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

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.

A Study Based on Metabolomics, Network Pharmacology, and Experimental Verification to Explore the Mechanism of Qinbaiqingfei Concentrated Pills in the treatment of Mycoplasma Pneumonia

“…Through the combined analysis of metabolomics and network pharmacology, it can be seen that QB mainly interfere with the G alpha (q) signaling events, GPCR downstream signaling, signal transduction, signaling by GPCR, spinal cord injury, GnRH signaling pathway, relationship between inflammation COX-2 and EGFR, and other interventions in the disease process, mainly the intervention of G-protein–coupled receptors, and EGFR. Through the analysis of the combined path of the two, G-protein–coupled receptors can directly promote the activation of the PI3K pathway ( Li et al, 2021 ), while EGFR directly promotes the expression of Twist2 ( Lehman et al, 2020 ). Both the STAT3 and PI3K pathways act as the direct upstream of the NF-κB pathway, directly or through Twist2, promoting the activation of the NF-κB pathway ( Figure 10 ).…”

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

“…To date, the interconnection between H 2 O 2 signaling and EMT in cancer is well established (Milton and Konrad, 2022), and the role of H 2 O 2 producers NADPH oxidase 4 (NOX4), dual oxidase 1 (DUOX1) and DUOX2 in cell motility and metastasis in cancer biology has been reviewed (Meitzler et al, 2019). Regarding NF-κB, it was demonstrated that inhibiting its activity resulted in an almost complete loss of expression of the Twist2 gene (Lehman et al, 2020). The effects of activating the JAK/STAT3 signaling pathway on EMT and the generation of CSCs have also been documented (Jin 2020).…”

Properties of flavonoids in the treatment of bladder cancer (Review)

“…In addition to the morphological changes, EMTcells possess stem cell properties. This phenomenon enables EMT and GSCs regulation by similar pathways, including the WNT, STAT3 and NF-κB and Hedgehog pathways (58,59). The PI3K/AKT/mTOR signal pathway is a classical pathway regulating cell growth and differentiation.…”