School of Life Science and Technology, Harbin Institute of Technology, 150080, Harbin, China.
Research Center of Basic Space Science, Space Environment Stimulation and Research Interface, Harbin Institute of Technology, 150080, Harbin, China.
Oncogene. 2019 May;38(22):4297-4309. doi: 10.1038/s41388-019-0719-4. Epub 2019 Jan 30.
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.
裸鼹鼠（nmr）由于大量产生超高分子量透明质酸（EHMW-HA）而具有抗癌症的能力。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来阐明 EHMW-HA 对乳腺癌的影响。首先，在二维（2D）和三维（3D）模型中，通过过表达 nmrHas2 来建立 4T1 和 BT549 细胞系的模拟肿瘤微环境。4T1/BT549-nmrHas2 细胞能够分泌 EHMW-HA（分子量高达 6 MDa），这与在裸鼹鼠中发现的相似。其次，EHMW-HA 在 2D 单层和 3D 球体中改变肿瘤微环境，显著增强了细胞凋亡，抑制了 4T1 和 BT549 细胞的增殖。EHMW-HA 在裸鼠中抑制肿瘤形成，进一步证实了其对癌细胞凋亡表型的显著抗癌作用。最后，EHMW-HA 显著诱导更高的 p53 蛋白表达，增强了乳腺癌细胞中的促凋亡蛋白 p21 和 Bax；这与裸鼹鼠细胞对早期接触抑制（ECI）的敏感性触发形成对比。这些结果对于基于 EHMW-HA 应用的治疗方法的设计具有重要意义。
