Beclin‑1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration

Abstract

Abstract. To investigate Beclin-1 expression in gastric cancer and its clinical relevance, 60 samples were collected from patients with gastric carcinoma, which were subjected to immunohistochemical staining and analysis. Associations of Beclin-1 expression with the clinical parameters of the patients, including tumor size, histological differentiation and metastatic status, were examined by statistical analysis. The results demonstrated that Beclin-1 expression in gastric carcinoma tissue was significantly associated with the tumor, node, metastasis stage and tumor invasion status. Further experiments indicated that Beclin-1 overexpression promoted MKN-45 gastric cancer cell apoptosis and inhibited their migration. These data suggested that Beclin-1 was a suppressor of tumorigenesis in gastric cancer and a potential therapeutic target for patients with gastric cancer. IntroductionAutophagy serves an important role in maintaining cell metabolism and homeostasis (1). Autophagy is a process of endogenous substrate digestion in cells; autophagosomes are formed, and mature proteins or damaged organelles in the cytoplasm are encased by lysosomes, in which lysosomal proteases degrade them.During tumorigenesis and tumor progression, autophagy exerts its role as a tumor suppressor by removing abnormally folded proteins and dysfunctional organelles such as mitochondria, inhibiting cell stress responses (2). However, in instances of nutritional deficiencies and hypoxia, autophagy supports tumor cell survival, which promotes cell proliferation and suppresses cell death (3). Compromised autophagy promotes chromosomal instability, including increased DNA damage, gene amplification and aneuploidy (4).As a key autophagy regulator associated with apoptosis and differentiation, the autophagy-associated protein Beclin-1 has been demonstrated to be involved in many types of cancer, including ovarian carcinoma (5), hepatocellular carcinoma (6), melanoma (7), rectal cancer (8) and tongue squamous cell carcinoma (9). It has been suggested that the endogenous Beclin-1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissues, whereas it is expressed ubiquitously at high levels in normal breast epithelia (10). Concomitantly, the autophagy-promoting activity in the MCF7 breast cancer cell line following transfection with Beclin-1 was observed to inhibit MCF7 proliferation, clonogenicity and tumorigenesis (10). A previous in vivo study demonstrated that mice with inactivated or deleted Beclin-1 were susceptible to tumors including lymphoma, lung cancer and liver cancer (11,12).Beclin-1 modulates cancer initiation and progression by affecting a wide range of pathological events, including extracellular matrix degradation, epithelial-to-mesenchymal transition, tumor angiogenesis and alterations to the tumor microenvironment (13). However, the effect of Beclin-1 in cancer development is complex, as a number of reports have indicated the pro-neoplastic and anti-neoplastic functions for Beclin-1, as revi...

<p>Autophagy-Related Beclin 1 and Head and Neck Cancers</p>

“… 55 In gastric carcinomas, Wang et al used IHC to show that Beclin 1 expression in tissues of gastric carcinomas was significantly decreased when compared to paracarcinoma tissues. 56 Beclin 1 expression was negatively associated with the TNM stage and invasion status. In MKN-45 gastric carcinoma cells, they also found that high expression of Beclin 1 might enhance apoptosis.…”

“…They suggested a possible mechanism where Beclin 1 may inhibit the anti-apoptotic factor Bcl-xL to induce the apoptosis pathway, as well as the mutual effect of autophagy and apoptosis on gastric tumorigenesis. 56 Shi et al detected Beclin 1 expression in seven hepatocellular carcinoma (HCC) cell lines (Hep G2, Hep3B, SMMC-7721, MHCC97-l, MHCC97-H, HCCLM3, and GCCLM6). 57 They found that Beclin 1 expression in all HCC cell lines was low, and Beclin 1 expression was significantly lower in high-grade malignant HCCs.…”

The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity

“…Besides autophagy, Beclin-1 is implicated in apoptotic cell death, representing a node of crosstalk between these mechanisms ( 28 ). In vitro experiments show that Beclin-1 overexpression in gastric cancer and glioblastoma cell lines induces apoptosis upon exposure to cytotoxic agents ( 29 , 30 ). These pro-apoptotic properties of Beclin-1 might be explained by two mechanisms.…”

Natural products targeting signaling pathways associated with regulated cell death in gastric cancer: Recent advances and perspectives

“…In fact, Beclin‐1 has been validated as a tumor suppressor factor in diverse cancer cells. Specifically in the aggressive development of GC, downregulation of Beclin‐1 is positively correlated with the proliferation, metastasis and invasion of tumor cells in patients with GC (Fei et al, 2016; Giatromanolaki et al, 2018; Wang, Xie, et al, 2017c). Low Beclin‐1 expression predicted poor prognosis and cancer phenotype in patients with gastric cancer (Xia et al, 2013).…”