Twist2 is NFkB-responsive when p120-catenin is inactivated and EGFR is overexpressed in esophageal keratinocytes

Sci Rep. 2020 Nov 2;10(1):18829. doi: 10.1038/s41598-020-75866-0.

Abstract

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive and fatal cancer types. ESCC classically progresses rapidly and frequently causes mortality in four out of five patients within two years of diagnosis. Yet, little is known about the mechanisms that make ESCC so aggressive. In a previous study we demonstrated that p120-catenin (p120ctn) and EGFR, two genes associated with poor prognosis in ESCC, work together to cause invasion. Specifically, inactivation of p120ctn combined with overexpression of EGFR induces a signaling cascade that leads to hyperactivation of NFkB and a resultant aggressive cell type. The purpose of this present study was to identify targets that are responsive to NFkB when p120ctn and EGFR are modified. Using human esophageal keratinocytes, we have identified Twist2 as an NFkB-responsive gene. Interestingly, we found that when NFkB is hyperactivated in cells with EGFR overexpression and p120ctn inactivation, Twist2 is significantly upregulated. Inhibition of NFkB activity results in nearly complete loss of Twist2 expression, suggesting that this potential EMT-inducing gene, is a responsive target of NFkB. There exists a paucity of research on Twist2 in any cancer type; as such, these findings are important in ESCC as well as in other cancer types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catenins / genetics
  • Catenins / metabolism*
  • Cell Line
  • Delta Catenin
  • Disease Progression
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma / genetics*
  • Esophageal Squamous Cell Carcinoma / pathology
  • Gene Expression
  • Humans
  • Keratinocytes / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism*

Substances

  • Catenins
  • NF-kappa B
  • Repressor Proteins
  • TWIST2 protein, human
  • Twist-Related Protein 1
  • EGFR protein, human
  • ErbB Receptors
  • Delta Catenin
  • CTNND1 protein, human