本文選題：Hepcidin + 前列腺癌��； 參考：《蘇州大學(xué)》2014年博士論文

【摘要】：前列腺癌是男性常見(jiàn)的惡性腫瘤，在男性癌癥死亡人數(shù)中居第二位。新的研究認(rèn)為機(jī)體鐵代謝在前列腺癌的生長(zhǎng)，血管發(fā)生和轉(zhuǎn)移中起著重要的作用。鐵是人體維持機(jī)能必要的微量元素，廣泛參與人體的生長(zhǎng)代謝。很多腫瘤的發(fā)生發(fā)展對(duì)鐵的需要增加，被認(rèn)為是維持腫瘤細(xì)胞生長(zhǎng)和發(fā)展的基本物質(zhì)，有研究認(rèn)為，通過(guò)調(diào)控鐵代謝的變化，減少胞內(nèi)鐵的利用，可以影響腫瘤的進(jìn)展，作為抗腫瘤治療的方向。 Hepcidin由肝細(xì)胞合成和分泌，是已知的在機(jī)體鐵代謝調(diào)節(jié)中起重要作用的核心分子，稱之為鐵調(diào)素。它通過(guò)減少網(wǎng)狀內(nèi)皮細(xì)胞系統(tǒng)對(duì)胞內(nèi)游離鐵的釋放，同時(shí)通過(guò)減少十二指腸的鐵吸收，負(fù)性調(diào)節(jié)鐵代謝平衡，在機(jī)體鐵代謝中起到核心調(diào)控作用。已有的研究通過(guò)一系列動(dòng)物模型和已知的鐵代謝異常患者探討Hepcidin的作用機(jī)制，敲除Hepcidin基因的小鼠可出現(xiàn)鐵超載，而過(guò)表達(dá)Hepcidin的小鼠以及過(guò)分泌Hepcidin的人群都則表現(xiàn)為缺鐵性貧血。Hepcidin在腫瘤人群中的表達(dá)，對(duì)機(jī)體鐵代謝的作用已引起很多學(xué)者的重視。有研究表明，在機(jī)體鐵代謝中Hepcidin通過(guò)對(duì)其受體Ferroportin的調(diào)節(jié)，將細(xì)胞內(nèi)游離鐵轉(zhuǎn)運(yùn)至胞外，腫瘤細(xì)胞伴隨低表達(dá)的Ferroportin產(chǎn)生額外的胞內(nèi)游離鐵，使得腫瘤細(xì)胞更具有侵襲性，，而Hepcidin在前列腺癌中的作用未見(jiàn)有詳細(xì)論述。 因此，我們研究Hepcidin的表達(dá)與前列腺癌的相關(guān)性，對(duì)前列腺癌細(xì)胞的Hepcidin進(jìn)行干擾后對(duì)腫瘤細(xì)胞生物學(xué)功能的影響，以及Hepcidin調(diào)控前列腺癌細(xì)胞鐵代謝的作用機(jī)制，對(duì)Hepcidin通過(guò)調(diào)控鐵代謝對(duì)前列腺癌的進(jìn)展產(chǎn)生影響進(jìn)行探討。研究分三部分： 第一部分：Hepcidin的表達(dá)與前列腺癌的臨床相關(guān)性研究 目的：研究Hepcidin在前列腺癌患者中的表達(dá)變化以及與鐵代謝的臨床相關(guān)性。方法：采用酶聯(lián)免疫法（ELISA）測(cè)定前列腺癌骨轉(zhuǎn)移患者25例、前列腺癌無(wú)骨轉(zhuǎn)移患者30例和普通對(duì)照組前列腺增生患者30例的血清Hepcidin、IL-6、sTfR和BMP6的表達(dá)，以及檢測(cè)所有標(biāo)本的血紅蛋白（HB）；免疫組化檢測(cè)組織標(biāo)本的Hepcidin受體Ferroportin的表達(dá)，分析其與前列腺癌分級(jí)分期的相關(guān)性關(guān)系，研究Hepcidin與前列腺癌的臨床關(guān)聯(lián)。 結(jié)果：前列腺癌骨轉(zhuǎn)移患者的血清Hepcidin較前列腺癌無(wú)骨轉(zhuǎn)移組、普通對(duì)照前列腺增生組有明顯增高，有統(tǒng)計(jì)學(xué)差異（P0.05）；并且與IL-6、BMP6的表達(dá)呈正相關(guān)，與sTfR的表達(dá)呈負(fù)相關(guān)；前列腺癌組織中Hepcidin的受體Ferroportin表達(dá)較前列腺增生組織明顯減少，染色淺，差異明顯；Ferroportin的表達(dá)和前列腺癌的惡性程度呈反相關(guān)。 結(jié)論：前列腺癌患者的Hepcidin表達(dá)增高，受體Ferroportin表達(dá)降低，可能與機(jī)體的炎癥狀態(tài)、骨轉(zhuǎn)移的程度有關(guān)，Hepcidin可能作為臨床判斷前列腺癌的進(jìn)展程度的指標(biāo)，為前列腺癌的診斷提供新的方法。 第二部分:Hepcidin調(diào)控前列腺癌細(xì)胞生物學(xué)功能的研究 目的：探討Hepcidin在前列腺癌細(xì)胞中的表達(dá)變化，以及Hepcidin對(duì)前列腺癌細(xì)胞增殖、遷移和凋亡等細(xì)胞生物學(xué)功能的影響。 方法：測(cè)定Hepcidin在前列腺癌細(xì)胞中的表達(dá)；通過(guò)小干擾RNA的方法下調(diào)前列腺癌細(xì)胞株P(guān)C3、DU145中的Hepcidin，研究Si-Hepcidin前列腺癌細(xì)胞增殖、遷移、細(xì)胞周期、抗凋亡能力的表達(dá)變化情況；并將Si-Hepcidin前列腺癌細(xì)胞株P(guān)C3植入裸鼠體內(nèi)形成前列腺癌細(xì)胞移植瘤，分析Si-Hepcidin前列腺癌細(xì)胞成瘤與對(duì)照組在體內(nèi)的生長(zhǎng)差異。 結(jié)果：前列腺癌細(xì)胞的Hepcidin表達(dá)較正常前列腺細(xì)胞高，有統(tǒng)計(jì)學(xué)差異（P0.05）；Hepcidin干擾后的前列腺癌細(xì)胞株增殖、遷移、抗凋亡能力較空白對(duì)照組和陰性對(duì)照組明顯減弱，有統(tǒng)計(jì)學(xué)差異（P0.05）；Si-Hepcidin的前列腺癌細(xì)胞在裸鼠體內(nèi)成瘤體積較對(duì)照組小，有統(tǒng)計(jì)學(xué)差異（P0.05）。結(jié)論：Hepcidin在前列腺癌細(xì)胞中高表達(dá)；Si-Hepcidin對(duì)前列腺癌細(xì)胞的增殖、遷移、細(xì)胞周期、抗凋亡能力產(chǎn)生影響，并且引起前列腺癌細(xì)胞成瘤的改變，說(shuō)明Hepcidin可能通過(guò)鐵代謝的信號(hào)通路對(duì)腫瘤細(xì)胞的生長(zhǎng)和侵襲產(chǎn)生調(diào)控，在前列腺癌的進(jìn)展中起到重要作用。 第三部分：外源性Hepcidin調(diào)控前列腺癌細(xì)胞鐵代謝的分子機(jī)制研究 目的：探討Hepcidin與前列腺癌細(xì)胞中鐵代謝信號(hào)通路分子表達(dá)變化的關(guān)系，通過(guò)外源性Hepcidin對(duì)前列腺癌細(xì)胞生物學(xué)功能產(chǎn)生的變化及鐵代謝分子機(jī)制研究，說(shuō)明Hepcidin通過(guò)調(diào)控細(xì)胞鐵代謝對(duì)前列腺癌的進(jìn)展產(chǎn)生影響。 