The expression and significance of Beclin-1 in pancreatic ductal adenocarcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

KE Nengwen ,  LIU Xubao

Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

LIU Xubao, Email: xbliu@medmail.com.cn

Keywords：

pancreatic ductal adenocarcinoma; Beclin-1; autophagy; in vitro

DOI：

10.7507/1007-9424.201704018

Video：

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Objective To explore the relationship between Beclin-1 and the development of pancreatic ductal adenocarcinoma (PDAC). Methods ① Twenty-five PDAC specimens and 20 matched adjacent normal pancreatic tissues were obtained after radical surgery between April 2009 and November 2009 in West China Hospital of Sichuan University. Beclin-1 mRNA and protein expressions were examined by using real-time PCR and immunohistochemistry, respectively. Correlations between expressions of Beclin-1 protein with clinical data of PDAC patients were evaluated. ② PDAC cells were divided into 2 groups, cells of transfection group were transfected with PLenO-WPI-Beclin-1 vector, and cells of non-transfection group didn’t transfected with PLenO-WPI-Beclin-1 vector. Expressions levels of Beclin-1 mRNA in the 2 groups were detected by real-time PCR at 24 hours and 48 hours after transfection. ③ PDAC cells were divided into 3 groups, cells of transfection group were transfected with PLenO-WPI-Beclin-1 vector, cells of empty vector group transfected with PLenO-WPI, cells of blank control group didn’t accepted any vector. OD value was detected by MTT once a day during 1–7 days after transfection. Results ① Expression levels of Beclin-1 mRNA and its protein were significantly lower in PDAC tissue than those of adjacent normal pancreatic tissues (P<0.05). Increased Beclin-1 expression was associated with early TNM stage of Ⅰ and Ⅱ(P<0.05) and negative distant metastasis (P=0.011). ② At the same time point of 24 hours and 48 hours after transfection, the expression levels of Beclin-1 mRNA were higher in transfection group than those of non-transfection group (P<0.05). ③ MTT assay showed that PANC-1 cell proliferation ability was lower in the transfection group compared to the blank control group and empty vector groups in vitro on day 4–7 after transfection (P<0.05), but there was no significant in the cell proliferation ability among the 3 groups on day 1, 2, and 3 (P>0.05). Conclusions Down regulation of Beclin-1 and autophagy inhibition play an important role in the tumorigenesis and development of PDAC. Activating autophagy via overexpression of Beclin-1 may be a potential treatment for some PDACs and warrants further investigation.

Citation： KE Nengwen, LIU Xubao. The expression and significance of Beclin-1 in pancreatic ductal adenocarcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(6): 671-679. doi: 10.7507/1007-9424.201704018 Copy

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7.	Kondo Y, Kanzawa T, Sawaya R, et al. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer, 2005, 5(9): 726-734.
8.	Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer, 2007, 7(12): 961-967.
9.	White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer, 2012, 12(6): 401-410.
10.	Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 2006, 10(1): 51-64.
11.	Schwarze PE, Seglen PO. Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. Exp Cell Res, 1985, 157(1): 15-28.
12.	Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncegene, 2004, 23(16): 2891-2906．.
13.	Liang XH, Kleeman LK, Jiang HH, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J ViroI, 1998, 72(11): 8586-8596.
14.	Kang R, Zeh HJ, Lotze MT, et al. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ, 2011, 18(4): 571-580.
15.	Rosenfeldt MT, O’Prey J, Morton JP, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature, 2013, 504(7479): 296-300.
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17.	Aita VM, Liang XH, Murty VV, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomic, 1999, 59(1): 59-65.
18.	Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 1999, 402(6762): 672-676.
19.	Akar U, Ozpolat B, Mehta K, et al. Tissue transglutaminase inhibits autophagy in pancreatic cancer cells. Mol Cancer Res, 2007, 5(3): 241-249.
20.	Li X, Yan J, Wang L, et al. Beclin1 inhibition promotes autophagy and decreases gemcitabine-induced apoptosis in Miapaca2 pancreatic cancer cells. Cancer Cell Int, 2013, 13(1): 26.
21.	Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest, 2003, 112(12): 1809-1820．.
22.	Rohatgi RA, Janusis J, Leonard D, et al. Beclin 1 regulates growth factor receptor signaling in breast cancer. Oncogene, 2015, 34(42): 5352-5362.
23.	Katagiri H, Nakayama K, Razia S, et al. Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas. Int J Oncol, 2015, 47(6): 2037-2044.
24.	康凯夫, 王晓蔚, 陈小伍, 等. Beclinl 在原发性肝细胞癌中的表达及其临床意义. 南方医科大学学报, 2009, 29(1): 151-153.
25.	Li BX, Li CY, Peng RQ, et al. The expression of beclin 1 is associated with favorable prognosis in stage ⅢB colon cancers. Autophagy, 2009, 5(3): 303-306.
26.	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.
27.	Giatromanolaki A, Koukourakis MI, Koutsopoulos A, et al. High Beclin 1 expression defines a poor prognosis in endometrial adenocarcinomas. Gynecol Oncol, 2011, 123(1): 147-151.
28.	Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular self-digestion. Nature, 2008, 451(7182): 1069-1075.
29.	Boya P, Gonzalez-Polo RA, Casares N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol, 2005, 25(3): 1025-1040.
30.	Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-248.
31.	Gunn JM, Clark MG, Knowles SE, et al. Reduced rates of proteolysis in transformed cells. Nature, 1977, 266(5597): 58-60.
32.	Kisen GO, Tessitore L, Costelli P, et al. Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis, 1993, 14(12): 2501-2505.
33.	Kirkegaard K, Taylor MP, Jackson WT. Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol, 2004, 2(4): 301-314.
34.	Otsuka H, Moskowitz M. Differences in the rates of protein degradation in untransformed and transformed cell lines. Exp Cell Res, 1978, 112(1): 127-135.
35.	Tóth S, Nagy K, Pálfia Z, et al. Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res, 2002, 309(3): 409-416.
36.	Chau YP, Lin SY, Chen JH, et al. Endostatin induces autophagic cell death in EAhy926 human endothelial cells. Histol Histopathol, 2003, 18(3): 715-726.

