ERK1/2、P16~(INK4a)、P-gp的表达与宫颈腺癌耐药的关系及其临床意义
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摘要
目的：
化疗是宫颈腺癌常规治疗的重要部分，而耐药是宫颈腺癌化疗成功的最大障碍，并成为宫颈腺癌复发和治疗失败的主要原因之一。探讨细胞外信号调节激酶1，2（extracellular signal-regulated kinase1/2，ERK1/2）、P16~(INK4a)及P-糖蛋白（P-glycoprotein，P-gp）与宫颈腺癌耐药的关系，并分析ERK1/2、P16~(INK4a)及P糖蛋白（P-glycoprotein，P-gp）的表达与宫颈腺癌患者3年生存率的关系。
方法：
1.收集1997年1月至2008年12月接受两程以铂类为基础的新辅助化疗的Ⅰb1期～Ⅱb期宫颈腺癌患者治疗前的活检组织石蜡标本共39例，参照实体瘤疗效评价标准（2000）将这39例宫颈腺癌患者分为化疗敏感组及耐药组，其中化疗敏感组14例，耐药组25例。
2.采用免疫组化（PV-9000）法检测39例宫颈腺癌活检组织中ERK1/2、P16~(INK4a)及P-gp蛋白的表达情况。免疫组化结果分级：-、+、++、+++，“++、+++”定义为高表达。
3.分析39例宫颈腺癌组织中ERK1/2、P16~(INK4a)及P-gp蛋白的表达情况及三者在化疗敏感组及耐药组中的表达差异。
4.分析ERK1/2、 P16~(INK4a)及P-gp的表达相关性，并初步探讨ERK1/2、P16~(INK4a)与宫颈腺癌耐药的关系。
5.分析ERK1/2、 P16~(INK4a)及P-gp的表达与宫颈腺癌患者3年生存率的关系。
结果：
1. ERK1/2、P16~(INK4a)及P-gp在宫颈腺癌组织中的阳性表达率分别为89.7%（35/39）、82.1%（32/39）及84.6%（33/39）。
2. ERK1/2在耐药组及敏感组的高表达率分别为72.0%（18/25）及35.7%（5/14），差异有统计学意义（P<0.05）；P16~(INK4a)蛋白在耐药组及敏感组的高表达率分别为76.0%（19/25）及42.9%（6/14），差异无统计学意义（P>0.05）； P-gp在耐药组的高表达率为76.0%（19/25）显著高于敏感组的28.6%（4/14），差异有统计学意义（P<0.05）。
3. ERK1/2与P16~(INK4a)的表达呈正相关（r=0.571，P<0.001），ERK1/2与P-gp的表达呈正相关（r=0.364，P<0.05），P16~(INK4a)与P-gp的表达无明显相关性（r=0.254, P>0.05）。
4. ERK1/2高表达与低表达患者的3年生存率分别为60.9%和93.8%，差异有统计学意义（P<0.05），P16~(INK4a)及P-gp高表达与低表达的宫颈腺癌患者的3年生存率差异无统计学意义(P>0.05)。
结论：
1. ERK1/2高表达可能与宫颈腺癌耐药相关。
2. P-gp高表达与宫颈腺癌耐药相关。
3. ERK1/2的表达与宫颈腺癌患者的预后有关。
4. ERK1/2、P16~(INK4a)在宫颈腺癌耐药中的作用有待进一步扩大样本的前瞻性研究。
Objective:
Chemotherapy is an important part in the regular management of cervicaladenocarcinoma. Drug resistance appears as the biggest obstacle to successfulchemotherapy and has becoming the leading cause of relapse and therapeutic failurein cervical adenocarcinoma. This study aims to explore relation between theexpressions of extracellular signal-regulated kinase1/2(ERK1/2), P16~(INK4a),P-glycoprotein (P-gp) and the chemoresistance of cervical adenocarcinoma, and toinvestigate their association with the3-year survival rate of these patients.
Methods:
1. Collecting39paraffin-embedded biopsy specimens of stagingⅠb1～Ⅱbcervical adenocarcinoma patients who had received two cycles of platinum-basedchemotherapy. According to the Response Evaluate Criteria in Solid Tumor (2000),these39patients were classified into two groups: chemothsensitive group (14patients)and chemoresistant group (25patients).
2. Using immunohistochemistry (PV-9000) to detect the expressions of ERK1/2,P16~(INK4a)and P-gp in the biopsy specimens of cervical adenocarcinoma.Immunohistochemical staining intensities were classified into four grades:-,+,++,+++. And “++、+++” were defined as high expression.
