Inhibition of Delta-like Ligand 4 enhances the radiosensitivity and inhibits migration in cervical cancer via the reversion of epithelial-mesenchymal transition

Shan-Shan Yang; De-Yang Yu; Yu-Ting Du; Le Wang; Lina Gu; Yun-Yan Zhang; Min Xiao

doi:10.1186/s12935-020-01434-1

Inhibition of Delta-like Ligand 4 enhances the radiosensitivity and inhibits migration in cervical cancer via the reversion of epithelial-mesenchymal transition

Cancer Cell Int. 2020 Jul 28:20:344. doi: 10.1186/s12935-020-01434-1. eCollection 2020.

Authors

Shan-Shan Yang^#¹, De-Yang Yu^#², Yu-Ting Du¹, Le Wang¹, Lina Gu¹, Yun-Yan Zhang¹, Min Xiao³

Affiliations

¹ Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, No. 150 HaPing Road, Nangang District, Harbin, 150081 China.
² Department of Radiation Physics, Harbin Medical University Cancer Hospital, Harbin, 150081 China.
³ Department of Breast Surgery, Harbin Medical University Cancer Hospital, No. 150 HaPing Road, Nangang District, Harbin, 150081 China.

^# Contributed equally.

Abstract

Background: Concurrent chemoradiotherapy is the common first-line treatment for patients with advanced cervical cancer. However, radioresistance remains a major clinical challenge, which results in recurrence and poor survival. Many studies have shown the potential of Delta-like Ligand 4 (DLL4) as a novel prognostic biomarker and therapeutic target in many solid tumors. Previously, we have found that high DLL4 expression in tumor cells may predict the pelvic lymph node metastasis and poor prognosis in patients with cervical cancer. In our present study, we further studied the effects of DLL4 on the biological behavior and radiosensitivity of cervical cancer cells.

Methods: The expression of DLL4 and epithelial-mesenchymal transition (EMT) phenotype markers in cervical cancer cell lines or tissues were detected using Western blotting, and the expression of DLL4 mRNA in cervical cancer cell lines or tissues was detected using Quantitative real-time PCR. The effect of DLL4 on cell proliferation, migration, and radiosensitivity was evaluated using the CCK8 assay, flow cytometry, Transwell assays for cell invasion and migration, and Immunofluorescence staining in vitro.

Results: The expression of DLL4 in radiotherapy-resistant SiHa cells was significantly higher than that in radiotherapy-sensitive Me-180 cells. Furthermore, downregulation of DLL4 enhanced the radiosensitivity of SiHa and Caski cells via the inhibition of cell proliferation, promotion of radiation-induced apoptosis, and inhibition of the DNA damage repair. Moreover, downregulation of DLL4 inhibited the EMT and reduced the proliferation, invasion, and migration ability in SiHa and Caski cells. Consistent with the DLL4 expression in the cell lines, the expression of DLL4 in the tissues of the radioresistant group was also higher than that of the radiosensitive group.

Conclusions: Downregulation of DLL4 inhibited the progression and increased the radiosensitivity in cervical cancer cells by reversing EMT. These results indicated the promising prospect of DLL4 against the radioresistance and metastasis of cervical cancer and its potential as a predictive biomarker for radiosensitivity and prognosis in patients with cervical cancer patients receiving concurrent chemoradiotherapy (cCRT).

Keywords: Cervical cancer; DLL4; Epithelial–mesenchymal transition; Progression; Radiosensitivity.