抑郁通过肠源性血清素对乳腺癌骨转移的影响及机制研究

发布时间：2018-03-31 10:25

本文选题：抑郁　切入点：血清素　出处：《重庆医科大学》2016年博士论文

【摘要】：乳腺癌骨转移机制复杂,涉及乳腺癌细胞与骨基质之间的相互作用—土壤和种子(soil and seed)学说。当乳腺癌出现骨转移时,骨组织内成骨细胞和破骨细胞的平衡被打破并产生一些活性因子直接或间接地激活骨微环境中的破骨细胞,而破骨细胞的激活同样可以释放生长因子(如TGF-β)反过来刺激肿瘤细胞的生长,最终导致骨溶解。这种在乳腺癌细胞和骨微环境中的双向互动性导致的恶性循环(vicious cycle)是乳腺癌骨转移的主要机制之一。抑郁在乳腺癌女性患者中较为常见,发病率可达到10-25%。研究发现,进展期乳腺癌患者出现抑郁时的死亡率要明显高于非抑郁患者,然而其机制目前仍不是很清楚。最近研究报道,抑郁的患者会出现骨密度(bone mineral density,BMD)的下降和骨吸收。进一步研究发现,在抑郁状态时,肠源性血清素的再摄取出现障碍,导致血液循环中的血清素增加,引起成骨细胞增殖活动受抑制,这可能是导致骨质疏松的重要原因之一。近来有研究证实,人乳腺癌表达4种不同的血清素受体,分别是1A、1B、2B和4。在人乳腺癌细胞株,外源性性的血清素可以诱导甲状旁腺激素相关蛋白(parathyroid hormone-related peptide,PTHrP)和转移相关转录因子Runx2/Cbfa1表达的增加。因此,我们推测在抑郁状态下,肠源性血清素有可能直接通过破坏骨组织重建平衡(即成骨细胞与破骨细胞之间的活动平衡),导致乳腺癌细胞易于在骨组织着落和增殖,或者血清素间接通过乳腺癌细胞破坏骨微环境而导致骨组织溶解性破坏。基于以上研究,我们首先利用乳腺癌细胞株MDA-MB-231通过左心注射建立乳腺癌骨转移裸小鼠动物模型;在注射乳腺癌细胞前对小鼠进行慢性温和刺激以建立抑郁模型。我们设计人RUNX-2基因的shRNA以沉默RUNX-2基因,通过shRUNX-2转染乳腺癌细胞来研究RUNX-2基因在乳腺癌骨转移中的作用。利用共培养体系来研究乳腺癌细胞对成骨分化和破骨分化的影响。实验发现,抑郁可以促进乳腺癌骨转移的发生,这种作用可能是通过刺激破骨细胞分化和抑制成骨细胞分化来实现的。外源性的血清素引起乳腺癌细胞内RUNX-2的明显表达,通过PTHrP/RANKL途径来抑制成骨分化和促进破骨分化,导致骨转移部位溶解性骨破坏。此外,抑郁引起的乳腺癌骨转移可以用肠源性血清素抑制剂LP533401来抑制,提示肠源性血清素在其中发挥重要作用。RUNX-2基因沉默后发现,乳腺癌骨转移明显减少,提示RUNX-2基因在骨转移中起到关键作用。总之,抑郁可能通过刺激肠源性的血清素来促进乳腺癌的骨转移;循环中的血清素增加可以破坏成骨细胞和破骨细胞间的平衡关系,导致成骨抑制和破骨活动增加,显示可以通过抑制肠源性的血清素来减少抑郁引起的乳腺癌骨转移的发生。
[Abstract]:The mechanism of breast cancer bone metastasis is complex and involves the interaction between breast cancer cells and bone matrix soil and seed soil and seed.When breast cancer has bone metastasis, The balance of osteoblasts and osteoclasts in bone tissue is broken and some active factors are produced to activate osteoclasts in bone microenvironment directly or indirectly. The activation of osteoclasts also releases growth factors (such as TGF- 尾), which in turn stimulates the growth of tumor cells. Ultimately, osteolysis, a vicious cycle of two-way interaction in breast cancer cells and bone microenvironments, is one of the main mechanisms of bone metastasis in breast cancer. Depression is more common in women with breast cancer. The incidence rate can reach 10-25. The study found that the mortality rate of patients with advanced breast cancer is significantly higher than that of patients with non-depression, but the mechanism is still not clear. Recent research reported that the mortality rate of patients with advanced breast cancer is significantly higher than that of patients with non-depression. Patients with depression have decreased bone mineral density (BMD) and bone resorption. Further studies have found that during depression, the reuptake of enterogenic serotonin is impaired, leading to an increase in serotonin in the blood circulation. The inhibition of osteoblast proliferation may be one of the important factors leading to osteoporosis. Recent studies have confirmed that human breast cancer expresses four different serotonin receptors, 1A1BN-2B and 4. in human breast cancer cell lines, Exogenous serotonin can induce increased expression of parathyroid hormone-related peptidetin (PTHrP) and metastasis related transcription factor (Runx2/Cbfa1). It is possible that enterogenic serotonin can cause breast cancer cells to easily locate and proliferate in bone tissue by directly destroying the balance between osteoblasts and osteoclasts. Or serotonin indirectly destroys bone microenvironment through breast cancer cells and leads to the destruction of bone tissue solubility. Based on the above study we first established nude mice model of breast cancer bone metastasis by injecting breast cancer cell line MDA-MB-231 through left heart. We designed the shRNA of human RUNX-2 gene to silence the RUNX-2 gene. The role of RUNX-2 gene in bone metastasis of breast cancer was studied by shRUNX-2 transfection. The effects of RUNX-2 gene on osteogenesis and osteoclast differentiation were studied by co-culture system. Depression can promote bone metastasis in breast cancer, which may be achieved by stimulating osteoclast differentiation and inhibiting osteoblast differentiation. Exogenous serotonin can induce the expression of RUNX-2 in breast cancer cells. PTHrP/RANKL pathway inhibits osteogenic differentiation and promotes osteoclast differentiation, leading to osteolytic destruction in bone metastases. In addition, depressive breast cancer bone metastasis can be inhibited by enterogenic serotonin inhibitor LP533401. The results suggest that enterogenic serotonin plays an important role in this process. After silencing the RUNX-2 gene, it is found that bone metastasis in breast cancer decreases significantly, suggesting that RUNX-2 gene plays a key role in bone metastasis. Depression may promote bone metastasis in breast cancer by stimulating enterogenic serotonin; increased serotonin in circulation can disrupt the balance between osteoblasts and osteoclasts, leading to osteogenic inhibition and increased osteoclast activity. It has been shown that depression-induced bone metastasis can be reduced by inhibiting enterogenic serotonin.
【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9

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