LOXL2 Status Correlates with Tumor Stage and Regulates Integrin Levels to Promote Tumor Progression in ccRCC
LOXL2 Status Correlates with Tumor Stage and Regulates Integrin Levels to Promote Tumor Progression in ccRCC
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DOI：
10.1158/1541-7786.mcr-14-0233
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发表时间：
2014-12-01
影响因子：
5.2
通讯作者：
Tsujikawa, Kazutake
中科院分区：
文献类型：
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作者：
Hase, Hiroaki;Jingushi, Kentaro;Tsujikawa, Kazutake
肾透明细胞癌(CcRCC)是肾细胞癌(RCC)中最常见的亚型。为了明确肾小管上皮细胞癌发生发展的分子机制，我们重点研究了类LOX蛋白2(LOXL2)，它是胶原和弹性蛋白交联的第一步。外显子阵列分析和定量验证表明，与癌旁非癌肾组织相比，LOXL2在临床标本中显著上调，且这种上调与肾细胞癌的病理分期有关。RNAi介导的LOXL2基因敲除导致ccRCC细胞应力纤维和局灶性黏附的形成受到显著抑制。此外，LOXL2 siRNA敲除显著抑制了细胞的生长、迁移和侵袭。在机制上，LOXL2通过依赖于蛋白酶和蛋白酶体的系统调节整合素α5(ITGAV5)和β1(ITGB1)的降解。在临床肾细胞癌组织中，LOXL2和整合素α5的表达水平与肿瘤的病理分级有关。综上所述，LOXL2是整合素α5和整合素β1蛋白水平的有效调节者，并在ccRCC的促肿瘤能力中发挥作用。(C)2014年AACR。
Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined subtype of renal cell carcinoma (RCC). To define the molecular mechanism in the progression of ccRCC, we focused on LOX-like protein 2 (LOXL2), which is critical for the first step in collagen and elastin cross-linking. Using exon array analysis and quantitative validation, LOXL2 was shown to be significantly upregulated in clinical specimens of human ccRCC tumor tissues, compared with adjacent noncancerous renal tissues, and this elevated expression correlated with the pathologic stages of ccRCC. RNAi-mediated knockdown of LOXL2 resulted in marked suppression of stress-fiber and focal adhesion formation in ccRCC cells. Moreover, LOXL2 siRNA knockdown significantly inhibited cell growth, migration, and invasion. Mechanistically, LOXL2 regulated the degradation of both integrins alpha 5 (ITGAV5) and beta 1 (ITGB1) via protease-and proteasome-dependent systems. In clinical ccRCC specimens, the expression levels of LOXL2 and integrin alpha 5 correlated with the pathologic tumor grades. In conclusion, LOXL2 is a potent regulator of integrin alpha 5 and integrin beta 1 protein levels and functions in a tumor-promoting capacity in ccRCC. (C)2014 AACR.