BTB/POZ-ZF结构蛋白DPZF在肝细胞癌中的表达及其临床意义
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摘要
一、研究背景和目的
肝细胞性肝癌(简称肝癌,Hepatocellular Carcinoma,HCC)是我国最常见的恶性肿瘤之一,目前的研究认为:肝炎病毒感染及其他致癌因素是肝癌发生的主要外因。同时,肝癌和其它恶性肿瘤一样,其发生发展是由体内多基因多蛋白参与、多步骤协同的复杂过程。因此,寻找肝癌相关蛋白有助于研究肝癌发生及发展的机制,从而为肝癌的预防、诊断及治疗提供理论基础。
BTB/POZ-ZF(broad complex,tramtrack,and bric a brac;poxvirus and zinc finger-zincfinger)结构域家族是一类转录因子,其N末端含共同的保守结构域(BTB/POZ),能介导蛋白质间自联作用,C端则含各种不同的锌指结构域(以C2H2锌指为多),能介导与DNA的相互作用。包括BCL-6(B cell lymphoma 6)、PLZF(promyelocytic leukemia zincfinger)等在内的该家族成员参与多种细胞功能,如转录调节、细胞增殖、凋亡等,在DNA损伤反应、肿瘤形成及发育过程中起重要作用。DPZF(dendritic cell-derived BTB/POZ zincfinger)是该家族的一个成员,是从人类DC细胞中克隆鉴定并得名,又名Zbtb20、HOF、Znf288及Zfp288等。它编码形成两个剪接体(分别称HOF~L和HOF~S),其N端含有一个BTB/POZ结构域,C端含有4个C2H2锌指结构。该基因定位在3号染色体(3q27),广泛表达于造血系统及部分血液系统恶性肿瘤细胞中,同时也表达于神经系统,参与神经发育,促进椎体神经元形成并能调控新生神经元的细胞命运转化。目前,尚无DPZF在实体肿瘤如肝癌组织中表达与作用的相关研究报道。本研究旨在通过研究DPZF在肝癌组织中的表达及分布,结合相关临床资料探讨其表达与肝癌发生发展的关系,为寻找肝癌基因治疗的新靶点提供实验和理论依据。
二、材料和方法
收集2003-2006年间第二军医大学附属东方肝胆外科医院的手术切除肝细胞癌标本148例(男122,女26),平均年龄52.5(23～76)岁,患者术前未经任何抗癌治疗,每例标本均包括肝癌组织及距肿瘤边缘≤2 cm的癌旁组织;正常肝组织12例取自直径小于5cm的肝血管瘤周围2cm以上部位的肝组织,标本经分装后将用于免疫组化检测的样本行甲醛固定,Western Blot和RT-PCR检测的标本行液氮保存,所有病例均经临床和病理检查明确诊断。
应用免疫组织化学方法检测DPZF在组织中的表达及分布,进一步用Western blot及RT-PCR验证其在肝癌及癌旁组织中的差异表达,并应用SPSS统计软件对结果进行统计分析。
三、结果
免疫组化法检测发现:(1)DPZF在人正常肝脏组织中的表达呈弱阳性表达,阳性着色主要位于肝细胞的细胞核,也见于胞浆;(2)在人肝癌组织中的表达明显增强,呈阳性或强阳性表达,与正常肝脏组织相比有显著差异(P＜0.05),阳性着色主要位于肝细胞的细胞核,胞浆中染色也增强;(3)DPZF在癌旁组织中的表达略有增强,与肝癌组织相比有显著差异(P＜0.05),阳性着色位于肝细胞胞核,也见于胞浆及炎细胞;(4)DPZF在HBsAg阴性肝癌组织中的表达呈阴性或弱阳性表达,与HBsAg阳性肝癌组织相比有显著差异(P＜0.05);(4) DPZF在移性肝癌(结肠癌和胃癌肝转移)中的表达基本为阴性,而在胆囊腺癌及肝门部胆管癌中为弱阳性表达。
Western blot检测发现DPZF在Huh7、7721、PLC及HepG2等肝癌细胞系中有较明显表达,在L02等正常肝细胞系中有低水平表达。同时证实DPZF蛋白在正常肝组织中存在较低水平的表达,在肝癌中的表达高于正常肝及癌旁。RT-PCR同样证实DPZF在肝癌组织中存在转录水平的上调。
与肿瘤的临床病理特征的关系相关统计学分析发现:DPZF在HBsAg阳性肝癌中的表达高于HBsAg阴性组,二者差异有统计学意义(P＜0.0001);在伴肝硬化的肝癌中的表达高于不伴肝硬化组(P＜0.0001);在伴门静脉癌栓和子灶的肝癌中的表达高于不伴癌栓和子灶组(P＜0.05);在有复发或转移的肝癌中的表达高于无复发或转移组(P＜0.0001)。而DPZF的表达与患者性别、年龄、甲胎蛋白(AFP)、肿瘤大小、病理分级、有无淋巴结转移及包膜无明显相关性。多因素Logistic回归分析发现男性、直径较大肿瘤(＞50mm)、血清AFP阳性以及DPZF高表达均是肝癌复发的独立危险性因素。
四、结论
1.DPZF在人正常肝组织中呈弱阳性表达,主要位于肝细胞的细胞核,在胞浆中也有表达。
2.DPZF在肝癌中表达明显增强,与正常肝及癌旁组织相比有显著差异(P＜0.05),提示其可能参与肝癌的发生发展。
3.DPZF在HBV感染的肝癌组织中表达水平较未感染者高(P＜0.05),提示其可能与HBV感染及炎症相关的肝癌形成有关。
4.DPZF在伴随有癌栓和子灶的肝癌以及出现术后复发或肝外转移的肝癌中表达明显高于对照组(P＜0.05),提示其可能与肝癌的复发转移相关。
5.建立肝癌复发危险因素的多因素Logistic回归模型发现DPZF高表达是肝癌复发的独立危险性因素(P＜0.05)。
Background & Objective:
Hepatocelluar carcinoma(HCC) is one of the most prevalent malignant tumor in China. The development and progression of HCC is a complicated process involving multiple genes and transforming steps.Up to now,though over 20 genes have been found to be relative to hepatocarcinogenesis,the mechanisms underlying the development of HCC remain unclear. Therefore,searching for new HCC associated molecules may give some clues to study the mechanism of HCC.
