發(fā)布時(shí)間：2018-09-13 06:49

【摘要】：癌癥是嚴(yán)重危害人類健康和生命的惡性疾病。在世界范圍內(nèi),腫瘤死亡率前三位依次是肺癌、胃癌和肝癌。近年來(lái)肝癌的發(fā)病率不斷上升,對(duì)肝癌的治療和預(yù)防以及相關(guān)機(jī)理探索一直是腫瘤領(lǐng)域的研究熱點(diǎn)。目前對(duì)于肝癌的治療方案主要有外科手術(shù)切除、放射治療、化學(xué)藥物治療以及肝移植等,但這些方法還不能從根本上解決其復(fù)發(fā)和轉(zhuǎn)移問(wèn)題,肝癌的預(yù)防和治療仍然面臨巨大的挑戰(zhàn)。癌干細(xì)胞(cancer stem cell,CSCs)是惡性腫瘤組織中具有很強(qiáng)增殖能力、表現(xiàn)干細(xì)胞特性的細(xì)胞亞群,具備高度自我更新和分化潛能,不僅是惡性腫瘤的啟動(dòng)細(xì)胞,而且是形成不同分化程度癌細(xì)胞和癌癥復(fù)發(fā)、轉(zhuǎn)移及預(yù)后不良的根源,在癌癥復(fù)發(fā)、轉(zhuǎn)移中起決定作用,其靶向干預(yù)是癌癥治療的全新策略。癌癥的發(fā)生發(fā)展是一個(gè)多因素調(diào)控的復(fù)雜過(guò)程,受到多種力學(xué)、化學(xué)因素的影響。在CSCs靶向干預(yù)的抗癌策略中,如何阻止CSCs轉(zhuǎn)移或誘導(dǎo)CSCs分化都是CSCs靶向干預(yù)的重要手段,但目前人們對(duì)于力學(xué)、化學(xué)因素調(diào)控CSCs侵襲轉(zhuǎn)移和分化等生物學(xué)行為的特征及相關(guān)機(jī)理還缺乏系統(tǒng)認(rèn)識(shí)。為此,本課題以肝癌干細(xì)胞(liver cancer stem cells,LCSCs)為研究對(duì)象,首先考察了LCSCs的生物力學(xué)特質(zhì),然后研究了力學(xué)因素(剪切應(yīng)力shear stress,SS)、化學(xué)因素(鹽霉素salinomycin,Sal)對(duì)LCSCs轉(zhuǎn)移、分化行為的影響及相關(guān)分子機(jī)制。本研究工作的主要內(nèi)容和結(jié)果如下:(1)LCSCs的富集、鑒定及生物力學(xué)特質(zhì)分析采用無(wú)血清干細(xì)胞專用培養(yǎng)液通過(guò)體外腫瘤球培養(yǎng)方法從高轉(zhuǎn)移性肝癌細(xì)胞MHCC97H中篩選、富集LCSCs,對(duì)其癌干細(xì)胞特征及生物力學(xué)特質(zhì)進(jìn)行了分析。結(jié)果發(fā)現(xiàn),篩選出的細(xì)胞相比母代MHCC97H細(xì)胞高表達(dá)癌干細(xì)胞標(biāo)志物CD133、CD90、Oct3/4,具有更強(qiáng)的克隆形成能力、抗癌藥物耐藥性和裸鼠體內(nèi)成瘤能力,表明篩選出的細(xì)胞具有癌干細(xì)胞表型,符合癌干細(xì)胞特征。Transwell遷移實(shí)驗(yàn)發(fā)現(xiàn),LCSCs比MHCC97H細(xì)胞具有更強(qiáng)的遷移能力。原子力顯微鏡(atomic force microscopy,AFM)檢測(cè)顯示,LCSCs的楊氏模量顯著小于MHCC97H細(xì)胞。激光共聚焦顯微鏡觀察發(fā)現(xiàn),LCSCs的細(xì)胞骨架F-actin呈點(diǎn)狀結(jié)構(gòu),而MHCC97H細(xì)胞呈明顯的絲狀結(jié)構(gòu)。Western blot實(shí)驗(yàn)進(jìn)一步發(fā)現(xiàn),與MHCC97H細(xì)胞相比,LCSCs中細(xì)胞骨架F-actin的表達(dá)顯著減少。這些結(jié)果表明,LCSCs的生物力學(xué)特質(zhì)與其高轉(zhuǎn)移潛能有很密切的關(guān)系。(2)剪切應(yīng)力通過(guò)FAK-ERK1/2-β-catenin信號(hào)通路促進(jìn)LCSCs的遷移采用平行平板流動(dòng)腔系統(tǒng)建立模擬體內(nèi)lcscs血道轉(zhuǎn)移模型,考察了血流剪切應(yīng)力作用下lcscs遷移行為的變化及相關(guān)分子機(jī)制。實(shí)驗(yàn)結(jié)果發(fā)現(xiàn),2dyne/cm2剪切應(yīng)力加載6h后明顯促進(jìn)lcscs的遷移能力,粘著斑激酶(focaladhesionkinase,fak)和細(xì)胞外信號(hào)調(diào)節(jié)激酶1/2(extracellularsignalregulatedkinase1/2,erk1/2)磷酸化水平明顯增加,β-鏈蛋白(β-catenin)的表達(dá)也明顯增加,抑制fak或erk1/2激活或沉默β-catenin后,剪切應(yīng)力促進(jìn)的lcscs遷移受到明顯抑制。免疫熒光染色觀察發(fā)現(xiàn),剪切應(yīng)力加載后lcscsf-actin的表達(dá)下降,抑制fak、erk1/2后,也抑制了剪切應(yīng)力誘導(dǎo)的f-actin下調(diào)。進(jìn)一步利用afm檢測(cè)了細(xì)胞楊氏模量的變化,結(jié)果發(fā)現(xiàn)剪切應(yīng)力加載顯著降低了lcscs的楊氏模量;抑制fak、erk1/2或β-catenin后,下降的lcscs楊氏模量得到了恢復(fù)。此外,fak抑制劑可阻斷剪切應(yīng)力誘導(dǎo)的erk1/2磷酸化以及β-catenin蛋白的表達(dá),erk1/2抑制劑可阻斷β-catenin蛋白的表達(dá)。上述結(jié)果提示,剪切應(yīng)力可能通過(guò)fak-erk1/2-β-catenin信號(hào)途徑使lcscs的細(xì)胞骨架f-actin重排,降低細(xì)胞硬度,從而增加lcscs的遷移能力。