GA6与SHP2蛋白在肝细胞癌中的临床意义及其作用机制的研究
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摘要
1、实验目的：研究GA6（Hematopoietic PBX-interacting protein）蛋白在肝细胞癌中表达的临床意义及其在肝细胞癌中的致癌作用的分子生物学机制。
2、研究方法：纳入2000年至2007年在中国人民解放军总医院行手术治疗的肝细胞癌（HCC）标本328例（均包括肿瘤组织T及相应的癌旁非肿瘤组织NT）。构建组织芯片，通过免疫组化染色分析GA6的表达与临床特征的相关性及其与预后的关系；纳入新鲜HCC标本49例（均含肿瘤组织及对应癌旁非肿瘤组织）并通过Western blot检测GA6蛋白的表达；在肝癌细胞系中，通过GA6的过表达及干扰技术，进行生长曲线、平板克隆形成、软琼脂克隆形成、细胞周期测定及裸鼠移植瘤等实验，研究GA6蛋白对肝癌细胞生长、增殖能力的影响。
3、研究结果：（1）免疫组化显示HCC肿瘤组织GA6蛋白的表达明显高于癌旁组织（T：1.39±0.63，NT：0.92±0.57，P<0.001）：肿瘤组织阳性率94.5%（310/328），癌旁组织阳性率85.4%（280/328，P<0.001）。肿瘤组织中GA6的表达与HCC各临床指标之间均无相关性，生存分析示GA6的表达与HCC患者预后无关（P=0.687）。（2）在肝癌细胞系中通过GA6的过表达及干扰技术，生长曲线实验、克隆形成实验、裸鼠移植瘤实验均显示，GA6可促进肝癌细胞生长和增殖；细胞周期及相关蛋白的表达测定显示，GA6可影响细胞周期调节蛋白的表达，使大量细胞通过G2/M期检测点，进入M期分裂，从而促进肿瘤细胞增殖。
4、结论：体内与体外研究显示，GA6可促进肝癌细胞的生长与增殖；免疫组化显示，HCC肿瘤组织中GA6蛋白的表达明显高于癌旁组织，但与患者预后无关。GA6在肝细胞癌中的作用仍有待进一步研究。
1、研究背景：研究发现蛋白酪氨酸磷酸酶SHP2（Src homology2domaincontaining phosphotyrosine phosphatase2）在多种恶性肿瘤中发挥了癌基因的作用，但近年来对其抑癌作用也有报道，本研究室在前期研究中通过质谱分析发现SHP2与在肝细胞癌（HCC）的发病中起重要促癌作用的YAP2蛋白存在相互作用。本研究的目的是在大样本临床标本中检测SHP2表达的临床意义，并通过细胞培养及分子生物学技术研究SHP2与YAP2的相互作用。
2、研究方法：纳入2000年至2007年在我院行手术治疗的肝细胞癌临床标本（每例均有肿瘤组织T及相应的癌旁非肿瘤组织NT）共333例，构建组织芯片，行免疫组化并进行生存分析与Cox多因素分析研究。收集31例新鲜临床HCC标本，行Western blot与qPCR以检测SHP2的表达。依据蛋白酪氨酸磷酸酶蛋白家族的作用机制，构建2种SHP2的底物捕获突变体，运用过表达、底物捕获Co-IP、双荧光素酶报告基因系统及酪氨酸磷酸化等多种技术研究在工具细胞系中SHP2对YAP2的调控作用。
3、研究结果：在肝细胞癌中，相对于癌旁非肿瘤组织，肿瘤组织中SHP2蛋白及其mRNA的表达均明显降低，肿瘤组织SHP2的蛋白表达阳性率为66.1%，而癌旁非肿瘤组织为96.7%。生存分析示SHP2的低表达与HCC患者较短的生存期显著相关（P<0.001），SHP2的表达降低（ΔSHP2）是HCC患者预后差的一个独立危险因素（P=0.023，HR：0.628，95%CI：0.420～0.939）。通过细胞培养及分子生物学技术，我们发现SHP2蛋白与YAP2蛋白确实存在相互作用，如SHP2轻度上调内源性YAP2的表达、突变型SHP2-DM与YAP2的Co-IP及SHP2-DM对YAP2的酪氨酸磷酸化作用等，但研究发现，SHP2对YAP2的表达、活性及酸磷化水平的影响不显著。
4、结论：尽管PTPN11一直被认为是一个原癌基因，但SHP2蛋白在肝细胞癌中发挥抑癌作用并可作为一个新的预后指标。SHP2蛋白与YAP蛋白存在较弱的相互作用，但这可能并不是其抑癌作用的主要机制。由于SHP2的对肿瘤的作用具有组织特异性，基于人类PTPN11基因的靶向治疗及SHP2在肝细胞癌中的作用仍有待进一步的研究。
Objective：This research was performed to study the clinical significance of theGA6protein expression in human hepatocellular carcinoma (HCC), and to explorethe mechanism of the tumorigenesis function of GA6in HCC.
