人体肝癌发生过程中HBx及p38MAPK通路相关因子的研究
摘要
目的：研究肝细胞癌(HCC)发生过程中不同阶段乙型肝炎病毒X蛋白(HBx)、丝裂原活化蛋白激酶(MAPK)途径p38MAPK蛋白及p38MAPK通路相关因子Cdc25B、p34Cdc2、CyclinB_1的表达及其相互关系，探讨HCC发生机制。
方法：应用免疫组织化学方法检测正常肝组织、慢性肝炎、肝硬化、癌周肝硬化和肝癌共86例标本中的HBx、p38MAPK、Cdc25B、CyclinB_1和p34Cdc2的表达情况，用半定量积分法进行结果判断，并用统计学方法对结果进行分析。
结果：HBx蛋白阳性信号主要定位于胞核，HBx的表达以肝炎组及肝癌组多见，肝癌组与正常组之间的差异有统计学意义(P＜0.05)，慢性肝炎组与正常组、肝硬化组、癌周肝硬化组之间的差异有统计学意义(P＜0.05)；p38MAPK蛋白及其通路相关因子Cdc25B蛋白阳性信号定位于胞核和／或胞浆，p38MAPK和Cdc25B的表达均以肝癌组最强，分别为78％和81％，在癌周肝硬化组中的表达仅次于肝癌组，分别为67％和78％，其与正常组的差异均有统计学意义(P＜0.05)。CyclinB_1蛋白阳性信号定位于胞核和胞浆，p34Cdc2蛋白阳性信号主要定位于胞核，两者在肝癌组都呈现出过表达现象，与正常组间的差异有统计学意义(P＜0.05)。
P38MAPK、Cdc25B、CyclinB_1和p34cdc2四种蛋白从正常组、慢性肝炎组、肝硬化组、癌周肝硬化组到肝癌组中的表达呈逐渐增强的趋势，且在癌周肝硬化中的表达均高于不伴癌的肝硬化，其差异有统计学意义(P＜0.05)。5项指标的检测在肝癌组中分化好者与分化差者之间差异均无统计学意义(P＞0.05)。相关性分析发现，HBx与p38MAPK的表达成正相关，相关系数为0.326(P＜0.05)；CyclinB_1与p34cdc2的表达成正相关，相关系数为0.896(P＜0.05)。
结论1、HBx通过p38MAPK途径引起细胞周期G2／M检验点活化，使细胞周期从G2期向M期转化的相关因子Cdc25B、p34Cdc2和CyclinB_1的表达发生改变，造成肿瘤细胞的异常增殖可能是肝细胞癌发生的机制之一。2、首次发现癌周肝硬化中p38MAPK、细胞周期G2／M期调控相关因子Cdc25B、CyclinB_1和p34cdc2蛋白表达的阳性率均介于癌周肝硬化和不伴癌的肝硬化之间，说明癌周肝硬化肝细胞与不伴蕉的肝硬化肝细胞很可能是性质不同的细胞群体，更具有癌前病变性质，可能是肝细胞癌变的关键时期。
Objective: To investigate the expression of HBx protein and the factors Cdc25B、CyclinB1、p34cdc2 which are correlated to the p38MAPK pathway in human hepatocarcinogenesis.
Methods: Expression of HBx、p38MAPK、Cdc25B、CyclinB1、p34cdc2 was detected in the tissues of nomal liver, chronic hepatitis, liver cirrhosis, paratumor cirrhosis and HCC (86 samples, totally) by s-p immunohistochemistry. All data were processed by SPSS 11.5 version in the computer.
Results: HBx was localized in nuclear of chronic hepatitis and HCC. The expression of HBx in HCC was stronger than that in nomal liver and paratumor cirrhosis (p＜0.05), however the expression of HBx in chronic hepatitis was stronger than that in other three groups(p＜0.05). P38MAPK and Cdc25B was localized in cytoplasm and/or nuclear. The expression of p38MAPK and Cdc25B was the highest in HCC and the positive rates of them in paratumor cirrhosis was just lower than that in HCC.The expression of p38MAPK and Cdc25B in HCC and paratumor cirrhosis showed significant difference compared with normal liver(p＜0.05). CyclinB_1 protein was localized in cytoplasm and nuclear and p34cdc2 protein was localized in nuclear. There was overexpression of CyclinB_1 and p34cdc2 in HCC and the expression showed significant difference between HCC and normal liver(p＜0.05). The expression of p38MAPK、Cdc25B、CyclinB_1 and p34cdc2 gradually increased from normal liver、chronic hepatitis、liver cirrhosis、paratumor cirrhosis to HCC and the expression between liver cirrhosis and paratumor cirrhosis showed significant difference (p＜0.05). Significant positive correlation was found between the expression of HBx and p38MAPK and the expression of CyclinB_1 and p34cdc2 in HCC.
