乳腺浸润性癌中P-ERK与CXCL14的表达及临床意义
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摘要
目的分析人乳腺组织中P-ERK和CXCL14表达的变化,探讨P-ERK和CXCL14在乳腺癌中预后、鉴别诊断的作用。方法应用免疫组织化学S-P法检测P-ERK和CXCL14,在乳腺正常上皮(15例)、导管原位癌(20例)、乳腺非特殊类型浸润性癌(浸润性导管癌)(60例)中阳性表达情况;应用免疫组化方法检测P-ERK和CXCLl4在乳腺非特殊类型浸润性癌(浸润性导管癌)与乳腺浸润性小叶癌中表达,检测乳腺非特殊类型浸润性癌(浸润性导管癌)中CXCLl4的表达与乳腺非特殊类型浸润性癌(浸润性导管癌)分子分型的关系;乳腺非特殊类型浸润性癌(浸润性导管癌)及正常乳腺组织中应用Western blot方法 ,检测P-ERK、CXCL14蛋白表达情况。结果①乳腺正常组织、导管原位癌、乳腺非特殊类型浸润性癌(浸润性导管癌)中P-ERK阳性率分别为20.0%、50.0%、53.3%,CXCL14阳性率分别为73.3%、30%、26.7%。②CXCLl4在乳腺非特殊类型浸润性癌(浸润性导管癌)与乳腺浸润性小叶癌中,阳性表达率无统计学意义。③CXCL14阳性率与乳腺非特殊类型浸润性癌(浸润性导管癌)组织学分级、淋巴结癌组织转移(P<0.05)相关,ER和PgR阳性表达不相关(P>0.05);P-ERK的阳性率与乳腺癌的组织学分级相关(P<0.05)。④乳腺非特殊类型浸润性癌(浸润性导管癌)中CXCLl4阳性率与分子分型不相关。⑤60例乳腺非特殊类型浸润性癌(浸润性导管癌)P-ERK和CXCL14阳性表达呈负相关性(rs=-0.418,P<0.01)。⑥Western blot结果表明乳腺非特殊类型浸润性癌(浸润性导管癌)组织中CXCL14蛋白表达量(CXCL14:0.086±0.010)低于癌旁正常乳腺组织中CXCL14蛋白表达量(CXCL14∶1.35±0.028)(P<0.05)。结论乳腺非特殊类型浸润性癌(浸润性导管癌)中CXCL14低表达,P-ERK高表达,P-ERK和CXCL14具有负相关性。乳腺非特殊类型浸润性癌(浸润性导管癌)中调控P-ERK表达可以负性调控CXCL14的表达,同时检测P-ERK和CXCL14对于乳腺良性病变、恶性病变的鉴别以及对乳腺非特殊类型浸润性癌(浸润性导管癌)诊断的治疗、预后评估有重要参考价值。
Objective To investigate the expression of P-ERK and CXCL14 in breast tissues and their relation in the breast carcinoma. Methods The P-ERK and CXCL14 protein expression was detected in 15 cases of normal tissue, 20 cases of ductal caicinoma in situ, 60 cases of invasive ductal carcinoma(NST) and 20 cases of invasive lobular carcinoma of the breast by immunohistochemical SP method. Western blot was used to detect the P-ERK and CXCL14 protein in breast cancer tissue and paired breast normal tissue. Results Immunohistochemical analysis showed that the expression of CXCL14 was lower in breast invasive carcinoma(NST) tissues than that of normal tissues but P-ERK was higher in breast invasive carcinoma(NST) tissues than that of normal tissues. The expression level of CXCL14 was significantly correlated with higher histological grade(P<0.05), more advanced tumor stage(P<0.05) and lymphatic metastssis(P<0.05) in invasive carcinoma(NST). Spearman's correlation revealed that P-ERK expression was significantly correlated with CXCL14 expression in the invasive carcinoma(NST) specimens(rs=-0.418, P<0.01). Western blot analysis showed that P-ERK protein expression was significantly higher(P-ERK: 1.65±0.01)in breast tumor tissues than that of breast normal tissues(P-ERK: 0.13±0.005); but CXCL14 protein expression was significantly lower in breast tumors(CXCLl4:0.086±0.010) than that of breast normal tissues(CXCLl4: 1.35±0.028). Conclusion The results strongly suggest P-ERK expression is increased in breast tumor tissues, but CXCL14 expression is decreased in human breast cancer. We conclude that the expression of P-ERK is inhibited, which would make the increased expression of CXCL14 in breast cancer cells. Both P-ERK and CXCL14 are implicated in the differential diagnosis of breast benign and malignant lesions(especially for invasive ductal carcinoma, NOS), treatment and prognosis of the breast cancers.
Objective To investigate the expression of P-ERK and CXCL14 in breast tissues and their relation in the breast carcinoma. Methods The P-ERK and CXCL14 protein expression was detected in 15 cases of normal tissue, 20 cases of ductal caicinoma in situ, 60 cases of invasive ductal carcinoma(NST) and 20 cases of invasive lobular carcinoma of the breast by immunohistochemical SP method. Western blot was used to detect the P-ERK and CXCL14 protein in breast cancer tissue and paired breast normal tissue. Results Immunohistochemical analysis showed that the expression of CXCL14 was lower in breast invasive carcinoma(NST) tissues than that of normal tissues but P-ERK was higher in breast invasive carcinoma(NST) tissues than that of normal tissues. The expression level of CXCL14 was significantly correlated with higher histological grade(P<0.05), more advanced tumor stage(P<0.05) and lymphatic metastssis(P<0.05) in invasive carcinoma(NST). Spearman's correlation revealed that P-ERK expression was significantly correlated with CXCL14 expression in the invasive carcinoma(NST) specimens(rs=-0.418, P<0.01). Western blot analysis showed that P-ERK protein expression was significantly higher(P-ERK: 1.65±0.01)in breast tumor tissues than that of breast normal tissues(P-ERK: 0.13±0.005); but CXCL14 protein expression was significantly lower in breast tumors(CXCLl4:0.086±0.010) than that of breast normal tissues(CXCLl4: 1.35±0.028). Conclusion The results strongly suggest P-ERK expression is increased in breast tumor tissues, but CXCL14 expression is decreased in human breast cancer. We conclude that the expression of P-ERK is inhibited, which would make the increased expression of CXCL14 in breast cancer cells. Both P-ERK and CXCL14 are implicated in the differential diagnosis of breast benign and malignant lesions(especially for invasive ductal carcinoma, NOS), treatment and prognosis of the breast cancers.
