PIM1 is responsible for IL-6-induced breast cancer cell EMT and stemness via c-myc activation

Abstract

Background Interleukin-6 (IL-6) has been demonstrated to be a critical factor for breast cancer malignancy. However, the molecular mechanisms by which IL-6 induce breast cancer cells epithelial–mesenchymal-transition (EMT) and stemness remain elusive. Methods Breast cancer cell lines T47D and MCF7 were exposed to IL-6, the expression of PIM1 was examined by quantitative real-time PCR (qRT-PCR) and western blot. Luciferase reporter assay was used to determine the transcriptional modulation of PIM1 by IL-6 and STAT3 inhibitor. Transwell assay was used to detect the invading ability of breast cancer cells induced by IL-6 or PIM1. The expressions of EMT and stemness markers were determined by qRT-PCR. Results IL-6 promoted PIM1 expression in a dose- and time-dependent manner, and this induction could be abrogated by inhibiting STAT3 activation, subsequently suppressing the transcriptional level of PIM1. Moreover, we noticed that knocking down of PIM1 in cells which was exposed to IL-6 significantly impaired the invasion ability and the expression of EMT and stemness markers. On the contrary, overexpression of PIM1 promoted cell invasion and upregulated the expression of EMT and stemness markers. In addition, we demonstrated that c-myc, the cofactor of PIM1, involved in the pro-oncogenic roles of PIM1. Knocking down of c-myc attenuated the PIM1-induced cell EMT and stemness. Conclusion This study proposed the upregulation of PIM1 by IL-6 contributed to breast cancer cell aggressiveness and targeting PIM1 or c-myc could be novel approaches for breast cancer treatment.

Targeted Inhibition of miR-221/222 Promotes Cell Sensitivity to Cisplatin in Triple-Negative Breast Cancer MDA-MB-231 Cells

“…STAT3, as a widelyconfirmed downstream target gene of SOCS1 was further analyzed, showing inhibition in expression by anti-miR-221/222 ( Figures 5A-C). STAT3 transcriptionally regulates expression of a set of downstream genes including c-Myc and Bcl2 in control of tumorigenesis and chemo-resistance in cancer (Fathi et al, 2018;Gao et al, 2019). Our further analysis indicated the decrease of c-Myc and Bcl2 in expression by anti-miR-221/222, which is consistent with the upregulation of SOCS1 and downregulation of STAT3 ( Figures 5A-C).…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Increased interleukin production (IL-1α and IL-8) due to the action of PIM-3 [89] and PIM-2 as other serine/threonine kinases promotes the metastasis of BC via STAT3 activation and activated STAT3 upregulates PIM-2 expression by forming a positive feedback loop [90]. Furthermore, IL-6/JAK/STAT3 activation induces c-Myc expression through the upregulation of PIM-1 to enhance EMT and stemness [91].…”

Role of STAT3 signaling pathway in breast cancer

“…In addition, IL-11 is also found to regulate the JAK/STAT3 pathway in breast cancer-bone metastasis [55]. PIM1, a proto-oncogene responsible for promoting cell invasion and upregulating EMT expression in breast cancer, is found to be regulated by the IL-6/STAT3 signaling pathway [56]. MUC1-C, an oncogenic protein, can activate STAT3 and induce Twist transactivation to promote EMT [57].…”