Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
Int J Oncol. 2018 Dec;53(6):2579-2589. doi: 10.3892/ijo.2018.4557. Epub 2018 Sep 11.
Y-box binding protein-1 (YB-1) facilitates cancer chemoresistance through the upregulation of ATP-binding cassette (ABC) transporters associated with multidrug resistance, which is one of the primary obstacles in cancer treatment. Since aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is also implicated in chemoresistance in numerous human malignancies, the interaction between YB-1 and JAK/STAT signaling was explored underlying the chemoresistance of NUGC3 gastric cancer cells. It was demonstrated that YB-1 translocated into the nuclei of NUGC3 cells exposed to doxorubicin hydrochloride, suggesting its important role in chemoresistance. Consistently, knockdown of YB-1 significantly decreased the chemoresistance of cells to doxorubicin hydrochloride and epirubicin hydrochloride, as evidenced by a decrease in cell viability. Notably, JAK inhibitor AG490 treatment further decreased the cell viability caused by YB-1 inhibition and doxorubicin hydrochloride. It was also observed that YB-1 transcriptionally regulated the ABCC3 transporter, whereas STAT3 modulated ABCC2 transporter levels. These findings suggest that YB-1 and STAT3 act together to facilitate chemoresistance via modulating the expression of different ABC transporters in NUGC3 cells. Notably, siYB-1 did not exhibit any significant effect on STAT3 expression. Similarly, siSTAT3 failed to alter YB-1 expression, suggesting that the two may not regulate each other in a mutual manner. However, double knockdown of YB-1 and STAT3 led to a synergistic inhibition of cell invasion in NUGC3 cells. Nonetheless, the combined treatment of YB-1 antagonists with STAT3 inhibitors may serve as an effective therapy in gastric cancer.
Y 盒结合蛋白-1（YB-1）通过上调与多药耐药相关的三磷酸腺苷结合盒（ABC）转运蛋白，促进癌症的化疗耐药，这是癌症治疗中的主要障碍之一。由于异常的 Janus 激酶（JAK）/信号转导和转录激活因子（STAT）信号也与许多人类恶性肿瘤的化疗耐药有关，因此研究了 YB-1 与 JAK/STAT 信号转导之间的相互作用，以探讨 NUGC3 胃癌细胞的化疗耐药机制。结果表明，盐酸多柔比星处理后 YB-1 易位到 NUGC3 细胞的核内，提示其在化疗耐药中起重要作用。一致地，YB-1 敲低显著降低了细胞对盐酸多柔比星和表柔比星的化疗耐药性，细胞活力降低。值得注意的是，JAK 抑制剂 AG490 处理进一步降低了 YB-1 抑制和盐酸多柔比星引起的细胞活力降低。还观察到 YB-1 转录调节 ABCC3 转运蛋白，而 STAT3 调节 ABCC2 转运蛋白水平。这些发现表明，YB-1 和 STAT3 一起通过调节 NUGC3 细胞中不同 ABC 转运蛋白的表达来促进化疗耐药。值得注意的是，siYB-1 对 STAT3 表达没有显著影响。同样，siSTAT3 也没有改变 YB-1 表达，表明两者可能不会以相互的方式相互调节。然而，YB-1 和 STAT3 的双重敲低导致 NUGC3 细胞的细胞侵袭协同抑制。尽管如此，YB-1 拮抗剂与 STAT3 抑制剂的联合治疗可能是胃癌的有效治疗方法。
