Y染色体性别决定基因相关的高速泳动蛋白家族9和胃动蛋白1在胃癌中的表达及其与预后的关系
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摘要
目的探讨Y染色体性别决定基因相关的高速泳动蛋白家族9(SOX9)和胃动蛋白1(GKN1)在胃癌中的表达及其与患者临床病理特征和预后的关系。方法采用免疫组织化学染色法检测SOX9和GKN1在70例胃癌组织及相应癌旁组织(27例肠上皮化生和43例正常胃黏膜组织)中的表达情况,分析SOX9和GKN1在胃癌中的表达与患者临床病理因素和预后的关系。结果 SOX9在胃癌组织、肠化生组织和正常胃黏膜组织中的高表达率分别为92.9%(65/70)、77.8%(21/27)和55.8%(24/43),差异有统计学意义(χ~2=21.722,P<0.001)。胞核与胞浆均可见阳性染色。单独观察胞核内染色发现,SOX9在胃癌组织细胞核内的高表达率为67.1%,明显高于肠化生组织的37.0%(P=0.007)和正常胃黏膜组织的23.3%(P<0.001);GKN1的染色定位于胞浆,其在正常胃黏膜中的高表达率为76.7%,明显高于肠化生组织的44.4%(P=0.006)和胃癌组织的37.1%(P<0.001)。胃癌组织中,SOX9在胞核内的表达与组织分化程度相关(P=0.007),而GKN1的表达与组织分化程度(P=0.002)和病理类型是否为印戒细胞癌相关(P=0.009)。SOX9在胃癌组织细胞核内的表达与GKN1的表达呈显著负相关(χ~2=15.424,P<0.001)。70例胃癌患者中,SOX9在胞核内高表达组和低表达组的5年生存率(33.8%比67.5%,P=0.016)及GKN1高表达组和低表达组的5年生存率(60.0%比35.6%,P=0.044)差异均有统计学意义。37例SOX9胞核内高表达且GKN1低表达的胃癌患者5年生存率为28.8%。Cox多因素分析结果显示,TNM分期晚(Ⅱ期:HR=7.435,95%CI:1.313～42.096,P=0.023;Ⅲ期:HR=12.214,95%CI:2.677～55.721,P=0.001)和SOX9在细胞核的高表达(HR=3.297,95%CI:1.199～9.065,P=0.021)是影响胃癌患者预后的独立危险因素。结论 SOX9和GKN1的表达变化可能在胃癌的恶性生物学行为中发挥重要作用。SOX9可能是胃癌患者的潜在预后标志物,联合检测SOX9和GKN1的表达情况并进一步研究其分子作用机制可能为胃癌的早期诊断、靶向治疗以及预后评估提供新思路。
Objective To explore the expressions of Sry-related high mobility group box 9(SOX9)and gastrokine-1(GKN1) in gastric cancer tissues and their relationships with clinicopathologic features and prognosis of patients. Methods Immunohistochemistry was used to detect the expressions of SOX9 and GKN1 in 70 cases of gastric cancer tissues and corresponding paracancerous tissues including 27 cases of intestinal metaplasia and 43 cases of normal gastric mucosa. The relationships of SOX9 and GKN1 expressions with clinicopathological features and prognosis were analyzed in gastric cancer tissues. Results The high expression rates of SOX9 in gastric cancer tissues,intestinal metaplasia,and normal gastric mucosa were 92.9%(65/70),77.8%(21/27),and 55.8%(24/43),respectively(χ~2=21.722,P<0.001). Positive nuclear and cytoplasmic staining was observed. The high nuclear expression rate of SOX9 in gastric cancer tissues was 67.1%,which was significantly higher than those of intestinal metaplasia(37.0%,P=0.007)and normal gastric mucosa(23.3%,P<0.001). The high cytoplasmic expression rate of GKN1 in normal gastric mucosa was 76.7%,which was significantly higher than those of intestinal metaplasia(44.4%,P=0.006)and gastric cancer tissues(37.1%,P<0.001). Univariate analysis demonstrated that the nuclear expression of SOX9 in gastric cancer was associated with the degree of tissue differentiation(P=0.007),while the cytoplasmic expression of GKN1 was associated with both the degree of tissue differentiation(P=0.002)and whether the pathological type was a signet-ring cell carcinoma(P=0.009). Furthermore,the nuclear expression of SOX9 was negatively correlated with the expression of GKN1 in gastric cancer(χ~2=15.424,P<0.001). The 5-year survival rates of patients with high or low nuclear expression of SOX9 were 33.8% and 67.5%,respectively(P=0.016).The 5-year survival rates of patients with high or low expression of GKN1 were 60.0% and 35.6%,respectively(P=0.044). Further research indicated that 5-year survival rate of patients with high nuclear expression of SOX9 and low expression of GKN1 was 28.8%. Cox multivariate regression analysis showed that TNM stage(stage Ⅱ:HR=7.435,95%CI:1.313-42.096,P=0.023;stage Ⅲ:HR=12.214,95%CI:2.677-55.721,P=0.001)and nuclear expression level of SOX9(HR=3.297,95%CI:1.199-9.065,P=0.021)were independent risk factors for the prognosis of gastric cancer patients. Conclusions Changes in the expressions of SOX9 and GKN1 may be associated with the malignant biological behavior of gastric cancer. SOX9 may be a potential prognostic factor. The combined detection of SOX9 and GKN1 expression and the further study of their molecular mechanism may provide new clues for early diagnosis,targeted therapy,and prognostic prediction of gastric cancer.
