HGFK1通过EGF/EGFR信号通路抑制乳腺癌骨转移的机制研究

Up to 70% incidence of bone metastases occurs in breast cancer. It is difficult to find it at the beginning stages. Bone metastasis is an important reason for killing breast cancer patients. To make an unambiguous diagnosis at the beginning stages and effective interventions are hotspot in the field of research. However, no satisfying progress has been made in this research field. The preliminary study of our team confirmed HGFK1 gene can inhibit tumor cell proliferation and metastasis, and induce apoptosis in tumor cells. Expression of recombinant adeno-associated virus HGFK1 could significantly inhibit the bone metastases of nude mouse model of breast cancer. In the clinical specimens of breast cancer, reduced HGFK1 expression and the bone metastasis was significantly correlated. Decrease of HGFK1 serum levels was found in 57.2% of breast cancer patients with bone metastases and the decrease occurred three months before the diagnosis of bone metastases in breast cancer. In this study, we will take gene chip to screen HGFK1 downstream signaling pathways, GST pulldown combination of mass spectrometry and co-immunoprecipitation studies to explore protein interacting with HGFK1 and to build Gene function network regulated by HGFK1 in bone metastasis of breast cancer. On the basis of the above research, depth understanding the role of HGFK1 played in the inhibition of bone metastases. In addition to investigate HGFK1 expression and the beginning of breast cancer bone metastasis in the large sample clinical samples, theoretical foundation of the HGFK1 for early diagnosis and prevention of breast cancer bone metastasis will be made.

乳腺癌骨转移的发病率高达70%，发现时常为晚期，是造成乳腺癌患者死亡重要原因，在其发生的开始阶段发现并进行有效的干预是该领域的研究热点，然而此方面的研究进展不甚理想。项目组的前期研究证实，HGFK1基因能抑制肿瘤细胞增殖转移，并诱导肿瘤细胞凋亡；重组腺相关病毒表达HGFK1能显著抑制乳腺癌裸鼠模型的骨转移；临床标本中HGFK1的表达降低与乳腺癌骨转移显著相关；57.2%的乳腺癌患者HGFK1的血清水平在骨转移发生前3个月开始显著下降，提示HGFK1水平降低与乳腺癌骨转移的发生密切相关。本研究拟通过基因芯片筛选HGFK1的下游信号途径, GST pulldown结合质谱和免疫共沉淀等方法研究与HGFK1相互作用的蛋白，构建HGFK1调控的相关基因功能关联网络，深入理解HGFK1发挥抑制骨转移功能的分子机制，同时在大样本临床标本中验证其早期预测效力，为乳腺癌骨转移的早期诊断和防治奠定理论基础。

乳腺癌骨转移的发病率高达70%，发现时常为晚期，是造成乳腺癌患者死亡重要原因，在其发生的开始阶段发现并进行有效的干预是该领域的研究热点，然而此方面的研究进展不甚理想。项目组的前期研究证实，HGFK1基因能抑制肿瘤细胞增殖转移，并诱导肿瘤细胞凋亡；重组腺相关病毒表达HGFK1能显著抑制乳腺癌裸鼠模型的骨转移；临床标本中HGFK1的表达降低与乳腺癌骨转移显著相关；57.2%的乳腺癌患者HGFK1的血清水平在骨转移发生前3个月开始显著下降，提示HGFK1水平降低与乳腺癌骨转移的发生密切相关。本研究拟通过基因芯片筛选HGFK1的下游信号途径, GST pulldown结合质谱和免疫共沉淀等方法研究与HGFK1相互作用的蛋白，构建HGFK1调控的相关基因功能关联网络，深入理解HGFK1发挥抑制骨转移功能的分子机制，同时在大样本临床标本中验证其早期预测效力，为乳腺癌骨转移的早期诊断和防治奠定理论基础。