Sex‐determining region Y box (SOXs) are expressed in various cells and control cell fate and differentiation in a multitude of physiologic processes. SOX6, a main representative of SOXs, is involved in the regulation of carcinogenesis in various human malignancies. However, the role of SOX6 in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, SOX6 expression in ccRCC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor‐related function and the underlying molecular mechanism of SOX6 in ccRCC. We confirmed that SOX6 was frequently downregulated in ccRCC tissues and cell lines. Besides, downregulation of SOX6 was significantly associated with larger tumor sizes, advanced tumor stage, higher Fuhrman grades, and its expression could act as an independent prognostic factor for ccRCC (hazards ratio = 0.590, P = .026). Gain/loss‐of‐function experiments demonstrated that SOX6 could remarkably inhibit tumor cell growth and foci formation in vitro and xenograft tumorigenesis in vivo, respectively. Mechanistically, SOX6 could influence cell cycle by regulating the G1/the S phase transition and had an inhibitory effect on Wnt/β‐catenin signaling as well as its target genes, c‐Myc and cyclin D1. Interesting, the tumor‐suppressive function of SOX6 was proved to be dependent on its specific high‐mobility‐group (HMG) domain. In general, our findings indicated that SOX6 was a novel tumor suppressor and prognostic biomarker in ccRCC. SOX6 could inhibit tumor growth by negatively regulating the Wnt/β‐catenin signaling pathway in an HMG domain‐dependent manner in ccRCC, which might provide a novel therapeutic approach for ccRCC.

中文翻译：

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SOX6通过Wnt /β-catenin信号的HMG域依赖性调节来抑制透明细胞肾细胞癌的肿瘤生长。

决定性别的Y框（SOXs）在各种细胞中表达，并在许多生理过程中控制细胞的命运和分化。SOX6是SOX的主要代表，它参与多种人类恶性肿瘤的癌变调控。但是，尚不清楚SOX6在透明细胞肾细胞癌（ccRCC）中的作用。本研究调查了ccRCC中SOX6的表达及其临床意义。ccRCC中使用了体外和体内试验来探索SOX6的肿瘤相关功能和潜在分子机制。我们证实ccRCC组织和细胞系中SOX6经常下调。此外，SOX6的下调与更大的肿瘤大小，晚期肿瘤分期，更高的Fuhrman等级，P  = .026）。功能获得/功能丧失实验证明，SOX6可以分别显着抑制体外和体内异种移植肿瘤发生的肿瘤细胞生长和灶形成。从机制上讲，SOX6可以通过调节G1 / S相转变来影响细胞周期，并且对Wnt /β-catenin信号传导及其靶基因c-Myc和cyclin D1具有抑制作用。有趣的是，事实证明SOX6的肿瘤抑制功能取决于其特定的高迁移率族（HMG）域。总的来说，我们的发现表明SOX6是ccRCC中的新型肿瘤抑制物和预后生物标志物。SOX6可以通过在ccRCC中以HMG结构域依赖性方式负调控Wnt /β-catenin信号通路来抑制肿瘤生长，这可能为ccRCC提供了一种新颖的治疗方法。