A Crucial Interaction of p62 and Nrf2 in Mediating Metastasis of Esophageal Squamous Cell Cancer

Background: Sequestosome 1 (SQSTM1), also referred to as p62 and nuclear factor erythroid 2-related factor 2 (Nrf2) have implicated into the pathogenesis of esophageal squamous cell carcinoma (ESCC). While p62 and Nrf2 interact and influence each other in diverse pathological settings, in whether such interaction contributes to ESCC remains unclear. In this study, we aimed to explore the functional significance of p62 and Nrf2 in ESCC, and uncover a interaction between p62 and Nrf2 in mediating ESCC.Results: Herein, we show a critican interaction betwwen p62 and Nrf2 in ESCC. Huamn GEPIA database analysis revealed the expression of p62 and Nrf2 is upregulated in ESCC, which is further verified by biochemical assessements using a human tumor tissue bank. Genetic knockdown of p62 and/or Nrf2 demonstrated a mediator role of p62 and Nrf2 in the proliferation, migration and movement ability of ECSS cells. In addition, the downregulation of p62 or Nrf2 could change the morphology of ESCC cells, transforming them from shuttle to round shape, and inhibit their EMT. The knockdown approach also reveal a synergy between p62 and Nrf2 in promoting EMT and the invasive growth of ESCC cells. The xenograft assay in vivo revealed similar effects of p62 and/or Nrf2 knockdown on tumorigenesis and metastaisis of ESCC. Conclusions: These results indicate that p62 and Nrf2 promote EMT and metastasis of ESCC in a synergistic manner. Simultaneously targeting of p62 and Nrf2 may have a therapeutic potential in treating ESCC.