Inhibition of SALL4 reduces tumorigenicity involving epithelial-mesenchymal transition via Wnt/β-catenin pathway in esophageal squamous cell carcinoma

Abstract

BackgroundGrowing evidence suggests that SALL4 plays a vital role in tumor progression and metastasis. However, the molecular mechanism of SALL4 promoting esophageal squamous cell carcinoma (ESCC) remains to be elucidated.MethodsThe gene and protein expression profiles- were examined by using quantitative real-time PCR, immunohistochemistry and western blotting. Small hairpin RNA was used to evaluate the role of SALL4 both in cell lines and in animal models. Cell proliferation, apoptosis and invasion were assessed by CCK8, flow cytometry and transwell-matrigel assays. Sphere formation assay was used for cancer stem cell derivation and characterization.ResultsOur study showed that the transcription factor SALL4 was overexpressed in a majority of human ESCC tissues and closely correlated with a poor outcome. We established the lentiviral system using short hairpin RNA to knockdown SALL4 in TE7 and EC109 cells. Silencing of SALL4 inhibited the cell proliferation, induced apoptosis and the G1 phase arrest in cell cycle, decreased the ability of migration/invasion, clonogenicity and stemness in vitro. Besides, down-regulation of SALL4 enhanced the ESCC cells’ sensitivity to cisplatin. Xenograft tumor models showed that silencing of SALL4 decreased the ability to form tumors in vivo. Furthermore, our study demonstrated that SALL4 played a vital role in modulating the stemness of ESCC cells via Wnt/β-catenin signaling pathway and in epithelial-mesenchymal transition.ConclusionsOur results revealed that SALL4 might serve as a functional marker for ESCC cancer stem cell, a crucial marker for prognosis and an attractive candidate for target therapy of ESCC.

cPLA2α reversibly regulates different subsets of cancer stem cells transformation in cervical cancer

“…PKCζ affects β‐catenin stability, further affecting stem cell function . The Wnt/β‐catenin pathway plays an important role in tumor cell EMT and stemness; such report is consistent with our results from KEGG pathway analysis based on the differential genes between cPLA2α KD and KD/SCR CSCs and from mass spectrometry analysis. Many β‐catenin molecules bound to the cytomembrane with E‐cadherin, and less nuclear translocation of β‐catenin occurred when PKCζ was knocked down regulated by cPLA2α inhibition, leading to increased E‐cadherin‐mediated cell‐to‐cell adhesion and blockage of EMT and metastasis.…”

SALL4 promotes the tumorigenicity of cervical cancer cells through activation of the Wnt/β‐catenin pathway via CTNNB1

“…It had been reported that SALL4 induced myelodysplastic syndrome and acute myeloid leukemia by activating the Wnt/β‐catenin signaling pathway . In esophageal squamous cell carcinoma, inhibition of SALL4 reduces the tumorigenicity via the Wnt/β‐catenin signaling pathway . We investigated whether the function of SALL4 in cervical cancer cells was also associated with the Wnt/β‐catenin signaling pathway.…”

Tissue-guided LASSO for prediction of clinical drug response using preclinical samples

“…For example, the shRNA knockdown of CHI3L1, a gene identified for etoposide and cisplatin response in every tissue, has been shown to sensitize glioma cells to these two drugs, while its overexpression reduced their sensitivity [41]. As another example, the knockdown of SALL4 (identified in all tissues) in cancer cell lines has been shown to increase the sensitivity of lung cancer cells [42] and esophageal squamous cell carcinoma cells [43] to cisplatin. Supplementary Table S7 summarizes some of the evidence we curated from literature for the role of different genes identified by TG-LASSO in all tissue types for cisplatin, as an illustration.…”