3. Analyzing the expressions ERK1/2, P16~(INK4a)and P-gp in the biopsyspecimens of cervical adenocarcinoma and their differences between thechemosensitive group and chemoresistant group.
4. Analyzing the correlation among the expressions ERK1/2, P16~(INK4a)and P-gpand exploring their association with the chemoresistance of cervical adenocarcinoma.
5. Analyzing the relation between the expressions of ERK1/2, P16~(INK4a)and P-gpand the3-year survival rate of the patients with cervical adenocarcinoma.
Result:
1. The expression rates of ERK1/2, P16~(INK4a)and P-gp in the biopsy specimensof cervical adenocarcinoma are89.7%(35/39),82.1%(32/39) and84.6%(33/39) respectively.
2. The highly expressed rates of ERK1/2in chemoresistant group andchemosensitive group are72.0%(18/25) and35.7%(5/14) respectively. And there isstatistical significance between them (P<0.05); The highly expressed rates ofP16~(INK4a)in chemoresistant group and chemosensitive group are76.0%(19/25) and42.9%(6/14) respectively. While the difference between them is not statisticallysignificant (P>0.05); The highly expressed rate of P-gp is72.0%(18/25) inchemoresistant group which is obviously higher than that of chemosensitive group(35.7%(5/14)), and this difference is statistically significant(P<0.05).
3. The expression of ERK1/2is positively correlated with that of P16Ink4(r=0.571, P<0.001), and the expression of ERK1/2is positively correlated with thatof P-gp (r=0.364, P<0.05), while there is no obvious correlation between theexpression of P16~(INK4a)and the expression of P-gp (r=0.254, P>0.05).
4. The3-year survival rates of for ERK1/2highly expressed patients and lowlyexpressed patients were60.9%and93.8%, and there is statistical significancebetween them (P<0.05), while there is no statistical significance between the3-yearsurvival rates of the patients with different expressions of P16~(INK4a)and P-gp(P>0.05).
Conclusions
1. The high expression of ERK1/2may associate with the chemoresistance ofcervical adenocarcinoma.
2. The high expression of P-gp correlate with the chemoresistance of cervicaladenocarcinoma.
3. The expression of ERK1/2is related with the prognosis of cervicaladenocarcinoma patients.
4. The role of ERK1/2and P16~(INK4a)in chemoresistance of cervicaladenocarcinoma is to be further explored in prospective study with more samples.
化疗是宫颈腺癌常规治疗的重要部分，而耐药是宫颈腺癌化疗成功的最大障碍，并成为宫颈腺癌复发和治疗失败的主要原因之一。探讨细胞外信号调节激酶1，2（extracellular signal-regulated kinase1/2，ERK1/2）、P16~(INK4a)及P-糖蛋白（P-glycoprotein，P-gp）与宫颈腺癌耐药的关系，并分析ERK1/2、P16~(INK4a)及P糖蛋白（P-glycoprotein，P-gp）的表达与宫颈腺癌患者3年生存率的关系。
方法：
1.收集1997年1月至2008年12月接受两程以铂类为基础的新辅助化疗的Ⅰb1期～Ⅱb期宫颈腺癌患者治疗前的活检组织石蜡标本共39例，参照实体瘤疗效评价标准（2000）将这39例宫颈腺癌患者分为化疗敏感组及耐药组，其中化疗敏感组14例，耐药组25例。
2.采用免疫组化（PV-9000）法检测39例宫颈腺癌活检组织中ERK1/2、P16~(INK4a)及P-gp蛋白的表达情况。免疫组化结果分级：-、+、++、+++，“++、+++”定义为高表达。
3.分析39例宫颈腺癌组织中ERK1/2、P16~(INK4a)及P-gp蛋白的表达情况及三者在化疗敏感组及耐药组中的表达差异。
4.分析ERK1/2、 P16~(INK4a)及P-gp的表达相关性，并初步探讨ERK1/2、P16~(INK4a)与宫颈腺癌耐药的关系。
5.分析ERK1/2、 P16~(INK4a)及P-gp的表达与宫颈腺癌患者3年生存率的关系。
结果：
1. ERK1/2、P16~(INK4a)及P-gp在宫颈腺癌组织中的阳性表达率分别为89.7%（35/39）、82.1%（32/39）及84.6%（33/39）。
2. ERK1/2在耐药组及敏感组的高表达率分别为72.0%（18/25）及35.7%（5/14），差异有统计学意义（P<0.05）；P16~(INK4a)蛋白在耐药组及敏感组的高表达率分别为76.0%（19/25）及42.9%（6/14），差异无统计学意义（P>0.05）； P-gp在耐药组的高表达率为76.0%（19/25）显著高于敏感组的28.6%（4/14），差异有统计学意义（P<0.05）。
3. ERK1/2与P16~(INK4a)的表达呈正相关（r=0.571，P<0.001），ERK1/2与P-gp的表达呈正相关（r=0.364，P<0.05），P16~(INK4a)与P-gp的表达无明显相关性（r=0.254, P>0.05）。
4. ERK1/2高表达与低表达患者的3年生存率分别为60.9%和93.8%，差异有统计学意义（P<0.05），P16~(INK4a)及P-gp高表达与低表达的宫颈腺癌患者的3年生存率差异无统计学意义(P>0.05)。
结论：
1. ERK1/2高表达可能与宫颈腺癌耐药相关。
2. P-gp高表达与宫颈腺癌耐药相关。
3. ERK1/2的表达与宫颈腺癌患者的预后有关。