方法：體外培養(yǎng)前列腺癌細(xì)胞株P(guān)C3和Si-Hepcidin PC3，運(yùn)用Real-Time PCR和Western-blot檢測(cè)兩組中鐵代謝的膜轉(zhuǎn)運(yùn)蛋白Ferroportin的變化，免疫熒光法測(cè)定兩組細(xì)胞的胞內(nèi)鐵的表達(dá)；Si-Hepcidin PC3加入外源性Hepcidin500nm，與Si-HepcidinPC3組比較觀察Hepcidin對(duì)前列腺癌細(xì)胞增殖、遷移和抗凋亡能力的改變；Real-TimePCR和Western-blot檢測(cè)兩組中鐵代謝膜轉(zhuǎn)運(yùn)蛋白Ferroportin的變化，免疫熒光法測(cè)定兩組細(xì)胞的胞內(nèi)鐵的表達(dá)。 結(jié)果：Si-Hepcidin PC3中Hepcidin受體Ferroportin的表達(dá)升高，胞內(nèi)鐵含量減少，與PC3組比較有統(tǒng)計(jì)學(xué)差異（P0.05）；加入外源性Hepcidin后，+Hepcidin PC3組的增殖、遷移和抗凋亡能力增強(qiáng)，與Si-Hepcidin PC3組比較有統(tǒng)計(jì)學(xué)差異（P0.05）；加入外源性Hepcidin后，+Hepcidin PC3組Ferroportin的表達(dá)較Si-Hepcidin PC3組降低，胞內(nèi)鐵含量增加，有統(tǒng)計(jì)學(xué)差異（P0.05）。 結(jié)論：Hepcidin調(diào)控前列腺癌細(xì)胞鐵代謝中膜轉(zhuǎn)運(yùn)蛋白Ferroportin和胞內(nèi)游離鐵的表達(dá)，對(duì)前列腺癌細(xì)胞的增殖、遷移和抗凋亡能力產(chǎn)生影響。Hepcidin可作為治療前列腺癌進(jìn)展的新靶點(diǎn)，通過(guò)Hepcidin調(diào)控前列腺癌的鐵代謝，對(duì)前列腺癌治療起到積極的臨床意義。
[Abstract]:Prostate cancer is the most common malignant tumor in men and the second in the number of male cancer deaths. The new study suggests that iron metabolism plays an important role in the growth of prostate cancer, angiogenesis and metastasis. Iron is a necessary trace element for the maintenance of human body and is widely involved in the growth and metabolism of human body. Many tumors are developed and developed. The increase in iron needs is considered to be the basic substance to maintain the growth and development of tumor cells. Studies have suggested that the reduction in the use of intracellular iron by regulating changes in iron metabolism can affect the progression of tumors as a direction for antitumor treatment.
Hepcidin is synthesized and secreted by hepatocytes. It is known as the core molecule that plays an important role in the regulation of iron metabolism. It is called ferretin. It reduces the release of intracellular free iron by the reticuloendothelial cell system and reduces iron metabolism by reducing the iron absorption of the duodenum, and plays a core role in the iron metabolism of the body. Control. Previous studies have explored the mechanism of Hepcidin's action through a series of animal models and known patients with abnormal iron metabolism. The mice that knock out the Hepcidin gene can be overloaded with iron, and those who overexpress Hepcidin and those who have secreted Hepcidin are expressed as the expression of iron deficient blood poor.Hepcidin in the tumor population. The role of body iron metabolism has attracted many scholars' attention. Some studies have shown that in the body iron metabolism, Hepcidin transtransport the intracellular free iron to the extracellular by regulating its receptor Ferroportin, and the tumor cells accompany the low expression of Ferroportin to produce extra intracellular free iron, making the tumor cells more invasive, while Hepcidin is in the front. The role of adenocarcinoma in the adenocarcinoma has not been discussed in detail.
Therefore, we study the correlation between the expression of Hepcidin and prostate cancer, the influence of Hepcidin on the prostate cancer cells and the biological function of the tumor cells, and the mechanism of Hepcidin regulation of the iron metabolism in the prostate cancer cells, and explore the effect of Hepcidin on the progress of the prostate cancer by regulating iron metabolism. It is divided into three parts:
