NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition

J Cell Physiol. 2022 Jul;237(7):2770-2795. doi: 10.1002/jcp.30759. Epub 2022 May 13.

Abstract

Metastasis of tumor cells is a complex challenge and significantly diminishes the overall survival and prognosis of cancer patients. The epithelial-to-mesenchymal transition (EMT) is a well-known mechanism responsible for the invasiveness of tumor cells. A number of molecular pathways can regulate the EMT mechanism in cancer cells and nuclear factor-kappaB (NF-κB) is one of them. The nuclear translocation of NF-κB p65 can induce the transcription of several genes involved in EMT induction. The present review describes NF-κB and EMT interaction in cancer cells and their association in cancer progression. Due to the oncogenic role NF-κB signaling, its activation enhances metastasis of tumor cells via EMT induction. This has been confirmed in various cancers including brain, breast, lung and gastric cancers, among others. The ZEB1/2, transforming growth factor-β, and Slug as inducers of EMT undergo upregulation by NF-κB to promote metastasis of tumor cells. After EMT induction driven by NF-κB, a significant decrease occurs in E-cadherin levels, while N-cadherin and vimentin levels undergo an increase. The noncoding RNAs can potentially also function as upstream mediators and modulate NF-κB/EMT axis in cancers. Moreover, NF-κB/EMT axis is involved in mediating drug resistance in tumor cells. Thus, suppressing NF-κB/EMT axis can also promote the sensitivity of cancer cells to chemotherapeutic agents.

Keywords: EMT; NF-κB signaling; cancer therapy; chemoresistance; metastasis.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition*
  • Humans
  • NF-kappa B* / genetics
  • NF-kappa B* / metabolism
  • Neoplasms / pathology
  • Signal Transduction
  • Transforming Growth Factor beta / genetics

Substances

  • NF-kappa B
  • Transforming Growth Factor beta