The Involvement of WDHD1 in the Occurrence of Esophageal Cancer as a Downstream Target of PI3K/AKT Pathway

Abstract

Esophageal cancer is one of the most common malignant tumors in the world, which is characterized by high incidence, strong invasiveness, high mortality, and poor prognosis. At present, the therapies include surgery, endoscopic resection, radiotherapy and chemotherapy, targeted therapy, and immunotherapy. The five-year survival rate of esophageal cancer has not been significantly improved, although the medical level has been continuously improved and the management and application of different therapies have been improved day by day. At present, an abnormal gene expression is still regarded as an important factor in the occurrence and development of esophageal cancer. WD repeat and HMG-box DNA binding protein 1(WDHD1), as a key gene, plays an important role in the occurrence of esophageal cancer. It is known that the protein encoded by WDHD1 is the downstream target of the PI3K/AKT pathway. When PI3Ks is activated by extracellular signals, PI(4,5)P2 on the inner side of the plasma membrane will be converted into PI(3,4,5)P3. Then, PI(3,4,5)P3 can be converted into PI(3,4)P2,PI(4)P and PI(3)P by dephosphorylation of some regulatory factors. PI(3,4,5)P3 recruited AKT to the plasma membrane and combined with its pH domain, resulting in conformational change of AKT. Subsequently, AKT was completely activated by PDK1 and PDK2 and begins to move to the cytoplasm and nucleus. In this process, AKT continuously phosphorylates downstream substrates. WDHD1, as a downstream target of AKT, is also phosphorylated and induces DNA replication. Besides the abnormal regulation of cells by other downstream targets of AKT, it also becomes a potential pathway that may eventually lead to the occurrence of esophageal cancer.