‐small cell lung cancer, high SOX8 levels are significantly associated with larger tumor size, lymph node metastasis, and shorter patient survival, with its expression negatively regulated by miRNA‑124."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In cisplatin‐resistant tongue squamous cell carcinoma, increased SOX8 expression confers cancer stem cell–like properties and promotes epithelial–mesenchymal transition (EMT) via activation of the Wnt/β‑catenin pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while in triple‑negative breast cancer, SOX8 is transcriptionally activated by ZEB1 to help maintain stem‐like capacities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, SOX8 overexpression in colorectal and endometrial carcinomas is associated with advanced tumor stage, metastasis, and reduced overall survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In gestational trophoblastic neoplasia, activation of the RSK2/SOX8 signaling axis attenuates methotrexate‐induced reactive oxygen species (ROS) accumulation and thereby promotes chemoresistance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "; similarly, upregulation of SOX8 in castration‑resistant prostate cancer enhances Notch signaling and contributes to enzalutamide resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Additionally, in tongue squamous cell carcinoma, SOX8 directly binds the promoter of GOLPH3 to drive its overexpression and tumor growth"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", underscoring its role as a potent oncogenic driver.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic functions, SOX8 is crucial for normal development and differentiation. In the developing human gonad, SOX8 is expressed in somatic cells where it influences sex determination, with mutations or chromosomal rearrangements involving the SOX8 locus found in individuals with 46,XY disorders/differences of sex development, infertility, or primary ovarian insufficiency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In testicular tissue, SOX8 is essential in Sertoli cells for maintaining the blood‑testis barrier and supporting germ cell differentiation, although deleterious mutations may not be a major cause of male infertility in all populations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In the realm of skeletal development, SOX8 expression is regulated by SOX9 in chondrogenesis where both cooperate (along with SOX5 and SOX6) to drive the expression of chondrogenic molecules such as COL2A1 without affecting hypertrophy markers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Moreover, recent mechanistic insights reveal that SOX8, as part of the SOXE subgroup (with SOX9 and SOX10), utilizes a bipartite transactivation mechanism involving central and C‑terminal activation domains with a conserved minimal transactivation motif essential for its function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Finally, additional observations in the spectrum of 46,XY differences/disorders of sex development further support the importance of proper SOX8 function in normal reproductive development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sebastian Hoff, Florian Zeller, Claus Werner Hann von Weyhern, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Quantitative assessment of glial cells in the human and guinea pig enteric nervous system with an anti-Sox8/9/10 antibody."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Comp Neurol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cne.21769"}], "href": "https://doi.org/10.1002/cne.21769"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18512230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18512230"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shunsuke Kimura, Nobuhide Kobayashi, Yutaka Nakamura, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Oncogenicity of the transcription factor SOX8 in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-014-0918-3"}], "href": "https://doi.org/10.1007/s12032-014-0918-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24643625"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24643625"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Chao Xie, Yunwei Han, Yi Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miRNA-124 down-regulates SOX8 expression and suppresses cell proliferation in non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2014)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25400731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25400731"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "S-L Xie, S Fan, S-Y Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SOX8 regulates cancer stem-like properties and cisplatin-induced EMT in tongue squamous cell carcinoma by acting on the Wnt/β-catenin pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.31134"}], "href": "https://doi.org/10.1002/ijc.31134"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29071717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29071717"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hailin Tang, Bo Chen, Peng Liu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Over-expression of SOX8 predicts poor prognosis in colorectal cancer: A retrospective study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000016237"}], "href": "https://doi.org/10.1097/MD.0000000000016237"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31277140"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31277140"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Wenyan Tian, Zhanghuan Li, Lu Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The oncogenic role of SOX8 in endometrial carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384047.2020.1840318"}], "href": "https://doi.org/10.1080/15384047.2020.1840318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33190587"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33190587"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shaobin Wu, Mingjie Shao, Yi Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of RSK2 upregulates SOX8 to promote methotrexate resistance in gestational trophoblastic neoplasia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lab Invest (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41374-021-00651-0"}], "href": "https://doi.org/10.1038/s41374-021-00651-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34373588"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34373588"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Zhongbo Du, Xiaobin Chen, Pingyu Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SOX8 Knockdown Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting the Notch Signaling Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2022/9235837"}], "href": "https://doi.org/10.1155/2022/9235837"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36246971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36246971"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Shuwei Chen, Huan Li, Xiyuan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High SOX8 expression promotes tumor growth and predicts poor prognosis through GOLPH3 signaling in tongue squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cam4.3041"}], "href": "https://doi.org/10.1002/cam4.3041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32307911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32307911"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Marie-France Portnoi, Marie-Charlotte Dumargne, Sandra Rojo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy037"}], "href": "https://doi.org/10.1093/hmg/ddy037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29373757"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29373757"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Xu Zhang, Yunna Ning, Wen Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variation analysis of SOX8 gene in Chinese men with non-obstructive azoospermia or oligozoospermia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Andrologia (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/and.13531"}], "href": "https://doi.org/10.1111/and.13531"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32048324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32048324"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Sarah R Herlofsen, Torill Høiby, Davide Cacchiarelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Brief report: importance of SOX8 for in vitro chondrogenic differentiation of human mesenchymal stromal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.1642"}], "href": "https://doi.org/10.1002/stem.1642"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24449344"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24449344"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Abdul Haseeb, Véronique Lefebvre "}, {"type": "b", "children": [{"type": "t", "text": "The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkz523"}], "href": "https://doi.org/10.1093/nar/gkz523"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31194875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31194875"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Khouloud Rjiba, Soumaya Mougou-Zerelli, Imen Hadj Hamida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Biol Endocrinol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12958-022-01045-7"}], "href": "https://doi.org/10.1186/s12958-022-01045-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36631813"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36631813"}]}]}]}