Effects of Three-Dimensional Stiffness on the Proliferation, Stemness And Invasion of Hepatic Cancer Stem Cells

Q4 Biochemistry, Genetics and Molecular Biology

Molecular & Cellular Biomechanics Pub Date : 2019-01-01 DOI:10.32604/mcb.2019.07154

Mengyue Wang, Runze Zhao, Fan Feng, Tingting Xia, Li Yang

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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC) is the third most common cancer in the world. Previous studies have shown that hard matrix promotes the proliferation of liver tumor cells. However, the role of matrix stiffness on hepatic cancer stem cells (HCSCs) is still unclear. Three-dimensional hydrogels with different stiffness were used to mimic the normal liver tissue (4kPa) and cancerous liver tissue (26kPa) stiffness. The proliferation, stemness and invasion properties of HCSCs under 3D different stiffness were detected. METHOD: HSCSs were screened and cultured by enrichment method, and the effect of matrix stiffness on HCSCs was studied by three-dimensional culture of HCSCs in hydrogels of different stiffness. CCK-8, clonal size measurement and QRT-PCR were used to examine the effects of different matrix stiffness on the proliferation of HCSCs. CD133 and CD90 were used to examine the effects of different matrix stiffness on the stemness of HCSCs. Immunofluorescence was used to detect epithelial mesenchymal transition-related proteins to investigate the effects of different matrix stiffness on the invasion ability of HCSCs. RESULTS: The matrix stiffness of 4 kPa significantly inhibited the proliferation, stemness maintenance and invasion ability of HCSCs. The matrix stiffness of 26 kPa significantly promoted the proliferation, stemness maintenance and invasion ability of HCSCs. Subsequently, we culture the HCSCs in 4kPa and 26kPa hydrogels for matrix stiffness exchange. The results showed that the stemness and invasive ability of HCSCs in 26kPa-4kPa decreased significantly, while the stem cell stemness of liver cancer within 4kPa-26kPa and the invasive ability is significantly increased. Animal experiments have further validated this result. CONCLUSION: The mechanical environment of HCSCs has a significant regulatory effect on their proliferation, stemness and invasion ability. The stiffness of pathological liver tissue plays a significant role in promoting the occurrence and development of tumor. Our study provides new ideas for further understanding the pathogenesis and treatment of liver cancer.

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三维刚度对肝癌干细胞增殖、干性和侵袭的影响

肝细胞癌(HCC)是世界上第三大常见癌症。既往研究表明，硬基质促进肝肿瘤细胞的增殖。然而，基质硬度在肝癌干细胞(HCSCs)中的作用尚不清楚。采用不同刚度的三维水凝胶模拟正常肝组织(4kPa)和癌变肝组织(26kPa)的刚度。在三维不同刚度条件下检测造血干细胞的增殖、干性和侵袭性。方法:采用富集法筛选培养hscs，在不同刚度的水凝胶中对hscs进行三维培养，研究基质刚度对hscs的影响。采用CCK-8、克隆大小测定和QRT-PCR检测不同基质刚度对hscs增殖的影响。利用CD133和CD90检测不同基质刚度对造血干细胞干性的影响。采用免疫荧光法检测上皮间充质过渡相关蛋白，探讨不同基质硬度对HCSCs侵袭能力的影响。结果:4 kPa的基质刚度显著抑制hscs的增殖、干细胞维持和侵袭能力。26 kPa的基质刚度可显著促进hscs的增殖、维持干性和侵袭能力。随后，我们在4kPa和26kPa的水凝胶中培养HCSCs进行基质刚度交换。结果显示，26kPa-4kPa范围内HCSCs的干性和侵袭能力显著降低，而4kPa-26kPa范围内肝癌干细胞的干性和侵袭能力显著增强。动物实验进一步验证了这一结果。结论:机械环境对造血干细胞的增殖、干性和侵袭能力有明显的调节作用。病理性肝组织的僵硬对肿瘤的发生发展起着重要的促进作用。本研究为进一步认识肝癌的发病机制和治疗提供了新的思路。

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来源期刊

Molecular & Cellular Biomechanics CELL BIOLOGYENGINEERING, BIOMEDICAL&-ENGINEERING, BIOMEDICAL

CiteScore

1.70

自引率

0.00%

发文量

期刊介绍： The field of biomechanics concerns with motion, deformation, and forces in biological systems. With the explosive progress in molecular biology, genomic engineering, bioimaging, and nanotechnology, there will be an ever-increasing generation of knowledge and information concerning the mechanobiology of genes, proteins, cells, tissues, and organs. Such information will bring new diagnostic tools, new therapeutic approaches, and new knowledge on ourselves and our interactions with our environment. It becomes apparent that biomechanics focusing on molecules, cells as well as tissues and organs is an important aspect of modern biomedical sciences. The aims of this journal are to facilitate the studies of the mechanics of biomolecules (including proteins, genes, cytoskeletons, etc.), cells (and their interactions with extracellular matrix), tissues and organs, the development of relevant advanced mathematical methods, and the discovery of biological secrets. As science concerns only with relative truth, we seek ideas that are state-of-the-art, which may be controversial, but stimulate and promote new ideas, new techniques, and new applications.