Wang Wei-Wei, Wang Yu-Bao, Wang Dong-Qiang, Lin Zhu, Sun Ren-Jun
Department of Emergency, Tianjin First Central Hospital Tianjin 300192 China.
Institute of Infectious Diseases, The Second Hospital of Tianjin Medical University Tianjin 300211 China.
Int J Clin Exp Med. 2015 Feb 15;8(2):3063-71. eCollection 2015.
Hepatic cancer is a class of cancer that is relatively insensitive to chemotherapy, and cancers that harbor EGFR active mutations are more sensitive to EGFR-TK inhibitor such as gefitinib, which becomes the first-line treatment of this subtype of cancer. However, almost all patients treated with gefitinib will develop drug resistance. Here we show that a protein called integrin beta-8 (ITGB8) when over-expressed, is correlated with the gefitinib resistance of hepatic cancer cell line HepG2/G. After ITGB8 silencing, the drug resistance is reversed as the cell proliferation decreases and apoptosis rate increases significantly by gefitinib treatment when compared to HepG2/G. We demonstrated that multi-drug resistant proteins ABCB1, ABCC2 and ABCG2, anti-apoptosis proteins like survivin and Bcl-2, and cycle promoting protein CDK1 are involved in drug resistance of HepG2/G. Other drug-resistance relative proteins like SOD, GST, TS and HIF-1 are also modulated by ITGB8 silencing, but their role in this gefitinib resistance might be indirect. TGF beta pathway could be a critical pathway by which ITGB8 modulates the sensitivity of HepG2/G to gefitinib.
肝癌是一类对化疗相对不敏感的癌症，而携带表皮生长因子受体（EGFR）活性突变的癌症对吉非替尼等EGFR - TK抑制剂更为敏感，吉非替尼因此成为这类癌症亚型的一线治疗药物。然而，几乎所有接受吉非替尼治疗的患者都会产生耐药性。在此我们表明，一种名为整合素β - 8（ITGB8）的蛋白质过度表达时，与肝癌细胞系HepG2/G对吉非替尼的耐药性相关。ITGB8沉默后，耐药性得到逆转，与HepG2/G相比，经吉非替尼处理后细胞增殖减少且凋亡率显著增加。我们证明，多药耐药蛋白ABCB1、ABCC2和ABCG2、抗凋亡蛋白如生存素和Bcl - 2以及细胞周期促进蛋白CDK1都与HepG2/G的耐药性有关。其他与耐药相关的蛋白如超氧化物歧化酶（SOD）、谷胱甘肽 - S - 转移酶（GST）、胸苷合成酶（TS）和缺氧诱导因子 - 1（HIF - 1）也受ITGB8沉默的调节，但其在这种吉非替尼耐药性中的作用可能是间接的。转化生长因子β（TGFβ）信号通路可能是ITGB8调节HepG2/G对吉非替尼敏感性的关键信号通路。
