Bian Rong, Zhao Jinkai, Yao Zhongcai, Cai Yajun, Shou Chenting, Lou Dayong, Zhou Liqin, Qian Yuanyuan
Medication Department, Zhuji People's Hospital of Zhejiang Province, Shaoxing, China.
Basic Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
J Gastrointest Oncol. 2022 Jun;13(3):1255-1265. doi: 10.21037/jgo-22-458.
To clarify the molecular mechanism of hepatocellular carcinoma (HCC), conducive to developing an effective HCC therapy. Owing to the severe drug resistance, the clinical use of sorafenib, which is approved for HCC treatment, is limited. The precise molecular mechanisms of sorafenib drug resistance remain unclear. In the current work, we evaluated the role of Obg-like ATPase 1 (OLA1) in sorafenib resistance in HCC.
The survival of HCC patients between OLA1 expression and sorafenib treatment was analyzed by Kaplan-Meier plotter. Cell viability was measured by cell counting kit-8 (CCK-8) and colony formation assays. Cell death was detected by propidium iodide (PI) and trypan blue staining. The mRNA and protein levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB), respectively.
We found that OLA1 was highly correlated with sorafenib resistance of HCC through a public database. Further study showed that knockdown of OLA1 enhanced cell proliferation inhibition and cell death induced by sorafenib, along with a reduction of proliferation-associated proteins (c-Myc and cyclin D1) and increase of apoptosis-related proteins (cleaved caspase-3 and cleaved PARP) in HCC cells. In addition, knockdown of OLA1 reduced the activation of glycogen synthase kinase 3β (GSK-3β)/β-catenin.
Our results proved that OLA1 can be a potential target to enhance sorafenib sensitivity in HCC.
为阐明肝细胞癌（HCC）的分子机制，以利于开发有效的HCC治疗方法。由于严重的耐药性，已获批用于HCC治疗的索拉非尼的临床应用受到限制。索拉非尼耐药的确切分子机制仍不清楚。在当前的研究中，我们评估了Obg样ATP酶1（OLA1）在HCC对索拉非尼耐药中的作用。
通过Kaplan-Meier绘图仪分析OLA1表达与索拉非尼治疗之间HCC患者的生存率。通过细胞计数试剂盒-8（CCK-8）和集落形成试验测量细胞活力。通过碘化丙啶（PI）和台盼蓝染色检测细胞死亡。分别通过实时定量聚合酶链反应（RT-qPCR）和蛋白质印迹（WB）测量mRNA和蛋白质水平。
我们通过公共数据库发现OLA1与HCC对索拉非尼的耐药性高度相关。进一步研究表明，敲低OLA1可增强索拉非尼诱导的细胞增殖抑制和细胞死亡，同时降低HCC细胞中增殖相关蛋白（c-Myc和细胞周期蛋白D1）的表达，并增加凋亡相关蛋白（裂解的半胱天冬酶-3和裂解的PARP）的表达。此外，敲低OLA1可降低糖原合酶激酶3β（GSK-3β）/β-连环蛋白的激活。
我们的结果证明，OLA1可能是增强HCC对索拉非尼敏感性的潜在靶点。
