肿瘤中的聚簇蛋白:肿瘤抑制基因和致癌基因的双重作用

R. Kadam, T. Teni
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引用次数: 3

摘要

聚簇蛋白(CLU)是一种异二聚体和硫酸糖蛋白,与多种生理功能有关。这种分子伴侣蛋白在多种组织中普遍表达,并在物种间保守。不同的亚细胞定位和可能存在的不同CLU异构体可能导致其功能的多样性。与正常组织相比,CLU在几种癌症中表达增加或减少,因此其在肿瘤发生中的作用存在争议。几项研究的证据表明,根据信号和细胞背景,CLU可能具有肿瘤抑制基因或致癌基因的双重作用。CLU可能通过抑制细胞凋亡、激活自噬、调节IGF-1/IGFR、EGFR、NF-kB、PI3K/AKT、TGFp和部分mirna等信号通路发挥其致瘤作用。CLU可能通过调节细胞周期和诱导细胞凋亡来发挥其抑瘤作用。在癌症中,杂合性缺失(LOH)、CLU位点拷贝数缺失、表观遗传修饰和选择性mirna的表达可能导致CLU下调。Custirsen (OGX-011)是第二代反义寡核苷酸,可抑制CLU表达并增加癌细胞对化疗药物的敏感性,目前正处于III期临床试验。CLU在多种癌症中是一个有吸引力的靶点,然而为了有效靶向,必须知道它在特定的组织/细胞环境中是作为癌基因还是肿瘤抑制基因。本文试图讨论CLU在癌症中的两种不同作用及其相关的调控机制。这篇综述还揭示了复杂的CLU剪接变异体、支持CLU在癌症中的双重作用的各种功能属性以及值得注意的CLU研究的局限性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Clusterin in cancer: Dual role as a tumor suppressor gene and an oncogene
Clusterin (CLU), a heterodimeric and sulfated glycoprotein has been associated with various physiological functions. This molecular chaperone protein is ubiquitously expressed in diverse tissues and conserved across species. Differences in subcellular localization and possible existence of different CLU isoforms may contribute to its functional diversity. Increased or decreased expression of CLU has been observed in several cancers versus normal tissues and hence its role in tumorigenesis is controversial. Evidences from several studies imply that CLU may have a dual role as a tumor suppressor gene or an oncogene depending on the signal and cellular context. CLU possibly exerts its oncogenic role by inhibiting apoptosis, activating autophagy and modulating several signaling pathways like IGF-1/IGFR, EGFR, NF-kB, PI3K/AKT, TGFp and select miRNAs. CLU may exert its tumor suppressive effects by regulating cell cycle and inducing apoptosis. In cancer, loss of heterozygosity (LOH), copy number loss at CLU locus, epigenetic modifications and expression of select miRNAs may lead to the downregulation of CLU. Custirsen (OGX-011), a second generation antisense oligonucleotide that inhibits CLU expression and increases sensitivity of cancer cells to chemotherapeutic drugs, is currently in phase III clinical trials. CLU is an attractive target in several cancers, however for effective targeting, it is essential to know whether it acts as an oncogene or a tumor suppressor gene in a specific tissue/cellular context. The current review attempts to discuss the two contrasting roles of CLU in cancer and associated regulatory mechanisms. This review also sheds light on the complex CLU splice variants, the varied functional attributes supporting the dual roles in cancer and limitations of the CLU research that warrant attention.
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