The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis

Abstract

NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IκBα downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-κB target gene expression and poor prognosis in human patients.

CD147 promotes progression of head and neck squamous cell carcinoma via NF‐kappa B signaling

“…The activation of NF‐kappa B induced the formation of the IKK (IκB kinase) protein complex and some protein regulate the complex as IKK interactors, such as Hsp70, Hsp90. And some NF‐kappa B targeted genes promote tumor growth, invasion and metastasis, such as MMP‐9 and IL‐6 . There are reports shown that CD147 promoted the expression of MMP‐9, which might be a mechanism that CD147 promoted tumor progression and invasion in HNSCC via regulating NF‐kappa B signaling .…”

“…The mechanisms underlying CD147 induced activation of NF‐kappa B in HNSCC were still not clear. Reports showed that different stimuli could activate the NF‐kappa B signaling, including cytokine, growth factor, DNA damages and oncogenic stress . The activation of NF‐kappa B induced the formation of the IKK (IκB kinase) protein complex and some protein regulate the complex as IKK interactors, such as Hsp70, Hsp90.…”

“…CD147, a transmembrane glycoprotein, belongs to the immunoglobulin superfamily and is widely expressed on the surface of cancer cells . Reports showed that CD147 was over‐expressed in many types of cancer, such as human malignant melanoma, hepatocellular carcinoma, lung cancer, gastric cancer, breast cancer and so on . CD147 is also reported to involve in tumor progression, angiogenic function and immune response …”

“…Furthermore, many studies demonstrated that CD147 could stimulate the activation of nuclear factor kappa B (NF‐kappa B) pathway . The NF‐kappa B pathway is reported to elevate cancer cell proliferation, metastasis and reduce cancer cell apoptosis . And the family of NF‐kappa B transcription factors consists of RelA/p65, c‐Rel, RelB, NF‐κB1 (p50), and NF‐κB2(p52) and are kept silenced in the cytoplasm .…”

Inhibition of bromodomain and extra‐terminal proteins increases sensitivity to venetoclax in chronic lymphocytic leukaemia

“…21 1 μg of total RNA was used for reverse transcription with iScript cDNA Synthesis Kit (Bio-Rad) according to the manufacturer's protocol. 21 1 μg of total RNA was used for reverse transcription with iScript cDNA Synthesis Kit (Bio-Rad) according to the manufacturer's protocol.…”