Lin28 Mediates Radiation Resistance of Breast Cancer Cells via Regulation of Caspase, H2A.X and Let-7 Signaling

Abstract

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.

Significant association of combination of OCT4, NANOG, and SOX2 gene polymorphisms in susceptibility and response to treatment in North Indian breast cancer patients

“…On the contrary, a recent report showed correlation of increased expression of OCT4 and NANOG with cisplatin resistance in oral squamous cell carcinoma [52]. So far, there is a single study on LIN28, showing it could be a potential target for overcoming radiation resistance in breast cancer [57]. To the best of our knowledge, this is the first study evaluating the role of OCT4, NANOG, SOX2, and LIN28 genetic variants with breast cancer response to NACT.…”

The LIN28/let-7 Pathway in Cancer

“…While stable expression of Lin28 in cancer cells with low Lin 28 levels significantly reduced their sensitivity to paclitaxel, LIN28A knockdown in T47D cells effectively sensitized them to the drug. In another study, LIN28A was reported to be responsible for breast cancer cell resistance to radiation (Wang et al, 2013). Highest expression level of LIN28A was found in T47D cancer cells which were most resistant to radiation treatment.…”

MicroRNAs: Novel Players in Cancer Diagnosis and Therapies

“…Restoration of let-7a expression significantly resensitized cells to radiation treatment [69]. Wang et al found that miR-23b expression was down in radiation resistant lines of pancreatic cancer cells.…”