TGF-β regulates both the tumor-forming and migratory abilities of various types of cancer cells. However, it is unclear how the loss of TGF-β signaling components affects these abilities in clear-cell renal cell carcinoma (ccRCC). In this study, we investigated the role of TGFBR3 (TGF-β type III receptor, also known as betaglycan) in ccRCC. Database analysis revealed decreased expression of TGFBR3 in ccRCC tissues, which correlated with poor prognosis in patients. Orthotopic inoculation experiments using immunocompromised mice indicated that low TGFBR3 expression in ccRCC cells enhanced primary tumor formation and lung metastasis. In the presence of TGFBR3, TGF-β2 decreased the aldehyde dehydrogenase (ALDH)-positive ccRCC cell population, in which renal cancer-initiating cells are enriched. Loss of TGFBR3 also enhanced cell migration in cell culture and induced expression of several mesenchymal markers in a TGF-β-independent manner. Increased lamellipodium formation by FAK-PI3K signaling was observed with TGFBR3 downregulation, and this contributed to TGF-β-independent cell migration in ccRCC cells. Taken together, our findings reveal that loss of TGFBR3 endows ccRCC cells with multiple metastatic abilities through TGF-β-dependent and independent pathways.

中文翻译：

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通过TGF-β依赖性和非依赖性机制，降低的TGFBR3 /β聚糖表达增强了肾癌细胞的转移能力。

TGF-β调节各种类型癌细胞的肿瘤形成和迁移能力。然而，尚不清楚TGF-β信号传导成分的损失如何影响透明细胞肾细胞癌（ccRCC）中的这些能力。在这项研究中，我们研究了TGFBR3（TGF-βIII型受体，也称为β聚糖）在ccRCC中的作用。数据库分析显示ccRCC组织中TGFBR3的表达减少，这与患者预后不良有关。使用免疫受损小鼠的原位接种实验表明，ccRCC细胞中TGFBR3的低表达增强了原发肿瘤的形成和肺转移。在存在TGFBR3的情况下，TGF-β2降低了醛脱氢酶（ALDH）阳性ccRCC细胞的数量，其中富集了肾癌起始细胞。TGFBR3的丢失还增强了细胞培养中的细胞迁移，并以TGF-β独立的方式诱导了几种间充质标记物的表达。通过TGFBR3下调观察到通过FAK-PI3K信号产生的lamellipodium形成增加，这有助于ccRCC细胞中TGF-β非依赖性细胞迁移。两者合计，我们的发现表明，TGFBR3的缺失通过依赖TGF-β的途径和独立途径赋予ccRCC细胞多种转移能力。