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Published in: Tumor Biology 12/2014

01-12-2014 | Research Article

Autophagic LC3B overexpression correlates with malignant progression and predicts a poor prognosis in hepatocellular carcinoma

Authors: Dong-Hao Wu, Chang-Chang Jia, Jie Chen, Ze-Xiao Lin, Dan-Yun Ruan, Xing Li, Qu Lin, Min-Dong, Xiao-Kun Ma, Xiang-Bo Wan, Na Cheng, Zhan-Hong Chen, Yan-Fang Xing, Xiang-Yuan Wu, Jing-Yun Wen

Published in: Tumor Biology | Issue 12/2014

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Abstract

Autophagy is a process that involves lysosomal degradations of cellular organelles and closely related to tumor occurrence and progression. However, its importance in hepatocellular carcinoma (HCC) was still controversial. Therefore, this study is aimed to address the clinicopathologic effect of microtubule-associated protein 1 light chain 3B (LC3B) and Beclin-1, as autophagic markers, in HCC patients. Tissue microarray-based immunohistochemistry was used to examine the expression of LC3B and another autophagy key regulator (Beclin-1) in 156 operable HCC patients. Kaplan-Meier analysis, chi-square test, and Spearman’s correlation analysis were used to analyze correlation of LC3B and Beclin-1 and their influence on clinical characteristics and prognosis. We found that the expression level of LC3B was significantly associated with vascular invasion (P = 0.008), lymph node metastasis (P < 0.001), and Beclin-1 expression level (P < 0.001). However, LC3B was not related to other clinicopathological features, including hepatitis B virus infection, liver cirrhosis, tumor number, tumor size, pathology grade, and tumor-node-metastasis (TNM) stage. Besides, correlation between the expression of Beclin-1 and clinicopathological features were not identified. Survival analysis showed that patients with high LC3B expression had a poorer 5-year overall survival (OS) rate than those with low LC3B expression (high vs. low: 79.5 % vs. 20.5 %, P = 0.026). And high LC3B expression tended to be related with shorter progression-free survival (PFS) (P = 0.074), whereas the expression level of Beclin-1 did not show statistically significant association with OS or PFS. Further multivariate analysis revealed that lymph node metastasis (P = 0.047) and LC3B expression level (P = 0.047) were independent factors to predict the prognosis of OS in all patients. Our study demonstrated that high expression of LC3B, correlated with vascular invasion and lymph node metastasis, might be a novel prognostic biomarker and would be a potential therapy target for HCC, especially in operable patients.
Literature
1.
go back to reference Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: globocan 2008. Int J Cancer. 2010;127:2893–917.CrossRef Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: globocan 2008. Int J Cancer. 2010;127:2893–917.CrossRef
2.
go back to reference Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.CrossRef Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.CrossRef
3.
go back to reference Shukla PJ, Barreto SG. Surgery for malignant liver tumors. J Cancer Res Ther. 2009;5:154–60.CrossRef Shukla PJ, Barreto SG. Surgery for malignant liver tumors. J Cancer Res Ther. 2009;5:154–60.CrossRef
4.
go back to reference Said A, Lucey MR. Liver transplantation: an update 2008. Curr Opin Gastroenterol. 2008;24:339–45.CrossRef Said A, Lucey MR. Liver transplantation: an update 2008. Curr Opin Gastroenterol. 2008;24:339–45.CrossRef
5.
go back to reference Tsoulfas G, Mekras A, Agorastou P, Kiskinis D. Surgical treatment for large hepatocellular carcinoma: does size matter? ANZ J Surg. 2012;82:510–7.CrossRef Tsoulfas G, Mekras A, Agorastou P, Kiskinis D. Surgical treatment for large hepatocellular carcinoma: does size matter? ANZ J Surg. 2012;82:510–7.CrossRef
6.
go back to reference Zhao YJ, Ju Q, Li GC. Tumor markers for hepatocellular carcinoma. Mol Clin Oncol. 2013;1:593–8.CrossRef Zhao YJ, Ju Q, Li GC. Tumor markers for hepatocellular carcinoma. Mol Clin Oncol. 2013;1:593–8.CrossRef
7.
go back to reference Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007;8:931–7.CrossRef Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007;8:931–7.CrossRef
8.
go back to reference Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5:886–97.CrossRef Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5:886–97.CrossRef
9.
go back to reference Eisenberg-Lerner A, Kimchi A. The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 2009;14:376–91.CrossRef Eisenberg-Lerner A, Kimchi A. The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 2009;14:376–91.CrossRef
