PDF(Pubmed)
Abstract：
Systemic therapies, the ultimate strategies for patients with advanced hepatocellular carcinoma (HCC), are suffering from serious clinical challenges, such as the occurrence and development of drug resistance. Treatment resistance aggravates tumor progression partly by inducing tumor metastasis. Regorafenib-resistant HCC cells exhibit a highly striking metastatic phenotype, but the detailed mechanisms underlying these aggressive behaviors remain elusive. Here, we conduct transcriptome sequencing analysis to identify COL5A2 as a crucial driver of the metastatic characteristics of regorafenib-resistant HCC cells. COL5A2 is aberrantly highly expressed in resistant cells, and its genetic depletion significantly suppresses proliferation, migration, invasion, vasculogenic mimicry (VM) formation and lung metastasis in vitro and in vivo, concomitant with the downregulation of VE-cadherin, EphA2, Twist1, p-p38 and p-STAT3 expressions. LIFR is confirmed to be an essential downstream molecule of COL5A2, and its expression is observably elevated by COL5A2 depletion. Ectopic overexpression of LIFR drastically attenuates the proliferation, migration, invasion and VM of regorafenib-resistant cells and represses the expressions of VM-related molecules and the activation of p38/STAT3 signaling pathway. Interestingly, rescue experiments show that the inhibition of the above aggressive features of resistant cells by COL5A2 loss is clearly alleviated by silencing of LIFR. Collectively, our results reveal that COL5A2 promotes the ability of regorafenib-resistant HCC cells to acquire a metastatic phenotype by attenuating LIFR expression and suggest that therapeutic regimens targeting the COL5A2/LIFR axis may be beneficial for HCC patients with therapeutic resistance.
摘要：
系统性治疗,晚期肝细胞癌（HCC）患者的最终策略，正在遭受严重的临床挑战，如耐药性的发生和发展。治疗抵抗部分通过诱导肿瘤转移而加重肿瘤进展。对Regorafenib耐药的HCC细胞表现出非常惊人的转移表型，但是这些攻击行为背后的详细机制仍然难以捉摸。这里,我们进行了转录组测序分析,以确定COL5A2是瑞戈非尼耐药HCC细胞转移特征的关键驱动因素.COL5A2在抗性细胞中异常高表达，它的遗传耗竭显著抑制了增殖，迁移,入侵,体内外血管生成拟态（VM）形成和肺转移，伴随着VE-钙粘蛋白的下调，EphA2、Twist1、p-p38和p-STAT3表达。LIFR被证实是COL5A2的必需下游分子,并且其表达通过COL5A2耗尽而显著升高。LIFR的异位过表达急剧减弱增殖，迁移,并抑制VM相关分子的表达和p38/STAT3信号通路的激活。有趣的是,挽救实验表明，通过LIFR沉默，COL5A2损失对抗性细胞的上述侵袭性特征的抑制明显减轻。总的来说，我们的结果显示,COL5A2通过减弱LIFR表达,促进了对regorafenib耐药的HCC细胞获得转移表型的能力,并提示靶向COL5A2/LIFR轴的治疗方案可能对治疗耐药的HCC患者有益.
