Abstract
Choriocarcinoma stem-like cells (CSLCs) might be at the origin of choriocarcinoma development associated with drug resistance or relapse. Spalt-like transcription factor 4 (SALL4), which is considered to be a stemness-related gene, can be regulated by miRNAs. In this study, SALL4 result is associated with progression-free survival of choriocarcinoma patients and CSLC’s stemness characteristics. In addition, it could be downregulated by miR-497-5p by direct binding. miR-497-5p silencing by hypermethylation promoted malignant CSLC phenotype in vitro and in vivo. Furthermore, increased DNA methyltransferases (DNMTs) by SALL4 upregulation inhibited miR-497-5p expression via hypermethylation promotion. SALL4 appeared to be a key factor in promoting stemness phenotype of choriocarcinoma. Silencing miR-497-5p and SALL4 promotes choriocarcinoma progression and forms a feedback loop with DNMT-mediated epigenetic regulation, playing a crucial role in stemness maintenance in choriocarcinoma.
Highlights
Choriocarcinoma is a gestational, highly malignant trophoblastic neoplasia, often arising after normal pregnancy, hydatidiform moles, or spontaneous abortions [1]
Spalt-like transcription factor 4 (SALL4) expression is the independent risk factor correlated with the progression-free survival (PFS) of choriocarcinoma (Table 2, HR = 7.045, P = 0.016).To evaluate the role of SALL4 in choriocarcinoma, SALL4 protein expression was analyzed in normal, untreated, and refractory groups by immunohistochemistry (IHC)
Our results showed that DNMT1 and DNMT3b were highly expressed in choriocarcinoma stem-like cells (CSLCs) compared with JEG-3 cells (Fig. 6A, B, P < 0.05)
Summary
Choriocarcinoma is a gestational, highly malignant trophoblastic neoplasia, often arising after normal pregnancy, hydatidiform moles, or spontaneous abortions [1]. Cancer stem cells are considered as involved in tumorigenesis [3], progression, and recurrence after therapy since they regulate long-term tumor growth and progression [4]. Our previous study isolated the choriocarcinoma stem-like cells (CSLCs) from the JEG-3 cells, the most typical cell model of choriocarcinoma [5]. Spalt-like transcription factor 4 (SALL4) is a zinc-finger transcription factor detected in fetal gonadal germ cells [6]. Due to its oncogenic role, SALL4 has emerged as a tumor marker in many tumors [7], especially germ cell tumors [8, 9]. Aberrant SALL4 expression results in cell proliferation promotion in choriocarcinoma [10], and SALL4 is a useful biomarker to distinguish it from other trophoblastic tumors [11]
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