The BTB/POZ-ZF[Broad complex,Tramtrack,Bric a' brac(BTB) or poxvirus and zinc finger(POZ)-zinc finger]protein family comprises a diverse group of transcription factors. These factors are so named because of a distinct and unique N-terminal BTB/POZ domain and C-terminal DNA-binding zinc fingers domains.POZ-ZF proteins have been implicated in many biological processes,including B cell fate determination,DNA damage responses,cell cycle progression and a multitude of developmental events.Consequently,dysfunction of vertebrate POZ-ZF proteins,such as promyelocytic leukemia zinc finger(PLZF),B cell lymphoma 6(Bcl-6),has been linked to tumorigenesis.
DPZF(dendritic cell-derived BTB/POZ zinc finger) is a novel BTB/POZ zinc finger gene identified from human dendritic cells(DC),which encodes a 733-residue protein with a BTB/POZ domain at the N-terminal and 4 C2H2 zinc fingers at C-terminal.It is localized on chromosome 3q27 and is widely expressed in hematopoietic tissues and nervous tissues. DPZF protein expression is detectable in lymphoid neoplasm with a molecular mass of about 100 kDa,especially in B lymphoma.It is a transcription factor may be involved in hematopoiesis,immune responses,development and oncogenesis.
This research was focused on the elucidation of DPZF gene's role in the development and progression of HCC,through detecting its expression level in HCC tissues by immunohistochemistry,Western blot,RT-PCR and statistic analysis based on the clinicapathologic data.
Materials & Methods:
The sections of 12 normal hepatic tissues and 148 HCC tissues were collected from the East Hepatobiliary Hospital affiliated to Second Military Medical University during the year of 2003-2006.HCC patients were 122 males and 26 females,with a mean age of 52.5 years (range,23-76 years).Serum hepatitis B surface antigen(HBsAg) was positive in 113 cases. The Edmonson staging of these patients was based on the clinical and pathological diagnosis. Informed consent was obtained from each patient before operation.The expression of DPZF in the samples was detected by immunohistochemical staining,Western blot and RT-PCR.
Results:
Immunohistochemical staining showed that:(1)The expression of DPZF in human normal hepatic tissue was weakly positive.And it was mainly located in nucleus,occasionally in cytoplasm.(2)The expression of DPZF in HCC tissue was strongly positive.The level of DPZF expression in the HCC was higher than the corresponding para-cancerous tissues and the normal hepatic tissue(p＜0.05).And it was mainly located in nucleus,occasionally in cytoplasm.(3)The expression of DPZF in HBsAg positive HCC tissue was substantially higher than the HBsAg negative HCC tissue(p＜0.05).(4) The expression of DPZF in secondary liver cancer were negative and the expression in hilar cholangiocarcinoma and cholecyst adencarcinoma were weakly positive.