10.
go back to reference Zois CE, Koukourakis MI. Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radio-sensitization policies? Autophagy. 2009;5:442–50.CrossRef Zois CE, Koukourakis MI. Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radio-sensitization policies? Autophagy. 2009;5:442–50.CrossRef
11.
go back to reference Cheong H, Klionsky DJ. Biochemical methods to monitor autophagy-related processes in yeast. Methods Enzymol. 2008;451:1–26.CrossRef Cheong H, Klionsky DJ. Biochemical methods to monitor autophagy-related processes in yeast. Methods Enzymol. 2008;451:1–26.CrossRef
12.
go back to reference Czaja MJ. Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology. 2011;140:1895–908.CrossRef Czaja MJ. Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology. 2011;140:1895–908.CrossRef
13.
go back to reference Mann SS, Hammarback JA. Molecular characterization of light chain 3. A microtubule binding subunit of map1a and map1b. J Biol Chem. 1994;269:11492–7.CrossRef Mann SS, Hammarback JA. Molecular characterization of light chain 3. A microtubule binding subunit of map1a and map1b. J Biol Chem. 1994;269:11492–7.CrossRef
14.
go back to reference He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.CrossRef He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.CrossRef
15.
go back to reference Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. Lc3, a mammalian homologue of yeast apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19:5720–8.CrossRef Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. Lc3, a mammalian homologue of yeast apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19:5720–8.CrossRef
16.
go back to reference Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.CrossRef Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.CrossRef
17.
go back to reference Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005;115:2679–88.CrossRef Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005;115:2679–88.CrossRef
18.
go back to reference Eskelinen EL, Saftig P. Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta. 2009;1793:664–73.CrossRef Eskelinen EL, Saftig P. Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta. 2009;1793:664–73.CrossRef
19.
go back to reference Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, et al. A protein conjugation system essential for autophagy. Nature. 1998;395:395–8.CrossRef Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, et al. A protein conjugation system essential for autophagy. Nature. 1998;395:395–8.CrossRef
20.
go back to reference Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152:657–68.CrossRef Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001;152:657–68.CrossRef
21.
go back to reference Huang X, Bai HM, Chen L, Li B, Lu YC. Reduced expression of lc3b-ii and beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J Clin Neurosci. 2010;17:1515–9.CrossRef Huang X, Bai HM, Chen L, Li B, Lu YC. Reduced expression of lc3b-ii and beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J Clin Neurosci. 2010;17:1515–9.CrossRef
22.
go back to reference Ko YH, Cho YS, Won HS, Jeon EK, An HJ, Hong SU, et al. Prognostic significance of autophagy-related protein expression in resected pancreatic ductal adenocarcinoma. Pancreas. 2013;42:829–35.CrossRef Ko YH, Cho YS, Won HS, Jeon EK, An HJ, Hong SU, et al. Prognostic significance of autophagy-related protein expression in resected pancreatic ductal adenocarcinoma. Pancreas. 2013;42:829–35.CrossRef
23.
go back to reference Giatromanolaki A, Sivridis E, Mendrinos S, Koutsopoulos AV, Koukourakis MI. Autophagy proteins in prostate cancer: relation with anaerobic metabolism and gleason score. Urol Oncol. 2014;32:11–39.CrossRef Giatromanolaki A, Sivridis E, Mendrinos S, Koutsopoulos AV, Koukourakis MI. Autophagy proteins in prostate cancer: relation with anaerobic metabolism and gleason score. Urol Oncol. 2014;32:11–39.CrossRef
24.
go back to reference Lazova R, Camp RL, Klump V, Siddiqui SF, Amaravadi RK, Pawelek JM. Punctate lc3b expression is a common feature of solid tumors and associated with proliferation, metastasis, and poor outcome. Clin Cancer Res. 2012;18:370–9.CrossRef Lazova R, Camp RL, Klump V, Siddiqui SF, Amaravadi RK, Pawelek JM. Punctate lc3b expression is a common feature of solid tumors and associated with proliferation, metastasis, and poor outcome. Clin Cancer Res. 2012;18:370–9.CrossRef
25.
go back to reference Wu XY, Chen J, Cao QH, Dong M, Lin Q, Fan XJ, et al. Beclin 1 activation enhances chemosensitivity and predicts a favorable outcome for primary duodenal adenocarcinoma. Tumour Biol. 2013;34:713–22.CrossRef Wu XY, Chen J, Cao QH, Dong M, Lin Q, Fan XJ, et al. Beclin 1 activation enhances chemosensitivity and predicts a favorable outcome for primary duodenal adenocarcinoma. Tumour Biol. 2013;34:713–22.CrossRef