1. Hidalgo M, Cascinu S, Kleeff J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology, 2015, 15(1): 8-18.
2. Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2013. Ann Oncol, 2013, 24(3): 792-800.
3. Li D, Xie K, Wolff R, et al. Pancreatic cancer. Lancet, 2004, 363(9414): 1049-1057.
4. Haller DG. New perspectives in the management of pancreas cancer. Semin Oncol, 2003, 30(4 Suppl 11): 3-10.
5. Wang Z, Li Y, Ahmad A, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol, 2011, 8(1): 27-33.
6. Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl), 1990, 181(3): 195-213.
7. Kondo Y, Kanzawa T, Sawaya R, et al. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer, 2005, 5(9): 726-734.
8. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer, 2007, 7(12): 961-967.
9. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer, 2012, 12(6): 401-410.
10. Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 2006, 10(1): 51-64.
11. Schwarze PE, Seglen PO. Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. Exp Cell Res, 1985, 157(1): 15-28.
12. Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncegene, 2004, 23(16): 2891-2906．.
13. Liang XH, Kleeman LK, Jiang HH, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J ViroI, 1998, 72(11): 8586-8596.
14. Kang R, Zeh HJ, Lotze MT, et al. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ, 2011, 18(4): 571-580.
15. Rosenfeldt MT, O’Prey J, Morton JP, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature, 2013, 504(7479): 296-300.
16. Jonckheere N, Vincent A, Van Seuningen I. Of autophagy and in vivo pancreatic carcinogenesis: the p53 status matters! Clin Res Hepatol Gastroenterol, 2014, 38(4): 423-425.
17. Aita VM, Liang XH, Murty VV, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomic, 1999, 59(1): 59-65.
18. Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 1999, 402(6762): 672-676.
19. Akar U, Ozpolat B, Mehta K, et al. Tissue transglutaminase inhibits autophagy in pancreatic cancer cells. Mol Cancer Res, 2007, 5(3): 241-249.
20. Li X, Yan J, Wang L, et al. Beclin1 inhibition promotes autophagy and decreases gemcitabine-induced apoptosis in Miapaca2 pancreatic cancer cells. Cancer Cell Int, 2013, 13(1): 26.
21. Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest, 2003, 112(12): 1809-1820．.
22. Rohatgi RA, Janusis J, Leonard D, et al. Beclin 1 regulates growth factor receptor signaling in breast cancer. Oncogene, 2015, 34(42): 5352-5362.
23. Katagiri H, Nakayama K, Razia S, et al. Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas. Int J Oncol, 2015, 47(6): 2037-2044.
24. 康凯夫, 王晓蔚, 陈小伍, 等. Beclinl 在原发性肝细胞癌中的表达及其临床意义. 南方医科大学学报, 2009, 29(1): 151-153.
25. Li BX, Li CY, Peng RQ, et al. The expression of beclin 1 is associated with favorable prognosis in stage ⅢB colon cancers. Autophagy, 2009, 5(3): 303-306.
26. 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.
27. Giatromanolaki A, Koukourakis MI, Koutsopoulos A, et al. High Beclin 1 expression defines a poor prognosis in endometrial adenocarcinomas. Gynecol Oncol, 2011, 123(1): 147-151.
28. Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular self-digestion. Nature, 2008, 451(7182): 1069-1075.
29. Boya P, Gonzalez-Polo RA, Casares N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol, 2005, 25(3): 1025-1040.
30. Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell, 2005, 120(2): 237-248.
31. Gunn JM, Clark MG, Knowles SE, et al. Reduced rates of proteolysis in transformed cells. Nature, 1977, 266(5597): 58-60.
32. Kisen GO, Tessitore L, Costelli P, et al. Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis, 1993, 14(12): 2501-2505.
33. Kirkegaard K, Taylor MP, Jackson WT. Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol, 2004, 2(4): 301-314.
34. Otsuka H, Moskowitz M. Differences in the rates of protein degradation in untransformed and transformed cell lines. Exp Cell Res, 1978, 112(1): 127-135.
35. Tóth S, Nagy K, Pálfia Z, et al. Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res, 2002, 309(3): 409-416.
36. Chau YP, Lin SY, Chen JH, et al. Endostatin induces autophagic cell death in EAhy926 human endothelial cells. Histol Histopathol, 2003, 18(3): 715-726.

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The expression and significance of Beclin-1 in pancreatic ductal adenocarcinoma

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