摘要
一、经典Wnt信号通路在大、小鼠肝前体细胞活化中的调节作用
研究背景和目的
肝脏是是人体最大的外分泌器官,具有极强的再生功能。在正常生理状态下或轻度肝损伤时,肝细胞参与增殖和分化,维持肝脏的正常功能。当出现广泛和慢性的肝损伤导致肝细胞大量破坏和丢失而且肝细胞的增殖能力被抑制时,肝脏通过前体细胞的增殖和分化来完成肝脏再生。肝前体细胞同时表达肝系标志物和胆系标志物,并且能够向肝细胞或胆管上皮细胞分化。肝前体细胞被发现参与一系列肝脏损伤性疾病,并且在肝纤维化和肝脏肿瘤发生中发挥重要作用。
β-Catenin既是细胞连接的重要组成部分,又是经典Wnt信号通路的关键信号分子。Wnt/β-catenin信号通路在众多组织中是调控细胞增殖、分化和迁移的重要通路,在肝脏的各种生物学功能中同样发挥着重要作用。β-Catenin对于胚胎肝脏发育和肝切除术后的肝脏再生至关重要。在多种肝脏肿瘤,尤其是肝细胞癌中,普遍存在β-catenin在细胞浆的聚集和/或核转位。但是,Wnt/β-catenin信号通路在肝前体细胞活化中的重要作用依然尚未明确。
本研究拟首先通过建立大、小鼠肝前体细胞活化动物模型,观察在前体细胞活化过程中Wnt/β-catenin信号通路活性的变化情况;继而结合体内实验,观察经典Wnt信号通路的激活对肝前体细胞的活化或其参与肝脏再生能力的影响,从而从体内、体外两个水平证实Wnt/β-catenin信号通路对前体细胞的活化具有调节作用。
实验方法:
1、建立大鼠肝前体细胞活化模型;
2、用免疫组织化学和Western Blot等方法研究在大鼠肝前体细胞活化过程中Wnt/β-catenin信号通路活性的变化情况;
3、通过体外培养的肝前体细胞样细胞系研究Wnt/β-catenin信号通路的过度激活对细胞增殖特性的影响;
4、运用细胞移植的实验研究Wnt/β-catenin信号通路的过度激活对前体细胞参与肝再生能力的影响;
5、建立小鼠肝前体细胞活化模型;
6、通过免疫组织化学和染色质免疫共沉淀的方法研究在小鼠肝前体细胞活化过程中Wnt/β-catenin信号通路活性的变化情况;
7、通过质粒注射的方法从体内水平研究Wnt/β-catenin信号通路的过度激活对前体细胞活化的影响。
结果:
1、在大鼠肝前体细胞活化过程中,伴随Wnt/β-catenin信号通路活性的升高;
2、大鼠肝前体细胞具有更高的Wnt/β-catenin信号通路活性;
3、Wnt/β-catenin信号通路的激活不仅能在体外促进肝前体细胞样细胞系的增殖,而且能促进其参与肝脏再生的能力;
4、在小鼠肝前体细胞活化过程中,伴随Wnt/β-catenin信号通路活性的升高,并且小鼠肝前体细胞同样具有更高的Wnt/β-catenin信号通路活性;
5、通过质粒注射的方法提高Wnt/β-catenin信号通路活性能促进肝前体细胞的活化。
结论:
本研究在大鼠和小鼠两种肝前体细胞活化模型中研究了Wnt/β-catenin信号通路的重要作用,不仅发现了在肝前体细胞活化中伴随着Wnt/β-catenin信号通路活性的显著升高,而且发现肝前体细胞具有较高的Wnt/β-catenin信号通路活性。更重要的是发现提高前体细胞中Wnt/β-catenin信号通路的活性,能够促进前体细胞的活化及其参与肝再生的能力。
二、Wnt/β-Catenin信号通路对OV6~+肝癌前体细胞的调节作用
研究背景和目的
干细胞代表着具有自我更新能力、能分化为子代细胞来修复组织的一个数量非常少的细胞亚群。在许多实体肿瘤的发生和进展中存在干/前体细胞起源和肿瘤细胞等级模型,具备自我更新能力的干/前体细胞可能是众多肿瘤的起源。随着肝干细胞生物学的进展,人们认为在肝细胞癌中也存在着肿瘤干/前体细胞,并且他们与肝痛的发生密切相关。
Wnt/β-catenin信号通路在众多组织中是调控细胞增殖、分化和迁移的重要通路,与造血干细胞、神经干细胞和上皮干细胞等众多组织来源的干细胞的功能维持密切相关。在肝脏,Wnt/β-catenin信号通路与肝脏发育中的细胞增殖、肝再生和肿瘤生长也存在紧密联系,但其在肝干/前体细胞中的功能仍知之甚少。
本研究将从人肝细胞癌标本和体外培养的肝癌细胞系入手,结合肝前体细胞标志物OV6,一方面鉴定、分选出这样一个具有前体细胞特性的细胞亚群,并研究其细胞特性;另一方面,详细阐述Wnt/β-catenin信号通路对这部分前体细胞功能的调节,尤其是对其自我更新能力和其它干/前体细胞特性的调节作用。
实验方法:
1、用免疫组织化学的方法检测OV6~+肝前体细胞在正常肝脏、肝硬化、肝细胞癌中的分布情况;
2、用流式细胞仪检测在体外培养的肝癌细胞系中OV6~+肝癌细胞的比例;
3、使用MACS的方法从肝癌绌胞系中分选出这部分OV6~+肝癌细胞,并用RT-PCR的方法分析这部分OV6~+肝癌细胞的特性;
4、观察这部分OV6~+肝癌细胞成瘤性;
5、流式细胞仪检测Wnt/β-catenin信号通路的激活(BIO刺激)对OV6~+肝癌细胞自我更新能力的影响;
6、构建干扰β-catenin慢病毒所需质粒,包装、纯化慢病毒;
7、流式细胞仪检测通过干扰β-catenin慢病毒降低Wnt/β-catenin信号通路活性对OV6~+肝癌细胞自我更新能力的影响;
8、检测OV6~+肝癌细胞对常规化疗药物的耐受性(克隆形成实验);
9、观察通过干扰β-catenin慢病毒降低Wnt/β-catenin信号通路活性对OV6~+肝癌细胞药物耐受性的影响。
结果:
1、在正常肝脏、肝硬化、肝细胞癌标本中均发现OV6~+肝前体细胞的存在;
2、在体外培养的肝癌细胞系中也存在OV6~+肝癌细胞,其比例为0.2%到3%;
3、OV6~+肝痛细胞具有干/前体细胞特性,在NOD/SCID小鼠体内具有更高的成瘤性;
4、Wnt/β-catenin信号通路的激活能显著提高这部分OV6~+肝癌绌胞的比例,并促进其自我更新;干扰β-catenin的慢病毒能降低Wnt/β-catenin信号通路活性并降低了其自我更新的能力;
5、OV6~+肝癌细胞对常规化疗药物具有更高的耐受性;
6、干扰β-catenin的慢病毒能降低Wnt/β-catenin信号通路活性并提高这部分OV6~+肝癌细胞对药物的敏感性;
结论:
