Cervical cancer is one of the leading malignancies causing morbidity and mortality in women in developing countries, and cervical cancer has the fourth highest incidence and mortality rate among female tumors. It is estimated that there are more than 600,000 new cases of cervical cancer and more than 340,000 deaths worldwide [1]. While patients with early-stage cervical cancer have a good prognosis, it can be worsened by recurrence or metastasis. For advanced cervical cancer, cisplatin-based chemotherapy is preferred, but its efficacy is unsatisfactory, and the overall survival rate of patients at 5 years is only 68% [2], [3].Cervical squamous cell carcinoma (CESC) is the main pathological type of cervical cancer. 70%− 80% of cervical cancers are squamous and 20%− 25% are adenocarcinomas [4], [5]. Hence, it is still necessary to explore the mechanism of CESC development, identify suitable biomarkers and seek new targets for treatment.

The zinc finger structure of the cerebellum (ZIC) family includes ZIC1, ZIC2, ZIC3, ZIC4, and ZIC5, each encoding a zinc finger transcription factor [6]. The key feature of ZIC proteins is a highly conserved zinc finger structural domain that contains five tandem C2H2 zinc finger structures. In vertebrates, five ZIC genes have been identified and studied during embryonic development [7]. ZIC proteins play a key role in vertebrate development and are essential for cell cycle regulation in mammals [8]. ZIC1 determines the pattern of the cerebellar lobes in mice mainly by regulating cell proliferation in the ectodermal layer. ZIC2 is essential for the formation of neural crest and hindbrain patterns during mouse development. In addition, ZIC3 functions in the early stages of left-right (LR) somatotopic axis formation, which is associated with human somatotopic abnormalities. In zebrafish, ZIC1 and ZIC4 regulate the specification of the parietal plate and the morphogenesis of the hindbrain ventricles [9], [10]. Loss-of-function mutant phenotypes of the ZIC genes have been found to cause a range of congenital malformations. ZIC5-deficient mutant mice exhibit neural tube defects and hypoplasia of head neural crest derivatives [11]. There is increasing evidence that ZIC5 is involved in various pathological events of human diseases, such as cancer. In recent years, ZIC5 has been reported to be associated with a variety of malignancies, such as non-small cell lung cancer, melanoma, pancreatic cancer, gastric cancer, hepatocellular carcinoma, glioma [12], [13], [14], [15], [16], [17]. However, the expression and molecular function of ZIC5 in CESC is unknown.

In this study, we evaluated the expression of ZIC5 in CESC tissues and cell lines and explored its impact on patient prognosis and survival, as well as its effect on cell proliferation and migration in vitro and in vivo. Further studies confirmed that ZIC5 promotes the development and progression of CESC by regulating cancer stem cells (CSCs). To sum up, this study reveals an unspecified role of ZIC5 in CESC and provides new ideas for clinical treatment and prediction of prognosis.