Song Yanan, He Saifei, Ma Xing, Zhang Miao, Zhuang Juhua, Wang Guoyu, Ye Ying, Xia Wei
Central Laboratory, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine 358 Datong Road, Pudong, Shanghai 200137, P. R. China.
Department of Nuclear Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine 358 Datong Road, Pudong, Shanghai 200137, P. R. China.
Am J Cancer Res. 2020 Nov 1;10(11):3644-3665. eCollection 2020.
Hepatocellular carcinoma (HCC) is one of the top five causes of cancer death. The interaction of RNA binding proteins and long no coding RNA play vital role in malignant tumor progression, and even contribute to chemoresistance. RNA binding protein X (RBMX) plays a vital role in binding and stabilizing many proteins. In this study, we have identified RBMX significantly contributes to the tumorigenesis and sorafenib resistance of hepatocellular carcinoma (HCC). We observed that RBMX was highly expressed in both the HCC patient tissues and HCC cell lines. The HCC cell's viability, proliferation, and sorafenib resistance ability were both increased when RBMX was overexpressed. Additional, RBMX also promotes HCC development and chemoresistance . Further, we found that the autophagy level was increased in HCC cells, which RBMX was up regulated, with sorafenib processing. Interestingly, our study found that long no coding RNA bladder cancer associated transcript 1 (LncBLACAT1) was also raised in HCC. Mechanically, RIP, RNA pull-down and RNA Stability assay proved that RBMX could specially binds BLACAT1's mRNA and matins its expression, which is high degree of consistency with database prediction. This mechanism of action is beneficial for cancer cells proliferation, anti-apoptotic, and colony formation with sorafenib treatment. Further, the autophagy level and cancer cell stemness were also improved when RBMX/BLACAT1 upregulated. Our study indicated that hepatoma cells can improve their proliferation, colony ability and autophagy by RBMX stabilizing BLACAT1 expression then promote HCC development and drug resistance. Hence, RBMX could be considered as novel therapeutic target for HCC treatment strategies.
肝细胞癌（HCC）是导致癌症死亡的五大原因之一。RNA结合蛋白与长链非编码RNA的相互作用在恶性肿瘤进展中起着至关重要的作用，甚至导致化疗耐药。RNA结合蛋白X（RBMX）在许多蛋白质的结合和稳定中发挥着至关重要的作用。在本研究中，我们发现RBMX对肝细胞癌（HCC）的肿瘤发生和索拉非尼耐药性有显著影响。我们观察到RBMX在HCC患者组织和HCC细胞系中均高表达。当RBMX过表达时，HCC细胞的活力、增殖和索拉非尼耐药能力均增强。此外，RBMX还促进HCC的发展和化疗耐药。进一步地，我们发现索拉非尼处理后，RBMX上调的HCC细胞自噬水平升高。有趣的是，我们的研究发现长链非编码RNA膀胱癌相关转录本1（LncBLACAT1）在HCC中也升高。机制上，RIP、RNA下拉和RNA稳定性分析证明RBMX可以特异性结合BLACAT1的mRNA并维持其表达，这与数据库预测高度一致。这种作用机制有利于癌细胞在索拉非尼治疗下的增殖、抗凋亡和集落形成。此外，当RBMX/BLACAT1上调时，自噬水平和癌细胞干性也得到改善。我们的研究表明，肝癌细胞可以通过RBMX稳定BLACAT1的表达来提高其增殖、集落形成能力和自噬，从而促进HCC的发展和耐药。因此，RBMX可被视为HCC治疗策略的新型治疗靶点。
