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      The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance

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          Abstract

          Background

          A role for autophagy, a conserved cellular response to stress, has recently been demonstrated in human cancers. Aberrant expression of Beclin-1, an important autophagic gene, has been reported in various human cancers. In the present study, we investigated the significance and relationship between Beclin-1 expression and cell proliferation, apoptosis, microvessel density (MVD) and clinical pathological changes or prognosis in human hepatocellular carcinoma (HCC).

          Methods

          A total of 103 primary HCC patients were involved in the study. Expression of Beclin-1, PCNA, NET-1, Bcl-2, Bax, Survivin in cancer cells and CD34 in stromal microvessels were evaluated immunohistochemically in tissue microarrays comprising 103 cases of HCC and 57 matched adjacent nontumor liver tissues. Correlations between clinicopathological characteristics and survival of HCC patients were explored.

          Results

          The positive rate of Beclin-1 was significantly lower in HCC tissues than adjacent tissues (72.8 vs. 89.5%, χ2 = 6.085, P = 0.015). In HCC, Beclin-1 expression was negatively correlated with cirrhosis background (r = −0.216, P = 0.029), Edmondson grade (r = −0.249, P = 0.011), vascular invasion (r = −0.246, P = 0.012), PCNA (r = −0.242, P = 0.014), NET-1 (r = −0.245, P = 0.013), anti-apoptosis protein Bcl-2 (r = −0.245, P = 0.013) and MVD (r = −0.292, P = 0.003), and positively correlated with pro-apoptosis protein Bax (r = 0.242, P = 0.014).

          Significant differences in the 5-year survival rates were seen among patients with Beclin-1 strong positive (++) (59.1%, 13/22), moderate positive (+) (28.3%, 15/53) and weak negative expression (−) (14.6%, 7/28) ( P = 0.043). Significant differences were detected between Beclin-1 (++) and either Beclin-1 (+) ( P = 0.036) or Beclin-1 (−) groups ( P = 0.008), but no significant difference between Beclin-1 (+) and Beclin-1 (−) groups ( P = 0.281) was observed.

          Survival rates were positively related to high Beclin-1 co-expressed with low PCNA, NET-1, or Bcl-2, lower MVD, and high Bax. Univariate and multivariate Cox regression analysis revealed that Beclin-1 expression was an independent indicator for overall survival in HCC patients ( P < 0.05).

          Conclusions

          The pathogenesis and progression of HCC are associated with reduced autophagy. The expression of Beclin-1 and Bax in HCC tissues may provide a synergistic effect towards inhibiting HCC proliferation, infiltration, metastasis and angiogenesis. Beclin-1 expression may be a valuable prognostic marker of HCC.

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          Most cited references28

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

          The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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            The role of autophagy in cancer development and response to therapy.

            Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?
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              • Article: not found

              Cell biology: autophagy and cancer.

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                Author and article information

                Contributors
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2014
                9 May 2014
                : 14
                : 327
                Affiliations
                [1 ]Department of Pathological Anatomy, Nantong University, Qixiu road 19#, Nantong, Jiangsu Province, China 226001
                [2 ]Nantong Tumor Hospital, Nantong, P.R. China
                Article
                1471-2407-14-327
                10.1186/1471-2407-14-327
                4020872
                24885292
                e3bc7b41-eff7-4612-9d79-db63673282a9
                Copyright © 2014 Qiu et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 January 2014
                : 28 April 2014
                Categories
                Research Article

                Oncology & Radiotherapy
                beclin-1,autophagy,hcc,prognosis proliferation, apoptosis,microvessels
                Oncology & Radiotherapy
                beclin-1, autophagy, hcc, prognosis proliferation, apoptosis, microvessels

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