中文版 | English
Title

热带爪蛙皮肤色素瘤移植模型及其迁移机制研究

Alternative Title
TRANSPLANTATION MODEL OF CUTANEOUS PIGMENT CELL TUMORS IN XENOPUS TROPICALIS AND ITS MIGRATION MECHANISM
Author
Name pinyin
RAN Rensen
School number
11849486
Degree
博士
Discipline
0710 生物学
Subject category of dissertation
07 理学
Supervisor
陈永龙
Mentor unit
生物系
Publication Years
2022-10-23
Submission date
2023-01-03
University
哈尔滨工业大学
Place of Publication
哈尔滨
Abstract

黑色素瘤是一种转移性强、预后差、死亡率高的癌症。在已有的黑色素瘤动物模型中,很难在活体内原位病灶处捕获转移初始阶段的黑色素瘤细胞进行转移机制研究。本课题拟在热带爪蛙中建立黑色素瘤同种异体移植模型,即供体热带爪蛙黑色素瘤模型和受体无色素免疫缺陷热带爪蛙模型,以期示踪和捕获转移初始阶段的黑色素瘤细胞。

Trp53/tp53敲除的背景下,在黑色素细胞中转基因表达BRAFV600E是构建黑色素瘤动物模型常用的方法之一。所以本课题拟先敲除热带爪蛙tp53,为后续建立热带爪蛙黑色素瘤动物模型奠定基础。Trp53-/-小鼠没有黑色素瘤的发生,tp53-/-斑马鱼黑色素瘤的发生率低于0.2%。然而在本课题建立的tp53敲除热带爪蛙品系中,22%的tp53-/-纯合子热带爪蛙自发生成痣和黑色素瘤,这表明tp53-/-热带爪蛙提供了一种新的黑色素瘤动物模型。CDKN2B常在人类黑色素瘤发展过程中和CDKN2A一起丢失。在小鼠黑色素瘤及一些鱼类黑色素瘤模型中,敲除Cdkn2a或是Cdkn2b可以促进黑色素瘤的发展。进而,同时敲除热带爪蛙cdkn2b和tp53,cdkn2b-/-/tp53-/-热带爪蛙自发生成黑色素瘤的外显率高达81%,其提供了一种外显率更高的热带爪蛙黑色素瘤模型。

BRAFV600E驱动大部分人类黑色素瘤的发生,所以许多小鼠和斑马鱼黑色素瘤模型都是转基因表达BRAFV600E于黑色素细胞而建立的动物模型。因此用CRISPR/Cas9介导外源基因靶向整合技术,将BRAFV600E靶向整合到热带爪蛙mitf基因座(mitf-BRAFV600E),建立了只有一个BRAFV600E拷贝整合的line 1热带爪蛙品系和多个BRAFV600E拷贝整合的line 2热带爪蛙品系。Line 1和line 2热带爪蛙的黑色素细胞和黄色素细胞都会异常增殖成相应的色素细胞痣,但不会自发形成相应的色素细胞瘤。当Line 1和line 2热带爪蛙与cdkn2b或tp53热带爪蛙突变体交配后,发现cdkn2b或tp53缺失只能够引起mitf-BRAFV600E热带爪蛙形成黄色素瘤,而不是黑色素瘤。

进一步,为了提供适用于肿瘤移植的受体热带爪蛙品系,同时考虑到mitf是脊椎动物黑色素细胞发育所必需的主调节因子,以及prkdc和il2rg同时敲除的斑马鱼缺乏具有活性功能的T淋巴细胞、B淋巴细胞和NK细胞,所以拟建立mitf、prkdc和il2rg三重敲除的热带爪蛙品系,以期其可以用于多种肿瘤细胞移植和活体观察捕捉转移性肿瘤细胞。在研究中发现,mitf-/-热带爪蛙皮肤中没有黑色素细胞、黄色素细胞和颗粒腺,所以幼蛙皮肤呈透明状态。最后,同时敲除mitf、prkdc、il2rg导致mitf-/-/prkdc-/-/il2rg-/-热带爪蛙无色素且免疫缺陷。将黑色素瘤和黄色素瘤移植到mitf-/-/prkdc-/-/il2rg-/-无色素免疫缺陷热带爪蛙背部皮肤上,观察到了黄色素瘤细胞的转移和转移初始阶段黑色素瘤细胞的迁移,其中转移初始阶段黑色素瘤细胞是以类似间充质细胞的形态进行迁移。

总上所述,建立了热带爪蛙黑色素瘤、黄色素瘤模型和无色素免疫缺陷热带爪蛙模型,将黑色素瘤和黄色素瘤进行了同种异体移植到mitf-/-/prkdc-/-/il2rg-/-热带爪蛙,观察到了黑色素瘤细胞的迁移和黄色素瘤细胞的转移,为进一步研究黑色素瘤转移的细胞和分子机制奠定了基础。

Keywords
Language
Chinese
Training classes
联合培养
Enrollment Year
2018
Year of Degree Awarded
2022-12
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Academic Degree Assessment Sub committee
生物系
Domestic book classification number
R739.5
Data Source
人工提交
Document TypeThesis
Identifierhttp://kc.sustech.edu.cn/handle/2SGJ60CL/417934
DepartmentDepartment of Biology
Recommended Citation
GB/T 7714
冉仁森. 热带爪蛙皮肤色素瘤移植模型及其迁移机制研究[D]. 哈尔滨. 哈尔滨工业大学,2022.
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