SKP2在食管癌中的扩增和表达变化及其作用机制研究
摘要
蛋白泛素化及随后的蛋白酶体降解途径在许多细胞生命活动中发挥重要的作用,如细胞周期的进展、细胞的生长与分化、凋亡、基因转录和信号传导等。SCF(SKP1,Cullin/CDC53,F-box蛋白)复合物是一种保守的E3泛素连接酶,参与蛋白的泛素化降解,其中的F-box蛋白与底物相互作用,负责底物的识别。S期激酶相关蛋白2(SKP2)是F-box蛋白家族的成员之一,在SCF~(SKP2)复合物中发挥作用。本实验室前期的比较基因组杂交(CGH)结果发现5号染色体短臂在食管癌中的扩增比较常见,而SKP2基因恰好位于该染色体短臂的一区三带(5p13),本研究旨在探讨SKP2在食管癌中的扩增状态和表达水平及其在食管癌发生发展中的作用。
我们首先采用荧光原位杂交方法检测了SKP2在50例食管癌中的扩增情况,发现扩增频率为46%(23/50),且其扩增与肿瘤分期和淋巴结转移相关(P＜0.05)。Real-time PCR检测的10对食管癌及其癌旁配对标本中,5例肿瘤组织存在SKP2的扩增。RT-PCR和Western-blotting检测发现SKP2扩增病例的蛋白表达水平也升高,说明基因扩增是SKP2过表达的原因之一。140例标本的免疫组化结果表明SKP2在食管癌组织中表达升高,其过表达与肿瘤分期和淋巴结转移显著相关(P＜0.05),但与预后相关无显著性。
通过RNA干扰敲降SKP2表达对EC9706细胞周期和生长无明显影响,但可抑制细胞的运动和侵袭能力,增加EC9706细胞的失巢凋亡,降低其软琼脂集落形成能力,并且可抑制裸鼠皮下肿瘤的生长和肺转移。针对SKP2影响EC9706细胞抗失巢凋亡能力这一现象,我们进一步探讨了其分子机制。敲降SKP2表达后检测了PI3K-Akt、MAPK和EGFR信号通路关键蛋白的变化,发现只影响Akt的活化,对Erk和EGFR激活无影响。同时,加入PI3K抑制剂后,对照组细胞的失巢凋亡也增加。
以上结果表明SKP2在食管癌中存在扩增和过表达,可影响食管癌细胞的运动和侵袭能力,并且可通过PI3K-Akt信号通路增强食管癌细胞的抗失巢凋亡能力,进而影响食管癌的转移。
Ubiquitin-dependent degradation plays an essential role in many important cellular processes including cell-cycle,differenciation,apoptosis,gene transcription and signal transduction.The gene of SKP2,located on chromosome 5p13,is an F-box protein constituting the substrate recognitionsubunit of the SCF~(SKP2) ubiquitin ligase complex and is implicated in ubiquitin-mediated degradation of several cyclin-dependent kinase inhibitors including p27~(KIP1),p21~(cip1),p57~(kip2).Previous studies in our laboratory revealed that gain of chromosome 5p was often observed in esophageal squamous cell carcinoma(ESCC).The present study is to investigate the amplification status and expression level of SKP2 in ESCC and the underlying mechanisms through which SKP2 takes part in the carcinogenesis and development of the disease.
Amplification of SKP2 by analysis of fluorescence in situ hybridization(FISH) was observed in 23 out of 50(46%) ESCC.Amplification of SKP2 was confirmed by real-time PCR expremient.Positive correlation was found between SKP2 amplification and tumor stage,lymph node metastase(P＜0.05).RT-PCR and Western-blotting results revealed that expression of SKP2 in the cases with amplification was increased as compared with that in non-amplification cases. Immunohistochemistry in 140 ESCC and adjacent normal tissues showed that the level of SKP2 protein was higher in tumors than that in normal epithelia.SKP2 overexpression was significantly associated with tumor stage and lymph nude metastase(P＜0.05),but no correlation was found between SKP2 expression and prognosis.
