Griffin Rachel L, Shuman Lauren, Yamashita Hironobu, Wu Qingqing, Chen Guoli, Brown Ryan M, Vander Griend Don, DeGraff David J, Warrick Joshua I
Department of Comparative Medicine, Penn State College of Medicine Hershey, PA, USA.
Department of Urology, Penn State College of Medicine Hershey, PA, USA.
Am J Clin Exp Urol. 2024 Apr 15;12(2):88-99. doi: 10.62347/MEQO6014. eCollection 2024.
Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer. The present study was thus undertaken to broadly investigate SOX2 in bladder cancer, with emphasis on associations with tumor stage, clinical outcomes, and tumorigenicity. Gene expression was quantified by immunohistochemistry in an established tissue microarray (n=303 cystectomy specimens, all stages) and whole tissue sections of noninvasive papillary urothelial carcinoma (n=25). Gene expression by RNA sequencing was evaluated in non-muscle invasive and muscle-invasive cohorts from publicly available repositories. By immunohistochemistry, SOX2 was expressed in 40% of whole tissue sections of noninvasive papillary carcinoma, which correlated with expression by RNA sequencing (r=0.6, P=0.001, Spearman correlation). Expression tended to be focal (median H-score =6). SOX2 was expressed in only 9% of TMA cases, consistent with focal expression. expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). expression associated with stage progression in lamina-propria invasive cancers (hazard ratio =2, P=0.05, Cox model, binary, RNA sequencing) but not noninvasive papillary cancers (P=0.5, Cox model, binary, RNA sequencing). expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested using murine allografts created with MB49 cells that express human SOX2 (MB49-SOX). MB49-SOX allografts expressed this protein focally by immunohistochemistry, much like human tumors. Compared with controls, MB49 allografts demonstrated larger tumor size (P=0.03, Wilcoxon rank sum test) and higher tumor burden in mesenteric metastases (P=0.009, Wilcoxon rank sum test). Though SOX2 expression is focal within tumors, it may drive tumorigenesis, increase growth rate, and promote aggressive features of bladder cancer, particularly stage progression of early-stage disease.
Y染色体性别决定区框蛋白2（SOX2）是一种转录因子，在胚胎发育中起核心作用。SOX2在几种癌症类型中也是一种癌基因。我们团队之前的研究表明，SOX2活性与早期膀胱癌的细胞周期失调有关。因此，本研究旨在广泛研究膀胱癌中的SOX2，重点关注其与肿瘤分期、临床结局和致瘤性的关系。通过免疫组织化学对已建立的组织微阵列（n = 303例膀胱切除标本，涵盖所有分期）和非侵袭性乳头状尿路上皮癌的全组织切片（n = 25）中的基因表达进行定量。通过RNA测序评估来自公开数据库的非肌肉浸润性和肌肉浸润性队列中的基因表达。通过免疫组织化学，SOX2在40%的非侵袭性乳头状癌全组织切片中表达，这与RNA测序的结果相关（r = 0.6，P = 0.001，Spearman相关性）。表达倾向于局灶性（中位H评分 = 6）。SOX2仅在9%的组织微阵列病例中表达，与局灶性表达一致。通过RNA测序，与非侵袭性乳头状尿路上皮癌相比，肌肉浸润性癌中的表达显著更高（P < 0.001，Wilcoxon秩和检验）。在固有层浸润性癌症中，表达与分期进展相关（风险比 = 2，P = 0.05，Cox模型，二元，RNA测序），但在非侵袭性乳头状癌中不相关（P = 0.5，Cox模型，二元，RNA测序）。在肌肉浸润性癌中，表达与总生存期无关。使用表达人SOX2的MB49细胞构建的小鼠异种移植模型来测试膀胱癌中SOX2的活性（MB49 - SOX）。MB49 - SOX异种移植通过免疫组织化学显示该蛋白呈局灶性表达，与人类肿瘤非常相似。与对照组相比，MB49异种移植显示肿瘤尺寸更大（P = 0.03，Wilcoxon秩和检验），肠系膜转移中的肿瘤负荷更高（P = 0.009，Wilcoxon秩和检验）。尽管SOX2在肿瘤内的表达是局灶性的，但它可能驱动肿瘤发生、提高生长速率并促进膀胱癌的侵袭性特征，特别是早期疾病的分期进展。
