蟾毒灵调控低氧诱导内质网应激抑制乳腺癌细胞干性机制研究

Breast cancer is one of the most common malignant tumor threatening to female health in the world. Recent studies reported that breast stem-like cancer are highly carcinogenesis, invasion and metastasis. Inhibition of cancers' stemness is the key to the treatment of breast cancer. Our previous study found that hypoxia induces the proliferation, also enhances the expression of endoplasmic reticulum stress effector BiP, and stem-like marker CD44, Nanog in breast cancer cells. Bufalin, one component from Traditional Chinese medicine Toad Venom, suppresses proliferation, clone formation, and the protein expression of BiP, CD44, Nanog in breast cancer cells induced by hypoxia . Therefore, we propose that hypoxia can induce endoplasmic reticulum stress(ERs), and enhance stemness of breast cancer cells. Bufalin inhibits stemness of breast cancer cells though the pathway of ERs induced by hypoxia. We will use some methods, such as Lenti-virus shRNA, Western-Bloting and qRT-PCR, to explore the important function and mechanism of ERs for stemness of breast cancer cells induced by hypoxia. We also investigate that bufalin inhibits breast cancer cells' stemness through the pathway of ERs induced by hypoxia .This study will provide the potential therapeutic strategy for the stemness of breast cancer, and discover an active lead-compound derived from traditional Chinese medicine for the therapy of breast cancer.

乳腺癌严重危害女性健康。目前研究发现具有干性的乳腺癌细胞有强致癌性和高转移侵袭性，抑制乳腺癌肿瘤干性是治疗乳腺癌的关键。本课题组前期发现：低氧诱导加快乳腺癌肿瘤细胞的增殖；增强内质网应激效应分子BiP、肿瘤细胞干性分子CD44、Nanog的表达。中药蟾酥中的成分蟾毒灵对低氧条件下乳腺癌细胞增殖、克隆形成有抑制作用；抑制BiP、CD44、Nanog的表达。由此我们提出，低氧能够诱导产生内质网应激，增强乳腺癌细胞干性；蟾毒灵可以通过负性调控低氧诱导的内质网应激，抑制乳腺癌肿瘤细胞干性。本课题拟通过lenti-virus shRNA技术、Western-Blot、qRT-PCR等实验方法，观察低氧诱导的内质网应激对乳腺癌干性的上调作用，研究蟾毒灵通过影响内质网应激抑制乳腺癌细胞干性的机制。本研究将为乳腺癌肿瘤干性靶点治疗提供相应的治疗策略，并且为乳腺癌的药物治疗提供来源于中药的活性先导化合物。

乳腺癌严重危害女性健康。具有干性的乳腺癌肿瘤细胞具有强致癌性和高转移、侵袭性。针对乳腺癌的干性治疗是治疗乳腺癌肿瘤的关键。本课题发现低氧诱导内质网应激激活乳腺癌肿瘤干性。内质网应激的信号分子BiP、ATF6、PERK等对维持、增强乳腺癌肿瘤干性起到重要作用。 我们发现中药活性单体蟾毒灵通过介导低氧条件下内质网应激，抑制乳腺癌肿瘤干性，同时我们在立足于本课题的研究基础上发现蟾毒灵能够负性调控HIF-1α介导Wnt/β-catenin信号通路抑制低氧条件下乳腺癌干性。本研究为乳腺癌的药物治疗提供来源于中药的小分子活性先导化合物。