Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro.
Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro.
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蛋白聚糖-4与HCC患者更长的生存期相关，并通过体外CD44增强索拉非尼和瑞非尼的有效性。
DOI：
10.1038/s41419-020-03180-8
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发表时间：
2020-11-16
影响因子：
9
通讯作者：
Giannelli G
中科院分区：
文献类型：
--
作者：
Dituri F;Scialpi R;Schmidt TA;Frusciante M;Mancarella S;Lupo LG;Villa E;Giannelli G
索拉非尼和瑞格非尼给药是治疗肝细胞癌（HCC）的首选方法之一，但没有提供令人满意的益处。癌细胞和周围微环境中存在的其他多种非癌细胞亚群之间发生的强烈串扰被认为会影响肿瘤进展。这种相互作用是由许多可溶性和结构性细胞外基质（ECM）蛋白质丰富的基质环境介导的。在这里，我们评估了ECM蛋白质蛋白聚糖4（PRG4）的HCC肿瘤表达及其单独或与索拉非尼和瑞格非尼联合的潜在药理学活性。在一项涉及78名HCC受试者的前瞻性研究中，PRG4 mRNA水平与HCC患者的生存率增加密切相关（p = 0.000）。我们接下来表明，转化生长因子β刺激PRG4的表达和分泌的原代人肝癌癌相关的成纤维细胞，非侵入性肝癌细胞系，和离体标本。通过功能测试，我们发现重组人PRG4（rhPRG4）削弱肝癌细胞的迁移。更重要的是，用rhPRG4处理表达CD44（主要PRG4受体）的HCC细胞显著增强了索拉非尼和瑞格非尼的生长限制能力，而不显著影响细胞增殖本身。相反，rhPRG4仅对低CD44表达或稳定CD44沉默的HCC细胞弱地增强药物有效性。总之，这些数据表明，生理产生的化合物PRG4可以通过加强索拉非尼和瑞格非尼在HCC治疗中的作用而作为新型肿瘤抑制剂发挥作用。
Sorafenib and regorafenib administration is among the preferential approaches to treat hepatocellular carcinoma (HCC), but does not provide satisfactory benefits. Intensive crosstalk occurring between cancer cells and other multiple non-cancerous cell subsets present in the surrounding microenvironment is assumed to affect tumor progression. This interplay is mediated by a number of soluble and structural extracellular matrix (ECM) proteins enriching the stromal milieu. Here we assess the HCC tumor expression of the ECM protein proteoglycan 4 (PRG4) and its potential pharmacologic activity either alone, or in combination with sorafenib and regorafenib. PRG4 mRNA levels resulted strongly correlated with increased survival rate of HCC patients (p = 0.000) in a prospective study involving 78 HCC subjects. We next showed that transforming growth factor beta stimulates PRG4 expression and secretion by primary human HCC cancer-associated fibroblasts, non-invasive HCC cell lines, and ex vivo specimens. By functional tests we found that recombinant human PRG4 (rhPRG4) impairs HCC cell migration. More importantly, the treatment of HCC cells expressing CD44 (the main PRG4 receptor) with rhPRG4 dramatically enhances the growth-limiting capacity of sorafenib and regorafenib, whereas not significantly affecting cell proliferation per se. Conversely, rhPRG4 only poorly potentiates drug effectiveness on low CD44-expressing or stably CD44-silenced HCC cells. Overall, these data suggest that the physiologically-produced compound PRG4 may function as a novel tumor-suppressive agent by strengthening sorafenib and regorafenib effects in the treatment of HCC.
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影响因子：
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作者：
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