Second Department of General Surgery, the First People's Hospital of Yunnan Province, No. 157 Jinbi Road, Kunming, 650032, Yunnan Province, China.
The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, 650032, Yunnan Province, China.
In Vitro Cell Dev Biol Anim. 2019 Jun;55(6):445-452. doi: 10.1007/s11626-019-00360-5. Epub 2019 May 28.
Gastric cancer (GC) is a commonly occurring neoplasm worldwide. The occurrence of multidrug resistance (MDR) in GC cells is the main obstacle to effective GC chemotherapy. The aim of the present study was to reveal the functional role and the underlying mechanisms of basic leucine zipper ATF-like transcription factor 2 (BATF2), a novel tumor suppressor, on MDR in GC cells. Here, we first found that SGC7901/VCR and SGC7901/ADR cells had higher drug resistance than SGC7901 cells using methylthiazol tetrazolium (MTT) and flow cytometry analysis. Moreover, MDR-related proteins and Wnt/β-catenin pathway markers were all upregulated in SGC7901/VCR cells compared to SGC7901 cells by quantitative reverse transcription-PCR (qRT-PCR) and western blot analyses. Subsequently, we observed BATF2 was downregulated in SGC7901/VCR cells and BATF2 overexpression significantly induced cell cycle G0/G1 phase arrest and apoptosis. Furthermore, overexpression of BATF2 could suppress Wnt/β-catenin signaling and increase drug susceptibility by downregulating Wnt/β-catenin pathway markers. In addition, knockdown of β-catenin imitated the effects of BATF2 overexpression on drug susceptibility. Importantly, enhancing the Wnt/β-catenin pathway could reverse the inhibitory effects of BATF2 on MDR. In conclusion, BATF2 was downregulated in MDR GC cells and overexpression of BATF2 could reverse the MDR of GC cells by inactivating the Wnt/β-catenin pathway.
胃癌（GC）是一种在全球范围内普遍发生的肿瘤。GC 细胞中多药耐药（MDR）的发生是有效 GC 化疗的主要障碍。本研究旨在揭示碱性亮氨酸拉链 ATF 样转录因子 2（BATF2）作为一种新的肿瘤抑制因子在 GC 细胞 MDR 中的功能作用及其潜在机制。在这里，我们首先通过噻唑蓝（MTT）和流式细胞术分析发现，SGC7901/VCR 和 SGC7901/ADR 细胞比 SGC7901 细胞具有更高的耐药性。此外，通过定量逆转录聚合酶链反应（qRT-PCR）和蛋白质印迹分析发现，与 SGC7901 细胞相比，SGC7901/VCR 细胞中 MDR 相关蛋白和 Wnt/β-连环蛋白通路标志物均上调。随后，我们观察到 SGC7901/VCR 细胞中 BATF2 下调，BATF2 过表达显著诱导细胞周期 G0/G1 期阻滞和细胞凋亡。此外，BATF2 的过表达可以通过下调 Wnt/β-连环蛋白通路标志物来抑制 Wnt/β-连环蛋白信号通路并增加药物敏感性。此外，β-连环蛋白的敲低模仿了 BATF2 过表达对药物敏感性的影响。重要的是，增强 Wnt/β-连环蛋白通路可以逆转 BATF2 对 MDR 的抑制作用。总之，MDR GC 细胞中 BATF2 下调，BATF2 过表达通过使 Wnt/β-连环蛋白通路失活可逆转 GC 细胞的 MDR。
