Multiple functions of the 37/67-kd laminin receptor make it a suitable target for novel cancer gene therapy.
Multiple functions of the 37/67-kd laminin receptor make it a suitable target for novel cancer gene therapy.
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DOI：
10.1038/mt.2009.199
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发表时间：
2010
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影响因子：
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通讯作者：
J. Scheiman;Jen-Chieh Tseng;Yun Zheng;D. Meruelo
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文献类型：
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作者：
J. Scheiman;Jen-Chieh Tseng;Yun Zheng;D. Meruelo
37/67kd的层粘连蛋白受体LAMR是一种多功能蛋白，它与40S核糖体亚基结合，也定位于细胞膜与细胞外基质相互作用。LAMR在多种肿瘤中高表达，在肿瘤细胞的迁移和侵袭中发挥重要作用。在这里，我们表明LAMR对肿瘤细胞的增殖、存活和蛋白质翻译也是至关重要的。小干扰RNA(SiRNA)通过改变细胞周期蛋白A2/B1、细胞周期蛋白依赖性蛋白激酶(CDKs)1/2、Survivin和p21的表达水平，抑制LAMR基因的表达，从而在体外诱导细胞周期进入G1期。我们还发现LAMR的核糖体功能对翻译至关重要，因为LAMR表达的减少导致新合成的蛋白质急剧减少。此外，LAMR低表达的细胞具有较少的40S亚基和80S单体，导致游离60S核糖体亚基增加。这些结果表明，LAMR能够在许多方面调节肿瘤的发展；进一步增强其作为基因治疗靶点的潜力。为了验证这一点，我们开发了一种新型的Sindbis/Lenti伪型载体，携带针对lamr的短发夹状RNA(ShRNA)。这种伪型载体有效地降低了LAMR的表达，并特异性地靶向体内的肿瘤。用这种伪型载体治疗携带肿瘤的严重联合免疫缺陷(SCID)小鼠可显著抑制肿瘤生长。因此，我们表明LAMR可以作为肿瘤减少和消除的新疗法的靶点。
The 37/67-kd laminin receptor, LAMR, is a multifunctional protein that associates with the 40S ribosomal subunit and also localizes to the cell membrane to interact with the extracellular matrix. LAMR is overexpressed in many types of cancer, playing important roles in tumor-cell migration and invasion. Here, we show that LAMR is also vital for tumor-cell proliferation, survival, and protein translation. Small-interfering RNA (siRNA)–mediated reduction in expression of LAMR leads to G1phase cell-cycle arrestin vitroby altering cyclins A2/B1, cyclin-dependent kinases (CDKs) 1/2, Survivin, and p21 expression levels.In vivo, reduction in LAMR expression results in inhibition of HT1080 cells to develop tumors. We also found that LAMR's ribosomal functions are critical for translation as reduction in LAMR expression leads to a dramatic decrease in newly synthesized proteins. Further, cells with lower expression of LAMR have fewer 40S subunits and 80S monosomes, causing an increase in free 60S ribosomal subunits. These results indicate that LAMR is able to regulate tumor development in many ways; further enhancing its potential as a target for gene therapy. To test this, we developed a novel Sindbis/Lenti pseudotype vector carrying short-hairpin RNA (shRNA) designed againstlamr. This pseudotype vector effectively reduces LAMR expression and specifically targets tumorsin vivo. Treatment of tumor-bearing severe combine immunodeficient (SCID) mice with this pseudotype vector significantly inhibits tumor growth. Thus, we show that LAMR can be used as a target in novel therapy for tumor reduction and elimination.