Methods：A retrospective cohort of328consecutive HCC specimens whounderwent surgical resection in the PLA general hospital from2000to2007wereincluded, both the tumor tissues (T) and self-matched adjacent non-tumor tissues(NT). By the construction of tissue microarray, immunohistochemical staining ofGA6protein was performed and the clinical and prognostic significance was explored.The GA6expression was also confirmed by the Western blot analysis of anothercohort of49fresh HCC specimens (both the T and self-matched adjacent NT tissues).By the GA6overexpression and GA6knockdown technique in HCC cell lines, weexplored the function of GA6protein in the growth and proliferation of HCC cells inthe experiments of growth curves assay, flat plate clone forming assay, soft agar cloneforming assay, cell cycle analysis and nude mice xenografts assay.
Results：1. Immunohistochemical staining found that the GA6protein expressionwas significantly higher in HCC tumor tissues than the adjacent NT tissues (H-scoreT:1.39±0.63, NT:0.92±0.57,P<0.001；positive expression rate T:94.5%, NT:85.4%,P<0.001). The high expression of GA6in HCC tumor tissues was not related to theclinical features of HCC and was also not related to short overall survival byKaplan-Meier analysis (P=0.687).2. Growth curves assay, clone forming assay andnude mice xenografts assay demonstrated that GA6overexpression could promote thegrowth of HCC cells while GA6knockdown could inhibit the growth of HCC cells.Cell cycle and the correlated protein analysis revealed that GA6could promote thegrowth and proliferation of HCC cells by adjusting the expression of G2/M phasecorrelated protein.
Conclusions：GA6protein can promote the growth and proliferation of HCCcells both in vitro and in vivo. By immunohistochemistry we found that theexpression of GA6in tumor tissues was significantly higher than that in NT tissues,however, no significant clinical significance was found for the higher GA6expression.Further researches are still needed to evaluate the function of GA6protein in HCC.
Objective：Nonreceptor protein-tyrosine phosphatase of SHP2(Src homologyphosphotyrosine phosphatase2) has been previously well identified as aproto-oncogene in a variety of malignancies. However, recently the tumor suppressorfunction of SHP2has also been reported. In our previous research we found by themass chromatographic analysis that YAP2protein which had an importantproto-oncogene role in the pathogenesis of hepatocellular carcinoma (HCC) had aninteraction with the SHP2protein. For this reason, the present study was conducted toinvestigate the expression of SHP2and its associated clinical significance in a largecohort of HCC specimens and to explore the interaction of SHP2protein with YAP2protein by the technique of cell culture and molecular biology.
Methods：HCC patients were retrieved from2000to2007in our hospital. Underthe inclusion/exclusion criteria, we included333HCC specimens and a tissuemicroarray of HCC tumor tissue and the self-matched adjacent non-tumor tissues wasconstructed. We also included31pairs of HCC fresh specimens. SHP2expressionwas determined by immunohistochemistry, Western blotting and quantitativepolymerase chain reaction. The association of SHP2expression with clinical featureswas analyzed, overall survival analysis and multivariate analysis were performed.Two plasmids with SHP2substrate trapping mutation were constructed, and theinteraction of SHP2with YAP2was investigated by the techniques of overexpression,substrate trapping co-immunoprecipitation, dual luciferase reporter gene assay andtyrosine phosphorylation.
Results：Significantly decreased SHP2expression in tumor tissues compared withadjacent non-tumor tissues could be detected and the positive rate was66.1%and96.7%, respectively. Survival analysis showed low SHP2expression was significantlyassociated with short overall survival (P<0.001). Multivariate analysis showed thedecrease of SHP2expression (ΔSHP2) was an independent prognostic marker (P=0.023, HR:0.628,95%CI:0.420-0.939). By cell culture and the molecularbiology experiments, we found a weak interaction of SHP2with the YAP2protein,for example, SHP2slightly up-regulates the endogenous YAP2expression, SHP2-DM(double substrate trapping mutations) co-immunoprecipitates with YAP2andSHP2-DM up-regulates the tyrosine phosphorylation of YAP2. However, SHP2didnot have a predominant effect in the aspects of YAP2expression, YAP2downstreamactivity and YAP2tyrosine phosphorylation.
Conclusion：Although human gene PTPN11was previously well interpreted as aproto-oncogene, SHP2protein is a tumor suppressor and a new prognostic marker inhepatocellular carcinoma. The weak interaction of SHP2protein with the YAP2protein may be not the major mechanism of its tumor suppressor function inhepatocellular carcinoma. For the oncogenic role of SHP2was tissue-specific, thetherapeutic target of PTPN11and its associated mechanism should be furtherresearched.
