ID1对非小细胞肺癌EGFR-TKI耐药的影响

Relationship between ID1 and EGFR-TKI Resistance in Non-small Cell Lung Cancer

背景与目的非小细胞肺癌(non-small cell lung cancer,NSCLC)是当今世界上发病率和死亡率最高的恶性肿瘤之一,而表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKI)整体有效率为30%-40%,无进展生存期(progression-free survival,PFS)为12个月。但EGFR-TKI在临床中的耐药现象也很普遍,严重影响了其抑瘤作用。因此,克服耐药、寻找一种新的与肺癌耐药相关的预后因子势在必行。本研究旨在通过体内外实验探讨DNA结合抑制因子1(differentiation inhibitory factor 1,ID1)与NSCLCEGFR-TKI耐药之间的关系,看其是否有统计学意义,并初步探讨其机制。方法免疫组化(immunohistochemistry,IHC)检测手术标本(肺癌组织和癌旁组织)1D1的表达;q RT-PCR、Western-blot检测并比较肺癌细胞敏感株与耐药株中ID1的表达变化;MTT检测吉非替尼对ID1慢病毒载体处理肺癌细胞的细胞增殖情况,将肺癌细胞接种至裸鼠腋下,待肿瘤生长至一定体积使用吉非替尼治疗,估算肿瘤体积。结果 ID1在肺癌组织中的表达明显高于正常组织(P<0.05);ID1的表达与NSCLC EGFR-TKI耐药呈正相关(P<0.05)。结论 ID1在NSCLC中高表达,并且参与了NSCLC EGFRTKI的耐药,其机制可能与STAT3磷酸化程度增加有关。

Background and objective Non-small cell lung cancer （NSCLC） presents the highest morbidity and mortality among malignant tumors worldwide. The overall effective rate of epidermal growth factor receptor-tyrosine kinase inhibitor （EGFR-TKI） is 30% to 40%, and PFS （progression-free sruvival） is 12 months. However, EGFR-TKI resistance is typical in clinical observations, and this phenomenon significantly affects tumor suppression. To overcome this resistance, a new prognostic factor associated with lung cancer drug resistance should be discovered. This study investigated the rela- tionship between the inhibitor of differentiation 1 （ID 1） and non-small cell lung cancer EGFR-TKI resistance in vivo and in vitro to determine any statistical significance and discuss the underlying mechanism. Methods Western blot and qRT-PCR were used to quantify the expression of ID 1 in lung cancer. IHC was used to detect the expression of ID 1 in pathological tissues （lung cancer tissues and adjacent tissues）. MTr was used to detect cell proliferation, in which the cells were treated with gefitinib after being transfected by ID 1 slow virus vector. Lung cancer cells were inoculated in nude mice until the tu- mor diameter grew to certain measurement. Gefitinib treatment was started, and the tumor volume was estimated. Results ID1 was highly expressed in NSCLC （P〈0.05）. Both ID1 expression and drug resistance of EGFR-TKI in NSCLC were positively correlated （P〈0.05）. The treatment group with gefitinib showed obviously less expression than the control group. Conclusion ID 1 is highly expressed in NSCLC. ID 1 expression was positively related to drug resistance of EGFR-TKI in NSCLC. Gefitinib can be used to effectively treat NSCLC, and the mechanism may be associated with an increased level of STAT3 phosphorylation.