C1ql4 regulates breast cancer cell stemness and epithelial-mesenchymal transition through PI3K/AKT/NF-κB signaling pathway

Abstract

BackgroundThe stemness characteristic of breast cancer (BC) is a crucial factor underlying cancer recurrence and metastasis after operative therapy and chemoradiotherapy. Understanding the potential mechanism of breast cancer stem cells (BCSCs) may ameliorate the prognosis of patients.MethodsWe collected clinical specimens of BC patients for staining and statistical analysis to verify the expression status and clinical significance of complement C1q-like 4 (C1ql4). Western blot and qRT-PCR were employed to detect the expression of molecules. Flow cytometry was used to examine cell cycle, cell apoptosis and the portion of BCSCs. Wound healing and Transwell assays were used to detect cell metastasis. The effect of C1ql4 on breast cancer progression in vivo was examined in a nude mouse tumor bearing model.ResultsOur clinical analysis showed that C1ql4 was highly expressed in BC tissues and cell lines, and the high expression of C1ql4 was significantly corelated with the malignancy of BC patients. Moreover, we also found that C1ql4 was overexpressed in BCSCs. C1ql4 knockdown suppressed the BCSC and EMT properties, promoted cell cycle progression, enhanced BC cell apoptosis, and inhibited cell migration and invasion, whereas the C1ql4 overexpression exhibited the opposite effects. Mechanistically, C1ql4 promoted the activation and nuclear location of NF-κB and the expression of downstream factors TNF-α and IL-1β. Moreover, inhibition of PI3K/AKT signaling suppressed the C1ql4-induced stemness and EMT.ConclusionsOur findings suggest that C1ql4 promotes the BC cell stemness and EMT via modulating the PI3K/AKT/NF-κB signaling, and provides a promising target for BC treatment.

Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer

“…The co-administration with chemotherapy would lead to a less resistant population because TICs would have lost their stemness characteristics, as we discuss in the following paragraphs. The regulation of breast cancer progression through regulation of breast cancer stem cell-like properties has been recently described, probably mediated by the NF-κB cell signaling pathway [82,83], and the connection between chemoresistance, mesenchymal plasticity, and cancer stem cells in metastasis origin [84][85][86][87][88].…”

Versatile function of NF-ĸB in inflammation and cancer

“…In order to improve stemness and CSC features, the PI3K/Akt axis is required for the regulation of NF-κB. C1ql4 induces the PI3K/Akt axis to upregulate NF-κB expression, inducing EMT and causing stemness in breast tumors [ 170 ]. The NF-κB axis induction can cause the secretion of a number of proteins in the stemness acceleration.…”