EGFR through STAT3 modulates ΔN63α expression to sustain tumor‐initiating cell proliferation in squamous cell carcinomas

Abstract

Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the ΔNp63α isoform. Here, we investigated the regulation of ΔNp63α expression upon EGFR activation and the role of the EGFR-ΔNp63α axis in proliferation of SCC tumor-initiating cells (TICs). SCC cell lines A-431, Cal-27, and SCC-25 treated with EGF showed a time-dependent increase in ΔNp63α expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating ΔNp63α expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or ΔNp63α impaired the TICs ability to grow under non-differentiating conditions. Radiation treatment, which triggers EGFR activation, induced ΔNp63α accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non-differentiating conditions. Together, our findings provide evidence that ΔNp63α expression is regulated by EGFR activation through STAT3 and that the EGFR-ΔNp63α axis is crucial for proliferation of TICs present in SCCs.

Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

“…STAT3 is crucial for cancer development and metastasis as well as cancer inflammation [39–43] and frequently activated in different types of cancers such as breast, lung, renal, prostate, pancreatic, colon, gastric, cervical, and ovarian cancers [44–47]. SH003 inhibited STAT3 transcriptional activity, while each component did not affect it.…”

Tuberatolide B Suppresses Cancer Progression by Promoting ROS-Mediated Inhibition of STAT3 Signaling

“…In addition, excessive ROS affects various signaling pathways in cancer cells, including Akt, ERK, JNK, p38, NFκB, and STAT3 [12,13,14]. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family, which is important for development, apoptosis, proliferation, cell cycle progression, angiogenesis, inflammation, and cancer metastasis [15,16,17,18]. Moreover, STAT3 is frequently activated in nearly 70% of different cancer types, including breast, lung, colon, prostate, cervical, renal, pancreatic, and ovarian cancers [19,20,21,22,23].…”

Induction of autophagy by an oleanolic acid derivative, SZC017, promotes ROS‐dependent apoptosis through Akt and JAK2/STAT3 signaling pathway in human lung cancer cells

“…Furthermore, previous studies have demonstrated that JAK2/STAT3 pathway has also played an important role in regulating cell proliferation, angiogenesis, apoptosis, and oncogenesis in cancer cells (Yu and Jove, ; Zhou et al, ; Ripamonti et al, ). As far as is known, many antitumor signaling pathways may be activated thus inducing tumor cell apoptosis, such as the STAT3 signaling pathway, which has been reported (Zhu et al, ), along with the ROS‐dependent pathway found in this study.…”

“…Furthermore, previous studies have demonstrated that JAK2/STAT3 pathway has also played an important role in regulating cell proliferation, angiogenesis, apoptosis, and oncogenesis in cancer cells (Yu and Jove, 2004;Zhou et al, 2006;Ripamonti et al, 2013). As far as is known, Figure 5 Docking models of JAK2 with OA and SZC017.…”