Down-regulation of TAK1 inhibits migration and invasion of p-NENs by regulating JNK signaling pathway through interaction with PDZD2

Abstract Pancreatic neuroendocrine neoplasmas (p-NENs) is a rare type of disease among digestive malignancy tumors, but its mechanics are still unclear. It has been found that TAK1 plays a crucial role in the progression of many tumors. We discovered TAK1 was highly expressed in BON-1 compared to two other pancreatic cell lines（CFPAC-1and hTERT-HPNE). Inhibition of TAK1 could significantly suppress the migration and invasion of p-NENs cell line (BON-1). Furthermore, the down-regulation of TAK1 suppressed the process of epithelial mesenchymal transition[1],which increased the epithelial marker E-cadherin and decreased the mesenchymal marker vimentin and N-cadherin. Through mass spectrometry analysis, we found that TAK1 is potentially blinded to PDZ domain containing 2(PDZD2) and negatively regulates its expression. In addition, down-regulation of TAK1 resulted in decrease of p-JNK.JNK activator (Anisomycin) significantly enhanced invasion and migration in comparison with TAK1 knockdown groups without activator. And silence of PDZD2 could rescue the changes in cancer cells’ phenotype and JNK expression caused by TAK1. All in all, the results of this study indicate that TAK1 regulates the JNK pathway in controlling p-NENs migration and invasion through its interaction with PDZD2, providing us with a new target for the treatment of p-NENs.