Abstract
Beclin 1 is encoded by Becn1, and plays a role in tumorigenesis, neurodegeneration, apoptosis and autophagy. Here, the aggressive phenotypes and relevant proteins were examined after Beclin 1 expression was altered in gastric cancer cells. We also observed the effects of Beclin 1 on gastric carcinogenesis using Becn1 knockout mice. Finally, clinicopathological significances of Beclin 1 expression were analyzed using meta- and bioinformatics analyses. Becn1 overexpression was found to inhibit proliferation, glucose metabolism, migration and invasion of gastric cancer cells, whereas its knockdown caused the opposite effects. Beclin 1 suppressed the tumor growth by decreasing proliferation and increasing apoptosis. The heterozygous abrogation of Becn1 in gastric pit, parietal and chief cells could not cause any epithelial lesion. Beclin 1-mediated chemoresistance was closely linked to the autophagy, Bax underexpression, and the overexpression of Bcl-2, LRP1, MDR1, and ING5. Bioinformatics analysis showed higher Becn1 mRNA expression in intestinal- than diffuse-type carcinomas (P<0.05), and in male than female gastric cancer patients (P<0.05). Becn1 hyperexpression was positively associated with both overall and progression-free survival rates of the cancer patients (P<0.05). Meta-analysis showed that down-regulated Beclin 1 expression in gastric cancer was positively with lymph node metastasis, TNM staging, dedifferentiation and poor prognosis (P<0.05). Becn1-related signal pathways in gastric cancer included prostate, lung, renal, colorectal, endometrial and thyroid cancers, glioma, and leukemia, the metabolism of amino acid, lipid and sugar, and some signal pathways of insulin, MAPK, TRL, VEGF, JAK-STAT, chemokine, p53, lysosome, peroxidome and ubiquitin-mediated protein degradation (P<0.05). These suggested that Beclin 1 might be considered as a potential marker of gastric carcinogenesis, aggressiveness and prognostic prediction, and as a target of gene therapy in gastric cancer.
Highlights
There are a worldwide decrease in morbidity and mortality and rapid development in diagnostic and operative techniques, but gastric cancer still challenges the human health
Beclin 1 was successfully overexpressed in BGC-823 and MKN28 cells according to real-time RT-PCR and Western blot (Figure 1A, P
Beclin 1 overexpression suppressed the proliferation of both cancer cells, evidenced by cell counting kit-8 (CCK-8) (Figure 1B, P
Summary
There are a worldwide decrease in morbidity and mortality and rapid development in diagnostic and operative techniques, but gastric cancer still challenges the human health. Autophagy is a conserved intracellular degradation pathway via autophagosomes formation, essential for protein development, homeostasis and survival, and mainly mediated by Beclin 1 [3, 4]. Beclin 1 binds to Bcl-2, Bcl-w, and Bcl-xL via BH3 receptor domain by phosphorylation and ubiquitination of Beclin 1 [6]. Beclin 1 is phosphorylated at ser-90 by PP2A and DAPK3 to control autophagy [7]. The phosphorylated Beclin 1 at S409 by CK1 is essential for p300 binding and Beclin 1 acetylation at lysine 430 and 437 [8]. Caspase 3mediated hydrolysis of Beclin 1 suppresses autophagy or enhances apoptosis by translocating Bax to the mitochondria for the release of cytochrome c [13, 14], whereas ABHD5 directly competes with Caspase 3 for binding to Beclin 1, and prevents Beclin 1 from cleavage [15]
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