Oncolytic adenovirus-mediated dual knockdown of survivin and OCT4 improves therapeutic efficacy in esophageal cancer

Chunguang Li; Maoling Zhu; Qijue Lu; Boyao Yu; Yang Yang; Bin Li; Zhangxiao Peng; Zhigang Li

doi:10.21037/atm-22-4499

Oncolytic adenovirus-mediated dual knockdown of survivin and OCT4 improves therapeutic efficacy in esophageal cancer

Ann Transl Med. 2023 Mar 15;11(5):193. doi: 10.21037/atm-22-4499. Epub 2023 Mar 6.

Authors

Chunguang Li^#¹, Maoling Zhu^#², Qijue Lu^#³, Boyao Yu¹, Yang Yang¹, Bin Li¹, Zhangxiao Peng⁴, Zhigang Li¹

Affiliations

¹ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
² Department of Gastroenterology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
³ Department of Thoracic Surgery, Naval Medical Center, Naval Medical University, Shanghai, China.
⁴ Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Centre for Liver Cancer, Naval Medical University, Shanghai, China.

^# Contributed equally.

Abstract

Background: Survivin and octamer-binding transcription factor 4 (OCT4) are reportedly up-regulated in esophageal cancer (EC) and have been correlated with high tumor proliferative activity and poor prognosis. Oncolytic viruses encoding specific transgenes have been considered as therapeutic methods to increase therapeutic efficacy in a variety of solid tumors.

Methods: In this study, an oncolytic adenovirus carrying short hairpin RNA (shRNA) of survivin (shSRVN) and OCT4 (shOCT4) was constructed to achieve dual knockdown of survivin and OCT4 and to explore the potential effect of the oncolytic adenovirus in EC.

Results: The oncolytic adenovirus replicated abundantly in human EC cells, with the replication multiplying by up to 192,085 and 620,055 times in esophageal carcinoma (Eca)-109 cells transfected with purified and completed recombinant adenoviruses called AdSProE1a-dual shRNA (shSRVN + shOCT4) and TE1 cells transfected with AdSProE1a-survivin shRNA (shSRVN) 96 hours after infection, respectively. The shRNAs targeting survivin and OCT4 significantly downregulated the expression levels of survivin and OCT4 in cells, thereby inhibiting the proliferative activity of cancer cells. Furthermore, E-cadherin and vimentin, which are both considered epithelial mesenchymal transition (EMT) markers, were found to be upregulated and downregulated, respectively, in cancer cells after exposure to the viral infection. The interference of survivin and OCT4 also contributed to cell cycle arrest and apoptosis, the half maximal inhibitory concentrations (IC50s) of oncolytic adenovirus loaded with AdSProE1a-shSRVN + shOCT4 in the Eca109 cells and the TE1 cells were 0.7271 and 0.1032 pfu/mL, respectively. Xenograft experiments in vivo showed that oncolytic adenovirus-mediated dual knockdown of survivin and OCT4 effectively inhibited the growth of xenografts and induced cancer cell apoptosis. We concluded that therapies targeting survivin and OCT4 have great potential for improving the therapeutic efficacy in EC.

Conclusions: The dual target design strategy ensured the efficacy and safety of the treatment system and provided a novel and effective adjuvant target therapy for EC.

Keywords: Esophageal cancer (EC); octamer-binding transcription factor 4 (OCT4); oncolytic virus; survivin; xenograft.