Expression of DPZF was detectable in Huh7、7721、PLC、HepG2 and L02 cell lines by Western blot.Western blot and RT-PCR analysis confirmed over expression of DPZF in HCC tissues compared with corresponding para-cancerous tissues and normal liver tissues.
To elucidate the significance of DPZF in HCC,its expression was correlated with various clinicopathological features.Increased DPZF expression levels in HCC were positively correlated with hepatic cirrhosis(P＜0.0001),HBV infection(P＜0.0001),portal vein invasion(P=0.019),and satellite nodules involvement(P=0.0001).Importantly,the recurrence or metastasis rates of HCCs with higher DPZF expression were markedly greater than those of HCCs with lower expression(P=0.0001,P=0.0001,respectively).However, there was no significant correlation between DPZF expression and other variable parameters, including age,gender,serum AFP level,tumor size,formation of tumor capsule and Edmonson's grade of HCC.Furthermore,Multivariate analysis confirmed that DPZF overexpression(P=0.005),male(P=0.006),larger tumor size(≥50mm)(P=0.009),and serum AFP positive(P=0.016) were the independent risk factors for the recurrence of HCC by using multivariate logistic analysis.
Conclusions:
1.The expression of DPZF in human normal hepatic tissue was weakly positive and it was located in nucleus,occasionally in cytoplasm.
2.The expression of DPZF in HCC tissue was strongly positive.The level of DPZF expression in the HCC was higher than the corresponding para-cancerous tissues and the normal hepatic tissue.It indicated that DPZF may be associated with the genesis and development of HCC.
3.The expression of DPZF in HBsAg positive HCC tissue was higher compared with HBsAg negative HCC tissue.It indicated that DPZF may be associated with the mechanism of hepatocarcinogenesis induced by infection of HBV.
4.DPZF level was significantly higher(p＜0.05) in portal vein thrombus,satellite nodules,recurrence and metastasis involvement groups than in the control groups. This indicated that DPZF may be associated with the recurrence and metastasis of HCC.
5.Multivariate logistic analysis confirmed higher expression of DPZF(P=0.005) was the independent risk factor for the reccurence of HCC.
肝细胞性肝癌(简称肝癌,Hepatocellular Carcinoma,HCC)是我国最常见的恶性肿瘤之一,目前的研究认为:肝炎病毒感染及其他致癌因素是肝癌发生的主要外因。同时,肝癌和其它恶性肿瘤一样,其发生发展是由体内多基因多蛋白参与、多步骤协同的复杂过程。因此,寻找肝癌相关蛋白有助于研究肝癌发生及发展的机制,从而为肝癌的预防、诊断及治疗提供理论基础。
BTB/POZ-ZF(broad complex,tramtrack,and bric a brac;poxvirus and zinc finger-zincfinger)结构域家族是一类转录因子,其N末端含共同的保守结构域(BTB/POZ),能介导蛋白质间自联作用,C端则含各种不同的锌指结构域(以C2H2锌指为多),能介导与DNA的相互作用。包括BCL-6(B cell lymphoma 6)、PLZF(promyelocytic leukemia zincfinger)等在内的该家族成员参与多种细胞功能,如转录调节、细胞增殖、凋亡等,在DNA损伤反应、肿瘤形成及发育过程中起重要作用。DPZF(dendritic cell-derived BTB/POZ zincfinger)是该家族的一个成员,是从人类DC细胞中克隆鉴定并得名,又名Zbtb20、HOF、Znf288及Zfp288等。它编码形成两个剪接体(分别称HOF~L和HOF~S),其N端含有一个BTB/POZ结构域,C端含有4个C2H2锌指结构。该基因定位在3号染色体(3q27),广泛表达于造血系统及部分血液系统恶性肿瘤细胞中,同时也表达于神经系统,参与神经发育,促进椎体神经元形成并能调控新生神经元的细胞命运转化。目前,尚无DPZF在实体肿瘤如肝癌组织中表达与作用的相关研究报道。本研究旨在通过研究DPZF在肝癌组织中的表达及分布,结合相关临床资料探讨其表达与肝癌发生发展的关系,为寻找肝癌基因治疗的新靶点提供实验和理论依据。
