Overexpression of HSP27 and HSP70 is associated with decreased survival among patients with esophageal adenocarcinoma
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摘要
BACKGROUND Overexpression of heat shock proteins(HSPs) is associated with several malignancies and contributes to the development, progression, and metastasis of cancer, in addition to the inhibition of cellular death. In recent years, there has been active research into using HSP inhibitors in several malignancies. Due to the poor prognosis of esophageal adenocarcinoma(EAC), it would be valuable to find new biomarkers for the development of cancer treatments.AIM To evaluate the expressions of HSP27 and HSP70 and their effect on survival in EAC.METHODS Immunohistochemical analyses and evaluations of HSP27 and HSP70 expression were performed on all available samples from 93 patients diagnosed with EACbetween 1990 and 2007 at two university hospitals. Fifteen cases with Barrett's metaplasia and 5 control cases from the same patient population were included in the analysis. HSP expression was quantitatively assessed and classified as high or low. Kaplan-Meier analyses and Cox regression models adjusting for age and sex as well as tumor site, stage, and grade were used to evaluate the effect on survival.RESULTS Tumor stage and surgical treatment were the main prognostic factors. High HSP27 expression in cancer cases was a strong negative predictive factor, with a mean survival of 23 mo compared to the 49 mo in cases with a low expression(P= 0.018). The results were similar for HSP70, with a poorer survival of 17 mo in cases with high HSP70 expression, in contrast to 40 mo(P = 0.006) in cases with a low expression. A Cox regression survival analysis was performed, adjusting for possible confounding factors, and higher HSP27 and HSP70 expressions remained an independent negative prognostic factor. The HSPs' correlation with survival was not affected by cancer treatments. When the analysis was adjusted for all factors, the odds ratios for HSP27 and HSP70 were 3.3(CI: 1.6–6.6, P =0.001) and 2.2(CI: 1.2–3.9, P = 0.02), respectively.CONCLUSION HSP27 and HSP70 overexpression is associated with poor survival in EAC, which is, to the best of our knowledge, reported for the first time.
BACKGROUND Overexpression of heat shock proteins(HSPs) is associated with several malignancies and contributes to the development, progression, and metastasis of cancer, in addition to the inhibition of cellular death. In recent years, there has been active research into using HSP inhibitors in several malignancies. Due to the poor prognosis of esophageal adenocarcinoma(EAC), it would be valuable to find new biomarkers for the development of cancer treatments.AIM To evaluate the expressions of HSP27 and HSP70 and their effect on survival in EAC.METHODS Immunohistochemical analyses and evaluations of HSP27 and HSP70 expression were performed on all available samples from 93 patients diagnosed with EACbetween 1990 and 2007 at two university hospitals. Fifteen cases with Barrett's metaplasia and 5 control cases from the same patient population were included in the analysis. HSP expression was quantitatively assessed and classified as high or low. Kaplan-Meier analyses and Cox regression models adjusting for age and sex as well as tumor site, stage, and grade were used to evaluate the effect on survival.RESULTS Tumor stage and surgical treatment were the main prognostic factors. High HSP27 expression in cancer cases was a strong negative predictive factor, with a mean survival of 23 mo compared to the 49 mo in cases with a low expression(P= 0.018). The results were similar for HSP70, with a poorer survival of 17 mo in cases with high HSP70 expression, in contrast to 40 mo(P = 0.006) in cases with a low expression. A Cox regression survival analysis was performed, adjusting for possible confounding factors, and higher HSP27 and HSP70 expressions remained an independent negative prognostic factor. The HSPs' correlation with survival was not affected by cancer treatments. When the analysis was adjusted for all factors, the odds ratios for HSP27 and HSP70 were 3.3(CI: 1.6–6.6, P =0.001) and 2.2(CI: 1.2–3.9, P = 0.02), respectively.CONCLUSION HSP27 and HSP70 overexpression is associated with poor survival in EAC, which is, to the best of our knowledge, reported for the first time.
