Anticancer effect of YWHAZ silencing via inducing apoptosis and autophagy in gastric cancer cells

Abstract

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.

Long Noncoding RNA MLK7-AS1 Promotes Non-Small-Cell Lung Cancer Migration and Invasion via the miR-375-3p/YWHAZ Axis

“…YWHAZ enhances metastasis and is related to the poor survival in hepatocellular carcinoma (30). YWHAZ strengthens the gastric cancer cells growth ability by suppressing cell apoptosis and autophagy (24).…”

“…The potential target genes of miR-375-3p were predicted by StarBase v2.0. Among many candidates, YWHAZ was identified as an oncogene in several tumors (24,25). Thus, YWHAZ was chosen as a prior candidate for miR-375-3p.…”

The role of YWHAZ in cancer: A maze of opportunities and challenges

“…In GC, YWHAZ was downregulated in cells transfected with miR-375 and luciferase reporter indicated that miR-375 targets the 3′ UTR of YWHAZ [20,22]. Silencing of YWHAZ accelerated miR-375-induced apoptosis by caspase-3/ caspase-7 activation and promoted autophagy by PI3K/AKT/mTOR signaling pathway [22,23], as well as inhibiting cell proliferation, migration/invasion and EMT in GC [20,21].…”

Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells

“…These findings are important because if the specific sets of antigens can reflect the ongoing pathophysiological processes that are upregulated in fibrotic lesions, we can determine the molecular events that occur in the disease environment through examination of patient sera [12]. Sera from IPF patients react with molecules associated with TGF-β and fibroblast activation (transgelin 2 [83], transgelin 3 [84], LIM domain-binding protein 2 [85], HLA complex P5 [86], PHGDH [87], NAT6 [88], CDK9 [89], SEPT4 [90]), cell death regulation (14-3-3 protein zeta/delta [91], Trefoil factor 2 protein [92], RAS-like family 11 member B [93], MRPS11 [94], RSU1 [95], PLCG2 [96], IFI44L [97], YTHDF2 [98], AMOTL2 [99], ROGDI [100]), and airway clearance (sperm flagellar 1 [101], cilia and flagella associated protein 410 [102], t-complex 10 like [103]) ( Table 1). Natural autoantibodies are thought to reflect the ongoing disease environment [10,11].…”