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首页> 外文期刊>Oncogene >Bioengineered tumor microenvironments with naked mole rats high-molecular-weight hyaluronan induces apoptosis in breast cancer cells
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Bioengineered tumor microenvironments with naked mole rats high-molecular-weight hyaluronan induces apoptosis in breast cancer cells

机译：裸鼹鼠高分子量透明质酸的生物工程肿瘤微环境诱导乳腺癌细胞凋亡

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摘要

The naked mole rat (nmr) is cancer resistant due to the abundant production of extremely high-molecular-weight hyaluronan (EHMW-HA). However, whether EHMW-HA has similar anti-cancer effects in mice and humans remains to be determined. The present study used breast cancer cells to clarify the effect of EHMW-HA on breast cancer. First, the overexpression of nmrHas2 in 4T1 and BT549 cell lines in both two-dimensional (2D) and three-dimensional (3D) models to mimic tumor microenvironment was established. The 4T1/BT549-nmrHas2 cells could secrete EHMW-HA (with a molecular weight of up to 6 MDa), which was similar to that found in the naked mole rat. Second, EHMW-HA altering tumor microenvironment in both 2D monolayers and 3D spheroids significantly enhanced apoptosis, inhibiting the proliferation of 4T1 and BT549 cells. The prominent anticancer effects of EHMW-HA on the cancer-cell apoptosis phenotype were further confirmed by inhibiting tumor formation in nude mice. Finally, EHMW-HA significantly induced higher p53 protein expression, which enhanced pro-apoptotic proteins p21 and Bax in breast cancer cells; this is in contrast with the triggering of hypersensitivity of the naked mole rat cells to early contact inhibition (ECI). These results have important implications for the design of therapeutic approaches based on the application of EHMW-HA.
机译：裸鼹鼠 （nmr） 由于大量产生极高分子量透明质酸 （EHMW-HA） 而具有抗癌性。然而，EHMW-HA在小鼠和人类中是否具有相似的抗癌作用仍有待确定。本研究使用乳腺癌细胞阐明了EHMW-HA对乳腺癌的影响。首先，在二维（2D）和三维（3D）模型中建立了nmrHas2在4T1和BT549细胞系中的过表达，以模拟肿瘤微环境。4T1/BT549-nmrHas2细胞可以分泌EHMW-HA（分子量高达6 MDa），这与裸鼹鼠相似。其次，EHMW-HA改变2D单层和3D球状体中的肿瘤微环境显著增强细胞凋亡，抑制4T1和BT549细胞的增殖。通过抑制裸鼠肿瘤形成，进一步证实了EHMW-HA对癌细胞凋亡表型的显著抗癌作用。最后，EHMW-HA显著诱导p53蛋白表达升高，增强乳腺癌细胞中促凋亡蛋白p21和Bax;这与裸鼹鼠细胞对早期接触抑制 （ECI） 的超敏反应的触发形成鲜明对比。这些结果对基于EHMW-HA应用的治疗方法设计具有重要意义。

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