(3)剪切應(yīng)力通過(guò)wnt/β-catenin信號(hào)通路調(diào)控lcscs的分化行為對(duì)lcscs施加2dyne/cm2剪切應(yīng)力加載2天后,通過(guò)流式細(xì)胞術(shù)檢測(cè)lcscs癌干細(xì)胞標(biāo)志物cd133、cd90、oct3/4的表達(dá)。實(shí)驗(yàn)結(jié)果發(fā)現(xiàn),剪切應(yīng)力作用后cd133、cd90、oct3/4的表達(dá)顯著下降。腫瘤球體形成實(shí)驗(yàn)發(fā)現(xiàn),經(jīng)2dyne/cm2剪切應(yīng)力加載2天后,lcscs的球體形成能力顯著下降;licl預(yù)處理激活wnt/β-catenin信號(hào)通路,剪切應(yīng)力抑制的球體形成能力得到了恢復(fù)。藥物敏感實(shí)驗(yàn)顯示,2dyne/cm2剪切應(yīng)力加載2天后,lcscs對(duì)順鉑(cisplatin)和5-氟尿嘧啶(5-fu)的敏感度增高,生存率明顯下降。afm分析發(fā)現(xiàn)剪切應(yīng)力加載后lcscs楊氏模量顯著增加;利用licl激活β-catenin,抑制了剪切應(yīng)力增加的細(xì)胞楊氏模量。westernblot檢測(cè)發(fā)現(xiàn),2dyne/cm2剪切應(yīng)力作用lcscs2天后,β-catenin的表達(dá)明顯下降,利用licl激活β-catenin,剪切應(yīng)力促進(jìn)的lcscs分化受到明顯抑制,cd133、cd90、oct3/4的表達(dá)顯著恢復(fù)。裸鼠體內(nèi)致瘤實(shí)驗(yàn)表明,lcscs經(jīng)剪切應(yīng)力作用2天后,其致瘤能力明顯下降,激活β-catenin,致瘤能力得到恢復(fù)。上述結(jié)果提示,2dyne/cm2剪切應(yīng)力作用lcscs2天后可通過(guò)wnt/β-catenin信號(hào)通路使其發(fā)生分化。(4)鹽霉素通過(guò)fak-erk1/2信號(hào)通路調(diào)控lcscs的運(yùn)動(dòng)能力transwell法檢測(cè)發(fā)現(xiàn),鹽霉素明顯抑制lcscs的遷移和侵襲能力,并在一定濃度范圍內(nèi)呈現(xiàn)濃度依賴性。westernblot檢測(cè)表明,鹽霉素作用lcscs后,fak和erk1/2磷酸化水平明顯降低。此外,fak、erk1/2抑制劑也可抑制lcscs的遷移和侵襲能力。因此,鹽霉素可能通過(guò)FAK-ERK1/2信號(hào)通路抑制LCSCs遷移和侵襲。明膠酶譜實(shí)驗(yàn)表明,鹽霉素抑制LCSCs基質(zhì)金屬蛋白酶2(matrix metalloproteinase 2,MMP-2)和基質(zhì)金屬蛋白酶9(matrix metalloproteinase 9,MMP-9)分泌。此外,免疫熒光染色觀察發(fā)現(xiàn)鹽霉素作用后LCSCs F-actin的表達(dá)上升,FAK、ERK1/2抑制劑也可促進(jìn)F-actin上調(diào)。進(jìn)一步利用AFM檢測(cè)發(fā)現(xiàn)鹽霉素處理顯著增加了LCSCs的楊氏模量,FAK、ERK1/2抑制劑作用后也升高了LCSCs的楊氏模量。上述結(jié)果提示,鹽霉素可能通過(guò)FAK-ERK1/2信號(hào)通路促進(jìn)F-actin表達(dá),增加細(xì)胞硬度,減少M(fèi)MP-2、MMP-9的分泌,從而抑制了LCSCs的運(yùn)動(dòng)能力。(5)鹽霉素通過(guò)Wnt/β-catenin信號(hào)通路調(diào)控LCSCs的分化行為利用鹽霉素對(duì)LCSCs處理2天后,通過(guò)流式細(xì)胞術(shù)檢測(cè)發(fā)現(xiàn)LCSCs癌干細(xì)胞標(biāo)志物CD133、CD90、Oct3/4的表達(dá)顯著下降。腫瘤球體形成實(shí)驗(yàn)發(fā)現(xiàn),經(jīng)鹽霉素處理后LCSCs的球體形成能力顯著下降,利用LiCl激活β-catenin,腫瘤球體形成能力得到了恢復(fù)。藥物敏感實(shí)驗(yàn)發(fā)現(xiàn),鹽霉素作用2天后的LCSCs,對(duì)于Cisplatin和5-FU的敏感度增高,生存率明顯下降。此外,進(jìn)一步利用AFM檢測(cè)發(fā)現(xiàn)鹽霉素可以顯著增加LCSCs的楊氏模量。利用LiCl激活β-catenin后,細(xì)胞的楊氏模量得到明顯恢復(fù)。Western blot檢測(cè)表明,鹽霉素作用LCSCs 2天后,β-catenin的表達(dá)明顯下降,利用LiCl激活β-catenin,剪切應(yīng)力促進(jìn)的LCSCs分化受到明顯抑制,LCSCs的癌干細(xì)胞標(biāo)志物CD133、CD90、Oct3/4的表達(dá)顯著恢復(fù)。裸鼠體內(nèi)致瘤實(shí)驗(yàn)表明,LCSCs經(jīng)鹽霉素作用后,瘤體大小明顯下降,激活β-catenin,致瘤能力得到恢復(fù)。上述結(jié)果提示,鹽霉素作用LCSCs 2天后可通過(guò)Wnt/β-catenin信號(hào)通路使其發(fā)生了分化。綜合上述結(jié)果,剪切應(yīng)力在調(diào)控LCSCs轉(zhuǎn)移、分化行為過(guò)程中起到了至關(guān)重要的作用,此外發(fā)現(xiàn)鹽霉素可以抑制LCSCs轉(zhuǎn)移、促使其分化。本研究結(jié)果為深入認(rèn)識(shí)力、化學(xué)因素對(duì)LCSCs的作用機(jī)制提供了實(shí)驗(yàn)依據(jù),為臨床上通過(guò)靶向LCSCs治療肝癌提供了理論指導(dǎo)。