二、材料和方法
收集2003-2006年间第二军医大学附属东方肝胆外科医院的手术切除肝细胞癌标本148例(男122,女26),平均年龄52.5(23～76)岁,患者术前未经任何抗癌治疗,每例标本均包括肝癌组织及距肿瘤边缘≤2 cm的癌旁组织;正常肝组织12例取自直径小于5cm的肝血管瘤周围2cm以上部位的肝组织,标本经分装后将用于免疫组化检测的样本行甲醛固定,Western Blot和RT-PCR检测的标本行液氮保存,所有病例均经临床和病理检查明确诊断。
应用免疫组织化学方法检测DPZF在组织中的表达及分布,进一步用Western blot及RT-PCR验证其在肝癌及癌旁组织中的差异表达,并应用SPSS统计软件对结果进行统计分析。
三、结果
免疫组化法检测发现:(1)DPZF在人正常肝脏组织中的表达呈弱阳性表达,阳性着色主要位于肝细胞的细胞核,也见于胞浆;(2)在人肝癌组织中的表达明显增强,呈阳性或强阳性表达,与正常肝脏组织相比有显著差异(P＜0.05),阳性着色主要位于肝细胞的细胞核,胞浆中染色也增强;(3)DPZF在癌旁组织中的表达略有增强,与肝癌组织相比有显著差异(P＜0.05),阳性着色位于肝细胞胞核,也见于胞浆及炎细胞;(4)DPZF在HBsAg阴性肝癌组织中的表达呈阴性或弱阳性表达,与HBsAg阳性肝癌组织相比有显著差异(P＜0.05);(4) DPZF在移性肝癌(结肠癌和胃癌肝转移)中的表达基本为阴性,而在胆囊腺癌及肝门部胆管癌中为弱阳性表达。
Western blot检测发现DPZF在Huh7、7721、PLC及HepG2等肝癌细胞系中有较明显表达,在L02等正常肝细胞系中有低水平表达。同时证实DPZF蛋白在正常肝组织中存在较低水平的表达,在肝癌中的表达高于正常肝及癌旁。RT-PCR同样证实DPZF在肝癌组织中存在转录水平的上调。
与肿瘤的临床病理特征的关系相关统计学分析发现:DPZF在HBsAg阳性肝癌中的表达高于HBsAg阴性组,二者差异有统计学意义(P＜0.0001);在伴肝硬化的肝癌中的表达高于不伴肝硬化组(P＜0.0001);在伴门静脉癌栓和子灶的肝癌中的表达高于不伴癌栓和子灶组(P＜0.05);在有复发或转移的肝癌中的表达高于无复发或转移组(P＜0.0001)。而DPZF的表达与患者性别、年龄、甲胎蛋白(AFP)、肿瘤大小、病理分级、有无淋巴结转移及包膜无明显相关性。多因素Logistic回归分析发现男性、直径较大肿瘤(＞50mm)、血清AFP阳性以及DPZF高表达均是肝癌复发的独立危险性因素。
四、结论
1.DPZF在人正常肝组织中呈弱阳性表达,主要位于肝细胞的细胞核,在胞浆中也有表达。
2.DPZF在肝癌中表达明显增强,与正常肝及癌旁组织相比有显著差异(P＜0.05),提示其可能参与肝癌的发生发展。
3.DPZF在HBV感染的肝癌组织中表达水平较未感染者高(P＜0.05),提示其可能与HBV感染及炎症相关的肝癌形成有关。
4.DPZF在伴随有癌栓和子灶的肝癌以及出现术后复发或肝外转移的肝癌中表达明显高于对照组(P＜0.05),提示其可能与肝癌的复发转移相关。
5.建立肝癌复发危险因素的多因素Logistic回归模型发现DPZF高表达是肝癌复发的独立危险性因素(P＜0.05)。
Background & Objective:
Hepatocelluar carcinoma(HCC) is one of the most prevalent malignant tumor in China. The development and progression of HCC is a complicated process involving multiple genes and transforming steps.Up to now,though over 20 genes have been found to be relative to hepatocarcinogenesis,the mechanisms underlying the development of HCC remain unclear. Therefore,searching for new HCC associated molecules may give some clues to study the mechanism of HCC.
The BTB/POZ-ZF[Broad complex,Tramtrack,Bric a' brac(BTB) or poxvirus and zinc finger(POZ)-zinc finger]protein family comprises a diverse group of transcription factors. These factors are so named because of a distinct and unique N-terminal BTB/POZ domain and C-terminal DNA-binding zinc fingers domains.POZ-ZF proteins have been implicated in many biological processes,including B cell fate determination,DNA damage responses,cell cycle progression and a multitude of developmental events.Consequently,dysfunction of vertebrate POZ-ZF proteins,such as promyelocytic leukemia zinc finger(PLZF),B cell lymphoma 6(Bcl-6),has been linked to tumorigenesis.
