泛素-蛋白酶体系统在非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂继发性耐药中的作用

Effect of USP in Non-small cell lung cancer EGFR-TKI secondary drug resistance

目的探讨泛素-蛋白酶体系统(UPS)在非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)继发性耐药中的作用及机制。方法选取经病理证实肺腺癌患者98例,其中49例患者存在EGFR基因敏感突变且EGFR-TKI治疗敏感,采集其组织标本作为EGFR-TKI敏感组(n=49),另49例患者行EGFR-TKI治疗出现获得性耐药,采集其组织标本作为EGFR-TKI耐药组(n=49)。应用连续荧光监测法检测两组组织标本中UPS标志物CT-L的活性;分别从基因及蛋白水平检测UPS标志物-蛋白酶体亚基蛋白酶体亚基C2及mTOR的表达。结果 EGFR-TKI耐药组CT-L活性显著高于EGFR-TKI敏感组,差异有显著性(P<0.05);免疫组化检测蛋白酶体亚基C2在EGFR-TKI耐药组的阳性率为73.5%,显著高于EGFR-TK1敏感组的19.7%(P<0.05);mTOR的表达在EGFR-TKI耐药组的阳性率为77.6%,显著高于EGFR-TKI敏感组的25.6%(P<0.05);蛋白酶体亚基C2与mTOR的表达呈正相关(r_s=0.8)。结论 UPS在肺腺癌EGFR-TKI耐药过程中发挥重要作用,其作用与mTOR的增高相关,为逆转耐药和个体化治疗提供了新思路。

Objective To investigate the effects and the mechanisms of UPS on non-small cell lung cancers with acquired secondary resistance to EGFR-TKI.Method 98 cases patients with pathological confirmation of adenocarcinoma of lung were selected,among them,49 cases were sensitive to EGFR-TKI,and whose specimens were acted as EGFR-TKI sensitive group（n = 49）,the others were resistant to EGFR-TKI,and whose specimens were acted as EGFR-TKI resistant group（n=49）.Continuous fluorescence detection method was used to detect the activity of CT-L,which was a marker of UPS;RT-PCR and immunohistochemistry were used to detect the expression of PMSC2 and mTOR.Result The activity of CT-L in patients with EGFR-TKI resistance was higher than that of sensitive ones（P0.05）.73.5%patients of EGFR-TKI resistance had a positive PMSCl expression,which was significantly higher than that 19.7%in the sensitive ones by immunohistochemistry（P0.05）;77.6%patients of mTOR resistance had a positive PMSC2 expression,which was significantly higher than that 25.6%in the sensitive ones by immunohistochemistry（P0.05）;PMSC2 and mTOR had a positive correlation expression（r_s =0.8）.Conclusion UPS plays an important role in non-small cell lung with EGFR-TKI resistance.It may be related with the higher expression of mTOR,and thus will give a new idea on drug resistance reversal and individualized treatment.