J Cancer 2020; 11(2):301-310. doi:10.7150/jca.33983 This issue

Research Paper

E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma

Kun Zhang1, Bo Zhang2, Yun Bai2✉, Limeng Dai2✉

1. Department of Pathogenic Biology, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China;
2. Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, PR China.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Zhang K, Zhang B, Bai Y, Dai L. E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma. J Cancer 2020; 11(2):301-310. doi:10.7150/jca.33983. Available from https://www.jcancer.org/v11p0301.htm

File import instruction

Abstract

Cisplatin is an essential chemotherapy drug in esophageal squamous cell carcinoma (ESCC). Some studies suggested that the expression of E2F1 is increased in ESCC cells after cisplatin treatment, but its mechanism remains obscure. Here, we found that miR-26b is upregulated in ESCC cell lines with cisplatin treatment, and it relies on the expression of E2F1 because E2F1 directly binds to the promoter of the miR-26b gene, thus activating the transcriptional activity of miR-26b. Cell cycle analysis suggested that miR-26b inhibits the G1/S phase transition, thus inhibiting the cell growth of ESCC cells. The cisplatin-induced cycle arrest also closely depends on the expression of miR-26b. In vivo assays revealed that the sensitivity of ESCC cells to cisplatin is decreased when the E2F1/miR-26b pathway is disturbed. A nude mouse xenograft model of cisplatin treatment showed that the tumor volume was increased in the Si-E2F1 group compared with that in the group with cisplatin treatment alone. The effect may be due to the cellular DNA damage response, because that miR-26b could target the mRNA of ATM and Rb genes via binding to their 3'UTRs, thus leading to decreased protein expression of ATM and Rb. In conclusion, our results indicate that E2F1 promotes the chemosensitization to cisplatin in ESCC. The effect may be due to the upregulation of miR-26b because cisplatin-induced cycle arrest depends on miR-26b, which may also disturb the DNA damage response by reducing the expression of ATM and Rb.

Keywords: E2F1, miR-26b, ATM, esophageal squamous cell carcinoma, cisplatin.