Objective To explore the expressions of Sry-related high mobility group box 9(SOX9)and gastrokine-1(GKN1) in gastric cancer tissues and their relationships with clinicopathologic features and prognosis of patients. Methods Immunohistochemistry was used to detect the expressions of SOX9 and GKN1 in 70 cases of gastric cancer tissues and corresponding paracancerous tissues including 27 cases of intestinal metaplasia and 43 cases of normal gastric mucosa. The relationships of SOX9 and GKN1 expressions with clinicopathological features and prognosis were analyzed in gastric cancer tissues. Results The high expression rates of SOX9 in gastric cancer tissues,intestinal metaplasia,and normal gastric mucosa were 92.9%(65/70),77.8%(21/27),and 55.8%(24/43),respectively(χ~2=21.722,P<0.001). Positive nuclear and cytoplasmic staining was observed. The high nuclear expression rate of SOX9 in gastric cancer tissues was 67.1%,which was significantly higher than those of intestinal metaplasia(37.0%,P=0.007)and normal gastric mucosa(23.3%,P<0.001). The high cytoplasmic expression rate of GKN1 in normal gastric mucosa was 76.7%,which was significantly higher than those of intestinal metaplasia(44.4%,P=0.006)and gastric cancer tissues(37.1%,P<0.001). Univariate analysis demonstrated that the nuclear expression of SOX9 in gastric cancer was associated with the degree of tissue differentiation(P=0.007),while the cytoplasmic expression of GKN1 was associated with both the degree of tissue differentiation(P=0.002)and whether the pathological type was a signet-ring cell carcinoma(P=0.009). Furthermore,the nuclear expression of SOX9 was negatively correlated with the expression of GKN1 in gastric cancer(χ~2=15.424,P<0.001). The 5-year survival rates of patients with high or low nuclear expression of SOX9 were 33.8% and 67.5%,respectively(P=0.016).The 5-year survival rates of patients with high or low expression of GKN1 were 60.0% and 35.6%,respectively(P=0.044). Further research indicated that 5-year survival rate of patients with high nuclear expression of SOX9 and low expression of GKN1 was 28.8%. Cox multivariate regression analysis showed that TNM stage(stage Ⅱ:HR=7.435,95%CI:1.313-42.096,P=0.023;stage Ⅲ:HR=12.214,95%CI:2.677-55.721,P=0.001)and nuclear expression level of SOX9(HR=3.297,95%CI:1.199-9.065,P=0.021)were independent risk factors for the prognosis of gastric cancer patients. Conclusions Changes in the expressions of SOX9 and GKN1 may be associated with the malignant biological behavior of gastric cancer. SOX9 may be a potential prognostic factor. The combined detection of SOX9 and GKN1 expression and the further study of their molecular mechanism may provide new clues for early diagnosis,targeted therapy,and prognostic prediction of gastric cancer.
引文
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[14] Yoon JH,Song JH,Zhang C,et al.Inactivation of the Gastrokine 1 gene in gastric adenomas and carcinomas[J].J Pathol,2015,223(5):618- 625.DOI:10.1002/path.2838.
[15] Mao W,Chen J,Peng TL,et al.Downregulation of gastrokine- 1 in gastric cancer tissues and restoration of its expression induced gastric cancer cells to apoptosis[J].J Exp Clin Canc Res,2012,31(1):49.DOI:10.1186/1756- 9966- 31- 49.
[16] Yoon JH,Seo HS,Choi SS,et al.Gastrokine 1 inhibits the carcinogenic potentials of Helicobacter pylori CagA[J].Carcinogenesis,2014,35(11):2619- 2629.DOI:10.1093/carcin/bgu199.
[17] Yoon JH,Choi WS,Kim O,et al.Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression[J].Gastric Cancer,2016,20(2):274- 285.DOI:10.1007/s10120- 016- 0617- 1.
[18] Xing R,Li W,Cui J,et al.Gastrokine 1 induces senescence through p16/Rb pathway activation in gastric cancer cells[J].Gut,2012,61(1):43- 52.DOI:10.1136/gut.2010.230623.
[19] 方义湖,徐芳英,黄琼,等.SOX9在结直肠癌中的表达及其意义[J].实用肿瘤杂志,2008,23(5):425- 428.DOI:10.3969/j.issn.1001- 1692.2008.05.009.
[20] Moss SF,Lee JW,Sabo E,et al.Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer:influence of tumor histology and relationship to prognosis[J].Clin Cancer Res,2008,14(13):4161- 4167.DOI:10.1158/1078- 0432.CCR- 07- 4381.
