Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking.
Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking.
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DOI：
10.1002/path.5311
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发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
Nam KT
中科院分区：
文献类型：
--
作者：
Jeong H;Lim KM;Kim KH;Cho Y;Lee B;Knowles BC;Roland JT;Zwerner JP;Goldenring JR;Nam KT
Rab25在不同组织中作为肿瘤抑制剂或肿瘤促进剂发挥作用。在这里，我们已经证明并澄清Rab25作为皮肤鳞状细胞癌（SCC）发展的关键肿瘤抑制因子的作用。Rab25缺失与人类和小鼠的肿瘤转化密切相关。Rab25缺失与人SCC中细胞增殖增加和分化不良密切相关。虽然Rab25基因敲除（KO）在小鼠中不会自发诱导肿瘤，但在小鼠体内两阶段皮肤癌发生模型中，它显著加速肿瘤生成并促进恶性转化。异种移植的Rab25缺陷的人角质形成细胞系，HaCaT，也引起了肿瘤转化。值得注意的是，Rab 25缺乏导致整合素β1、β4和α6调节异常，这与表皮增殖和细胞凋亡增加以及桥粒紧密连接形成受损非常匹配。Rab25缺陷导致整合素再循环障碍，导致整合素的不适当表达。与此一致，在Rab25缺陷的人SCC中鉴定到整合素β1、β4和α6的表达显著减弱。总的来说，这些结果表明，Rab25的损失促进SCC的发展和肿瘤性转变，通过失调和贩运的整合素。
Rab25 functions as either a tumor suppressor or tumor promoter across different tissues. Here we have demonstrated and clarified the role of Rab25 as a pivotal tumor suppressor of the skin squamous cell carcinoma (SCC) development. Rab25 loss was closely associated with the neoplastic transition in both humans and mice. Rab25 loss was well correlated with increased cell proliferation and poor differentiation in human SCC. While Rab25 knock-out (KO) in mice did not induce tumor spontaneously, it significantly accelerated tumor generation and promoted malignant transformation in the mouse two-stage skin carcinogenesis model in vivo. Xenograft of a Rab25 deficient-human keratinocyte cell line, HaCaT, also elicited the neoplastic transformation. Notably, Rab25 deficiency led to dysregulation of integrin β1, β4 and α6, which matched well with increased epidermal proliferation and apoptosis, and impaired desmosome-tight junction formation. Rab25 deficiency induced impairment of integrin recycling, leading to the improper expression of integrins. In line with this, significantly attenuated expression of integrin β1, β4 and α6 was identified in human SCC where Rab25 was deficient. Collectively, these results suggest that loss of Rab25 promotes the development and neoplastic transition of SCC through dysregulation and trafficking of integrins.
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