Part one: the correlation between the expression of Hepcidin and prostate cancer.
Objective: To study the expression of Hepcidin in patients with prostate cancer and the clinical correlation with iron metabolism. Methods: the expression of serum Hepcidin, IL-6, sTfR and BMP6 in 25 patients with prostate cancer, 30 cases of prostate cancer without bone metastases and 30 patients with benign prostatic hyperplasia by enzyme linked immunosorbent assay (ELISA). And the detection of hemoglobin (HB) of all specimens; immunohistochemical detection of the expression of Hepcidin receptor Ferroportin in tissue specimens, analysis of the correlation with the classification and staging of prostate cancer, and to study the clinical association of Hepcidin with prostate cancer.
Results: the serum Hepcidin of the patients with bone metastasis of prostate cancer was higher than that of prostate cancer without bone metastasis, and there was a significant increase in the normal control prostatic hyperplasia group (P0.05), and it was positively correlated with the expression of IL-6, BMP6, and negative correlation with the expression of sTfR; the expression of Hepcidin receptor Ferroportin in prostate cancer tissue was more than that of the prostate. There was a significant decrease in the number of tissues and a slight difference in staining. The expression of Ferroportin was negatively correlated with the malignancy of prostate cancer.
Conclusion: the expression of Hepcidin in the patients with prostate cancer is higher and the expression of receptor Ferroportin is reduced. It may be related to the inflammatory state of the body and the degree of bone metastasis. Hepcidin may be used as an indicator of the progression of prostate cancer, which provides a new method for the diagnosis of prostate cancer.
The second part: Hepcidin regulates the biological function of prostate cancer cells.
Objective: To investigate the changes in the expression of Hepcidin in prostate cancer cells and the effect of Hepcidin on the cell biological functions such as proliferation, migration and apoptosis of prostate cancer cells.
Methods: the expression of Hepcidin in prostate cancer cells was measured. The expression of prostate cancer cell line PC3 and Hepcidin in DU145 was downregulated by small interference RNA, and the expression of the proliferation, migration, cell cycle, anti apoptosis ability of Si-Hepcidin prostate cancer cells was studied, and Si-Hepcidin prostate cancer cell line PC3 was implanted in the nude mice. A prostate cancer cell transplant tumor was formed to analyze the growth difference between Si-Hepcidin prostate cancer cells and the control group in vivo.
