CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction.
CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction.
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DOI：
10.1158/0008-5472.can-14-0579
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发表时间：
2014-12-01
期刊：
影响因子：
11.2
通讯作者：
Féral CC
中科院分区：
文献类型：
--
作者：
Estrach S;Lee SA;Boulter E;Pisano S;Errante A;Tissot FS;Cailleteau L;Pons C;Ginsberg MH;Féral CC
CD98hc(SLC3A2)是二聚体跨膜糖蛋白CD98的重链成分，由细胞内的大分子中性氨基酸转运蛋白LAT1(SLC7A5)组成。CD98hc的过度表达广泛存在于肿瘤细胞中，临床上与预后不良有关，但其在肿瘤发生中的确切作用尚不清楚。在这项研究中，我们证明了CD98hc的遗传缺陷对RAS诱导的皮肤癌具有保护作用。在肿瘤诱导后删除CD98hc也足以导致现有肿瘤的消退。对这些作用基础的研究确定了CD98hc的两个新功能，它们在CD98hc对肿瘤细胞增殖的内在作用之外，还参与了上皮性癌症的发生。首先，CD98hc增加了肿瘤微环境的刚性。其次，CD98hc增强了细胞对基质刚性的反应能力，基质刚性是肿瘤发展的关键因素。在机制上，CD98hc通过增加Rho激酶(ROCK)的活性来介导这种僵硬感觉，导致机械信号的核继电器YAP/TAZ介导的转录增加。我们的结果表明，CD98hc通过放大正反馈环路而促进癌症的发生，正反馈环路既增加了细胞外基质硬度，又增加了由此产生的细胞反应。这项工作支持了探索将CD98hc抑制剂用作癌症治疗药物的理论基础，
CD98hc (SLC3A2) is the heavy chain component of the dimeric transmembrane glycoprotein CD98, which comprises the large neutral amino acid transporter LAT1 (SLC7A5) in cells. Overexpression of CD98hc occurs widely in cancer cells, and is associated with poor prognosis clinically, but its exact contributions to tumorigenesis are uncertain. In this study, we showed that that genetic deficiency of CD98hc protects against Ras-driven skin carcinogenesis. Deleting CD98hc after tumor induction was also sufficient to cause regression of existing tumors. Investigations into the basis for these effects defined two new functions of CD98hc that contribute to epithelial cancer beyond an intrinsic effect on CD98hc on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Second, CD98hc amplified the capacity of cells to respond to matrix rigidity, an essential factor in tumor development. Mechanistically, CD98hc mediated this stiffness-sensing by increasing Rho kinase (ROCK) activity, resulting in increased transcription mediated by YAP/TAZ, a nuclear relay for mechanical signals. Our results suggest that CD98hc contributes to carcinogenesis by amplifying a positive feedback loop which increases both extracellular matrix stiffness and resulting cellular responses. This work supports a rationale to explore the use of CD98hc inhibitors as cancer therapeutics,