BACKGROUND Overexpression of heat shock proteins(HSPs) is associated with several malignancies and contributes to the development, progression, and metastasis of cancer, in addition to the inhibition of cellular death. In recent years, there has been active research into using HSP inhibitors in several malignancies. Due to the poor prognosis of esophageal adenocarcinoma(EAC), it would be valuable to find new biomarkers for the development of cancer treatments.AIM To evaluate the expressions of HSP27 and HSP70 and their effect on survival in EAC.METHODS Immunohistochemical analyses and evaluations of HSP27 and HSP70 expression were performed on all available samples from 93 patients diagnosed with EACbetween 1990 and 2007 at two university hospitals. Fifteen cases with Barrett's metaplasia and 5 control cases from the same patient population were included in the analysis. HSP expression was quantitatively assessed and classified as high or low. Kaplan-Meier analyses and Cox regression models adjusting for age and sex as well as tumor site, stage, and grade were used to evaluate the effect on survival.RESULTS Tumor stage and surgical treatment were the main prognostic factors. High HSP27 expression in cancer cases was a strong negative predictive factor, with a mean survival of 23 mo compared to the 49 mo in cases with a low expression(P= 0.018). The results were similar for HSP70, with a poorer survival of 17 mo in cases with high HSP70 expression, in contrast to 40 mo(P = 0.006) in cases with a low expression. A Cox regression survival analysis was performed, adjusting for possible confounding factors, and higher HSP27 and HSP70 expressions remained an independent negative prognostic factor. The HSPs' correlation with survival was not affected by cancer treatments. When the analysis was adjusted for all factors, the odds ratios for HSP27 and HSP70 were 3.3(CI: 1.6–6.6, P =0.001) and 2.2(CI: 1.2–3.9, P = 0.02), respectively.CONCLUSION HSP27 and HSP70 overexpression is associated with poor survival in EAC, which is, to the best of our knowledge, reported for the first time.
引文
1 Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet 2017; 390:2383-2396[PMID:28648400 DOI:10.1016/S0140-6736(17)31462-9]
2 Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med 2014; 371:2499-2509[PMID:25539106DOI:10.1056/NEJMra1314530]
3 Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci 2017;38:226-256[PMID:28012700 DOI:10.1016/j.tips.2016.11.009]
4 Wang X, Chen M, Zhou J, Zhang X. HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy(Review). Int J Oncol 2014; 45:18-30[PMID:24789222 DOI:10.3892/ijo.2014.2399]
5 Wang XW, Shi XH, Tong YS, Cao XF. The Prognostic Impact of Heat Shock Proteins Expression in Patients with Esophageal Cancer:A Meta-Analysis. Yonsei Med J 2015; 56:1497-1502[PMID:26446629DOI:10.3349/ymj.2015.56.6.1497]
6 Rantanen T, Honkanen T, Paavonen T, Rantanen L, Oksala N. Altered expression of HSP27 and HSP70in distal oesophageal mucosa in patients with gastro-oesophageal reflux disease subjected to fundoplication. Eur J Surg Oncol 2011; 37:168-174[PMID:21095095 DOI:10.1016/j.ejso.2010.10.013]
7 Chatterjee S, Burns TF. Targeting Heat Shock Proteins in Cancer:A Promising Therapeutic Approach.Int J Mol Sci 2017; 18:E1978[PMID:28914774 DOI:10.3390/ijms18091978]
8 Rice TW, Blackstone EH, Rusch VW. 7th edition of the AJCC Cancer Staging Manual:esophagus and esophagogastric junction. Ann Surg Oncol 2010; 17:1721-1724[PMID:20369299 DOI:10 .1245/s10434-010-1024-1]
9 Bauer K, Nitsche U, Slotta-Huspenina J, Drecoll E, von Weyhern CH, Rosenberg R, H?fler H, Langer R.High HSP27 and HSP70 expression levels are independent adverse prognostic factors in primary resected colon cancer. Cell Oncol(Dordr)2012; 35:197-205[PMID:22535481 DOI:10.1007/s13402-012-0079-3]