4. ERK1/2、P16~(INK4a)在宫颈腺癌耐药中的作用有待进一步扩大样本的前瞻性研究。
Objective:
Chemotherapy is an important part in the regular management of cervicaladenocarcinoma. Drug resistance appears as the biggest obstacle to successfulchemotherapy and has becoming the leading cause of relapse and therapeutic failurein cervical adenocarcinoma. This study aims to explore relation between theexpressions of extracellular signal-regulated kinase1/2(ERK1/2), P16~(INK4a),P-glycoprotein (P-gp) and the chemoresistance of cervical adenocarcinoma, and toinvestigate their association with the3-year survival rate of these patients.
Methods:
1. Collecting39paraffin-embedded biopsy specimens of stagingⅠb1～Ⅱbcervical adenocarcinoma patients who had received two cycles of platinum-basedchemotherapy. According to the Response Evaluate Criteria in Solid Tumor (2000),these39patients were classified into two groups: chemothsensitive group (14patients)and chemoresistant group (25patients).
2. Using immunohistochemistry (PV-9000) to detect the expressions of ERK1/2,P16~(INK4a)and P-gp in the biopsy specimens of cervical adenocarcinoma.Immunohistochemical staining intensities were classified into four grades:-,+,++,+++. And “++、+++” were defined as high expression.
3. Analyzing the expressions ERK1/2, P16~(INK4a)and P-gp in the biopsyspecimens of cervical adenocarcinoma and their differences between thechemosensitive group and chemoresistant group.
4. Analyzing the correlation among the expressions ERK1/2, P16~(INK4a)and P-gpand exploring their association with the chemoresistance of cervical adenocarcinoma.
5. Analyzing the relation between the expressions of ERK1/2, P16~(INK4a)and P-gpand the3-year survival rate of the patients with cervical adenocarcinoma.
Result:
1. The expression rates of ERK1/2, P16~(INK4a)and P-gp in the biopsy specimensof cervical adenocarcinoma are89.7%(35/39),82.1%(32/39) and84.6%(33/39) respectively.
2. The highly expressed rates of ERK1/2in chemoresistant group andchemosensitive group are72.0%(18/25) and35.7%(5/14) respectively. And there isstatistical significance between them (P<0.05); The highly expressed rates ofP16~(INK4a)in chemoresistant group and chemosensitive group are76.0%(19/25) and42.9%(6/14) respectively. While the difference between them is not statisticallysignificant (P>0.05); The highly expressed rate of P-gp is72.0%(18/25) inchemoresistant group which is obviously higher than that of chemosensitive group(35.7%(5/14)), and this difference is statistically significant(P<0.05).
3. The expression of ERK1/2is positively correlated with that of P16Ink4(r=0.571, P<0.001), and the expression of ERK1/2is positively correlated with thatof P-gp (r=0.364, P<0.05), while there is no obvious correlation between theexpression of P16~(INK4a)and the expression of P-gp (r=0.254, P>0.05).
4. The3-year survival rates of for ERK1/2highly expressed patients and lowlyexpressed patients were60.9%and93.8%, and there is statistical significancebetween them (P<0.05), while there is no statistical significance between the3-yearsurvival rates of the patients with different expressions of P16~(INK4a)and P-gp(P>0.05).
Conclusions
1. The high expression of ERK1/2may associate with the chemoresistance ofcervical adenocarcinoma.
2. The high expression of P-gp correlate with the chemoresistance of cervicaladenocarcinoma.
3. The expression of ERK1/2is related with the prognosis of cervicaladenocarcinoma patients.
4. The role of ERK1/2and P16~(INK4a)in chemoresistance of cervicaladenocarcinoma is to be further explored in prospective study with more samples.
引文
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