Department of Ultrasound, China-Japan Union Hospital, Jilin University, Changchun, China.
Department of Gastrointestinal Surgery, China-Japan Union Hospital, Jilin University, Changchun, China.
Neoplasma. 2018 Sep 19;65(5):693-700. doi: 10.4149/neo_2018_170922N603. Epub 2018 Jun 17.
YWHAZ (14-3-3ζ) has been reported to be a prognostic marker for various tumors and play a crucial role in many oncogenic processes, including proliferation, migration and invasion. However, the functional role and mechanism of YWHAZ in gastric cancer (GC) are not in detail and still remain to be studied. In the present study, the endogenous expression of YWHAZ in gastric cancer cell line BGC-823 was silenced by YWHAZ-specific short hairpin RNA (shRNA). Our data showed that YWHAZ silencing resulted in cell cycle arrest in BGC-823 cells. Further, YWHAZ-silenced BGC-823 cells acquired increased apoptosis rate, which was confirmed by increased levels of cleaved caspase-3, cleaved PARP, and Bax, and decreased level of Bcl-2. Suppression of YWHAZ also promoted autophagy, confirming by the upregulation of LC3II /LC3I ratio, and downregulation of p62 level. Moreover, YWHAZ suppression inhibited the activation of PI3K/AKT/mTOR signaling pathway in BGC-823 cells. LY294002 (PI3K/AKT inhibitor, 200 nM) further promoted YWHAZ silencing-induced apoptosis and autophagy in BGC-823 cells, while insulin-like growth factor-1 (IGF-1; PI3K/AKT agonist, 10 ng/ml) had the opposite role. Finally, suppression of YWHAZ inhibited the growth of the xenograft tumor in vivo. This study provides extended evidence that YWHAZ can be a potential therapeutic target for GC.
YWHAZ（14-3-3ζ）已被报道为多种肿瘤的预后标志物，并在许多致癌过程中发挥关键作用，包括增殖、迁移和侵袭。然而，YWHAZ 在胃癌（GC）中的功能作用和机制尚不清楚，仍有待研究。在本研究中，通过 YWHAZ 特异性短发夹 RNA（shRNA）沉默胃癌细胞系 BGC-823 中的内源性 YWHAZ 表达。我们的数据表明，YWHAZ 沉默导致 BGC-823 细胞周期停滞。此外，YWHAZ 沉默的 BGC-823 细胞获得了增加的凋亡率，这通过增加的 cleaved caspase-3、cleaved PARP 和 Bax 水平和降低的 Bcl-2 水平得到证实。YWHAZ 的抑制还促进了自噬，这通过 LC3II/LC3I 比值的上调和 p62 水平的下调得到证实。此外，YWHAZ 抑制抑制了 BGC-823 细胞中 PI3K/AKT/mTOR 信号通路的激活。LY294002（PI3K/AKT 抑制剂，200 nM）进一步促进了 BGC-823 细胞中 YWHAZ 沉默诱导的凋亡和自噬，而胰岛素样生长因子-1（IGF-1；PI3K/AKT 激动剂，10 ng/ml）则起到相反的作用。最后，抑制 YWHAZ 抑制了异种移植肿瘤在体内的生长。本研究提供了更多证据表明 YWHAZ 可能成为 GC 的潜在治疗靶点。
