hsa_circ_0005358 suppresses cervical cancer metastasis by interacting with PTBP1 protein to destabilize CDCP1 mRNA

Yixuan Cen; Tingjia Zhu; Yanan Zhang; Lu Zhao; Jiawei Zhu; Lingfang Wang; Junfen Xu; Tian Ding; Xing Xie; Xinyu Wang; Weiguo Lu

doi:10.1016/j.omtn.2021.11.020

hsa_circ_0005358 suppresses cervical cancer metastasis by interacting with PTBP1 protein to destabilize CDCP1 mRNA

Mol Ther Nucleic Acids. 2021 Nov 29:27:227-240. doi: 10.1016/j.omtn.2021.11.020. eCollection 2022 Mar 8.

Authors

Yixuan Cen¹, Tingjia Zhu¹, Yanan Zhang¹, Lu Zhao¹, Jiawei Zhu¹, Lingfang Wang¹, Junfen Xu², Tian Ding², Xing Xie^{1

2}, Xinyu Wang^{1

2

3}, Weiguo Lu^{1

2

3}

Affiliations

¹ Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
² Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou 310006, China.
³ Cancer Center, Zhejiang University, Hangzhou 310058, China.

Abstract

Metastasis is the main cause of cervical cancer lethality, but to date, no effective treatment has been developed to block metastasis. Circular RNAs (circRNAs) were recently found to be involved in cancer metastasis. In this study, we identified a downregulated circRNA derived from the host gene Gli1 (hsa_circ_0005358) in cervical cancer tissues, which was expressed at lower levels in tissues with extracervical metastasis than in those without extracervical metastasis. Upregulation of hsa_circ_0005358 significantly suppressed the migration and invasion of cervical cancer cells in vitro, and downregulation of hsa_circ_0005358 had the opposite effect. A mouse model revealed that cervical cancer cells overexpressing hsa_circ_0005358 possessed weaker metastatic potential in vivo. RNA-pull-down assay, mass spectrometry, and RNA immunoprecipitation validated the findings that hsa_circ_0005358 functions via its 215-224 sequence, which interacts with polypyrimidine tract-binding protein 1 (PTBP1). RNA-sequencing profiling revealed that CUB-domain-containing protein 1 (CDCP1) is a common target for hsa_circ_0005358 and PTBP1. We further confirmed that hsa_circ_0005358 sequestered PTBP1, preventing it from stabilizing CDCP1 mRNA, reducing CDCP1 protein translation and ultimately suppressing cancer metastasis. Our findings reveal the function of hsa_circ_0005358 in tumor metastasis, which may be applied to a potential therapeutic approach for patients with metastatic cervical cancer.

Keywords: CDCP1; PTBP1; cervical cancer; circular RNA; hsa_circ_0005358; metastasis.