本文選題：抑郁　切入點：血清素　出處：《重慶醫(yī)科大學(xué)》2016年博士論文

【摘要】：乳腺癌骨轉(zhuǎn)移機制復(fù)雜,涉及乳腺癌細胞與骨基質(zhì)之間的相互作用—土壤和種子(soil and seed)學(xué)說。當(dāng)乳腺癌出現(xiàn)骨轉(zhuǎn)移時,骨組織內(nèi)成骨細胞和破骨細胞的平衡被打破并產(chǎn)生一些活性因子直接或間接地激活骨微環(huán)境中的破骨細胞,而破骨細胞的激活同樣可以釋放生長因子(如TGF-β)反過來刺激腫瘤細胞的生長,最終導(dǎo)致骨溶解。這種在乳腺癌細胞和骨微環(huán)境中的雙向互動性導(dǎo)致的惡性循環(huán)(vicious cycle)是乳腺癌骨轉(zhuǎn)移的主要機制之一。抑郁在乳腺癌女性患者中較為常見,發(fā)病率可達到10-25%。研究發(fā)現(xiàn),進展期乳腺癌患者出現(xiàn)抑郁時的死亡率要明顯高于非抑郁患者,然而其機制目前仍不是很清楚。最近研究報道,抑郁的患者會出現(xiàn)骨密度(bone mineral density,BMD)的下降和骨吸收。進一步研究發(fā)現(xiàn),在抑郁狀態(tài)時,腸源性血清素的再攝取出現(xiàn)障礙,導(dǎo)致血液循環(huán)中的血清素增加,引起成骨細胞增殖活動受抑制,這可能是導(dǎo)致骨質(zhì)疏松的重要原因之一。近來有研究證實,人乳腺癌表達4種不同的血清素受體,分別是1A、1B、2B和4。在人乳腺癌細胞株,外源性性的血清素可以誘導(dǎo)甲狀旁腺激素相關(guān)蛋白(parathyroid hormone-related peptide,PTHrP)和轉(zhuǎn)移相關(guān)轉(zhuǎn)錄因子Runx2/Cbfa1表達的增加。因此,我們推測在抑郁狀態(tài)下,腸源性血清素有可能直接通過破壞骨組織重建平衡(即成骨細胞與破骨細胞之間的活動平衡),導(dǎo)致乳腺癌細胞易于在骨組織著落和增殖,或者血清素間接通過乳腺癌細胞破壞骨微環(huán)境而導(dǎo)致骨組織溶解性破壞�；谝陨涎芯�,我們首先利用乳腺癌細胞株MDA-MB-231通過左心注射建立乳腺癌骨轉(zhuǎn)移裸小鼠動物模型;在注射乳腺癌細胞前對小鼠進行慢性溫和刺激以建立抑郁模型。我們設(shè)計人RUNX-2基因的shRNA以沉默RUNX-2基因,通過shRUNX-2轉(zhuǎn)染乳腺癌細胞來研究RUNX-2基因在乳腺癌骨轉(zhuǎn)移中的作用。利用共培養(yǎng)體系來研究乳腺癌細胞對成骨分化和破骨分化的影響。實驗發(fā)現(xiàn),抑郁可以促進乳腺癌骨轉(zhuǎn)移的發(fā)生,這種作用可能是通過刺激破骨細胞分化和抑制成骨細胞分化來實現(xiàn)的。外源性的血清素引起乳腺癌細胞內(nèi)RUNX-2的明顯表達,通過PTHrP/RANKL途徑來抑制成骨分化和促進破骨分化,導(dǎo)致骨轉(zhuǎn)移部位溶解性骨破壞。此外,抑郁引起的乳腺癌骨轉(zhuǎn)移可以用腸源性血清素抑制劑LP533401來抑制,提示腸源性血清素在其中發(fā)揮重要作用。RUNX-2基因沉默后發(fā)現(xiàn),乳腺癌骨轉(zhuǎn)移明顯減少,提示RUNX-2基因在骨轉(zhuǎn)移中起到關(guān)鍵作用�？傊�,抑郁可能通過刺激腸源性的血清素來促進乳腺癌的骨轉(zhuǎn)移;循環(huán)中的血清素增加可以破壞成骨細胞和破骨細胞間的平衡關(guān)系,導(dǎo)致成骨抑制和破骨活動增加,顯示可以通過抑制腸源性的血清素來減少抑郁引起的乳腺癌骨轉(zhuǎn)移的發(fā)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.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R737.9

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