探索CD24靶向的肿瘤细胞识别及突变型p53功能恢复的精准治疗

Metastatic prostate cancer is a leading cause of cancer death in men, but the underlying mechanism remains elusive. CD24 is not expressed in normal prostate epithelial cells, but it is often over-expressed in metastatic prostate cancers. Of note, oncogenic function of CD24 has been demonstrated by multiple functional studies. Recently, we discovered a new concept of CD24-causing inactivation of mutant p53, which is a frequently mutated gene found in metastatic prostate cancer. For human prostate cancer samples, TP53 mutations is often associated with overexpression of CD24 that are correlated with prostate cancer metastasis, suggesting that CD24-causing inactivation of mutant p53 may contribute to tumor metastasis in patients with prostate cancer. In this proposed study, using cell and animal models, we will determine the molecular mechanism of CD24-causing inactivation of mutant p53 during tumor metastasis and develop the targeting therapy of CD24 for reactivation of mutant p53 to block tumor metastasis. Thus, targeting CD24 and mutant p53 will become a potential approach for restoration of mutant p53 as well as effective therapy for patients with metastatic prostate cancer.

前列腺癌的转移是该疾病死亡的根本原因，但其发生的分子机理仍不明确。我们的研究显示CD24在正常的前列腺上皮细胞中不表达，但在晚期及转移性前列腺癌中高表达。CD24的原癌基因功能已被异位表达、诱导性表达、靶向突变、基因沉默及抗体阻断等方式证实。重要的是，我们前期研究发现，CD24和突变型p53常联合表达并与转移性前列腺癌密切相关，且功能研究显示CD24促进突变型p53的失活，而沉默CD24能复原突变型p53的功能。因此，靶向CD24是潜在恢复突变型p53功能及治疗转移性前列腺癌的新途径。本研究中，我们将利用细胞模型和动物模型，在体内和体外鉴定CD24促进突变型p53失活对前列腺癌转移的影响及分子机理和探索CD24靶向的肿瘤细胞识别及突变型p53功能恢复的精准治疗。我们的目标是为前列腺癌转移的分子机制提供新概念，同时也为转移性前列腺癌患者提供新的治疗策略。

前列腺癌的转移是该疾病死亡的根本原因，但其发生的分子机理仍不明确。我们的研究显示CD24在正常的前列腺上皮细胞中不表达，但在晚期及转移性前列腺癌中高表达。CD24的原癌基因功能已被异位表达、诱导性表达、靶向突变、基因沉默及抗体阻断等方式证实。本研究中，我们利用细胞模型和动物模型，在体内和体外鉴定CD24促进突变型p53失活对前列腺癌转移的影响及分子机理和探索CD24靶向的肿瘤细胞识别及突变型p53功能恢复的精准治疗。结果表明：CD24 与前列腺癌进展及转移密切相关，同时CD24 导致的突变型p53 失活与前列腺癌转移也存在相关性；重要的是，由于CD24 导致的突变型p53失活与前列腺癌转移密切相关， CD24 和突变型p53 作为一个整合评估因子，可能成为有效地预测或评估肿瘤转移的生物学标记物；进而我们的初步研究也表明，靶向CD24 或利用靶向CD24 携带有效的治疗药物消灭转移或复发的肿瘤细胞，有潜力成为从而实现对肿瘤细胞精准而有效的靶向治疗。上述成果为探讨前列腺癌转移的分子机制提供新概念，同时也为转移性前列腺癌患者提供新的治疗策略.