PO.BCS01.16 · 生物信息与计算
MUC13在HCC中的临床病理学和分子学意义
Clinicopathological and molecular significance of MUC13 in HCC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：黏蛋白13（MUC13）是一种细胞表面糖蛋白，在多种上皮性癌中异常表达。然而在肝癌中MUC13尚未得到全面研究。本研究阐明了MUC13表达在肝癌样本中的临床和分子学相关性，随后探讨其在肝脏癌变中的作用。
方法：采用结合生物信息学和分子生物学的整合方法，在HCC样本的MUC13阳性和阴性亚组中研究了MUC13的意义及其对肝细胞癌（HCC）的影响。我们对从石蜡包埋（FFPE）组织中提取的蛋白样本进行了蛋白质组学分析。通过生物信息学指导的质谱和功能富集分析识别差异表达蛋白。在选取样本进行蛋白质组学分析之前，先在HCC组织中确认了MUC13表达状态。随后我们在HCC、MSLD、MASH和纤维化样本中进行了MUC13 IHC表达分析。此外，通过夹心ELISA测定血清样本中的MUC13表达，同时使用细胞因子芯片进行细胞因子谱分析。
结果：我们的深度数据挖掘和生物信息学分析表明，与正常肝脏相比，MUC13在HCC样本中表达更高，我们的蛋白质组学分析也观察到类似模式。有趣的是，在蛋白质组学分析中，我们观察到与MUC13阴性HCC样本相比，MUC13阳性HCC亚组存在显著的分子水平变化。一些关键的差异表达蛋白与若干重要通路相关，如PTK2信号、NF-KB激活、TLR信号、MAP激酶激活和AKT信号。而DNA修复、凋亡和TP53相关通路则被耗竭。IHC和ELISA分析表明，与正常肝组织/血清样本中极微弱或无表达相比，HCC肿瘤/血清样本中MUC13表达强烈。此外，我们观察到HCC患者与健康正常血清样本之间若干细胞因子（骨桥蛋白、PDGFs、EMMPRIN/CD147、MIF、ICAM-1、VEGF）呈现出不同的表达模式。
结论：这项全面的研究提示：1）MUC13在HCC中高表达；2）MUC13阳性HCC患者亚组与MUC13阴性HCC患者亚组及正常肝组织样本相比具有显著不同的分子图谱；3）与健康正常血清样本相比，HCC患者呈现出相对不同的细胞因子谱。这些引人关注的发现提示MUC13在HCC中发挥关键作用，可作为疗效反应和预后的有用指标。
查看英文原文 English abstract
Background: Mucin 13 (MUC13), a cell surface glycoprotein aberrantly expressed in multiple epithelial carcinomas. Although in liver cancer MUC13 has not been comprehensively investigated. This study elucidates the clinical and molecular relevance of MUC13 expression in liver cancer samples followed by its role in liver carcinogenesis.
Methods: The significance of MUC13 and its impact on hepatocellular carcinoma (HCC) was investigated in MUC13 positive and negative subsets of HCC samples using an integrated approach combining bioinformatics and molecular biology. We performed proteomics analysis on protein samples extracted from paraffin embedded (FFPE) tissues. Differentially expressed proteins were identified by bioinformatics guided mass spectrometry and functional enrichment analyses. The MUC13 expression status was conformed in HCC tissue before samples selected for proteomics analysis. Later we performed MUC13 IHC expression analysis in HCC, MSLD, MASH, and fibrosis samples. Further, MUC13 expression in serum samples were determined by sandwich ELISA while cytokines profiling analyses were performed using cytokines arrays.
Result: Our deep data mining and bioinformatics analyses demonstrated higher expression of MUC13 in HCC samples as compared to normal liver and a similar pattern was observed in our proteomics analysis. Interestingly, in our proteomics analysis, we observed remarkable molecular level changes in MUC13+ve HCC subset as compared MUC13-ve HCC samples. Some of the key differentially expressed proteins are associated with several important pathways like PTK2 signaling, NF-KB activation, TLR signaling, MAP kinase activation, and AKT signaling. Whereas DNA repair, apoptosis, and TP53 associated pathways were depleted. IHC and ELISA analyses demonstrated strong MUC13 expression in HCC tumors/serum samples as compared to very faint or no expression in normal liver tissues/serum samples. Additionally, we observed a distinct expression pattern of several cytokine (Osteopontin, PDGFs, EMMPRIN/CD147, MIF, ICAM-1, VEGF) in HCC patients versus healthy normal serum samples.
Conclusion: This comprehensive study suggests 1) high expression of MUC13 in HCC, 2) MUC13+ve HCC patients' subset has a remarkable differential molecular profile as compared to MUC13-ve HCC patients' subset and normal liver tissues samples 3) HCC patients represent a relatively differential cytokine profile as compared to healthy normal serum samples. These intriguing findings suggest a crucial role of MUC13 in HCC and can be a useful indicator for therapy response and prognosis.
利益披露 Disclosure
A. Dhasmana, None..
R. Baru, None..
A. Gomez, None..
I. A. Perez, None..
S. C. Chauhan, None.