DPZF(dendritic cell-derived BTB/POZ zinc finger) is a novel BTB/POZ zinc finger gene identified from human dendritic cells(DC),which encodes a 733-residue protein with a BTB/POZ domain at the N-terminal and 4 C2H2 zinc fingers at C-terminal.It is localized on chromosome 3q27 and is widely expressed in hematopoietic tissues and nervous tissues. DPZF protein expression is detectable in lymphoid neoplasm with a molecular mass of about 100 kDa,especially in B lymphoma.It is a transcription factor may be involved in hematopoiesis,immune responses,development and oncogenesis.
This research was focused on the elucidation of DPZF gene's role in the development and progression of HCC,through detecting its expression level in HCC tissues by immunohistochemistry,Western blot,RT-PCR and statistic analysis based on the clinicapathologic data.
Materials & Methods:
The sections of 12 normal hepatic tissues and 148 HCC tissues were collected from the East Hepatobiliary Hospital affiliated to Second Military Medical University during the year of 2003-2006.HCC patients were 122 males and 26 females,with a mean age of 52.5 years (range,23-76 years).Serum hepatitis B surface antigen(HBsAg) was positive in 113 cases. The Edmonson staging of these patients was based on the clinical and pathological diagnosis. Informed consent was obtained from each patient before operation.The expression of DPZF in the samples was detected by immunohistochemical staining,Western blot and RT-PCR.
Results:
Immunohistochemical staining showed that:(1)The expression of DPZF in human normal hepatic tissue was weakly positive.And it was mainly located in nucleus,occasionally in cytoplasm.(2)The expression of DPZF in HCC tissue was strongly positive.The level of DPZF expression in the HCC was higher than the corresponding para-cancerous tissues and the normal hepatic tissue(p＜0.05).And it was mainly located in nucleus,occasionally in cytoplasm.(3)The expression of DPZF in HBsAg positive HCC tissue was substantially higher than the HBsAg negative HCC tissue(p＜0.05).(4) The expression of DPZF in secondary liver cancer were negative and the expression in hilar cholangiocarcinoma and cholecyst adencarcinoma were weakly positive.
Expression of DPZF was detectable in Huh7、7721、PLC、HepG2 and L02 cell lines by Western blot.Western blot and RT-PCR analysis confirmed over expression of DPZF in HCC tissues compared with corresponding para-cancerous tissues and normal liver tissues.
To elucidate the significance of DPZF in HCC,its expression was correlated with various clinicopathological features.Increased DPZF expression levels in HCC were positively correlated with hepatic cirrhosis(P＜0.0001),HBV infection(P＜0.0001),portal vein invasion(P=0.019),and satellite nodules involvement(P=0.0001).Importantly,the recurrence or metastasis rates of HCCs with higher DPZF expression were markedly greater than those of HCCs with lower expression(P=0.0001,P=0.0001,respectively).However, there was no significant correlation between DPZF expression and other variable parameters, including age,gender,serum AFP level,tumor size,formation of tumor capsule and Edmonson's grade of HCC.Furthermore,Multivariate analysis confirmed that DPZF overexpression(P=0.005),male(P=0.006),larger tumor size(≥50mm)(P=0.009),and serum AFP positive(P=0.016) were the independent risk factors for the recurrence of HCC by using multivariate logistic analysis.
Conclusions:
1.The expression of DPZF in human normal hepatic tissue was weakly positive and it was located in nucleus,occasionally in cytoplasm.
2.The expression of DPZF in HCC tissue was strongly positive.The level of DPZF expression in the HCC was higher than the corresponding para-cancerous tissues and the normal hepatic tissue.It indicated that DPZF may be associated with the genesis and development of HCC.
3.The expression of DPZF in HBsAg positive HCC tissue was higher compared with HBsAg negative HCC tissue.It indicated that DPZF may be associated with the mechanism of hepatocarcinogenesis induced by infection of HBV.
4.DPZF level was significantly higher(p＜0.05) in portal vein thrombus,satellite nodules,recurrence and metastasis involvement groups than in the control groups. This indicated that DPZF may be associated with the recurrence and metastasis of HCC.
5.Multivariate logistic analysis confirmed higher expression of DPZF(P=0.005) was the independent risk factor for the reccurence of HCC.
引文
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