Results: the expression of Hepcidin in prostate cancer cells was higher than that of normal prostate cells (P0.05). The proliferation, migration and anti apoptosis ability of prostate cancer cell lines after Hepcidin interference were significantly lower than those in the blank control group and negative control group (P0.05), and the prostate cancer cells of Si-Hepcidin were formed in nude mice. The tumor volume is smaller than that of the control group (P0.05). Conclusion: Hepcidin is highly expressed in the prostate cancer cells. Si-Hepcidin affects the proliferation, migration, cell cycle, anti apoptotic capacity of prostate cancer cells, and causes changes in the tumor cell formation of prostate cancer cells, indicating that Hepcidin may be through the signal pathway of iron metabolism to the tumor. Regulation of cell growth and invasion plays an important role in the progression of prostate cancer.
The third part: molecular mechanism of exogenous Hepcidin regulating iron metabolism in prostate cancer cells.
Objective: To investigate the relationship between Hepcidin and the changes in the expression of iron metabolism signaling pathway in prostate cancer cells. Through the study of the changes in biological function of prostate cancer cells and the molecular mechanism of iron metabolism by exogenous Hepcidin, the effect of Hepcidin on the progression of prostatic adenocarcinoma by regulating cell iron metabolism is investigated.
Methods: PC3 and Si-Hepcidin PC3 of prostate cancer cell lines were cultured in vitro. The changes of membrane transporter Ferroportin in two groups of iron metabolism were detected by Real-Time PCR and Western-blot. The expression of intracellular iron in two groups of cells was measured by immunofluorescence; Si-Hepcidin PC3 was added to exogenous Hepcidin500nm, and Hepci was compared with Si-HepcidinPC3 group. The proliferation, migration and resistance to apoptosis of prostate cancer cells were changed by DIN; changes in Real-TimePCR and Western-blot were detected in two groups of iron metabolic membrane transporter Ferroportin, and the expression of intracellular iron in two groups of cells was measured by immunofluorescence.
Results: the expression of Hepcidin receptor Ferroportin in Si-Hepcidin PC3 increased and the intracellular iron content decreased, and there was a statistical difference between PC3 group and PC3 group (P0.05). After adding exogenous Hepcidin, the proliferation, migration and anti apoptotic ability of +Hepcidin PC3 group were enhanced, and there was a statistical difference from Si-Hepcidin PC3 group (P0.05). The expression of Ferroportin in +Hepcidin PC3 group was lower than that in Si-Hepcidin PC3 group, and there was a significant difference in intracellular iron content (P0.05).
Conclusion: Hepcidin regulates the expression of membrane transporter Ferroportin and intracellular free iron in the iron metabolism of prostate cancer cells. The effect of.Hepcidin on the proliferation, migration and resistance to apoptosis of prostate cancer cells can be used as a new target for the treatment of prostate cancer. It can be used to regulate the iron metabolism of prostate cancer and to treat the prostate cancer by Hepcidin. To the positive clinical significance.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R737.25

