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

Zhao et al. Cell Communication and Signaling https://doi.org/10.1186/s12964-023-01421-9 (2024) 22:68 Cell Communication and Signaling Open Access REVIEW The oncogenic mechanisms of the Janus kinase‑signal transducer and activator of transcription pathway in digestive tract tumors Ruihong Zhao1†, Zhangmin Hu1†, Xiaoli Zhang1, Shujuan Huang1, Guodong Yu1, Zhe Wu1, Wei Yu1, Juan Lu1* and Bing Ruan1* Abstract Digestive 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. Keywords JAK, STAT, Digestive tract tumors, Biological functions, Oncogenic mechanism † Ruihong Zhao and Zhangmin Hu contributed equally to this work. *Correspondence: Juan Lu Bing Ruan Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhao et al. Cell Communication and Signaling (2024) 22:68 Introduction The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a crucial cell signaling pathway that is frequently activated by an extensive repertoire of extracellular cytokines and growth factors [1– 3]. It plays a critical role in regulating essential biological processes, including cellular processes, inflammation, and immunological responses. As a result, it is evolutionarily conserved across different species [4–7]. Activation of the JAK-STAT pathway begins with the binding of an extracellular ligand to the cell surface receptor. This process triggers a cascade of complex steps, which includes the recruitment and subsequent phosphorylation of JAKs within the receptor complex, the phosphorylation and dimerization of STAT, the combination of STAT dimers with specific responsive element regions on the nucleus, and ultimately, the regulation of target gene transcription [8–11]. In this way, the extracellular signals and stimuli are relayed to the nucleus (Fig. 1). Under normal physiological conditions, the JAK-STAT signaling pathway regulates gene expression and cellular function by responding to extracellular signal molecules Page 2 of 18 such as cytokines and growth factors. Numerous studies have demonstrated that JAK-STAT is involved in multiple biological processes, including cell proliferation, differentiation, apoptosis, immune response, hematopoietic regulation and embryonic development. Specifically, in the immune system, it participates in regulating the development, proliferation, and function of T cells and B cells; in the hematopoietic system, it controls the proliferation and differentiation of blood cells; and in embryonic development, it plays a role in organ formation and cell fate determination. Furthermore, the JAK-STAT signaling pathway can interact with other signaling pathways to form complex network regulatory systems. This network regulation helps maintain the biological balance of normal cells and ensures the normal function of tissues and organs. The dysregulation of the JAK–STAT pathway has been found to contribute to carcinogenesis by promoting several oncogenic processes, including cell proliferation, invasion, metastasis, anti-apoptosis, immune escape, and angiogenesis [1, 12, 13]. Numerous studies have reported hyperactivation and frequent mutations Fig. 1 The components and activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway Zhao et al. Cell Communication and Signaling (2024) 22:68 in JAK–STAT signaling proteins in various human disorders, such as rheumatoid arthritis, inflammatory bowel disease, inflammatory skin conditions, myeloproliferative neoplasms, and solid tumors [14–17]. Considering its near-ubiquitous role in diverse diseases, an increasing number of small-molecule inhibitors or natural products targeting JAK-STAT proteins have been synthesized or developed [18–21]. Of them, many have been approved for clinical use and more selective inhibitors are currently undergoing clinical investigation [22–25]. Dig (...truncated)