Summary
Gastric adenocarcinoma (GC) is one of the most common malignancies in the world and one of the most frequent causes of cancer-related death. Autophagy is a highly regulated catabolic pathway responsible for the degradation of long-lived proteins and damaged intracellular organelles. However, the mechanism and guiding significance of autophagy in the development and progression of GC have remained to be elucidated. This study aimed to explore the clinicopathological significances and prognostic values of autophagy-related proteins AMBRA1 and Beclin-1 in GC. Quantum dots based immunofluorescence histochemistry (QDs-IHC) was performed to observe the expression of AMBRA1 and Beclin-1 proteins in the tissue microarrays including 163 specimens of GC and 20 noncancerous gastric tissues. Simultaneously, AMBRA1 and Beclin-1 proteins were detected by Western blotting in the 10 fresh GC and corresponding normal gastric tissues. The results showed that the expression levels of both AMBRA1 and Beclin-1 proteins were higher in GC tissues than in noncancerous gastric tissues by QDs-IHC and Western blotting (P<0.05). High AMBRA1 expression was detected in 90 of 163 (55.2%) GCs and high Beclin-1 expression was detected in 83 of 163 (50.9%) GCs. High AMBRA1 expression was closely related to depth of invasion, and lymph nodes metastasis (P<0.05). High expression of Beclin-1 protein was correlated with tumor grade (P<0.05). Positive correlation was observed between AMBRA1 and Beclin-1. Survival analysis indicated the high expression of AMBRA1 and Beclin- 1 was an independent factor in predicting poor overall survival (OS) of GC patients. These findings suggest the high expression of AMBRA1 and Beclin-1 proteins is significantly correlated with GC progression. High AMBRA1 and Beclin-1 expression heralds worse outcome of GC patients, suggesting a novel candidate prognostic marker and a therapeutic target for GC.
Similar content being viewed by others
References
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015,65(2): 87–108
Duraes C, Almeida GM, Seruca R, et al. Biomarkers for gastric cancer: prognostic, predictive or targets of therapy? Virchows Arch, 2014,464(3): 367–378
Group G, Oba K, Paoletti X, et al. Role of chemotherapy for advanced/recurrent gastric cancer: an individual-patient-data meta-analysis. Eur J Cancer, 2013,49(7): 1565–1577
White E, Mehnert JM, Chan CS. Autophagy, metabolism, and cancer. Clin Cancer Res, 2015,21(22): 5037–5046
White E. The role for autophagy in cancer. J Clin Invest, 2015,125(1): 42–46
Liang CY, Jung JU. Autophagy genes as tumor suppressors. Curr Opin Cell Biol, 2010,22(2): 226–233
White E, Di Paola RS. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res, 2009,15(17): 5308–5316
Sun WL. Ambra1 in autophagy and apoptosis: implications for cell survival and chemotherapy resistance. Oncol Lett, 2016,12(1): 367–374
Fimia GM, Stoykova A, Romagnoli A, et al. Ambra1 regulates autophagy and development of the nervous system. Nature, 2007,447(7148): 1121–1125
Fimia GM, Corazzari M, Antonioli M, et al. Ambra1 at the crossroad between autophagy and cell death. Oncogene, 2013,32(28): 3311–3318
Gu W, Wan DW, Qian QY, et al. Ambra1 is an essential regulator of autophagy and apoptosis in SW620 cells: Pro-survival role of Ambra1. Plos One, 2014,9(2),e90151
Toton E, Lisiak N, Sawicka P, et al. Beclin-1 and its role as a target for anticancer therapy. J Physiol Pharmacol, 2014,65(4): 459–467
Fu LL, Cheng Y, Liu B. Beclin-1: autophagic regulator and therapeutic target in cancer. Int J Biochem Cell Biol, 2013,45(5): 921–924
Kononen J, Bubendorf L, Kallionimeni A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 1998,4(7): 844–847