10 Giaginis C, Daskalopoulou SS, Vgenopoulou S, Sfiniadakis I, Kouraklis G, Theocharis SE. Heat Shock Protein-27,-60 and-90 expression in gastric cancer:association with clinicopathological variables and patient survival. BMC Gastroenterol 2009; 9:14[PMID:19203381 DOI:10.1186/1471-230X-9-14]
11 Lee HW, Lee EH, Kim S-H, Roh MS, Jung SB, Choi YC. Heat shock protein 70(HSP70)expression is associated with poor prognosis in intestinal type gastric cancer. Virchows Arch 2013; 463:489–495[PMID:23913168 DOI:10.1007/s00428-013-1461-x]
12 Kawanishi K, Shiozaki H, Doki Y, Sakita I, Inoue M, Yano M, Tsujinaka T, Shamma A, Monden M.Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus. Cancer 1999; 85:1649-1657[PMID:10223556 DOI:10 .1002/(SICI)1097-0142(19990415)85:8<1649::AID-CNCR2>3.0.CO;2-V]
13 Nakajima M, Kuwano H, Miyazaki T, Masuda N, Kato H. Significant correlation between expression of heat shock proteins 27, 70 and lymphocyte infiltration in esophageal squamous cell carcinoma. Cancer Lett 2002; 178:99-106[PMID:11849747 DOI:10.1016/S0304-3835(01)00825-4]
14 Berg D, Wolff C, Langer R, Schuster T, Feith M, Slotta-Huspenina J, Malinowsky K, Becker KF.Discovery of new molecular subtypes in oesophageal adenocarcinoma. PLoS One 2011; 6:e23985[PMID:21966358 DOI:10.1371/journal.pone.0023985]
15 Nakajima M, Kato H, Miyazaki T, Fukuchi M, Masuda N, Fukai Y, Sohda M, Ahmad F, Kuwano H.Tumor immune systems in esophageal cancer with special reference to heat-shock protein 70 and humoral immunity. Anticancer Res 2009; 29:1595-1606[PMID:19443372]
16 Langer R, Ott K, Specht K, Becker K, Lordick F, Burian M, Herrmann K, Schrattenholz A, Cahill MA,Schwaiger M, Hofler H, Wester HJ. Protein expression profiling in esophageal adenocarcinoma patients indicates association of heat-shock protein 27 expression and chemotherapy response. Clin Cancer Res2008; 14:8279-8287[PMID:19088045 DOI:10.1158/1078-0432.CCR-08-0679]
17 Slotta-Huspenina J, Berg D, Bauer K, Wolff C, Malinowsky K, Bauer L, Drecoll E, Bettstetter M, Feith M, Walch A, H?fler H, Becker KF, Langer R. Evidence of prognostic relevant expression profiles of heatshock proteins and glucose-regulated proteins in oesophageal adenocarcinomas. PLoS One 2012; 7:e41420[PMID:22911792 DOI:10.1371/journal.pone.0041420]
18 Slotta-Huspenina J, Wolff C, Drecoll E, Feith M, Bettstetter M, Malinowsky K, Bauer L, Becker K, Ott K, H?fler H, Becker KF, Langer R. A specific expression profile of heat-shock proteins and glucoseregulated proteins is associated with response to neoadjuvant chemotherapy in oesophageal adenocarcinomas. Br J Cancer 2013; 109:370-378[PMID:23839491 DOI:10.1038/bjc.2013.319]
19 Soldes OS, Kuick RD, Thompson IA 2nd, Hughes SJ, Orringer MB, Iannettoni MD, Hanash SM, Beer DG. Differential expression of Hsp27 in normal oesophagus, Barrett's metaplasia and oesophageal adenocarcinomas. Br J Cancer 1999; 79:595-603[PMID:10027336 DOI:10.1038/sj.bjc.6690094]
2 Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med 2014; 371:2499-2509[PMID:25539106DOI:10.1056/NEJMra1314530]
3 Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci 2017;38:226-256[PMID:28012700 DOI:10.1016/j.tips.2016.11.009]
4 Wang X, Chen M, Zhou J, Zhang X. HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy(Review). Int J Oncol 2014; 45:18-30[PMID:24789222 DOI:10.3892/ijo.2014.2399]
5 Wang XW, Shi XH, Tong YS, Cao XF. The Prognostic Impact of Heat Shock Proteins Expression in Patients with Esophageal Cancer:A Meta-Analysis. Yonsei Med J 2015; 56:1497-1502[PMID:26446629DOI:10.3349/ymj.2015.56.6.1497]
