Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers

Abstract

When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.

Keywords: JAK; PROTAC (proteolysis-targeting chimeric molecule); STAT; TNF; cancer; cytokines; gastric; oral.

Figure 1

Schematic representation of the generic domain structure of JAKs and STATs. (A) Functional domains of the most important human JAKs and STATs regulating the progression of solid malignancies; ND, N-terminal; CC, coiled-coil; DBD, DNA-binding; LK, linker; SH2, Src-homology; TAD, transcriptional activation domain; JH1, kinase; JH2, pseudo-kinase domain with the ezrin, radixin, moesin (FERM) and SH2 domains forming a JAK receptor-binding module and the PK domain restrains Tyr kinase activity by binding the kinase domain. The common V617F mutation in JAK2 is shown (red line). (B) STATs are activated by a multitude of cytokines and IFNs. The most important ligands, receptors and pairing of JAKs regulating the progression of solid malignancies are shown. Shared receptor subunits are indicated by identical coloring. (C) Simplified schematic representation of the JAK-STAT signaling pathway. JAK activation occurs upon the binding of ligand and receptor multiprotein assembly, at which point two JAKs are brought into close proximity, permitting trans-phosphorylation. Once activated, the JAKs are capable of phosphorylating further targets, firstly the intracellular tails of the receptors on specific tyrosines, which then act as docking sites for their preferred substrates, the STAT proteins. Each STAT contains a conserved tyrosine residue near to the C- terminus transactivation domain (TAD), which is phosphorylated by the JAK proteins. This phospho-tyrosine promotes STAT protein dimerization via binding of an adjacent SRC homology 2, (SH2) domain and leads to exposure of a nuclear localisation signal (NLS), translocation into the nucleus, where they activate the transcription of genes involved in many cellular processes.

Figure 2

Mechanistic diagram of JAK-STAT and TNFR signalling and modes of inhibition. (A) The gp130 receptor complex and signaling pathways for IL-6 and IL-11 are shown as key activators of STAT transcription factors. The intracellular domain of the gp130 receptor contains a membrane-proximal tyrosine (Y; red), which provides a docking site for the suppressor for SOCSs proteins (e.g. SOCS3) and SHP2, while the membrane-distal tyrosine (Y) sites permits interactions with the SH2 domain of STAT1/3. The membrane proximal Y sites are phosphorylated by JAKs and upon phosphorylation of the distal Y site, STAT1 and STAT3 are recruited, homo-dimerise and are translocated into the nucleus, where they bind to specific target genes to regulate their expression. (B) Simplified schematic diagram of TNF/TNFR1 signaling pathway with downstream interacting proteins indicated. (A, B) Red arrows indicate intervention/inhibition points within each pathway and red boxes list examples of JAK-STAT or cytokine inhibitors/modifying drugs with their target protein.

Figure 3

The role of cytokines and JAK/STAT in OSCC and GC in a step-wise model. The normal epithelium (left) progresses to (A) OSCC or (B) or GC, through a series of histopathological precursors. During early disease stage the immune system is activated by inflammatory stimuli, resulting in both pro-tumor and anti-tumor effects mediated by inflammatory cells. The cytokine and JAK-STAT pathway are dysregulated within the cells of the inflammatory microenvironment and target genes serve as fuel to control both apoptosis and inflammation. Pro-inflammatory cytokine mediators promote neoplastic growth and development, proliferation, tissue remodeling (EMT), angiogenesis and metastases. During this progression, several alterations in key genes also accumulate (e.g. KRAS, TP53) to progress tumorigenesis.