Li M, Chen H, Diao L, et al. Caveolin-1 and VEGF-C promote lymph node metastasis in the absence of intratumoral lymphangiogenesis in non-small cell lung cancer. Tumori, 2010,96(5): 734–743
Chen H, Xue J, Zhang Y, et al. Comparison of quantum dots immunofluorescence histochemistry and conventional immunohistochemistry for the detection of caveolin-1 and PCNA in the lung cancer tissue microarray. J Mol Histol, 2009,40(4): 261–268
Zhao X, He Y, Gao J, et al. Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer. PLoS One, 2013,8(3):e59102
Li J, Yang B, Zhou Q, et al. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition. Carcinogenesis, 2013,34(6): 1343–1351
Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Beclin 1 over-and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia. Br J Cancer, 2010,103(8): 1209–1214
Qian HR, Yang Y. Functional role of autophagy in gastric cancer. Oncotarget, 2016,7(14):17641–17651
Ko YH, Cho YS, Won HS, et al. Prognostic significance of autophagy-related protein expression in resected pancreatic ductal adenocarcinoma. Pancreas, 2013,42(5): 829–835
Nitta T, Sato Y, Ren XS, et al. Autophagy may promote carcinoma cell invasion and correlate with poor prognosis in cholangiocarcinoma. Int J Clin Exp Med, 2014,7(8): 4913–4921
Falasca L, Torino F, Marconi M, et al. AMBRA1 and SQSTM1 expression pattern in prostate cancer. Apoptosis, 2015,20(12): 1577–1586
Cianfanelli V, Cecconi F. AMBRA1: When autophagy meets cell proliferation. Autophagy, 2015,11(9): 1705–1707
Yu M, Gou WF, Zhao S, et al. Beclin 1 expression is an independent prognostic factor for gastric carcinomas. Tumour Biol, 2013,34(2): 1071–1083
Ahn CH, Jeong EG, Lee JW, et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS, 2007,115(12): 1344–1349
Fei BY, Ji FJ, Chen XB, et al. Expression and clinical significance of Beclin-1 in gastric cancer tissues of various clinical stages. Oncol Lett, 2016,11(3): 2271–2277
Yu M, Gou WF, Zhao S, et al. Beclin 1 expression is an independent prognostic factor for gastric carcinomas. Tumour Biol, 2013,34(2): 1071–1083
Won KY, Kim GY, Lim SJ, et al. Autophagy is related to the hedgehog signaling pathway in human gastric adenocarcinoma: prognostic significance of Beclin-1 and Gli2 expression in human gastric adenocarcinoma. Pathol Res Pract, 2015,211(4): 308–315
Chen YB, Hou JH, Feng XY, et al. Decreased expression of Beclin 1 correlates with a metastatic phenotypic feature and adverse prognosis of gastric carcinomas. J Surg Oncol, 2012,105(6): 542–547
He Y, Zhao X, Subahan NR, et al. The prognostic value of autophagy-related markers beclin-1 and microtubule-associated protein light chain 3B in cancers: a systematic review and meta-analysis. Tumour Biol, 2014,35(8): 7317–7326
Wan XB, Fan XJ, Chen MY, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy, 2010,6(3): 395–404
Author information
Authors and Affiliations
Corresponding authors
Additional information
This project was supported by grants from Natural Science Foundation of Hubei Province (No. 2016CFC718), Foundation of Wu Jieping Program of Funding and Cultivating the Medical Backbone of Youth and Middle-age of Wuhan City (No.320.6750.16215), and Science and Research Project from Health and Family Planning Commission of Wuhan City (No. WX13Z02 and No. WX16D04).
Rights and permissions
About this article
Cite this article
Qu, B., Yao, L., Ma, Hl. et al. Prognostic significance of autophagy-related proteins expression in resected human gastric adenocarcinoma. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 37, 37–43 (2017). https://doi.org/10.1007/s11596-017-1691-2
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-017-1691-2