中文摘要
恶性肿瘤是严重威胁人类健康的疾病，降低癌症危害的关键在于早期发现和早期治疗。本课题针对我国常见恶性肿瘤食管癌、肺癌、大肠癌及膀胱癌，根据其临床特点采集相应标本，研究获得了检测这些肿瘤的多个早期分子标志，包括染色体DNA探针组合和肿瘤过表达蛋白，建立了与细胞学相结合的实用原位分子标记方法。进而从机制方面，深入揭示了候选标志物分子可能用于肿瘤早期诊断的理论基础和科学依据，取得了多项重要发现：① CRT-STAT3-CTTN-PI3K-AKT是一条影响细胞失巢凋亡的新的信号通路。CTTN介导PI3K-AKT通路活化和细胞失巢凋亡抗性，参与肿瘤的侵袭性生长。CRT促使STAT3磷酸化，STAT3激活CTTN转录。② SKP2通过与CTTN不同的途径活化PI3K-AKT信号通路，增强肿瘤细胞的抗失巢凋亡和侵袭性生长能力，PRKCI以蛋白酶体依赖方式正调节SKP2的表达水平。③ PLK1抑制beta-catenin的泛素化降解，并且与survivin相互作用而增强细胞的凋亡抗性，共同促进肿瘤的侵袭性生长。这些发现将为开发针对上述肿瘤的早期分子诊断试剂和分子靶向药物提供重要理论基础。
英文摘要
Early detection and early diagnosis are of vital importance to the successful treatment of human cancers. The present study focused on early molecular alterations in esophageal cancer, lung cancer, colorectal cancer and bladder cancer. We found multiple combinations of molecular markers for early detection of the common malignancies, including DNA probes and proteins with over-expression in tumors. We established a practical technique of in situ labeling combined with cyto-morphology for early diagnosis of cancer. With esophageal cancer cells as a model, we revealed the mechanisms underlying the function of candidate molecules in the development and the progression of the diseases. We observed a novel pathway CRT-STAT3-CTTN-AKT in which CRT regulates the transcription of CTTN through STAT3, and CTTN plays a protective role from anoikis by the activation of the PI3K/AKT. Elevated expression of SKP2 protects cancer cells from anoikis, which is mediated by PI3K/AKT pathway. PRKCI is a candidate oncogene and enhances resistance to anoikis via the PRKCI-SKP2-AKT pathway. SKP2 is a downstream effector of PRKCI signaling in tumors. PLK1 promotes apoptosis via mitochondria signaling pathways through modulating beta-catenin protein levels by inhibiting its degradation. PLK1 interacts with survivin, and the latter is invo
结题摘要
恶性肿瘤是严重威胁人类健康的疾病，降低癌症危害的关键在于早期发现和早期治疗。本课题针对我国常见恶性肿瘤食管癌、肺癌、大肠癌及膀胱癌，根据其临床特点采集相应标本，研究获得了检测这些肿瘤的多个早期分子标志，包括染色体DNA探针组合和肿瘤过表达蛋白，建立了与细胞学相结合的实用原位分子标记方法。进而从机制方面，深入揭示了候选标志物分子可能用于肿瘤早期诊断的理论基础和科学依据，取得了多项重要发现：① CRT-STAT3-CTTN-PI3K-AKT是一条影响细胞失巢凋亡的新的信号通路。CTTN介导PI3K-AKT通路活化和细胞失巢凋亡抗性，参与肿瘤的侵袭性生长。CRT促使STAT3磷酸化，STAT3激活CTTN转录。② SKP2通过与CTTN不同的途径活化PI3K-AKT信号通路，增强肿瘤细胞的抗失巢凋亡和侵袭性生长能力，PRKCI以蛋白酶体依赖方式正调节SKP2的表达水平。③ PLK1抑制beta-catenin的泛素化降解，并且与survivin相互作用而增强细胞的凋亡抗性，共同促进肿瘤的侵袭性生长。这些发现将为开发针对上述肿瘤的早期分子诊断试剂和分子靶向药物提供重要理论基础。