The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

IF 1.5 Q3 UROLOGY & NEPHROLOGY American journal of clinical and experimental urology Pub Date : 2024-04-15 eCollection Date: 2024-01-01 DOI:10.62347/MEQO6014
Rachel L Griffin, Lauren Shuman, Hironobu Yamashita, Qingqing Wu, Guoli Chen, Ryan M Brown, Don Vander Griend, David J DeGraff, Joshua I Warrick
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Abstract

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 SOX2 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. SOX2 expression was substantially higher in muscle-invasive compared with noninvasive papillary urothelial carcinoma by RNA sequencing (P<0.001, Wilcoxon rank sum test). SOX2 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). SOX2 expression did not associate with overall survival in muscle-invasive carcinoma. Activity of SOX2 in bladder cancer was tested in vivo 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.

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膀胱癌中的转录因子性别决定区 Y-box 2 (SOX2)。
性别决定区 Y-box 2(SOX2)是一种转录因子,在胚胎发育过程中起着核心作用。SOX2 也是几种癌症类型的致癌基因。我们小组之前的研究表明,在早期膀胱癌中,SOX2 的活性与细胞周期失调有关。因此,本研究对膀胱癌中的 SOX2 进行了广泛调查,重点研究其与肿瘤分期、临床结果和致瘤性的关系。通过免疫组化方法对已建立的组织芯片(303 例膀胱切除标本,所有分期)和非浸润性乳头状尿路上皮癌(25 例)的整个组织切片中的基因表达进行了量化。通过 RNA 测序评估了来自公开资料库的非肌层浸润性和肌层浸润性队列中的基因表达。通过免疫组化,40%的非浸润性乳头状癌全组织切片中表达了SOX2,这与RNA测序的SOX2表达相关(r=0.6,P=0.001,Spearman相关性)。表达倾向于局灶性(H-评分中位数=6)。只有 9% 的 TMA 病例表达 SOX2,这与病灶表达一致。通过RNA测序,肌肉浸润性乳头状尿路上皮癌的SOX2表达远高于非浸润性乳头状尿路上皮癌(PSOX2表达与浸润性癌的分期进展相关(危险比=2,P=0.05,Cox模型,二元,RNA测序),但与非浸润性乳头状癌无关(P=0.5,Cox模型,二元,RNA测序)。SOX2的表达与肌肉浸润癌的总生存率无关。使用表达人类 SOX2 的 MB49 细胞(MB49-SOX)创建的鼠异体移植对 SOX2 在膀胱癌中的活性进行了体内测试。通过免疫组化,MB49-SOX 异体移植物局部表达了这种蛋白,与人类肿瘤非常相似。与对照组相比,MB49 异体移植物的肿瘤体积更大(P=0.03,Wilcoxon 秩和检验),肠系膜转移灶的肿瘤负荷更高(P=0.009,Wilcoxon 秩和检验)。虽然SOX2在肿瘤内的表达是局灶性的,但它可能会推动肿瘤发生,增加生长速度,促进膀胱癌的侵袭性特征,尤其是早期疾病的分期进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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