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.

中文翻译：

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裸mole鼠大鼠的生物工程化肿瘤微环境高分子量透明质酸可诱导乳腺癌细胞凋亡。

裸mole鼠（nmr）由于极高分子量的透明质酸（EHMW-HA）的大量生产而具有抗癌性。但是，EHMW-HA在小鼠和人类中是否具有类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对乳腺癌的作用。首先，建立了在二维（2D）和三维（3D）模型中模拟肿瘤微环境的4T1和BT549细胞系中nmrHas2的过表达。4T1 / BT549-nmrHas2细胞可以分泌EHMW-HA（分子量高达6 MDa），与裸mole鼠中的相似。其次，改变2D单层和3D椭球体中的肿瘤微环境的EHMW-HA显着增强了细胞凋亡，从而抑制了4T1和BT549细胞的增殖。通过抑制裸鼠中的肿瘤形成，进一步证实了EHMW-HA对癌细胞凋亡表型的显着抗癌作用。最后，EHMW-HA显着诱导了较高的p53蛋白表达，从而增强了乳腺癌细胞中促凋亡蛋白p21和Bax的表达。这与裸mole鼠大鼠细胞对早期接触抑制（ECI）的超敏性触发相反。这些结果对基于EHMW-HA的治疗方法设计具有重要意义。这与裸mole鼠大鼠细胞对早期接触抑制（ECI）的超敏性触发相反。这些结果对基于EHMW-HA的治疗方法设计具有重要意义。这与裸mole鼠大鼠细胞对早期接触抑制（ECI）的超敏性触发相反。这些结果对基于EHMW-HA的治疗方法设计具有重要意义。