Thyroid Cancer Gene Therapyt with Molecular Targeting by Radio-responsing genes

甲状腺滤泡细胞来源的癌在病理学上分为分化（乳头状和滤泡状）和未分化（间变性）癌。分化型甲状腺癌预后较好，但未分化型甲状腺癌侵袭性强、致死率高，治疗效果差。外照射加化疗可为甲状腺未分化癌患者提供相对长期生存的机会。迫切需要发现新的有效疗法。这一策略的一个候选者是基因治疗，它将选择性地具有细胞毒性或将增加对未分化甲状腺癌的电离辐射的敏感性。为了寻找癌症特异性靶点，我们挑战了SAGE筛选（DNA Sequence 2000）和基于PCR的减法（BBCR 2001）。在我们发现的候选基因中，我们集中于受p53结合同源元件转录调控的放射诱导hSNK基因（BBRC 2001）。接下来，我们阐明了电离辐射在甲状腺细胞中特异性诱导的信号转导途径。它涉及通过MKK 7介导电离辐射诱导的c-Jun激酶活化的PKC-δ（Oncogene 2001）。最后，我们在实验模型中展示了潜在的基因治疗方法（Cancer Gene Therapy 2001，Human Gene Therapy 2000）。

Thyroid follicular cell-derived carcinomas are classified pathologically as differentiated (papillary and follicular) and undifferentiated (anaplastic) carcinoma. Although differentiated carcinoma have relatively good prognosis, anaplastic thyroid carcinoma are highly aggressive and extremely lethal, with poor therapeutic response. External beam radiotherapy with chemotherapy would provide the chance for relative long-terrm survival of patients in thyroid anaplastic carcinoma. The discovery of new potent therapy is urgently warranted. A candidate of this strategy is gene therapy that will be selectively cytotoxic or will increase sensitivity to the ionizing radiationo for anaplastic thyroid cancer. To search the cancer-specific targets, we challenged SAGE screening (DNA Sequence 2000) and PCR-based subtraction (BBCR2001). Among the candidate genes that we found, we focused on radio-inducible hSNK gene which is transcriptionally regulated by p53 binding homology element (BBRC 2001). Next we elucidated a signal transduction pathway specifically induced by ionizing radiation in thyroid cells. It involved PKC-delta that mediates ionizing radiation-induced activation of c-Jun kinase through MKK7 (Oncogene 2001). Finally, we have demonstrated the potential gene therapy approachs in experimental model (Cancer Gene Therapy 2001, Human Gene Therapy 2000).