In vivo assay showed that inhibition of SKP2 expression decreased tumor growth and lung metastasis of esophageal cancer cells.At the molecular level,knockdown of SKP2 by RNA interference had no effect on cell cycle and proliferation of EC9706 cells,but inhibited cell migration and invasion.Decreased SKP2 expression sensitized cancer cells to anoikis,as demonstrated by activation of caspase-3 and increase of cleaved-PARP level.Treatment with phosphoinositidyl-3 kinase(PI3K) inhibitor (LY294002) also rendered cells sensitive to anoikis.These results provide the first evidence for SKP2 amplification and overexpression in ESCC.Elevated expression of SKP2 protected cancer cells from anoikis,which was mediated at least in part by the PI3K-Akt pathway.The data suggest that SKP2 is an oncogene candidate in the 5p13 amplicon and exerts functions on tumor metastasis in ESCC.
我们首先采用荧光原位杂交方法检测了SKP2在50例食管癌中的扩增情况,发现扩增频率为46%(23/50),且其扩增与肿瘤分期和淋巴结转移相关(P＜0.05)。Real-time PCR检测的10对食管癌及其癌旁配对标本中,5例肿瘤组织存在SKP2的扩增。RT-PCR和Western-blotting检测发现SKP2扩增病例的蛋白表达水平也升高,说明基因扩增是SKP2过表达的原因之一。140例标本的免疫组化结果表明SKP2在食管癌组织中表达升高,其过表达与肿瘤分期和淋巴结转移显著相关(P＜0.05),但与预后相关无显著性。
通过RNA干扰敲降SKP2表达对EC9706细胞周期和生长无明显影响,但可抑制细胞的运动和侵袭能力,增加EC9706细胞的失巢凋亡,降低其软琼脂集落形成能力,并且可抑制裸鼠皮下肿瘤的生长和肺转移。针对SKP2影响EC9706细胞抗失巢凋亡能力这一现象,我们进一步探讨了其分子机制。敲降SKP2表达后检测了PI3K-Akt、MAPK和EGFR信号通路关键蛋白的变化,发现只影响Akt的活化,对Erk和EGFR激活无影响。同时,加入PI3K抑制剂后,对照组细胞的失巢凋亡也增加。
以上结果表明SKP2在食管癌中存在扩增和过表达,可影响食管癌细胞的运动和侵袭能力,并且可通过PI3K-Akt信号通路增强食管癌细胞的抗失巢凋亡能力,进而影响食管癌的转移。
Ubiquitin-dependent degradation plays an essential role in many important cellular processes including cell-cycle,differenciation,apoptosis,gene transcription and signal transduction.The gene of SKP2,located on chromosome 5p13,is an F-box protein constituting the substrate recognitionsubunit of the SCF~(SKP2) ubiquitin ligase complex and is implicated in ubiquitin-mediated degradation of several cyclin-dependent kinase inhibitors including p27~(KIP1),p21~(cip1),p57~(kip2).Previous studies in our laboratory revealed that gain of chromosome 5p was often observed in esophageal squamous cell carcinoma(ESCC).The present study is to investigate the amplification status and expression level of SKP2 in ESCC and the underlying mechanisms through which SKP2 takes part in the carcinogenesis and development of the disease.
Amplification of SKP2 by analysis of fluorescence in situ hybridization(FISH) was observed in 23 out of 50(46%) ESCC.Amplification of SKP2 was confirmed by real-time PCR expremient.Positive correlation was found between SKP2 amplification and tumor stage,lymph node metastase(P＜0.05).RT-PCR and Western-blotting results revealed that expression of SKP2 in the cases with amplification was increased as compared with that in non-amplification cases. Immunohistochemistry in 140 ESCC and adjacent normal tissues showed that the level of SKP2 protein was higher in tumors than that in normal epithelia.SKP2 overexpression was significantly associated with tumor stage and lymph nude metastase(P＜0.05),but no correlation was found between SKP2 expression and prognosis.
In vivo assay showed that inhibition of SKP2 expression decreased tumor growth and lung metastasis of esophageal cancer cells.At the molecular level,knockdown of SKP2 by RNA interference had no effect on cell cycle and proliferation of EC9706 cells,but inhibited cell migration and invasion.Decreased SKP2 expression sensitized cancer cells to anoikis,as demonstrated by activation of caspase-3 and increase of cleaved-PARP level.Treatment with phosphoinositidyl-3 kinase(PI3K) inhibitor (LY294002) also rendered cells sensitive to anoikis.These results provide the first evidence for SKP2 amplification and overexpression in ESCC.Elevated expression of SKP2 protected cancer cells from anoikis,which was mediated at least in part by the PI3K-Akt pathway.The data suggest that SKP2 is an oncogene candidate in the 5p13 amplicon and exerts functions on tumor metastasis in ESCC.
引文
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