Conclusions: The p38MAPK signal transduction pathway could be activated by HBx protein so that cell cycle checkpoint of G2/M activated. The expression of Cdc25B、CyclinB1、p34cdc2 increaced and abnormal cells multiplicated out of the way. The p38MAPK signal transduction pathway activated by HBx may play a key role in human hepatocarcinogenesis. For the first time we found the positive rates of p38MAPK、Cdc25B、yclinB_1 and p34cdc2 were different between liver cirrhosis and paratumor cirrhosis which indicates that their characteristics maybe different.
方法：应用免疫组织化学方法检测正常肝组织、慢性肝炎、肝硬化、癌周肝硬化和肝癌共86例标本中的HBx、p38MAPK、Cdc25B、CyclinB_1和p34Cdc2的表达情况，用半定量积分法进行结果判断，并用统计学方法对结果进行分析。
结果：HBx蛋白阳性信号主要定位于胞核，HBx的表达以肝炎组及肝癌组多见，肝癌组与正常组之间的差异有统计学意义(P＜0.05)，慢性肝炎组与正常组、肝硬化组、癌周肝硬化组之间的差异有统计学意义(P＜0.05)；p38MAPK蛋白及其通路相关因子Cdc25B蛋白阳性信号定位于胞核和／或胞浆，p38MAPK和Cdc25B的表达均以肝癌组最强，分别为78％和81％，在癌周肝硬化组中的表达仅次于肝癌组，分别为67％和78％，其与正常组的差异均有统计学意义(P＜0.05)。CyclinB_1蛋白阳性信号定位于胞核和胞浆，p34Cdc2蛋白阳性信号主要定位于胞核，两者在肝癌组都呈现出过表达现象，与正常组间的差异有统计学意义(P＜0.05)。
P38MAPK、Cdc25B、CyclinB_1和p34cdc2四种蛋白从正常组、慢性肝炎组、肝硬化组、癌周肝硬化组到肝癌组中的表达呈逐渐增强的趋势，且在癌周肝硬化中的表达均高于不伴癌的肝硬化，其差异有统计学意义(P＜0.05)。5项指标的检测在肝癌组中分化好者与分化差者之间差异均无统计学意义(P＞0.05)。相关性分析发现，HBx与p38MAPK的表达成正相关，相关系数为0.326(P＜0.05)；CyclinB_1与p34cdc2的表达成正相关，相关系数为0.896(P＜0.05)。
结论1、HBx通过p38MAPK途径引起细胞周期G2／M检验点活化，使细胞周期从G2期向M期转化的相关因子Cdc25B、p34Cdc2和CyclinB_1的表达发生改变，造成肿瘤细胞的异常增殖可能是肝细胞癌发生的机制之一。2、首次发现癌周肝硬化中p38MAPK、细胞周期G2／M期调控相关因子Cdc25B、CyclinB_1和p34cdc2蛋白表达的阳性率均介于癌周肝硬化和不伴癌的肝硬化之间，说明癌周肝硬化肝细胞与不伴蕉的肝硬化肝细胞很可能是性质不同的细胞群体，更具有癌前病变性质，可能是肝细胞癌变的关键时期。
Objective: To investigate the expression of HBx protein and the factors Cdc25B、CyclinB1、p34cdc2 which are correlated to the p38MAPK pathway in human hepatocarcinogenesis.
Methods: Expression of HBx、p38MAPK、Cdc25B、CyclinB1、p34cdc2 was detected in the tissues of nomal liver, chronic hepatitis, liver cirrhosis, paratumor cirrhosis and HCC (86 samples, totally) by s-p immunohistochemistry. All data were processed by SPSS 11.5 version in the computer.
Results: HBx was localized in nuclear of chronic hepatitis and HCC. The expression of HBx in HCC was stronger than that in nomal liver and paratumor cirrhosis (p＜0.05), however the expression of HBx in chronic hepatitis was stronger than that in other three groups(p＜0.05). P38MAPK and Cdc25B was localized in cytoplasm and/or nuclear. The expression of p38MAPK and Cdc25B was the highest in HCC and the positive rates of them in paratumor cirrhosis was just lower than that in HCC.The expression of p38MAPK and Cdc25B in HCC and paratumor cirrhosis showed significant difference compared with normal liver(p＜0.05). CyclinB_1 protein was localized in cytoplasm and nuclear and p34cdc2 protein was localized in nuclear. There was overexpression of CyclinB_1 and p34cdc2 in HCC and the expression showed significant difference between HCC and normal liver(p＜0.05). The expression of p38MAPK、Cdc25B、CyclinB_1 and p34cdc2 gradually increased from normal liver、chronic hepatitis、liver cirrhosis、paratumor cirrhosis to HCC and the expression between liver cirrhosis and paratumor cirrhosis showed significant difference (p＜0.05). Significant positive correlation was found between the expression of HBx and p38MAPK and the expression of CyclinB_1 and p34cdc2 in HCC.