引文
[1] Ozawa S, Kato Y, Ito S,et al.Restoration of BRAK/CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma[J].Cancer Sci,2009,100(11):2202-2209.
[2] Ali S, Lazennec G.Chemokines: novel targets for breast cancer metastasis[J]. Cancer Metastasis Rev, 2007,26(3-4): 401-420.
[3] Shellenberger TD, Wang M, Gujrati M,et al. BRAK/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells[J]. Cancer Res,2004,64(22):8262-8270.
[4] Kurth I, Willimann K, Schaerli P, et al. Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development[J]. J Exp Med, 2001,194(6):855-861.
[5] Starnes T, Rasila KK, Robertson MJ,et al. The chemokine CXCL14 (BRAK) stimulates activated NK cell migration: Implications for the downregulation of CXCL14 in malignancy[J]. Exp Hematol,2006,34(8):1101-1105.
[6] Shurin GV, Ferris RL, Ferris R,et al. Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo[J]. J Immunol,2005,174(9):5490-5498.
[7] Meuter S, Schaerli P, Roos RS,et al. Murine CXCL14 is dispensable for dendritic cell function and localization within peripheral tissues[J]. Mol Cell Biol,2007(3),27:983-992.
[8] Nara N, Nakayama Y, Okamoto S,et al. Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance[J]. J Biol Chem,2007,282(42):30794-30803.
[9] Takahashi M,Takahashi Y, Takahashi K, et al. CXCL14 enhances insulin-dependent glucose uptake in adipocytes and is related to high-fat diet-induced obesity[J]. Biochem Biophys Res Commun,2007,364(4):1037-1042.
[10] Sjöberg E,Augsten M, Bergh J,et al.Expression of the chemokine CXCL14 in the tumour stroma is an independent marker of survival in breast cancer[J].Br J Cancer,2016,114(10):1117-1124.
[11] Nakayama R,Arikawa K, Bhawal UK,et al.The epigenetic regulation of CXCL14 plays a role in the pathobiology of oral cancers[J].J Cancer, 2017,8(15):3014-3027.
[12] Song EY,Shurin MR, Tourkova IL,et al.Epigenetic mechanisms of promigratory chemokine CXCLl4 regulation in human prostate cancer cells[J].Cancer Res,2010,70(11):4394-4401.
[13] Frederick MJ,Henderson Y, Xu X,et al.In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue[J].Am J Pathol,2000,156(6):1937-1950.
[14] Augsten M,Hagglof C, Olsson E,et al.CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth[J].PNAS,2009,106(9):3414-3419.
[2] Ali S, Lazennec G.Chemokines: novel targets for breast cancer metastasis[J]. Cancer Metastasis Rev, 2007,26(3-4): 401-420.
[3] Shellenberger TD, Wang M, Gujrati M,et al. BRAK/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells[J]. Cancer Res,2004,64(22):8262-8270.
[4] Kurth I, Willimann K, Schaerli P, et al. Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development[J]. J Exp Med, 2001,194(6):855-861.
[5] Starnes T, Rasila KK, Robertson MJ,et al. The chemokine CXCL14 (BRAK) stimulates activated NK cell migration: Implications for the downregulation of CXCL14 in malignancy[J]. Exp Hematol,2006,34(8):1101-1105.
[6] Shurin GV, Ferris RL, Ferris R,et al. Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo[J]. J Immunol,2005,174(9):5490-5498.
[7] Meuter S, Schaerli P, Roos RS,et al. Murine CXCL14 is dispensable for dendritic cell function and localization within peripheral tissues[J]. Mol Cell Biol,2007(3),27:983-992.
[8] Nara N, Nakayama Y, Okamoto S,et al. Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance[J]. J Biol Chem,2007,282(42):30794-30803.
[9] Takahashi M,Takahashi Y, Takahashi K, et al. CXCL14 enhances insulin-dependent glucose uptake in adipocytes and is related to high-fat diet-induced obesity[J]. Biochem Biophys Res Commun,2007,364(4):1037-1042.
[10] Sjöberg E,Augsten M, Bergh J,et al.Expression of the chemokine CXCL14 in the tumour stroma is an independent marker of survival in breast cancer[J].Br J Cancer,2016,114(10):1117-1124.
[11] Nakayama R,Arikawa K, Bhawal UK,et al.The epigenetic regulation of CXCL14 plays a role in the pathobiology of oral cancers[J].J Cancer, 2017,8(15):3014-3027.
[12] Song EY,Shurin MR, Tourkova IL,et al.Epigenetic mechanisms of promigratory chemokine CXCLl4 regulation in human prostate cancer cells[J].Cancer Res,2010,70(11):4394-4401.
[13] Frederick MJ,Henderson Y, Xu X,et al.In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue[J].Am J Pathol,2000,156(6):1937-1950.
[14] Augsten M,Hagglof C, Olsson E,et al.CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth[J].PNAS,2009,106(9):3414-3419.