[Abstract]:Cancer is a malignant disease that seriously endangers human health and life.In the world,the top three mortality rates of cancer are lung cancer,gastric cancer and liver cancer in turn.The incidence of liver cancer has been increasing in recent years.The treatment and prevention of liver cancer and the exploration of related mechanisms have been the focus of cancer research.At present,the treatment of liver cancer is the main program. Surgical resection, radiotherapy, chemotherapy and liver transplantation are needed, but these methods can not fundamentally solve the problem of recurrence and metastasis. The prevention and treatment of hepatocellular carcinoma still faces enormous challenges. Cell subsets, with a high degree of self-renewal and differentiation potential, are not only the initiator cells of malignant tumors, but also the source of formation of differentiated cancer cells and cancer recurrence, metastasis and poor prognosis. They play a decisive role in cancer recurrence and metastasis. Targeted intervention is a new strategy for cancer treatment. The complex process of multi-factor regulation is affected by many mechanical and chemical factors. In the anti-cancer strategy of CSCs targeted intervention, how to prevent CSCs from metastasis or induce CSCs differentiation is an important means of targeted intervention. However, at present, the characteristics and related mechanisms of biological behavior of CSCs are regulated by mechanical and chemical factors, such as invasion, metastasis and differentiation. In this study, the biomechanical properties of liver cancer stem cells (LCSCs) were investigated firstly, and then the effects of mechanical factors (shear stress, SS) and chemical factors (salinomycin, Sal) on the metastasis, differentiation and related molecular mechanisms of LCSCs were studied. The main contents and results of this study are as follows: (1) LCSCs enrichment, identification and biomechanical characteristics analysis. Serum-free stem cell culture medium was used to screen and enrich LCSCs from high metastatic hepatocellular carcinoma cell line MHCC97H in vitro. The characteristics and biomechanical characteristics of LCSCs were analyzed. Transwell migration assay showed that LCSCs were finer than MHCC97H cells in the morphology of cancer stem cells. Atomic force microscopy (AFM) showed that the Young's modulus of LCSCs was significantly lower than that of MHCC97H cells. Confocal laser microscopy showed that the F-actin cytoskeleton of LCSCs was dotted, while MHCC97H cells showed obvious filamentous structure. These results indicate that the biomechanical properties of LCSCs are closely related to their high metastatic potential. (2) Shear stress promotes the migration of LCSCs through FAK-ERK1/2-beta-catenin signaling pathway. Parallel plate flow chamber system is used to establish blood channel metastasis model of