6 Rantanen T, Honkanen T, Paavonen T, Rantanen L, Oksala N. Altered expression of HSP27 and HSP70in distal oesophageal mucosa in patients with gastro-oesophageal reflux disease subjected to fundoplication. Eur J Surg Oncol 2011; 37:168-174[PMID:21095095 DOI:10.1016/j.ejso.2010.10.013]
7 Chatterjee S, Burns TF. Targeting Heat Shock Proteins in Cancer:A Promising Therapeutic Approach.Int J Mol Sci 2017; 18:E1978[PMID:28914774 DOI:10.3390/ijms18091978]
8 Rice TW, Blackstone EH, Rusch VW. 7th edition of the AJCC Cancer Staging Manual:esophagus and esophagogastric junction. Ann Surg Oncol 2010; 17:1721-1724[PMID:20369299 DOI:10 .1245/s10434-010-1024-1]
9 Bauer K, Nitsche U, Slotta-Huspenina J, Drecoll E, von Weyhern CH, Rosenberg R, H?fler H, Langer R.High HSP27 and HSP70 expression levels are independent adverse prognostic factors in primary resected colon cancer. Cell Oncol(Dordr)2012; 35:197-205[PMID:22535481 DOI:10.1007/s13402-012-0079-3]
10 Giaginis C, Daskalopoulou SS, Vgenopoulou S, Sfiniadakis I, Kouraklis G, Theocharis SE. Heat Shock Protein-27,-60 and-90 expression in gastric cancer:association with clinicopathological variables and patient survival. BMC Gastroenterol 2009; 9:14[PMID:19203381 DOI:10.1186/1471-230X-9-14]
11 Lee HW, Lee EH, Kim S-H, Roh MS, Jung SB, Choi YC. Heat shock protein 70(HSP70)expression is associated with poor prognosis in intestinal type gastric cancer. Virchows Arch 2013; 463:489–495[PMID:23913168 DOI:10.1007/s00428-013-1461-x]
12 Kawanishi K, Shiozaki H, Doki Y, Sakita I, Inoue M, Yano M, Tsujinaka T, Shamma A, Monden M.Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus. Cancer 1999; 85:1649-1657[PMID:10223556 DOI:10 .1002/(SICI)1097-0142(19990415)85:8<1649::AID-CNCR2>3.0.CO;2-V]
13 Nakajima M, Kuwano H, Miyazaki T, Masuda N, Kato H. Significant correlation between expression of heat shock proteins 27, 70 and lymphocyte infiltration in esophageal squamous cell carcinoma. Cancer Lett 2002; 178:99-106[PMID:11849747 DOI:10.1016/S0304-3835(01)00825-4]
14 Berg D, Wolff C, Langer R, Schuster T, Feith M, Slotta-Huspenina J, Malinowsky K, Becker KF.Discovery of new molecular subtypes in oesophageal adenocarcinoma. PLoS One 2011; 6:e23985[PMID:21966358 DOI:10.1371/journal.pone.0023985]
15 Nakajima M, Kato H, Miyazaki T, Fukuchi M, Masuda N, Fukai Y, Sohda M, Ahmad F, Kuwano H.Tumor immune systems in esophageal cancer with special reference to heat-shock protein 70 and humoral immunity. Anticancer Res 2009; 29:1595-1606[PMID:19443372]
16 Langer R, Ott K, Specht K, Becker K, Lordick F, Burian M, Herrmann K, Schrattenholz A, Cahill MA,Schwaiger M, Hofler H, Wester HJ. Protein expression profiling in esophageal adenocarcinoma patients indicates association of heat-shock protein 27 expression and chemotherapy response. Clin Cancer Res2008; 14:8279-8287[PMID:19088045 DOI:10.1158/1078-0432.CCR-08-0679]
17 Slotta-Huspenina J, Berg D, Bauer K, Wolff C, Malinowsky K, Bauer L, Drecoll E, Bettstetter M, Feith M, Walch A, H?fler H, Becker KF, Langer R. Evidence of prognostic relevant expression profiles of heatshock proteins and glucose-regulated proteins in oesophageal adenocarcinomas. PLoS One 2012; 7:e41420[PMID:22911792 DOI:10.1371/journal.pone.0041420]
18 Slotta-Huspenina J, Wolff C, Drecoll E, Feith M, Bettstetter M, Malinowsky K, Bauer L, Becker K, Ott K, H?fler H, Becker KF, Langer R. A specific expression profile of heat-shock proteins and glucoseregulated proteins is associated with response to neoadjuvant chemotherapy in oesophageal adenocarcinomas. Br J Cancer 2013; 109:370-378[PMID:23839491 DOI:10.1038/bjc.2013.319]
19 Soldes OS, Kuick RD, Thompson IA 2nd, Hughes SJ, Orringer MB, Iannettoni MD, Hanash SM, Beer DG. Differential expression of Hsp27 in normal oesophagus, Barrett's metaplasia and oesophageal adenocarcinomas. Br J Cancer 1999; 79:595-603[PMID:10027336 DOI:10.1038/sj.bjc.6690094]