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The IKK/NF-?B signaling pathway requires Morgana to drive breast cancer metastasis.

ABSTRACT: NF-?B 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-?B is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-?B 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 I?B? substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by I?B? 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-?B target gene expression and poor prognosis in human patients.

SUBMITTER: Fusella F

PROVIDER: S-EPMC5696377 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Fusella Federica F Seclì Laura L Busso Elena E Krepelova Anna A Moiso Enrico E Rocca Stefania S Conti Laura L Annaratone Laura L Rubinetto Cristina C Mello-Grand Maurizia M Singh Vijay V Chiorino Giovanna G Silengo Lorenzo L Altruda Fiorella F Turco Emilia E Morotti Alessandro A Oliviero Salvatore S Castellano Isabella I Cavallo Federica F Provero Paolo P Tarone Guido G Brancaccio Mara M

Nature communications 20171121 1

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 substrat ...[more]

PMID: 29158506

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Project description:Breast cancer metastasis is the primary cause of mortality of patients with breast cancer. The present study aimed to explore the role and underlying mechanisms of IGJ in the invasion and metastasis of breast cancer. The Cancer Genome Atlas database was utilized to analyze the differential gene expression profiles in patients with breast cancer with or without metastasis; the target gene, joining chain of multimeric IgA and IgM (JCHAIN, also known as IGJ, as referred to herein), with significant expression and with prognostic value was screened. The expression levels of IGJ in human breast cancer paired tissues and cell lines were detected using reverse transcription‑quantitative PCR and western blot analysis. IGJ differential expression was detected in paired human breast cancer tissues using immunohistochemistry. The role of IGJ in breast cancer was verified using CCK‑8, invasion and migration assays, and scratch tests in vivo and in vitro. Further exploration of the role and mechanism of IGJ in breast cancer was conducted through Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes analysis, western blot analysis and immunofluorescence experiments. Through the analysis of gene expression profiles, it was found that IGJ was poorly expressed in patients with breast cancer with metastasis compared to patients with non‑metastatic breast cancer. The overexpression of IGJ was associated with an improved distant metastasis‑free survival and overall survival (OS). COX multivariate regression analysis demonstrated that IGJ was an independent prognostic factor for the OS and relapse‑free survival of patients with breast cancer. In comparison to healthy breast cancer adjacent tissues and cell lines, IGJ was poorly expressed in breast cancer tissues and cell lines (P<0.05). Further analyses indicated that the overexpression of IGJ suppressed the proliferation, invasion and metastasis of breast cancer cells in vivo and in vitro by inhibiting the occurrence of epithelial‑to‑mesenchymal transition (EMT) and suppressing the nuclear translocation of p65. Finally, rescue experiments indicated that IGJ restricted the proliferation and metastasis of breast cancer cells by regulating the NF‑κB signaling pathway. On the whole, the present study demonstrates that IGJ suppresses the invasion and metastasis of breast cancer by inhibiting both the occurrence of EMT and the NF‑κB signaling pathway. These findings may provide novel biomarkers and potential therapeutic targets for the treatment of metastatic breast cancer.

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The IKK/NF-?B signaling pathway requires Morgana to drive breast cancer metastasis.

Publications

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

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