[2] 王胤奎,李子禹,陕飞,等.我国早期胃癌的诊治现状——来自中国胃肠肿瘤外科联盟数据的启示[J].中华胃肠外科杂志,2018,21(2):168- 174.DOI:10.3760/cma.j.issn.1671- 0274.2018.02.010.
[3] Yoon JH,Kang YH,Choi YJ,et al.Gastrokine 1 functions as a tumor suppressor by inhibition of epithelial-mesenchymal transition in gastric cancers[J].J Cancer Res Clin Oncol,2011,137(11):1697- 1704.DOI:10.1007/s00432- 011- 1051- 8.
[4] Blache P,Wetering MVD,Duluc I,et al.SOX9 is an intestine crypt transcription factor,is regulated by the Wnt pathway,and represses the CDX2 and MUC2 genes[J].J Cell Biol,2004,166(1):37- 47.DOI:10.1083/jcb.200311021.
[5] Santos JC,Carrasco-Garcia E,Garcia-Puga M,et al.SOX9 elevation acts with canonical WNT signaling to drive gastric cancer progression[J].Cancer Res,2016,76(22):6735- 6746.DOI:10.1158/0008- 5472.CAN- 16- 1120.
[6] Washington K.7th edition of the AJCC cancer staging manual:stomach[J].Ann Surg Oncol,2010,17(12):3077- 3079.DOI:10.1245/s10434- 010- 1362-z.
[7] Foster JW,Dominguez-Steglich MA,GuioliS,et al.Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene[J].Nature,1994,372(6506):525- 530.DOI:10.1038/372525a0.
[8] Mori-Akiyama Y,van den Born M,van Es JH,et al.SOX9 is required for the differentiation of paneth cells in the intestinal epithelium[J].Gastroenterology,2007,133(2):539- 546.DOI:10.1053/j.gastro.2007.05.020.
[9] Liu JN,Guan YM S,Qi YZ,et al.The evaluation of SOX9 expression and its relationship with carcinoembryonic antigen-related cell adhesion molecule 1 in gastric neoplastic and nonneoplastic lesions[J].Ann Diagn Pathol,2012,16(4):235- 244.DOI:10.1016/j.anndiagpath.2011.10.003.
[10] Zhou CJ,Guo JQ,Zhu KX,et al.Elevated expression of SOX9 is related with the progression of gastric carcinoma[J].Diagn Cytopathol,2011,39(2):105- 109.DOI:10.1002/dc.21348.
[11] Sun M,Uozaki H,Hino R,et al.SOX9 expression and its methylation status in gastric cancer[J].Virchows Arch,2012,460(3):271- 279.DOI:10.1007/s00428- 012- 1201- 7.
[12] Choi YJ,Song JH,Yoon JH,et al.Aberrant expression of SOX9 is associated with gastrokine 1 inactivation in gastric cancers[J].Gastric Cancer,2014,17(2):247- 254.DOI:10.1007/s10120- 013- 0277- 3.
[13] Zhang N,Chai D,Du H,et al.Expression of Reg Ⅳ and SOX9 and their correlation in human gastric cancer[J].Bmc Cancer,2018,18(1):344.DOI:10.1186/s12885- 018- 4285-x.
[14] Yoon JH,Song JH,Zhang C,et al.Inactivation of the Gastrokine 1 gene in gastric adenomas and carcinomas[J].J Pathol,2015,223(5):618- 625.DOI:10.1002/path.2838.
[15] Mao W,Chen J,Peng TL,et al.Downregulation of gastrokine- 1 in gastric cancer tissues and restoration of its expression induced gastric cancer cells to apoptosis[J].J Exp Clin Canc Res,2012,31(1):49.DOI:10.1186/1756- 9966- 31- 49.
[16] Yoon JH,Seo HS,Choi SS,et al.Gastrokine 1 inhibits the carcinogenic potentials of Helicobacter pylori CagA[J].Carcinogenesis,2014,35(11):2619- 2629.DOI:10.1093/carcin/bgu199.
[17] Yoon JH,Choi WS,Kim O,et al.Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression[J].Gastric Cancer,2016,20(2):274- 285.DOI:10.1007/s10120- 016- 0617- 1.
[18] Xing R,Li W,Cui J,et al.Gastrokine 1 induces senescence through p16/Rb pathway activation in gastric cancer cells[J].Gut,2012,61(1):43- 52.DOI:10.1136/gut.2010.230623.
[19] 方义湖,徐芳英,黄琼,等.SOX9在结直肠癌中的表达及其意义[J].实用肿瘤杂志,2008,23(5):425- 428.DOI:10.3969/j.issn.1001- 1692.2008.05.009.
[20] Moss SF,Lee JW,Sabo E,et al.Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer:influence of tumor histology and relationship to prognosis[J].Clin Cancer Res,2008,14(13):4161- 4167.DOI:10.1158/1078- 0432.CCR- 07- 4381.
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