Department of Biotechnology, Graduate School of Natural and Applied Sciences, Ege University, Izmir 35100, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir 35100, Turkey.
Cells. 2023 May 11;12(10):1362. doi: 10.3390/cells12101362.
The heterogeneity of cancer strongly suggests the need to explore additional pathways to target. As cancer cells have increased proteotoxic stress, targeting proteotoxic stress-related pathways such as endoplasmic reticulum stress is attracting attention as a new anticancer treatment. One of the downstream responses to endoplasmic reticulum stress is endoplasmic reticulum-associated degradation (ERAD), a major degradation pathway that facilitates proteasome-dependent degradation of unfolded or misfolded proteins. Recently, SVIP (small VCP/97-interacting protein), an endogenous ERAD inhibitor, has been implicated in cancer progression, especially in glioma, prostate, and head and neck cancers. Here, the data of several RNA-sequencing (RNA-seq) and gene array studies were combined to evaluate the gene expression analysis on a variety of cancers, with a particular focus on breast cancer. The mRNA level of SVIP was found to be significantly higher in primary breast tumors and correlated well with its promoter methylation status and genetic alterations. Strikingly, the SVIP protein level was found to be low despite increased mRNA levels in breast tumors compared to normal tissues. On the other hand, the immunoblotting analysis showed that the expression of SVIP protein was significantly higher in breast cancer cell lines compared to non-tumorigenic epithelial cell lines, while most of the key proteins of gp78-mediated ERAD did not exhibit such an expression pattern, except for Hrd1. Silencing of SVIP enhanced the proliferation of p53 wt MCF-7 and ZR-75-1 cells but not p53 mutant T47D and SK-BR-3 cells; however, it increased the migration ability of both types of cell lines. Importantly, our data suggest that SVIP may increase p53 protein levels in MCF7 cells by inhibiting Hrd1-mediated p53 degradation. Overall, our data reveal the differential expression and function of SVIP on breast cancer cell lines together with in silico data analysis.
癌症的异质性强烈表明需要探索其他靶向途径。由于癌细胞的蛋白毒性应激增加，靶向内质网应激相关途径（如内质网应激）作为一种新的抗癌治疗方法引起了关注。内质网应激的下游反应之一是内质网相关降解（ERAD），这是一种主要的降解途径，可促进未折叠或错误折叠蛋白的蛋白酶体依赖性降解。最近，SVIP（小 VCP/97 相互作用蛋白），一种内源性 ERAD 抑制剂，被牵连到癌症的进展中，特别是在神经胶质瘤、前列腺癌和头颈部癌症中。在这里，我们综合了几个 RNA 测序（RNA-seq）和基因芯片研究的数据，对多种癌症进行了基因表达分析，特别关注乳腺癌。发现 SVIP 的 mRNA 水平在原发性乳腺癌肿瘤中显著升高，与启动子甲基化状态和遗传改变密切相关。引人注目的是，尽管 SVIP 的 mRNA 水平在乳腺癌肿瘤中高于正常组织，但 SVIP 蛋白水平却较低。另一方面，免疫印迹分析显示，SVIP 蛋白在乳腺癌细胞系中的表达明显高于非肿瘤上皮细胞系，而 gp78 介导的 ERAD 的大多数关键蛋白除外 Hrd1 除外，没有表现出这种表达模式。SVIP 的沉默增强了 p53 wt MCF-7 和 ZR-75-1 细胞的增殖，但对 p53 突变型 T47D 和 SK-BR-3 细胞没有影响；然而，它增加了两种类型的细胞系的迁移能力。重要的是，我们的数据表明，SVIP 通过抑制 Hrd1 介导的 p53 降解，可能增加 MCF7 细胞中的 p53 蛋白水平。总体而言，我们的数据揭示了 SVIP 在乳腺癌细胞系中的差异表达和功能，以及基于计算的数据分析。
