Elsevier

Human Pathology

Volume 43, Issue 1, January 2012, Pages 62-68
Human Pathology

Original contribution
Decreased Beclin-1 expression is correlated with the growth of the primary tumor in patients with squamous cell carcinoma and adenocarcinoma of the lung

https://doi.org/10.1016/j.humpath.2011.04.007Get rights and content

Summary

Beclin-1 is a Bcl-2–interacting protein, and it may delay cell cycle progression and induce autophagy. The function and expression of Beclin-1 and Bcl-2 in squamous cell carcinoma and adenocarcinoma of the lung remain largely unknown. Herein, we investigated the expression of Beclin-1 and Bcl-2 in squamous cell carcinoma and adenocarcinoma of the lung. Tissue samples from 262 cases were used in this study. Immunohistochemical staining for Beclin-1 and Bcl-2 were conducted using a tissue microarray. In squamous cell carcinoma, Beclin-1 expression was strongly positive in 48 (28.6%) of 168 samples, it was moderately positive in 42 (25.0%) of 168 samples, and it was negative or weakly positive in 78 (46.4%) of 168 samples. In adenocarcinoma, Beclin-1 expression was strongly positive in 26 (27.7%) of 94 samples, it was moderately positive in 27 (28.7%) of 94 samples, and it was negative or weakly positive in 41 (43.6%) of 94 samples. Beclin-1 expression was inversely correlated with the tumor size and the primary tumor stage (pT) in both types of tumor. Especially, the TNM stage of adenocarcinoma was inversely correlated with Beclin-1 expression. Our results suggest that a progressively reduced Beclin-1 expression is correlated with the primary tumor growth of squamous cell carcinoma and adenocarcinoma of the lung.

Introduction

Autophagy is the principal endogenous pathway for the degradation and recycling of long-lived proteins and organelles. Autophagic cell death is generally considered a type II programmed cell death [1]. Autophagy is known to be involved in many physiopathologic processes such as cell development, aging, stress responses, immune responses, and cancer [2]. In particular, emerging evidence has correlated impaired autophagy with tumor progression, although the results collected to date in this regard have been somewhat ambiguous [2]. The human beclin-1 gene, which is located on chromosome 17q21, has been previously identified as the mammalian orthologue of Atg6 [3], [4]. The beclin-1 gene is monoallelically deleted in 40% to 75% of the sporadic breast, prostate, and ovarian tumors [5], [6], [7]. Furthermore, Beclin-1 mutant mice suffer from a relatively high incidence of tumors, including mammary gland neoplasia, lymphomas, lung adenocarcinomas (ACs), and hepatocellular carcinomas [8], [9]. Based on these findings, Beclin-1 may be a haploinsufficient tumor suppressor gene. A reduced expression of Beclin-1 has also been demonstrated in some human cancers, including glioblastomas, ovarian cancers, and esophageal cancers [10], [11], [12]. However, an increased expression of Beclin-1 has been reported in colorectal and gastric cancer cells as compared with that of their normal counterparts [13]. These discrepant results indicate that Beclin-1 performs different functions in different tissues. Thus far, Beclin-1 expression and its clinical implications in squamous cell carcinoma (SCC) and AC have yet to be thoroughly elucidated.

Beclin-1 was first identified in a yeast 2-hybrid screen as a Bcl-2–interacting protein [14]. As an antiapoptotic protein, Bcl-2 physically interacts with Beclin-1; and it remains possible that Bcl-2 might be associated with the regulation of autophagy. Pattingre et al [15] previously demonstrated that Bcl-2 not only functions as an antiapoptotic protein but it also functions as an anti-autophagy protein via an inhibitory interaction with Beclin-1. The biological significance of the interaction between Beclin-1 and Bcl-2 in lung cancer has yet to be thoroughly explored. Therefore, we evaluated Beclin-1 and Bcl-2 expressions in SCC and AC tissue via immunohistochemical analysis, using a tissue microarray, in relation to survival and other prognostic factors.

Section snippets

Patients and tissue samples

Tissue samples from 168 cases of SCC and 94 cases of AC were used in the present study. All of the tumors were surgically resected at the Kyung Hee University Hospital from 1983 to 2006. For each case, 2 investigators (K. Y. Won and G. Y. Kim) reviewed all of the original hematoxylin and eosin–stained sections. The clinicopathologic variables were evaluated, including age, sex, the histologic grade, tumor size, the primary tumor (pT), and nodal (pN) and distant metastasis (M), the TNM stage

Beclin-1 expression and its association with the clinicopathologic variables

Beclin-1 was expressed strongly in the cytoplasm of the adjacent normal pneumocytes and bronchial epithelia (Fig. 1). In SCC, Beclin-1 expression was strongly positive in 48 (28.6%) of 168 samples (Fig. 2A), moderately positive in 42 (25.0%) of 168 samples (Fig. 2C), and it was negative or weakly positive in 78 of 168 samples (Fig. 2E). In AC, Beclin-1 expression was strongly positive in 26 (27.7%) of 94 samples (Fig. 2B), moderately positive in 27 (28.7%) of 94 samples (Fig. 2D), and negative

Discussion

In this study, we evaluated the character of Beclin-1 and Bcl-2 expressions in SCC and AC, as well as their correlations with several clinicopathologic parameters. We observed that 46.4% of the SCCs and 43.6% of the ACs showed a negative or weak Beclin-1 expression in the carcinoma areas. As compared to the carcinoma areas, the adjacent normal pneumocytes and bronchial epithelia showed a diffuse strong Beclin-1 expression. These findings suggest that the autophagy induced by Beclin-1 expression

Acknowledgment

This work was supported by a grant from the Kyung Hee University Research Fund in 2008 (KHU-20080608).

References (27)

  • Z. Yue et al.

    Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor

    Proc Natl Acad Sci U S A

    (2003)
  • X. Qu et al.

    Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene

    J Clin Invest

    (2003)
  • C. Miracco et al.

    Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours

    Int J Oncol

    (2007)
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