shRNA/mdr1表达载体构建及RNAi逆转肝细胞癌多药耐药
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摘要
研究背景 肝细胞肝癌(Hepatocullular carcinoma，HCC)的是常见的恶性肿瘤之一，发病呈逐年上升趋势，位居我国恶性肿瘤年死亡率的第二位，严重威胁人民群众的身体健康。由于HCC的独特生物学特性，发现时往往已是中晚期，只有30％～40％的患者适合根治性手术，大多数病人依靠化疗或介入化疗，而在化疗过程中，HCC对不同结构和功能的化疗药物产生耐受，即多药耐药(multidrug resistance，MDR)明显影响化疗的效果。为此，克服HCC的MDR是改善其化疗效果的关键。
为了逆转HCC的多药耐药性，近年来，各国的科学家一直在研究、寻找有效的方法。从最初的P糖蛋白(P-glycoprotein，P-gp)抑制剂(拮抗剂)、寡核苷酸技术、反义RNA技术到调节MDR相关基因的基因治疗，但均存在抑制效率低或特异性不强、插入突变、细胞毒性等限制，以故未能应用于临床。RNA干扰技术(RNA interference，RNAi)是近年新发展的一种基因技术，其基本原理是内源性或外源性双链短RNA与细胞内切酶形成诱导沉默复合体(RNA induced silencing complex，RISC)，
BACKGROUND Hepatocellular carcinoma (HCC) is common in China with increasing mobidity and the second mortality of malignant cancer. HCC is often diagnosed in terminal stage, which is only 30%～40% of them indicated for radical operation because of its unique biology. Therefore, most of the HCC patients need to be treated by chemotherapy and interventing chemotherapy to improve their outcome. However, multidrug resistance (MDR) resulting from the chemotherapy hinders the prognosis of HCC.
In order to reverse the MDR of HCC, scientist has been working hard to search efficient measurements such as inhibitors of P-glycoprotein (P-gp), oligonucleotide, antisense RNA techniques and other techniques in regulating MDR-related gene expression. These measurements failed to be applied in clinics because of their low efficiency and speciality, insertional mutagenesis, cis-activation of silent genes by their strong promoters. RNA interference (RNAi) is a recently new approach of gene therapy, whose principal is that RISC (RNA induced silencing complex-consisted of endogenous or exogenous duplex short RNA and incision enzyme) identifies and shears its homologous gene of siRNA, thus degradating sequence specific mRNA and suppressing the targeted gene expression. RNAi is charactered by high specificity, heritage, diffusivity and posttranscriptional suppression. Many reports showed that siRNA/mdr1 could effectively reverse the MDR of several kinds of cancer cells in vivo and in vitro. As our knowledge, there is no reports about the effect of RNAi on HCC MDR. To investigate the possibility of reversal of HCC MDR by RNAi, we perform this study to search a new gene therapeutic measurement for improving the outcome of HCC.
为了逆转HCC的多药耐药性，近年来，各国的科学家一直在研究、寻找有效的方法。从最初的P糖蛋白(P-glycoprotein，P-gp)抑制剂(拮抗剂)、寡核苷酸技术、反义RNA技术到调节MDR相关基因的基因治疗，但均存在抑制效率低或特异性不强、插入突变、细胞毒性等限制，以故未能应用于临床。RNA干扰技术(RNA interference，RNAi)是近年新发展的一种基因技术，其基本原理是内源性或外源性双链短RNA与细胞内切酶形成诱导沉默复合体(RNA induced silencing complex，RISC)，
BACKGROUND Hepatocellular carcinoma (HCC) is common in China with increasing mobidity and the second mortality of malignant cancer. HCC is often diagnosed in terminal stage, which is only 30%～40% of them indicated for radical operation because of its unique biology. Therefore, most of the HCC patients need to be treated by chemotherapy and interventing chemotherapy to improve their outcome. However, multidrug resistance (MDR) resulting from the chemotherapy hinders the prognosis of HCC.
In order to reverse the MDR of HCC, scientist has been working hard to search efficient measurements such as inhibitors of P-glycoprotein (P-gp), oligonucleotide, antisense RNA techniques and other techniques in regulating MDR-related gene expression. These measurements failed to be applied in clinics because of their low efficiency and speciality, insertional mutagenesis, cis-activation of silent genes by their strong promoters. RNA interference (RNAi) is a recently new approach of gene therapy, whose principal is that RISC (RNA induced silencing complex-consisted of endogenous or exogenous duplex short RNA and incision enzyme) identifies and shears its homologous gene of siRNA, thus degradating sequence specific mRNA and suppressing the targeted gene expression. RNAi is charactered by high specificity, heritage, diffusivity and posttranscriptional suppression. Many reports showed that siRNA/mdr1 could effectively reverse the MDR of several kinds of cancer cells in vivo and in vitro. As our knowledge, there is no reports about the effect of RNAi on HCC MDR. To investigate the possibility of reversal of HCC MDR by RNAi, we perform this study to search a new gene therapeutic measurement for improving the outcome of HCC.
引文
1．吴阶平 主编．黄家驷外科学(第六版)．北京：人民卫生出版社．2002：50—121
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31．罗华友，杨家印，严律南，等．反义硫代磷酸寡核苷酸逆转肝癌细胞多药耐药的实验研究．中国普外基础与临床杂志，2001；8：220—222
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