Sirt3对乳腺癌新生血管形成的调控及超声微血管显像的检测

Breast cancer is the most frequent cancer in the world. Tumor angiogenesis is essential for the growth，spread，invasion and metastasis of breast cancer cells.It is of significance to reveal the molecular mechanism of breast cancer angiogenesis and further find the switch molecule upstream on angiogenic pathway. Sirt3 can inhibit the HIF-1αactivity and VEGF expression, and there is a close relation between Sirt3 and the angiogenesis. Superb Microvascular Imaging（SMI）, as a novel technique to detect and characterize angiogenesis, can clearly demonstrate microvasculature with blood lower velocities of breast tumor, without using contrast agents. Also, it is important to increase the understanding of these abnormal microvascular actions.. This study will focus on the biological effects of Sirt3 and HIF-1αon breast tumor angiogenesis and its development by means of animal experiment and clinical investigation using SMI, in order to try to establish the basis of SMI molecular biology and pathological morphology, to reveal the control mechanism of Sirt3 over breast cancer angiogenesis and to provide a theoretical basis and experimental data of its target therapy. It can be expected to create a model of SMI and Sirt3 molecular diagnosis, i.e. composite biological markers of molecular imaging about tumor angiogenesis, and to build a platform for early detecting cancers, developing their medicines, and making individual anti-tumor-angiogenesis medicine schemes for follow-up therapy.

乳腺癌是全球女性发病率最高的恶性肿瘤。乳腺癌的发生、侵袭和转移具有明显的血管依赖性。深入揭示乳腺癌新生血管形成的分子机制，寻找到血管生成通路上游的开关分子意义重大。Sirt3可抑制HIF-1α活性及VEGF的表达，与血管新生密切相关。超声微血管显像（SMI）可在不使用造影剂情况下，检测到极细小的低流速血流，是研究肿瘤新生血管的崭新技术手段，其检测在体肿瘤新生血管功能及调控机制值得深入研究。 . 本研究拟通过动物实验及临床研究分别探讨Sirt3、HIF-1α在乳腺癌肿瘤新生血管发生及发展中的生物学作用，SMI的分子生物学及病理形态学基础；揭示Sirt3对新生血管的调控机制，为肿瘤靶向治疗提供理论基础和实验依据。预期建立SMI与Sirt3分子的诊断模型，即“分子影像复合生物标志物"，为肿瘤早期诊断、药物研发及肿瘤患者后续抗血管生成药物的个体化治疗搭建新的平台。

乳腺癌是全球女性发病率最高的恶性肿瘤，乳腺癌的发生、侵袭和转移具有明显的血管依赖性。深入揭示乳腺癌新生血管形成的分子机制，对乳腺癌新生血管评估意义重大。本研究通过动物实验及临床研究分别探讨Sirt3、HIF-1α在乳腺癌肿瘤新生血管发生及发展中的生物学作用，通过SMI技术评估乳腺肿瘤新生血管效能以研究其临床应用价值。结果显示Sirt3蛋白及HIF-1α蛋白在乳腺癌中的表达呈负相关，Sirt3蛋白在乳腺癌及乳腺癌细胞系中表达降低，HIF-1α蛋白在乳腺癌及乳腺癌细胞系中表达升高，过表达Sirt3组移植瘤体积及VI值小于Sirt3敲低组，提示Sirt3可能与抑制乳腺癌体积生长及抑制新生血管形成相关。SMI技术作为一项创新无创检测病变内微血管的多普勒技术，可通过定量评估病变内VI值和血流架构提高诊断效能，以4.05的VI值为识别良恶性病变的阈值，敏感性79.2%，特异性64.6%，曲线下面积0.762(0.72~0.81)；以残根状、蟹足状作为恶性血流架构，诊断敏感性58%，特异性95.8%，AUC曲线下面积0.795（95%CI:0.758-0.838），VI值与病理MVD相关较好，SMI技术有望成为术前无创评估血流丰富程度的定量指标，具有较高的临床应用价值。