Carbohydrate (Chondroitin 4) Sulfotransferase-11-Mediated Induction of Epithelial-Mesenchymal Transition and Generation of Cancer Stem Cells

Introduction: We have previously shown that the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) is elevated in human breast cancer tissues, and that its expression in human breast cancer cell lines is associated with aggressive behavior of cells. The clinical significance of CHST11 expression is unknown, and its function in breast cancer cells is not fully understood. Objective: The current study was performed to define the clinical significance of this gene and address its biological function in promoting the aggressive behavior of breast cancer cells. Methods: Publicly available datasets were analyzed to determine the correlation of CHST11 expression with breast cancer survival. MCF-7 cells were transfected with the human CHST11 gene, and MCF-7-CHST11 cells with stable expression of the gene were established. Morphology and metastatic capacity of transfected cells were monitored in vitro. E-cadherin and β-catenin expression was compared by immunofluorescence. The expression of genes involved in epithelial-mesenchymal transition (EMT) and pluripotency was determined using real-time PCR. The Wnt inhibitor, Wnt-C59, was used to examine the involvement of Wnt in CHST11-mediated morphology. Results: The elevated expression of CHST11 in breast tumor specimens was significantly associated with poor survival among patients. MCF-7-CHST11 cells displayed morphological characteristics consistent with EMT, together with a significantly higher proliferation rate, enhanced migratory potential, and more robust anchorage-independent growth. MCF-7-CHST11 cells showed decreased expression of E-cadherin and increased accumulation of β-catenin, as assessed by immunofluorescence. Consistently, increased expression of CHST11 resulted in upregulation of key EMT and stem cell markers. Morphological transition in MCF-7-CHST11 cells was partially reversed by co-incubation with an inhibitor of the Wnt pathway. Conclusions: Our findings support a role for CHST11 in induction of EMT and stem cell-like properties. Our data also associate the expression levels of CHST11 in breast tumor specimens with patients’ survival. The results have a significant implication for CHST11 expression level as a novel molecular signature for predictive and prognostic purposes in breast cancer. Moreover, with a possible role in driving tumor cell aggressiveness, CHST11 expression might be further considered as a potential therapeutic target for breast cancer.

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