Key Laboratory of Biotherapy of Zhejiang Province, Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
PLoS One. 2013 Jun 20;8(6):e67373. doi: 10.1371/journal.pone.0067373. Print 2013.
Resistance to radiation therapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to breast tumorigenesis; however, the relationship between Lin28 and radioresistance remains unknown. In this study, we investigated the association of Lin28 with radiation resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines. The results showed that the expression level of Lin28 was closely associated with resistance to radiation treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to radiation than MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which have low-level Lin28 expression. Transfection with Lin28 siRNA significantly led to an increase of sensitivity to radiation. By contrast, stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to radiation treatment. Stable expression of Lin28 also significantly inhibited radiation-induced apoptosis. Moreover, further studies have shown that caspases, H2A.X and Let-7 miRNA were the molecular targets of Lin28. Stable expression of Lin28 and treatment with radiation induced H2AX expression, while inhibited p21 and γ-H2A.X. Overexpression of Let-7 enhanced the sensitivities to radiation in breast cancer cells. Taken together, these results indicate that Lin28 might be one mechanism underlying radiation resistance, and Lin28 could be a potential target for overcoming radiation resistance in breast cancer.
对放射疗法的抵抗是癌症有效治疗的主要障碍。Lin28 已被证明有助于乳腺癌的发生；然而，Lin28 与放射抵抗之间的关系仍然未知。在这项研究中，我们研究了 Lin28 与放射抵抗之间的关联，并确定了 Lin28 在人乳腺癌细胞系中的作用机制。结果表明，Lin28 的表达水平与对放射治疗的抵抗密切相关。高表达 Lin28 的 T47D 癌细胞系比 MCF7、Bcap-37 或 SK-BR-3 癌细胞系更耐受放射，后者 Lin28 表达水平较低。Lin28 siRNA 的转染显著导致对放射的敏感性增加。相比之下，在乳腺癌细胞中稳定表达 Lin28 可有效降低对放射治疗的敏感性。Lin28 的稳定表达还显著抑制放射诱导的细胞凋亡。此外，进一步的研究表明，半胱氨酸天冬氨酸蛋白酶、H2A.X 和 Let-7 miRNA 是 Lin28 的分子靶标。Lin28 的稳定表达和放射处理诱导 H2AX 的表达，同时抑制 p21 和 γ-H2A.X。Let-7 的过表达增强了乳腺癌细胞对放射的敏感性。总之，这些结果表明 Lin28 可能是放射抵抗的一种机制，Lin28 可能是克服乳腺癌放射抵抗的潜在靶点。
