Abstract
BackgroundBeclin 1 and Beclin 2 are autophagy-related proteins that show similar amino acid sequences and domain structures. Beclin 1 established the first connection between autophagy and cancer. However, the role of Beclin 2 in cancer is unclear. The aims of this study were to analyze Beclin 1 and Beclin 2 expressions in oral cancer tissues and in cell lines, and to evaluate their possible roles in cancer progression.MethodsWe investigated Beclin 1 and Beclin 2 expressions by immunohistochemistry in 195 cases of oral cancer. The prognostic roles of Beclin 1 and Beclin 2 were analyzed statistically. In vitro, overexpression and knockdown of Beclin proteins were performed on an oral cancer cell line, SAS. The immunofluorescence and autophagy flux assays confirmed that Beclin proteins were involved in autophagy. The impacts of Beclin 1 and Beclin 2 on autophagy and tumor growth were evaluated by conversion of LC3-I to LC3-II and by clonogenic assays, respectively.ResultsOral cancer tissues exhibited aberrant expressions of Beclin 1 and Beclin 2. The cytoplasmic Beclin 1 and Beclin 2 expressions were unrelated in oral cancer tissues. In survival analyses, high cytoplasmic Beclin 1 expression was associated with low disease specific survival, and negative nuclear Beclin 1 expression was associated with high recurrent free survival. Patients with either high or low cytoplasmic Beclin 2 expression had significantly lower overall survival and disease specific survival rates than those with moderate expression. In oral cancer cells, overexpression of either Beclin 1 or Beclin 2 led to autophagy activation and increased clonogenic survival; knockdown of Beclin 2 impaired autophagy and increased clonogenic survival.ConclusionsOur results indicated that distinct patterns of Beclin 1 and Beclin 2 were associated with aggressive clinical outcomes. Beclin 1 overexpression, as well as Beclin 2 overexpression and depletion, contributed to tumor growth. These findings suggest Beclin proteins are associated with tumorigenesis.
Highlights
Oral cancer is one of the most common cancers and a growing problem worldwide
The cytoplasmic Beclin 1 and Beclin 2 expressions were unrelated in oral cancer tissues
High cytoplasmic Beclin 1 expression was associated with low disease specific survival, and negative nuclear Beclin 1 expression was associated with high recurrent free survival
Summary
Oral cancer is one of the most common cancers and a growing problem worldwide. High incidence rates occur in South and Southeast Asia, parts of Europe, parts of Latin America, and Pacific regions [1]. The incidence of oral cancer has increased, in economically developed countries [2]. The vast majority of oral cancer is squamous cell carcinoma, which arises from the squamous mucosa of oral surface. Despite the similar histologic phenotype, the molecular basis of oral cancer is highly complex, which exhibits multiple genetic and epigenetic mutations [3, 4]. Identifying new biomarkers for oral cancer could be applied in developing new therapeutic interventions. Beclin 1 and Beclin 2 are autophagy-related proteins that show similar amino acid sequences and domain structures. Beclin 1 established the first connection between autophagy and cancer. The role of Beclin 2 in cancer is unclear. The aims of this study were to analyze Beclin 1 and Beclin 2 expressions in oral cancer tissues and in cell lines, and to evaluate their possible roles in cancer progression
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