2、研究方法：纳入2000年至2007年在中国人民解放军总医院行手术治疗的肝细胞癌（HCC）标本328例（均包括肿瘤组织T及相应的癌旁非肿瘤组织NT）。构建组织芯片，通过免疫组化染色分析GA6的表达与临床特征的相关性及其与预后的关系；纳入新鲜HCC标本49例（均含肿瘤组织及对应癌旁非肿瘤组织）并通过Western blot检测GA6蛋白的表达；在肝癌细胞系中，通过GA6的过表达及干扰技术，进行生长曲线、平板克隆形成、软琼脂克隆形成、细胞周期测定及裸鼠移植瘤等实验，研究GA6蛋白对肝癌细胞生长、增殖能力的影响。
3、研究结果：（1）免疫组化显示HCC肿瘤组织GA6蛋白的表达明显高于癌旁组织（T：1.39±0.63，NT：0.92±0.57，P<0.001）：肿瘤组织阳性率94.5%（310/328），癌旁组织阳性率85.4%（280/328，P<0.001）。肿瘤组织中GA6的表达与HCC各临床指标之间均无相关性，生存分析示GA6的表达与HCC患者预后无关（P=0.687）。（2）在肝癌细胞系中通过GA6的过表达及干扰技术，生长曲线实验、克隆形成实验、裸鼠移植瘤实验均显示，GA6可促进肝癌细胞生长和增殖；细胞周期及相关蛋白的表达测定显示，GA6可影响细胞周期调节蛋白的表达，使大量细胞通过G2/M期检测点，进入M期分裂，从而促进肿瘤细胞增殖。
4、结论：体内与体外研究显示，GA6可促进肝癌细胞的生长与增殖；免疫组化显示，HCC肿瘤组织中GA6蛋白的表达明显高于癌旁组织，但与患者预后无关。GA6在肝细胞癌中的作用仍有待进一步研究。
1、研究背景：研究发现蛋白酪氨酸磷酸酶SHP2（Src homology2domaincontaining phosphotyrosine phosphatase2）在多种恶性肿瘤中发挥了癌基因的作用，但近年来对其抑癌作用也有报道，本研究室在前期研究中通过质谱分析发现SHP2与在肝细胞癌（HCC）的发病中起重要促癌作用的YAP2蛋白存在相互作用。本研究的目的是在大样本临床标本中检测SHP2表达的临床意义，并通过细胞培养及分子生物学技术研究SHP2与YAP2的相互作用。
2、研究方法：纳入2000年至2007年在我院行手术治疗的肝细胞癌临床标本（每例均有肿瘤组织T及相应的癌旁非肿瘤组织NT）共333例，构建组织芯片，行免疫组化并进行生存分析与Cox多因素分析研究。收集31例新鲜临床HCC标本，行Western blot与qPCR以检测SHP2的表达。依据蛋白酪氨酸磷酸酶蛋白家族的作用机制，构建2种SHP2的底物捕获突变体，运用过表达、底物捕获Co-IP、双荧光素酶报告基因系统及酪氨酸磷酸化等多种技术研究在工具细胞系中SHP2对YAP2的调控作用。
3、研究结果：在肝细胞癌中，相对于癌旁非肿瘤组织，肿瘤组织中SHP2蛋白及其mRNA的表达均明显降低，肿瘤组织SHP2的蛋白表达阳性率为66.1%，而癌旁非肿瘤组织为96.7%。生存分析示SHP2的低表达与HCC患者较短的生存期显著相关（P<0.001），SHP2的表达降低（ΔSHP2）是HCC患者预后差的一个独立危险因素（P=0.023，HR：0.628，95%CI：0.420～0.939）。通过细胞培养及分子生物学技术，我们发现SHP2蛋白与YAP2蛋白确实存在相互作用，如SHP2轻度上调内源性YAP2的表达、突变型SHP2-DM与YAP2的Co-IP及SHP2-DM对YAP2的酪氨酸磷酸化作用等，但研究发现，SHP2对YAP2的表达、活性及酸磷化水平的影响不显著。
4、结论：尽管PTPN11一直被认为是一个原癌基因，但SHP2蛋白在肝细胞癌中发挥抑癌作用并可作为一个新的预后指标。SHP2蛋白与YAP蛋白存在较弱的相互作用，但这可能并不是其抑癌作用的主要机制。由于SHP2的对肿瘤的作用具有组织特异性，基于人类PTPN11基因的靶向治疗及SHP2在肝细胞癌中的作用仍有待进一步的研究。
Objective：This research was performed to study the clinical significance of theGA6protein expression in human hepatocellular carcinoma (HCC), and to explorethe mechanism of the tumorigenesis function of GA6in HCC.