Conclusions: The p38MAPK signal transduction pathway could be activated by HBx protein so that cell cycle checkpoint of G2/M activated. The expression of Cdc25B、CyclinB1、p34cdc2 increaced and abnormal cells multiplicated out of the way. The p38MAPK signal transduction pathway activated by HBx may play a key role in human hepatocarcinogenesis. For the first time we found the positive rates of p38MAPK、Cdc25B、yclinB_1 and p34cdc2 were different between liver cirrhosis and paratumor cirrhosis which indicates that their characteristics maybe different.
引文
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[1] Tian W, Zhang Z, Cohen DM. MAPK signaling and the kidney. Am J Physiol Renal Physiol, 2000, 279:F593-F604
[2] 陈奕、缪泽鸿、丁健．p38MAPKs在细胞周期调控中的作用[J]．生理科学进展，2004，(4)：315-320
[3] Huang S, New L, Pan Z, et al Urokinase plasminogen activator/urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p38alphamitogen-activated protein kinase activity[J].JBiol Chem, 2000, 275 (16): 12266—12272
[4] Han J, Lee JD, Tobias PS, et al. Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem, 1993, 268:25009-25014
[5] Han J, Lee JD, Bibbs L, et al A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells[J].Science, 1994, 265 (5 173): 808—811
[6] Kyriakis JM, Avruch J. Sounding the alarm:protein kinase cascades activated by stress and inflammation [J].J Biol Chem, 1996, 271 (40): 24313—24316
[7] Ellinger-Ziegebauer H, Kelly K, Siebenlist U. Cell cycle arrest and Reversion of Ras-induced transformation by a conditionally activated form of mitogen- activated protein kinase kinase kinase 3. Mol Cell Biol, 1999, 19:3857-3868
[8] Bulavin DV, Kovalsky O, Hollander MC, et, al. Loss of oncogenic H-ras-induced Cell cycle arrest and p38 mitogen-activated protein kinase activatin by disruption of Gadd45a. Mol Cell Biol, 2003,23:3859-3871
[9] Donnaboo KK, Shames BD, Harken AH, et al.J Urol, 1999, 162 (1): 196-203 Meldrum KK, Meldrum DR, Hile KL, et al Am J Physiol Cell Physiol, 2001, 281 (2): 563-570
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[16] Morita Y,Naka T, Kawazoe Y, et al. Proc Natl Acad Sci USA, 2000,97(10):5405-54010
[17] Varghese J, Chattopadhaya S, Sarin A.J Immunol, 2001,166(11):6570-6577
[18] Roberts RA, James NH, Cosulich SC. Hepatilogy, 2000,31(2):420
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[20] Craig R, Larkin A, Mingo AM, et al. J Biol Chem, 2000,275(31):23814-23824
[21] Milich DR, Jones JE, Hughes JL, et al. Is a function of the secreted hepatitis B antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci U S A,1990, 87:6599-6603
[22] 毛华，袁爱力，赵敏芳等，分裂原激活蛋白激酶p38信号传导通路在抑制血管内皮细胞生长因子诱导肝癌转移的实验研究。中华消化杂志，2000，2(1)：14-16
[23] 毛华，袁爱力，赵敏芳等，p38MAPK信号传导通路调控VEGF诱导肝癌细胞粘附作用．世界华人消化杂志，2006，14(8)：778-783
[24] Spaziani A, Alisi A, Sanna D, Balsano C。Role of p38 MAPK and RNA-dependent protein kinase (PKR) in hepatitis C virus core-dependent nuclear delocalization of cyclin B1.。J Biol Chem. 2006 Apr 21;281(16):10983-9. Epub 2006 Jan 30
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[26] 栗光明，朱继业，刘燕南等．有丝分裂及上游调节信号在人肝癌中组织中的表达．中华普通外科杂志．2001，16(6)：368-370
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[1] Tian W, Zhang Z, Cohen DM. MAPK signaling and the kidney. Am J Physiol Renal Physiol, 2000, 279:F593-F604
[2] 陈奕、缪泽鸿、丁健．p38MAPKs在细胞周期调控中的作用[J]．生理科学进展，2004，(4)：315-320
