AKR1B10促乳腺癌细胞转移的分子机制研究

More than 1.38 million of new women breast cancers are diagnozed worldwide,accounting for 458,000 death annually. Cancer metastasis is a key factor of breat cancer patient deaths, and the cell adhesion and migration plays a critical role in cancer metastasis. Preliminary studies in our laboratory have shown that aldo-keto reductase 1B10 (AKR1B10) is overexpressed in breast cancer and promotes cell adhesion and migration. Our hypothesis is that AKR1B10 may enhance lipogenesis in breast cancer cells, stimulate the lipid secondary messenger system of phosphatidylinositol 4,5-bisphosphate (PIP2), and thus upregulate adhesion molecule integrin 5α (ITGA5) and extracellular matrix protein fibronection (FN). In this study, we will use AKR1B10-expressed or silenced breast cancer cell lines to test this hypothesis and define the effects of AKR1B10 expression on PIP2 lipid secondary messengers and PIP2-mediated PKC/ERK and PI3K/AKT signaling pathways. We will elucidate the regulatory mechanisms of ITGA5α and FN upregulation by AKR1B10 and the effects on the formation and function of focal adhesion. Finally, we will confirm the role of AKR1B10 in breast cancer metastasis using orthotopic breast tumor models in femal nude mice. The study results will define AKR1B10 as a metastatic oncogene and advance our understanding of breast cancer metatstasis, developing a novel target for breast cancer therapy.

全球每年新发女性乳腺癌达138万，死亡45.8万。癌症转移是导致乳腺癌患者死亡的关键因素，癌细胞的粘附与迁移在肿瘤转移中起关键性作用。我们前期研究表明，醛酮还原酶1B10（AKR1B10）在乳腺癌中过表达，促进癌细胞粘附与迁移。其机制可能与AKR1B10促进乳腺癌细胞脂质合成，激活磷脂酰肌醇二磷酸（PIP2）第二信使系统，上调粘附分子整合素5α（ITGA5）与细胞外基质纤连蛋白（FN）有关。本研究拟用AKR1B10高表达及沉默的乳腺癌细胞模型，深入探讨AKR1B10表达对PIP2脂质第二信使系统及其介导的PKC/ERK与PI3K/AKT信号通路的影响，阐明AKR1B10上调ITGA5与FN的机制及其在粘着斑形成与功能中的作用，进一步，用裸鼠体内原位乳腺癌与远处转移瘤模型验证AKR1B10促乳腺癌转移作用。本研究将率先确定AKR1B10促乳腺癌侵袭转移的作用与机制，为乳腺癌的治疗提供新靶点。

全球每年新发女性乳腺癌达138万，死亡45.8万。癌症转移是导致乳腺癌患者死亡的关键因素，癌细胞的粘附与迁移在肿瘤转移中起关键性作用。我们前期研究表明，醛酮还原酶1B10（AKR1B10）在乳腺癌中过表达，促进癌细胞粘附与迁移。其机制可能与AKR1B10促进乳腺癌细胞脂质合成，激活磷脂酰肌醇二磷酸（PIP2）第二信使系统，上调粘附分子整合素5α（ITGA5）与细胞外基质纤连蛋白（FN）有关。本研究拟用AKR1B10高表达及沉默的乳腺癌细胞模型，深入探讨AKR1B10表达对PIP2脂质第二信使系统及其介导的PKC/ERK与PI3K/AKT信号通路的影响，阐明AKR1B10上调ITGA5与FN的机制及其在粘着斑形成与功能中的作用，进一步，用裸鼠体内原位乳腺癌与远处转移瘤模型验证AKR1B10促乳腺癌转移作用。本研究将率先确定AKR1B10促乳腺癌侵袭转移的作用与机制，为乳腺癌的治疗提供新靶点。