LCSCs in vivo. The results showed that 2dyne/cm2 shear stress could significantly promote the migration of lcscs, focal adhesion kinase (fak) and extracellular signal regulated kinase 1/2 (erk1/2) phosphoric acid. Immunofluorescence staining showed that the expression of lcscsf-actin decreased after shear stress loading, and the expression of FAK and erk1/2 was inhibited after inhibiting the activation of FAK or erk1/2 or silencing of beta-catenin. Furthermore, AFM was used to detect the changes of young's modulus of lcscs. the results showed that shear stress loading significantly reduced the young's modulus of lcscs. after inhibiting fak, ERK1 / 2 or beta-catenin, the decreased young's modulus of LCSCs was restored. furthermore, FAK inhibitor could block shear stress-induced ERK1 / 2 phosphorylation and beta-catenin protein. These results suggest that shear stress may regulate the differentiation of LCSCs through the fak-erk1/2-beta-catenin signaling pathway through the fak-erk1/2-beta-catenin signaling pathway by rearranging the cytoskeleton F-actin and reducing the cell hardness. The expression of cd133, CD90 and OCT3 / 4 was detected by flow cytometry after loading LCSCs with 2dyne / cm2 shear stress for 2 days. the results showed that the expression of cd133, CD90 and OCT3 / 4 was significantly decreased after loading LCSCs with 2dyne / cm2 shear stress. LiCl pretreatment activated the Wnt / beta-catenin signaling pathway and restored the ability of sphere formation inhibited by shear stress. Young's modulus of LCSCs increased significantly after loading, and was inhibited by activation of beta-catenin with licl. Western blot analysis showed that the expression of beta-catenin decreased significantly after 2 days of shear stress, and the differentiation of LCSCs promoted by shear stress was inhibited by activation of beta-catenin with licl, cd133, cd90, oc. The expression of t3/4 was significantly restored in nude mice. The tumorigenic ability of LCSCs decreased significantly after 2 days of shear stress, and the tumorigenic ability of LCSCs was restored by activating beta-catenin. These results suggest that 2dyne/cm2 shear stress can differentiate LCSCs through wnt/beta-catenin signaling pathway after 2 days of shear stress. (4) Salinomycin can differentiate LCSCs through fak-erk1 signaling pathway. Transwell assay showed that salinomycin significantly inhibited the migration and invasion of LCSCs in a concentration-dependent manner. Western blot assay showed that the phosphorylation levels of FAK and ERK1 / 2 were significantly decreased after salinomycin acted on lcscs. Therefore, salinomycin may inhibit the migration and invasion of LCSCs through FAK-ERK1/2 