[3] Huang S, New L, Pan Z, et al Urokinase plasminogen activator/urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p38alphamitogen-activated protein kinase activity[J].JBiol Chem, 2000, 275 (16): 12266—12272
[4] Han J, Lee JD, Tobias PS, et al. Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem, 1993, 268:25009-25014
[5] Han J, Lee JD, Bibbs L, et al A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells[J].Science, 1994, 265 (5 173): 808—811
[6] Kyriakis JM, Avruch J. Sounding the alarm:protein kinase cascades activated by stress and inflammation [J].J Biol Chem, 1996, 271 (40): 24313—24316
[7] Ellinger-Ziegebauer H, Kelly K, Siebenlist U. Cell cycle arrest and Reversion of Ras-induced transformation by a conditionally activated form of mitogen- activated protein kinase kinase kinase 3. Mol Cell Biol, 1999, 19:3857-3868
[8] Bulavin DV, Kovalsky O, Hollander MC, et, al. Loss of oncogenic H-ras-induced Cell cycle arrest and p38 mitogen-activated protein kinase activatin by disruption of Gadd45a. Mol Cell Biol, 2003,23:3859-3871
[9] Donnaboo KK, Shames BD, Harken AH, et al.J Urol, 1999, 162 (1): 196-203 Meldrum KK, Meldrum DR, Hile KL, et al Am J Physiol Cell Physiol, 2001, 281 (2): 563-570
[10] Donnaboo KK, Shames BD, Harken AH, et al.J Urol, 1999, 162 (1): 196—203
[11] Minamino T, Yujiri T, Papst PJ, et al. Proc Natl Acad Sci USA, 1999,96 (26):15127-15132
[12] Ichijo H, Nishida E, Irie K, et al. Science, 1997,275(5296):90
[13] Tobiume K, Matsuzawa A, Takahashi T, et al. EMBO Rep, 2001, 2(3):222-228
[14] Valladares A, Alvarez AM, Ventura JJ, et al. Endocrinology, 2000, 141 (12): 4383—4395
[15] Remacle-Bonnet MM, Garrouste FL, Heller S, et al. Cancer, Res, 2000,60(7):2007-20
[16] Morita Y,Naka T, Kawazoe Y, et al. Proc Natl Acad Sci USA, 2000,97(10):5405-54010
[17] Varghese J, Chattopadhaya S, Sarin A.J Immunol, 2001,166(11):6570-6577
[18] Roberts RA, James NH, Cosulich SC. Hepatilogy, 2000,31(2):420
[19] Tsukahara K, Nakao A, Hiraguri M, et al. Int Arch Allergy Immunol, 1999,120:54-59
[20] Craig R, Larkin A, Mingo AM, et al. J Biol Chem, 2000,275(31):23814-23824
[21] Milich DR, Jones JE, Hughes JL, et al. Is a function of the secreted hepatitis B antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci U S A,1990, 87:6599-6603
[22] 毛华，袁爱力，赵敏芳等，分裂原激活蛋白激酶p38信号传导通路在抑制血管内皮细胞生长因子诱导肝癌转移的实验研究。中华消化杂志，2000，2(1)：14-16
[23] 毛华，袁爱力，赵敏芳等，p38MAPK信号传导通路调控VEGF诱导肝癌细胞粘附作用．世界华人消化杂志，2006，14(8)：778-783
[24] Spaziani A, Alisi A, Sanna D, Balsano C。Role of p38 MAPK and RNA-dependent protein kinase (PKR) in hepatitis C virus core-dependent nuclear delocalization of cyclin B1.。J Biol Chem. 2006 Apr 21;281(16):10983-9. Epub 2006 Jan 30
[25] Lin SB, Li CH, Lee SS, Kan LS, Triterpene-enriched extracts from Ganoderma lucidum inhibit growth of hepatoma cells via suppressing protein kinase C, activating mitogen-activated protein kinases and G2-phase cell cycle arrest., Life Sci. 2003 Apr 11;72(21):2381-90
[26] 栗光明，朱继业，刘燕南等．有丝分裂及上游调节信号在人肝癌中组织中的表达．中华普通外科杂志．2001，16(6)：368-370
[27] Wang HY, Cheng z, Malbon CC. Overexpression of mitogen—activated protein kinase phosphatases MKPI, MKF2 in hunman breast cancer[J] J. Cancer Lett, 2003. 191(2):229—237
[28] Yan FF, Wang B, Zhu XG, et al. Overexpression of P38MAPK protein in breast cancer and the regulation of preoperative chemotherapy[J]. Chin J Gen Surg, 2002,17(6): 343—345
[29] 孙泽群、徐少勇、邓长生、张丽、田林．蛋白在大肠癌中的表达及其临床意义[J]．中国肿瘤临床，2005，32(11)：635-637