Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation

Abstract

Overexpression of epithelial cell adhesion molecule (EpCAM) has been associated with chemotherapeutic resistance, leads to aggressive tumor behavior, and results in an adverse clinical outcome. The molecular mechanism by which EpCAM enrichment is linked to therapeutic resistance via Nrf2, a key regulator of antioxidant genes is unknown. We have investigated the link between EpCAM and the Nrf2 pathway in light of therapeutic resistance using head and neck squamous cell carcinoma (HNSCC) patient tumor samples and cell lines. We report that EpCAM was highly expressed in Nrf2-positive and HPV-negative HNSCC cells. In addition, cisplatin-resistant tumor cells consisted of a higher proportion of EpCAM high cells compared to the cisplatin sensitive counterpart. EpCAM high populations exhibited resistance to cisplatin, a higher efficiency in colony formation, sphere growth and invasion capacity, and demonstrated reduced reactive oxygen species (ROS) activity. Furthermore, Nrf2 expression was significantly higher in EpCAM high populations. Mechanistically, expression of Nrf2 and its target genes were most prominently observed in EpCAM high populations. Silencing of EpCAM expression resulted in the attenuation of expressions of Nrf2 and SOD1 concomitant with a reduction of Sox2 expression. On the other hand, silencing of Nrf2 expression rendered EpCAM high populations sensitive to cisplatin treatment accompanied by the inhibition of colony formation, sphere formation, and invasion efficiency and increased ROS activity. The molecular mechanistic link between EpCAM expression and activation of Nrf2 was found to be a concerted interaction of interleukin-6 (IL-6) and p62. Silencing of p62 expression in EpCAM high populations resulted in the attenuation of Nrf2 pathway activation suggesting that Nrf2 pathway activation promoted resistance to cisplatin in EpCAM high populations. We propose that therapeutic targeting the Nrf2-EpCAM axis might be an excellent approach to modulate stress resistance and thereby survival of HNSCC patients enriched in EpCAM high populations.

Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway

“…Interestingly, high levels of USP28 are correlated with resistance to chemotherapy in oesophageal- and lung squamous cancer (Fig. S3C ) [ 30 – 32 ]. Therefore, we stratified patient survival datasets for lung ADC and SCC regarding USP28 expression.…”

Genetic alterations of Keap1 confers chemotherapeutic resistance through functional activation of Nrf2 and Notch pathway in head and neck squamous cell carcinoma

“…This small population of CSCs that reside within HNSCC are relatively resistant to chemotherapies and are clinically predicted to contribute to tumor recurrence. Cisplatin-resistant tumor cells consist of a higher proportion of epithelial cell adhesion molecule (EpCAM) and induce the expression of IL-6 and tumorigenic cytokines that contribute to cisplatin-induced stemness [ 14 ]. Recently we have shown the Nrf2- associated mechanistic link by which HNSCC cells acquire therapeutic resistance to cisplatin [ 15 ].…”

Abnormal Glycosylation of Cancer Stem Cells and Targeting Strategies

“…In hepatocellular carcinoma, EpCAM+ CD133+ cells demonstrated elevated colony formation ability, expression of stem cell related genes and chemoresistance compared to EpCAM-CD133+ cells (111). Moreover, inhibition of EpCAM in resistant head and neck cancer cells sensitize them to cisplatin (64). EpCAM in carcinoma tissues presented elevated levels of glycosylation compared to normal epithelia (112).…”