SASH1是乳腺癌预后的一个新的生物标志物
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摘要
目的探讨乳腺癌组织中SASH1(SAM-and SH3-domain containing 1)的表达水平和临床意义,并对其潜在的预后价值进行综合分析。方法通过Oncomine数据库和免疫组织化学实验分析SASH1在乳腺癌病人及正常组织中的转录水平;通过bc Gen Ex Miner v4. 0(breast cancer gene-expression miner v4. 0)分析SASH1与乳腺癌病人临床病理学参数的关系,并采用免疫组织化学实验验证乳腺癌组织中SASH1表达水平以及与临床病理学参数的关系;其次使用在线数据库Kaplan-Meier Plotter评估SASH1 mRNA表达水平对乳腺癌患者预后的价值;最后通过c Bio Portal分析SASH1突变情况及SASH1突变对乳腺癌患者预后的影响。结果 Oncomine数据库和免疫组织化学法均证实乳腺癌组织中SASH1表达水平明显低于正常对照组,且差异有统计学意义(P<0.05)。乳腺癌患者SASH1 mRNA表达水平与年龄、Her2呈正相关,与SBR成负相关,而与雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和三阴乳腺癌(triple-negative breast cancer,TNBC)无关;免疫组织化学法也证实SASH1表达水平与年龄呈正相关,与肿瘤面积和组织学分级呈负相关,而与淋巴结转移无关。生存分析发现SASH1高表达能延长乳腺癌患者的无复发生存时间(recurrence-free survival,RFS),提高患者的预后,且差异有统计学意义(P<0.05)(226022-at数据集、213236-at数据集和41644-at数据集的HR分别为0. 78,0. 88和0. 87);然而,SASH1高表达与总体生存时间(overall survival,OS)之间尚无统计学差异(P>0.05)。同时,SASH1突变是否会影响患者的预后还需进一步的研究(P>0.05)。结论乳腺癌中SASH1 mRNA表达明显下调,且与病人临床病理学参数密切相关; SASH1 mRNA表达下调将显著降低患者生存时间,是乳腺癌预后不良的一个重要生物标志物。
Objective To explore the expression level and clinical significance of SASH1(SAM-and SH3-domain containing 1) in breast cancer tissues,and to analyze its potential prognostic value using bioinformatics analysis. Methods Oncomine database and immunohistochemical method were used to analyze the transcription level of SASH1 in breast cancer tissues and normal tissues. The association between SASH1 and clinicopathological parameters of breast cancer patients was analyzed by breast cancer gene-expression miner v4. 0(bcG enE xM iner v4. 0). The expression level of SASH1 in breast cancer tissue and its association with clinicopathological parameters were verified by immunohistochemical experiments. The Kaplan-Meier plotter database was used to evaluate the value of SASH1 mRNA expression level for the prognosis of breast cancer. The effect of SASH1 mutation on the prognosis of breast cancer patients was analyzed by cB ioP ortal. Results The expression level of SASH1 in breast cancer tissues was significantly lower than that in normal tissues,and the difference was statistically significant(P<0.05). The expression level of SASH1 mR NA in breast cancer patients was positively correlated with age and Her2,and negatively correlated with SBR,while it had no correlation with estrogen receptor,progesterone receptor and triple-negative breast cancer(TNBC). Immunohistochemistry results also confirmed that SASH1 expression level was positively correlated with age,and negatively correlated with tumor size and histological grade,but not correlated with lymph node metastasis. Survival analysis showed that high expression of SASH1 prolonged the recurrence-free survival(RFS) and improved the survival time of patients,and the difference was statistically significant(P<0.05)(HR of 226022-at dataset,213236-at dataset and 41644-at dataset respectively was 0. 78,0. 88 and 0. 87). However,there was no significant difference between SASH1 high expression and overall survival(OS)(P > 0. 05). At the same time,the effect of SASH1 mutation on the prognosis of patients still needed further study(P > 0. 05). Conclusion The mR NA expression of SASH1 in breast cancer is significantly down-regulated and closely related to the clinical pathological parameters of patients. The down-regulation of SASH1 mRNA expression significantly reduce the survival time of patients and may be an important biomarker for poor prognosis of breast cancer.
Objective To explore the expression level and clinical significance of SASH1(SAM-and SH3-domain containing 1) in breast cancer tissues,and to analyze its potential prognostic value using bioinformatics analysis. Methods Oncomine database and immunohistochemical method were used to analyze the transcription level of SASH1 in breast cancer tissues and normal tissues. The association between SASH1 and clinicopathological parameters of breast cancer patients was analyzed by breast cancer gene-expression miner v4. 0(bcG enE xM iner v4. 0). The expression level of SASH1 in breast cancer tissue and its association with clinicopathological parameters were verified by immunohistochemical experiments. The Kaplan-Meier plotter database was used to evaluate the value of SASH1 mRNA expression level for the prognosis of breast cancer. The effect of SASH1 mutation on the prognosis of breast cancer patients was analyzed by cB ioP ortal. Results The expression level of SASH1 in breast cancer tissues was significantly lower than that in normal tissues,and the difference was statistically significant(P<0.05). The expression level of SASH1 mR NA in breast cancer patients was positively correlated with age and Her2,and negatively correlated with SBR,while it had no correlation with estrogen receptor,progesterone receptor and triple-negative breast cancer(TNBC). Immunohistochemistry results also confirmed that SASH1 expression level was positively correlated with age,and negatively correlated with tumor size and histological grade,but not correlated with lymph node metastasis. Survival analysis showed that high expression of SASH1 prolonged the recurrence-free survival(RFS) and improved the survival time of patients,and the difference was statistically significant(P<0.05)(HR of 226022-at dataset,213236-at dataset and 41644-at dataset respectively was 0. 78,0. 88 and 0. 87). However,there was no significant difference between SASH1 high expression and overall survival(OS)(P > 0. 05). At the same time,the effect of SASH1 mutation on the prognosis of patients still needed further study(P > 0. 05). Conclusion The mR NA expression of SASH1 in breast cancer is significantly down-regulated and closely related to the clinical pathological parameters of patients. The down-regulation of SASH1 mRNA expression significantly reduce the survival time of patients and may be an important biomarker for poor prognosis of breast cancer.
