The oncogenic mechanisms of the Janus kinase-signal transducer and activator of transcription pathway in digestive tract tumors

Abstract

AbstractDigestive tract tumors are heterogeneous and involve the dysregulation of multiple signaling pathways. The Janus kinase-signal transducer and activator of transcription (JAK–STAT) pathway plays a notable role in the oncogenesis of digestive tract tumors. Typically activated by pro-inflammatory cytokines, it regulates important biological processes, such as cell growth, differentiation, apoptosis, immune responses, and inflammation. The aberrant activation of this pathway manifests in different forms, including mutations in JAKs, overexpression of cytokine receptors, and sustained STAT activation, and contributes to promoting the malignant characteristics of cancer cells, including uncontrolled proliferation, resistance to apoptosis, enhanced invasion and metastasis, angiogenesis, acquisition of stem-like properties, and drug resistance. Numerous studies have shown that aberrant activation of the JAK-STAT pathway is closely related to the development and progression of digestive tract tumors, contributing to tumor survival, angiogenesis, changes in the tumor microenvironment, and even immune escape processes. In addition, this signaling pathway also affects the sensitivity of digestive tract tumors to chemotherapy and targeted therapy. Therefore, it is crucial to comprehensively understand the oncogenic mechanisms underlying the JAK-STAT pathway in order to develop effective therapeutic strategies against digestive tract tumors. Currently, several JAK–STAT inhibitors are undergoing clinical and preclinical trials as potential treatments for various human diseases. However, further investigation is required to determine the role of this pathway, as well as the effectiveness and safety of its inhibitors, especially in the context of digestive tract tumors. In this review, we provide an overview of the structure, classic activation, and negative regulation of the JAK-STAT pathway. Furthermore, we discuss the pathogenic mechanisms of JAK-STAT signaling in different digestive tract tumors, with the aim of identifying potential novel therapeutic targets.