The Roles of Beclin 1 Expression in Gastric Cancer: A Marker for Carcinogenesis, Aggressive Behaviors and Favorable Prognosis, and a Target of Gene Therapy

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.

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

“…Downregulation of Beclin-1 is correlated to the incremental reprogramming in glucose metabolism, cell invasion and proliferation in gastric cancer. Specifically, reduced Beclin-1 expression increases lymph node metastasis and is associated with poor prognosis [ 161 ]. When comparing tissue samples from Colorectal Cancers (CRCs) to normal colon tissue, Beclin-1 was downregulated in the CRC tissue, which promoted CRC cell invasion [ 162 ].…”

An Overview of Autophagy in Helicobacter pylori Infection and Related Gastric Cancer

“…TGF-b is an important representative of the TGF-b family, which includes 3 subtypes (b1, b2 and b3). TGF-b1 was first discovered in lymphocytes and monocytes, which is the most common form of TGF-b (Zheng et al, 2020). The TGF-b signaling pathway is connected with the angiogenesis, invasion, metastasis in gastric cancer (Yue and Mulder, 2001).…”

Alcoholic extract of Tarantula cubensis (Theranekron®) induce autophagy on gastric cancer cells

“…Autophagy plays also tumor-suppressor and tumor-promoter role in gastric cancer [18]. Autophagy-related markers as Beclin1 might be considered as a potential marker of gastric carcinogenesis, aggressiveness and prognostic prediction, and as a target for gene therapy in gastric cancer [19] while autophagy inducers, such as rapamycin, show promise for gastric cancer treatment [20]. It was also reported that long-term Helicobacter pylori infection can disrupt autophagy process eventually promoting gastric cancer [21].…”