Methods：A retrospective cohort of328consecutive HCC specimens whounderwent surgical resection in the PLA general hospital from2000to2007wereincluded, both the tumor tissues (T) and self-matched adjacent non-tumor tissues(NT). By the construction of tissue microarray, immunohistochemical staining ofGA6protein was performed and the clinical and prognostic significance was explored.The GA6expression was also confirmed by the Western blot analysis of anothercohort of49fresh HCC specimens (both the T and self-matched adjacent NT tissues).By the GA6overexpression and GA6knockdown technique in HCC cell lines, weexplored the function of GA6protein in the growth and proliferation of HCC cells inthe experiments of growth curves assay, flat plate clone forming assay, soft agar cloneforming assay, cell cycle analysis and nude mice xenografts assay.
Results：1. Immunohistochemical staining found that the GA6protein expressionwas significantly higher in HCC tumor tissues than the adjacent NT tissues (H-scoreT:1.39±0.63, NT:0.92±0.57,P<0.001；positive expression rate T:94.5%, NT:85.4%,P<0.001). The high expression of GA6in HCC tumor tissues was not related to theclinical features of HCC and was also not related to short overall survival byKaplan-Meier analysis (P=0.687).2. Growth curves assay, clone forming assay andnude mice xenografts assay demonstrated that GA6overexpression could promote thegrowth of HCC cells while GA6knockdown could inhibit the growth of HCC cells.Cell cycle and the correlated protein analysis revealed that GA6could promote thegrowth and proliferation of HCC cells by adjusting the expression of G2/M phasecorrelated protein.
Conclusions：GA6protein can promote the growth and proliferation of HCCcells both in vitro and in vivo. By immunohistochemistry we found that theexpression of GA6in tumor tissues was significantly higher than that in NT tissues,however, no significant clinical significance was found for the higher GA6expression.Further researches are still needed to evaluate the function of GA6protein in HCC.
Objective：Nonreceptor protein-tyrosine phosphatase of SHP2(Src homologyphosphotyrosine phosphatase2) has been previously well identified as aproto-oncogene in a variety of malignancies. However, recently the tumor suppressorfunction of SHP2has also been reported. In our previous research we found by themass chromatographic analysis that YAP2protein which had an importantproto-oncogene role in the pathogenesis of hepatocellular carcinoma (HCC) had aninteraction with the SHP2protein. For this reason, the present study was conducted toinvestigate the expression of SHP2and its associated clinical significance in a largecohort of HCC specimens and to explore the interaction of SHP2protein with YAP2protein by the technique of cell culture and molecular biology.
Methods：HCC patients were retrieved from2000to2007in our hospital. Underthe inclusion/exclusion criteria, we included333HCC specimens and a tissuemicroarray of HCC tumor tissue and the self-matched adjacent non-tumor tissues wasconstructed. We also included31pairs of HCC fresh specimens. SHP2expressionwas determined by immunohistochemistry, Western blotting and quantitativepolymerase chain reaction. The association of SHP2expression with clinical featureswas analyzed, overall survival analysis and multivariate analysis were performed.Two plasmids with SHP2substrate trapping mutation were constructed, and theinteraction of SHP2with YAP2was investigated by the techniques of overexpression,substrate trapping co-immunoprecipitation, dual luciferase reporter gene assay andtyrosine phosphorylation.
Results：Significantly decreased SHP2expression in tumor tissues compared withadjacent non-tumor tissues could be detected and the positive rate was66.1%and96.7%, respectively. Survival analysis showed low SHP2expression was significantlyassociated with short overall survival (P<0.001). Multivariate analysis showed thedecrease of SHP2expression (ΔSHP2) was an independent prognostic marker (P=0.023, HR:0.628,95%CI:0.420-0.939). By cell culture and the molecularbiology experiments, we found a weak interaction of SHP2with the YAP2protein,for example, SHP2slightly up-regulates the endogenous YAP2expression, SHP2-DM(double substrate trapping mutations) co-immunoprecipitates with YAP2andSHP2-DM up-regulates the tyrosine phosphorylation of YAP2. However, SHP2didnot have a predominant effect in the aspects of YAP2expression, YAP2downstreamactivity and YAP2tyrosine phosphorylation.
Conclusion：Although human gene PTPN11was previously well interpreted as aproto-oncogene, SHP2protein is a tumor suppressor and a new prognostic marker inhepatocellular carcinoma. The weak interaction of SHP2protein with the YAP2protein may be not the major mechanism of its tumor suppressor function inhepatocellular carcinoma. For the oncogenic role of SHP2was tissue-specific, thetherapeutic target of PTPN11and its associated mechanism should be furtherresearched.
引文
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