26.
go back to reference Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–7.CrossRef Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–7.CrossRef
27.
go back to reference He JH, Luo RZ, Cai MY, Li M, Lu JB, Yuan ZY. Decreased expression of light chain 3 (lc3) increased the risk of distant metastasis in triple-negative breast cancer. Med Oncol. 2013;30:468.CrossRef He JH, Luo RZ, Cai MY, Li M, Lu JB, Yuan ZY. Decreased expression of light chain 3 (lc3) increased the risk of distant metastasis in triple-negative breast cancer. Med Oncol. 2013;30:468.CrossRef
28.
go back to reference Toshima T, Shirabe K, Matsumoto Y, Yoshiya S, Ikegami T, Yoshizumi T, et al. Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial beta-oxidation. J Gastroenterol 2014;49:907–16. Toshima T, Shirabe K, Matsumoto Y, Yoshiya S, Ikegami T, Yoshizumi T, et al. Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial beta-oxidation. J Gastroenterol 2014;49:907–16.
29.
go back to reference Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, et al. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 2008;99:1813–19. Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, et al. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci 2008;99:1813–19.
30.
go back to reference Tang JY, Hsi E, Huang YC, Hsu NC, Chu PY, Chai CY. High LC3 expression correlates with poor survival in patients with oral squamous cell carcinoma. Hum Pathol 2013;44:2558–62. Tang JY, Hsi E, Huang YC, Hsu NC, Chu PY, Chai CY. High LC3 expression correlates with poor survival in patients with oral squamous cell carcinoma. Hum Pathol 2013;44:2558–62.
31.
go back to reference He Y, Zhao X, Gao J, Fan L, Yang G, Cho WC, et al. Quantum dots-based immunofluorescent imaging of stromal fibroblasts caveolin-1 and light chain 3B expression and identification of their clinical significance in human gastric cancer. Int J Mol Sci 2012;13:13764–80. He Y, Zhao X, Gao J, Fan L, Yang G, Cho WC, et al. Quantum dots-based immunofluorescent imaging of stromal fibroblasts caveolin-1 and light chain 3B expression and identification of their clinical significance in human gastric cancer. Int J Mol Sci 2012;13:13764–80.
32.
go back to reference Lee YJ, Ha YJ, Kang YN, Kang KJ, Hwang JS, Chung WJ, et al. The autophagy-related marker LC3 can predict prognosis in human hepatocellular carcinoma. PLoS One 2013;8:e81540. Lee YJ, Ha YJ, Kang YN, Kang KJ, Hwang JS, Chung WJ, et al. The autophagy-related marker LC3 can predict prognosis in human hepatocellular carcinoma. PLoS One 2013;8:e81540.
33.
go back to reference Wada Y, Sun-Wada GH, Kawamura N, Aoyama M. Role of autophagy in embryogenesis. Curr Opin Genet Dev. 2014;27C:60–6.CrossRef Wada Y, Sun-Wada GH, Kawamura N, Aoyama M. Role of autophagy in embryogenesis. Curr Opin Genet Dev. 2014;27C:60–6.CrossRef
34.
go back to reference Zhao H, Yang M, Zhao J, Wang J, Zhang Y, Zhang Q. High expression of lc3b is associated with progression and poor outcome in triple-negative breast cancer. Med Oncol. 2013;30:475.CrossRef Zhao H, Yang M, Zhao J, Wang J, Zhang Y, Zhang Q. High expression of lc3b is associated with progression and poor outcome in triple-negative breast cancer. Med Oncol. 2013;30:475.CrossRef
35.
go back to reference Wang TT, Cao QH, Chen MY, Xia Q, Fan XJ, Ma XK, et al. Beclin 1 deficiency correlated with lymph node metastasis, predicts a distinct outcome in intrahepatic and extrahepatic cholangiocarcinoma. PLoS One. 2013;8:e80317.CrossRef Wang TT, Cao QH, Chen MY, Xia Q, Fan XJ, Ma XK, et al. Beclin 1 deficiency correlated with lymph node metastasis, predicts a distinct outcome in intrahepatic and extrahepatic cholangiocarcinoma. PLoS One. 2013;8:e80317.CrossRef
36.
go back to reference Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: Caution in the interpretation of LC3 localization. Autophagy 2007;3:323–28. Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: Caution in the interpretation of LC3 localization. Autophagy 2007;3:323–28.
Metadata
Title
Autophagic LC3B overexpression correlates with malignant progression and predicts a poor prognosis in hepatocellular carcinoma
Authors
Dong-Hao Wu
Chang-Chang Jia
Jie Chen
Ze-Xiao Lin
Dan-Yun Ruan
Xing Li
Qu Lin
Min-Dong
Xiao-Kun Ma
Xiang-Bo Wan
Na Cheng
Zhan-Hong Chen
Yan-Fang Xing
Xiang-Yuan Wu
Jing-Yun Wen
Publication date
01-12-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2531-7

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