引文
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[5]李述,贺勇,曾兴,等. SASH1-IQGAP1-E-cadherin信号轴可能调节乳腺癌转移[J].肿瘤,2017,37(6):633-641.
[6] Ren X,Liu Y,Tao Y,et al. Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma[J]. Oncol Lett,2016,11(5):3123-3130.
[7] Burgess JT,Bolderson E,Saunus JM,et al. SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer[J]. Oncotarget,2016,7(45):72807-72818.
[8] Gong X,Wu J,Wu J,et al. Correlation of SASH1 expression and ultrasonographic features in breast cancer[J]. Onco Targets Ther,2017,10:271-276.
[9] Sealfon SC,Chu TT. RNA and DNA microarrays[J]. Methods Mol Biol,2011,671:3-34.
[10] Sun C,Zhang Z,He P,et al. Involvement of PI3K/Akt pathway in the inhibition of hepatocarcinoma cell invasion and metastasis induced by SASH1 through downregulating Shh-Gli1 signaling[J]. Chem Biol Drug Des,2017,89:95-100.
[11] Fang Q,Yao S,Luo G,et al. Identification of differentially expressed genes in human breast cancer cells induced by 4-hydroxyltamoxifen and elucidation of their pathophysiological relevance and mechanisms[J]. Oncotarget,2018,9(2):2475-2501.
[12] Yang L,Zhang H,Yao Q,et al. Clinical Significance of SASH1Expression in Glioma[J]. Dis Markers,2015,2015:383046.
[13] Rimkus C,Martini M,Friederichs J,et al. Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer[J]. Br J Cancer,2006,95(10):1419-1423.
[14] Zeller C,Hinzmann B,Seitz S,et al. SASH1:a candidate tumor suppressor gene on chromosome 6q24. 3 is downregulated in breast cancer[J]. Oncogene,2003,22(19):2972-2983.
[15] Sheyu L,Hui L,Junyu Z,et al. Promoter methylation assay of SASH1 gene in breast cancer[J]. J buon,2013,18(4):891-898.
[16] Zhou N,Liu C,Wang X,et al. Downregulated SASH1 expression indicates poor clinical prognosis in gastric cancer[J]. Hum Pathol,2018,74:83-91.
[17] Wang Q,Dai H. SASH1,a potential therapeutic target for cancer[J]. Hum Pathol,2018,80:246.
[2] Torre LA,Bray F,Siegel RL,et al. Global cancer statistics,2012[J]. CA Cancer J Clin,2015,65(2):87-108.
[3] Desille-Gbaguidi H,Avigdor S,Body G,et al. Survival impact of primary site surgery on metastatic breast cancer patients at diagnosis[J]. J Gynecol Obstet Hum Reprod,2018:Epub ahead of print.
[4] Chen W,Zheng R,Baade PD,et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115-132.
[5]李述,贺勇,曾兴,等. SASH1-IQGAP1-E-cadherin信号轴可能调节乳腺癌转移[J].肿瘤,2017,37(6):633-641.
[6] Ren X,Liu Y,Tao Y,et al. Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma[J]. Oncol Lett,2016,11(5):3123-3130.
[7] Burgess JT,Bolderson E,Saunus JM,et al. SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer[J]. Oncotarget,2016,7(45):72807-72818.
[8] Gong X,Wu J,Wu J,et al. Correlation of SASH1 expression and ultrasonographic features in breast cancer[J]. Onco Targets Ther,2017,10:271-276.
[9] Sealfon SC,Chu TT. RNA and DNA microarrays[J]. Methods Mol Biol,2011,671:3-34.
[10] Sun C,Zhang Z,He P,et al. Involvement of PI3K/Akt pathway in the inhibition of hepatocarcinoma cell invasion and metastasis induced by SASH1 through downregulating Shh-Gli1 signaling[J]. Chem Biol Drug Des,2017,89:95-100.
[11] Fang Q,Yao S,Luo G,et al. Identification of differentially expressed genes in human breast cancer cells induced by 4-hydroxyltamoxifen and elucidation of their pathophysiological relevance and mechanisms[J]. Oncotarget,2018,9(2):2475-2501.
[12] Yang L,Zhang H,Yao Q,et al. Clinical Significance of SASH1Expression in Glioma[J]. Dis Markers,2015,2015:383046.
[13] Rimkus C,Martini M,Friederichs J,et al. Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer[J]. Br J Cancer,2006,95(10):1419-1423.
[14] Zeller C,Hinzmann B,Seitz S,et al. SASH1:a candidate tumor suppressor gene on chromosome 6q24. 3 is downregulated in breast cancer[J]. Oncogene,2003,22(19):2972-2983.
[15] Sheyu L,Hui L,Junyu Z,et al. Promoter methylation assay of SASH1 gene in breast cancer[J]. J buon,2013,18(4):891-898.
[16] Zhou N,Liu C,Wang X,et al. Downregulated SASH1 expression indicates poor clinical prognosis in gastric cancer[J]. Hum Pathol,2018,74:83-91.
[17] Wang Q,Dai H. SASH1,a potential therapeutic target for cancer[J]. Hum Pathol,2018,80:246.