本研究从人肝细胞癌标本和体外培养的肝癌细胞系两个方面,结合肝前体细胞标志物OV6,一方面首次鉴定、分选出具有前体细胞特性,具有更强成瘤性的细胞亚群;另一方面详细阐述了Wnt/β-catenin信号通路对这部分前体细胞功能的调节,尤其是对其自我更新能力和其它干/前体细胞特性的调节作用。本研究为进一步理解肝细胞癌发生、发展的机制提供了线索,并有助于探寻可能的靶向肿瘤干/前体细胞的治疗方法。
PartⅠWnt/β-Catenin Signaling Mediates Progenitor Cells Activation in Rodents
Adult hepatic progenitor cells (oval cells) are facultative stem cells in the liver that are activated during regeneration only during inhibition of innate hepatocyte proliferation. On the basis of its involvement in liver development, regeneration, and cancer, we investigated the role of the Wnt/β-catenin pathway in progenitor cell activation, which was initiated in rats with 2-acetylaminofluorine and two-third partial hepatectomy (PH) and in mice with treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine. First, we showed thatβ-catenin is highly expressed and mainly localized to the proliferating oval cells in both rat and mouse models, indicating the role of canonical Wnt/β-catenin pathway during the regenerative response. Furthermore, constitutive activation of Wnt/β-catenin signaling stimulated progenitor cell proliferation in vitro and caused a substantial clonal expansion of the transplanted rat oval cells in vivo, indicating that the activated Wnt/β-catenin signaling is required for progenitor cell expansion. Finally, the hyperplastic phenotype was consistently observed in the livers of DDC-fed mice that transiently overexpressed the constitutively activeβ-catenin. These results indicated that Wnt/β-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively activeβ-catenin mutant promotes expansion of the progenitor cell population in the regenerated liver.
PartⅡWnt/β-Catenin Signaling Contributes to Activation of Tumorigenic Liver Progenitor Cells
Transformed hematopoietic stem/progenitor cells with an enhanced or acquired self-renewal capability function as leukemic stem cells. In a variety of solid cancers, stem/progenitor cells could be also targets of carcinogenesis. In the present study, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/β-catenin signaling. These OV6-positive HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy as compared to OV6-negative tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation whereas inhibition ofβ-catenin signaling leads to a decrease in the proportion of OV6-positive cells. In addition, the chemoresistance of OV6-positive HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targetingβ-catenin. These results highlight the importance of the Wnt/β-catenin pathway in activation and expansion of oval cells in human HCCs. OV6-positive tumor cells may represent the cellular population that confers HCC chemoresistance and therapies targeted to the Wnt/β-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy.
引文
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