signaling pathway. Gelatin zymographic experiments showed that salinomycin inhibited the secretion of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in LCSCs. In addition, immunofluorescence staining was used to observe the effect of salinomycin on the secretion of matrix metalloproteinase 9 (MMP-9). It was found that the expression of F-actin in LCSCs increased after salinomycin treatment, and that FAK and ERK1/2 inhibitors could also promote the up-regulation of F-actin. Further, it was found that salinomycin treatment significantly increased the Young's modulus of LCSCs, FAK and ERK1/2 inhibitors also increased the Young's modulus of LCSCs. These results suggest that salinomycin may be through FAK-ERK1/2 signal. (5) Salinomycin regulates the differentiation of LCSCs by Wnt/beta-catenin signaling pathway. After two days of treatment with salinomycin, the expression of CD133, CD90 and Oct3/4 in LCSCs was detected by flow cytometry. Tumor spherogenesis test showed that the spherogenesis ability of LCSCs decreased significantly after salinomycin treatment, and the ability of tumor spherogenesis was restored by activating beta-catenin with LiCl. Drug sensitivity test showed that the sensitivity of LCSCs to Cisplatin and 5-FU increased and the survival rate decreased significantly after salinomycin treatment for 2 days. Furthermore, the Young's modulus of LCSCs was significantly increased by salinomycin. After activation of beta-catenin by LiCl, the Young's modulus of LCSCs was significantly restored. Western blot analysis showed that the expression of beta-catenin was significantly decreased after 2 days of salinomycin treatment, and the differentiation of LCSCs was promoted by shear stress after activation of beta-catenin by LiCl. The expression of CD133, CD90 and Oct3/4 in LCSCs was significantly restored. The tumorigenic experiments in nude mice showed that the size of LCSCs decreased significantly after salinomycin treatment, and the tumorigenicity was restored by activating beta-catenin. These results suggest that salinomycin can induce LCSCs to develop through Wnt/beta-catenin signaling pathway after 2 days. In conclusion, shear stress plays an important role in regulating the metastasis and differentiation of LCSCs. Salinomycin can inhibit the metastasis and promote the differentiation of LCSCs. The results of this study provide experimental evidence for further understanding of the mechanism of chemical factors on LCSCs and for clinical targeting of LCSCs. It provides theoretical guidance for the treatment of liver cancer.
【學(xué)位授予單位】：重慶大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.7

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