Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression
Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression
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人白细胞抗原F位点邻近转录本10过表达扰乱WISP1蛋白和mRNA表达促进肝细胞癌进展
DOI：
10.1002/hep.30105
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发表时间：
2018-12-01
期刊：
影响因子：
13.5
通讯作者：
Shao，Jianghua
中科院分区：
文献类型：
--
作者：
Yan，Jinlong;Lei，Jun;Shao，Jianghua
最近，转录组-蛋白质组关系的研究揭示了某些基因的mRNA/蛋白质表达不一致，并推测可能涉及蛋白质翻译后修饰（PTM）。然而，目前没有证据支持这一假设。Wnt诱导的分泌蛋白-1（WISP 1）是β-catenin的下游靶基因，在肿瘤的发生发展中起重要作用，但WISP 1在不同肿瘤类型中的表达及作用存在争议。在此，我们首次证实了WISP 1蛋白在肝细胞癌（HCC）组织中的表达显著下调，并且可能是HCC患者预后不良的独立预测因子。体内和体外证据表明，WISP 1可以抑制HCC细胞增殖。进一步的研究发现，WISP 1蛋白的低表达与人类白细胞抗原F位点邻近转录本10（FAT 10）的表达有关，FAT 10是一种特异性的泛素样蛋白，具有降解和稳定功能，在PTM中起重要作用。FAT 10过表达通过FAT 10化促进WISP 1降解，从而降低WISP 1蛋白表达，从而促进HCC增殖。有趣的是，我们发现并证明FAT 10过表达可导致WISP 1蛋白/mRNA表达不一致，蛋白表达降低，而mRNA表达增加。结论：FAT 10过表达可导致WISP 1蛋白和mRNA表达不一致，从而通过下调WISP 1蛋白表达促进HCC进展。
Recently, studies on transcriptome–proteome relationships have revealed mRNA/protein expression discordance for certain genes and speculated that protein posttranslational modification (PTM) may be involved. However, there is currently no evidence to support this hypothesis. Wnt‐induced secreted protein‐1 (WISP1) is the downstream target gene of β‐catenin and plays an important role in tumorigenesis and progression, but the expression and role of WISP1 in different tumor types are controversial. Here, we first confirmed that WISP1 protein expression was significantly down‐regulated in hepatocellular carcinoma (HCC) tissue and could be an independent predictor of poor prognosis for patients with HCC.In vivoandin vitroevidence was provided that WISP1 can suppress HCC cell proliferation. Further studies have found that low WISP1 protein expression was related to expression of human leukocyte antigen F locus adjacent transcript 10 (FAT10), a specific ubiquitin‐like protein with both degradation and stabilization functions, which plays an important role in PTM. FAT10 overexpression facilitated WISP1 degradation by FAT10ylation to decrease WISP1 protein expression, thus promoting HCC proliferation. Interestingly, we found and demonstrated that FAT10 overexpression could result in WISP1 protein/mRNA expression discordance, with protein expression decreasing while mRNA expression increased. The underlying mechanism is that FAT10 exerts substrate stabilization and degradation functions simultaneously, while FAT10 overexpression promotes WISP1 mRNA expression by stabilizing β‐catenin and directly degrades WISP1 protein.Conclusion: Our study demonstrated that overexpression of FAT10 results in expression discordance between WISP1 protein and mRNA, thereby promoting HCC progression by down‐regulating WISP1 protein expression.