非小细胞肺癌组织FOXM1基因表达和突变情况及其临床意义
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摘要
目的探讨非小细胞肺癌组织中FOXM1基因表达和突变情况及其临床意义。方法收集我院2014年-2016年的非小细胞肺癌手术切除病例的石蜡标本,采用免疫组织化学方法检测59例肺癌组织中FOXM1蛋白的表达水平,对其中的21例患者采用高通量测序方法检测肺癌组织中基因突变情况,收集病人的临床病例资料,分析FOXM1蛋白的表达水平和突变与病人临床病理例特征之间的相关关系。结果本组共收集非小细胞肺癌病例59个,男性45例,女性14例。在所有患者中FOXM1高表达病例29例,占49.2%;低表达30例,占50.8%;在FOXM1高表达患者中,20例分化程度低,占69.0%;低表达患者中12例分化程度低,占40%,有显著性差异(P<0.05);镜下见脉管内浸润患者,高表达组为9例,低表达组为3例,差异有统计学意义(P<0.05);21例病人中,有13例检测到FOXM1基因突变,其中9例肺癌标本检测到exon8:c.T1882C:p.S628P突变,其存在率达42.86%(9/21),远高于正常人群(<1%)。结论 FOXM1蛋白在非小细胞肺癌组织中表达水平升高,并与肿瘤的低分化程度和脉管内侵袭相关,非小细胞肺癌组织中FOXM1突变率显著升高,可能与肺癌发病存在高度相关性。
Objective To investigate the expression and gene mutation profile of FOXM1 in non small cell lung cancer tissues, and to analyze the relationship between FOXM1 expression and clinical characteristics. Methods 59 cases of lung cancer were collected to investigate their expression level of FOXM1 with immuohistochemical methods. High through sequencing method was employed to detect the FOXM1 gene mutation of 21 NSCLC tissues, and the clinical histories of all cases were collected to analyze the relationship between FOXM1 expression and clinical characteristics. Results The 59 NSCLC tissues including 45 male and14 female were collected. FOXM1 immuohistochemical staining results showed that 29 cases(49.2%) showed high expression, 30 cases(50.8%) showed low or no expression. 20 cases with high FOXM1 expression showed low differentiation, while 12 cases with low FOXM1 expression showed low differentiation(P<0.05). 9 cases with high FOXM1 expression showed vessel invasion, and 3 cases with low FOXM1 expression had vessel invasion(P<0.05). Of the 21 tissues tested by DNA sequencing, FOXM1 gene variations were found in 13 tissues. The variation exon8: c.T1882 C:p.S628 P was found in 42.86% tissues(9/21), which was much higher than that in healthy population(<1%). Conclusion The FOXM1 expression level of lung cancer tissues is significantly elevated,and a FOXM1 gene variation with aberrantly high frequency is identified,which suggested that FOXM1 and its mutation may play a role in the pathogenesis of non small cell lung cancers.
Objective To investigate the expression and gene mutation profile of FOXM1 in non small cell lung cancer tissues, and to analyze the relationship between FOXM1 expression and clinical characteristics. Methods 59 cases of lung cancer were collected to investigate their expression level of FOXM1 with immuohistochemical methods. High through sequencing method was employed to detect the FOXM1 gene mutation of 21 NSCLC tissues, and the clinical histories of all cases were collected to analyze the relationship between FOXM1 expression and clinical characteristics. Results The 59 NSCLC tissues including 45 male and14 female were collected. FOXM1 immuohistochemical staining results showed that 29 cases(49.2%) showed high expression, 30 cases(50.8%) showed low or no expression. 20 cases with high FOXM1 expression showed low differentiation, while 12 cases with low FOXM1 expression showed low differentiation(P<0.05). 9 cases with high FOXM1 expression showed vessel invasion, and 3 cases with low FOXM1 expression had vessel invasion(P<0.05). Of the 21 tissues tested by DNA sequencing, FOXM1 gene variations were found in 13 tissues. The variation exon8: c.T1882 C:p.S628 P was found in 42.86% tissues(9/21), which was much higher than that in healthy population(<1%). Conclusion The FOXM1 expression level of lung cancer tissues is significantly elevated,and a FOXM1 gene variation with aberrantly high frequency is identified,which suggested that FOXM1 and its mutation may play a role in the pathogenesis of non small cell lung cancers.
引文
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[3] GOLSON M L,KAESTNER K H.Fox transcription factors:from development to disease[J].Development,2016,143(24):4558–4570.
[4] WANG I C,CHEN Y J,HUGHES D,et al.Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase[J].Mol Cell Biol,2005,25(24):10875–10894.
[5] WANG I C,CHEN Y J,HUGHES D E,et al.FoxM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness[J].J Biol Chem,2008,283(30):20770-20778.
[6] LAOUKILI J,KOOISTRA M R,BRáS A,et al.FoxM1 is required for execution of the mitotic programme and chromosome stability[J].Nat Cell Biol,2005,7(2):126-136.
[7] HUI M K,CHAN K W,LUK J M,et al.Cytoplasmic forkhead box M1 (FoxM1) in esophageal squamous cell carcinoma significantly correlates with pathological disease stage[J].World J Surg,2012,36(1):90-97.
[8] MADUREIRA P A,VARSHOCHI R,CONSTANTINIDOU D,et al.The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells[J].J Biol Chem,2006,281(35):25167-25176.
[9] HUANG C,QIU Z,WANG L,et al.A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis[J].Cancer Res,2012,72(3):655-665.
[10] LI Q,ZHANG N,JIA Z,et al.Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression[J].Cancer Res,2009,69(8):3501-3509.
[11] XU N,JIA D,CHEN W,et al.FoxM1 is associated with poor prognosis of non-small cell lung cancer patients through promoting tumor metastasis[J].PLoS One,2013,8(3):e59412.
[12] KALINICHENKO V V,MAJOR M L,WANG X,et al.Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor[J].Genes Dev,2004,18(7):830-850.
[13] ZHANG Y,QIAO W B,SHAN L.Expression and functional characterization of FOXM1 in non-small cell lung cancer[J].Onco Targets Ther,2018,11:3385-3393.
[14] PAZ-ARES L,SOULIèRES D,MELEZíNEK I,et al.Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations:pooled analysis[J].J Cell Mol Med,2010,14(1/2):51-69.
[15] BALLI D,ZHANG Y,SNYDER J,et al.Endothelial cell-specific deletion of transcription factor FoxM1 increases urethane-induced lung carcinogenesis[J].Cancer Res,2011,71(1):40-50.
[16] CHAN D W,YU S Y,CHIU P M,et al.Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis[J].J Pathol,2008,215(3):245-252.
[17] LIU Y,CHEN X,GU Y,et al.FOXM1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and mediates sensitivity to cisplatin in A549 cells via the JNK/mitochondrial pathway[J].Neoplasma,2015,62(1):61-71.
[18] ZHOU J,WANG Y,WANG Y,et al.Foxm1 modulates cisplatin sensitivity by regulating EXO1 in ovarian cancer[J].PLoS One,2014,9(5):e96989.
[19] RADHAKRISHNAN S K,BHAT U G,HUGHES D E,et al.Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1[J].Cancer Res,2006,66(19):9731-9735.
[20] ZHANG X,ZENG J,ZHOU M,et al.The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia[J].Mol Cancer,2012,11:56.