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2 王鳳丹;多發(fā)性骨髓瘤、非霍奇金淋巴瘤及Castleman病例hepcidin mRNA的表達(dá)[D];北京協(xié)和醫(yī)學(xué)院;2009年

3 周萃星;Hepcidin和鐵代謝在前列腺癌進(jìn)展中的作用機(jī)制研究[D];蘇州大學(xué);2014年

4 張懷;人Hepcidin融合表達(dá)載體的構(gòu)建、在大腸桿菌中的表達(dá)及制備研究[D];北京化工大學(xué);2005年

5 趙敏;心理應(yīng)激對(duì)肝鐵代謝的影響及機(jī)制研究[D];第二軍醫(yī)大學(xué);2008年

6 王蕾;rHuEPO對(duì)高糖環(huán)境系膜細(xì)胞的作用和血透患者rHuEPO抵抗與Hepcidin關(guān)系研究[D];山東大學(xué);2012年

7 邢士超;大菱鲆基因克隆及真核表達(dá)研究[D];中國(guó)海洋大學(xué);2009年

8 楊明;養(yǎng)殖真鯛、黑鯛抗菌肽hepcidin的基因克隆、表達(dá)特性及其抗菌活性研究[D];廈門大學(xué);2006年

9 段明輝;人體內(nèi)血清pro-Hepcidin水平檢測(cè)及其在臨床診斷中應(yīng)用的初步研究[D];中國(guó)協(xié)和醫(yī)科大學(xué);2008年

10 崔蕊;1、骨髓增生異常綜合征鐵穩(wěn)態(tài)失衡與骨髓紅系無(wú)效造血關(guān)系的初步研究 2、伴環(huán)狀鐵粒幼紅細(xì)胞增多的骨髓增生異常綜合征SF3B1基因突變意義研究[D];北京協(xié)和醫(yī)學(xué)院;2013年

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1 汪磊;腹膜透析患者血清hepcidin水平及其與貧血和鐵代謝指標(biāo)的關(guān)系研究[D];蘇州大學(xué);2011年

2 李華;鯉魚抗菌肽hepcidin的基因克隆、表達(dá)及其功能的研究[D];山東師范大學(xué);2010年

3 徐霜清;血清FEP及尿液hepcidin-25檢測(cè)在兒童鐵缺乏早期診斷的初步研究[D];中南大學(xué);2012年

4 劉金玉;當(dāng)歸多糖抑制IDA大鼠hepcidin表達(dá)的研究及當(dāng)歸多糖鐵口服液的研制[D];華中科技大學(xué);2010年

5 趙冬梅;斑點(diǎn)叉尾洶（Ictalurus punctatus）hepcidin抗菌肽的基因工程制備[D];上海海洋大學(xué);2013年

6 于海燕;酒精性肝鐵過(guò)載中內(nèi)質(zhì)網(wǎng)應(yīng)激對(duì)hepcidin的調(diào)控及槲皮素的干預(yù)探討[D];華中科技大學(xué);2012年

7 謝坤瑩;血清hepcidin在診斷類風(fēng)濕關(guān)節(jié)炎合并慢性病貧血中的價(jià)值[D];川北醫(yī)學(xué)院;2014年

8 劉旭;黃鱔抗菌肽hepcidin基因ORF的克隆與原核表達(dá)[D];四川農(nóng)業(yè)大學(xué);2010年

9 李小媚;探討Hepcidin在慢性腎臟病患者中的表達(dá)水平以及臨床意義[D];暨南大學(xué);2013年

10 宋楠;馬屬抗菌肽Hepcidin在畢赤酵母中分泌表達(dá)及活性研究[D];甘肅農(nóng)業(yè)大學(xué);2010年

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