STAT۳ in pre-cancer inflammatory processes

INTRODUCTION STAT۳ is both a transcription activator and an oncogene that is tightly regulated under normal physiological conditions. However, abundant evidence indicates that STAT۳ is persistently activated in several cancers, with a crucial position in tumor onset and progression. In addition to its traditional role in cancer cell proliferation, invasion, and migration, STAT۳ also promotes cancer through altering gene expression via epigenetic modification, inducing epithelial–mesenchymal transition (EMT) phenotypes in cancer cells, regulating the tumor microenvironment, and promoting cancer stem cells (CSCs) . There are seven STAT proteins: STAT ۱, ۲, ۳, ۴, ۵A, ۵B, and ۶ encoded by genes clustered on different chromosomes. Each of them consists of six regions: (۱) a helical N-terminal domain (ND) for protein–protein interactions between adjacent STAT dimers on DNA; (۲) a coiled-coil (CC) domain for interactions with regulatory proteins that positively or negatively modulate the transcriptional activity; (۳) a DNA-binding domain (DBD) for the recognition of specific DNA-sequences of target genes; (۴) a helical linker (LK) domain involved in nuclear export and DNA binding; (۵) an Src homology ۲ (SH۲) domain for receptor binding and dimerization; (۶) a C-terminal transactivation domain (TAD) that contains specific residues that are phosphorylated upon transcriptional activation . STAT۳ is currently considered an oncogene, and aberrant regulation of STAT۳ has been reported in nearly ۷۰% of cancers . DISCATION Structure of signal transducer and activator of transcription ۳ (STAT۳). Functional domains: ND, NH۲-terminal domain; CCD, coiled-coil domain; DBD, DNA-binding domain; LK, linker domain; SH۲, Src homology ۲ domain; TAD, transactivation domain. STAT۳ activation is dependent on the phosphorylation (P) of a tyrosine residue Y۷۰۵, which is located between the SH۲ domain and TAD. Phosphorylation on serine (S) ۷۲۷ is required for maximal transcriptional activity. growth are mediated through the Jak/STAT۳ signaling pathway . Cytokine receptors, receptor tyrosine kinases, and non-receptor tyrosine kinases Cytokine receptors which function as receptors for the interleukin-۶ (IL-۶) family cytokines are the most well-known traditional activators of STAT۳. REASULT Let-۷ miRNA family members are widely considered to be tumor suppressors. Let-۷ re-expression in poorly differentiated PDAC cell lines can enhance the cytoplasmic expression of suppressor of cytokine signaling ۳ (SOCS۳), which blocks STAT۳ activation by JAK۲, and reduce the phosphorylation of STAT۳ and its downstream signaling. Conclusion Although, STAT۳ is an ideal target of cancer therapy because of its multiple regulatory pathways and pivotal biological functions in cancer; furthermore, various inhibitors targeting STAT۳ have been developed for cancer therapy, no candidate compounds are potent enough to provide beneficial therapeutic effects for cancer patients. As such, new directions for cancer therapy by targeting STAT۳ should be explored. For instance, small-molecule inhibitors of GPCR, TLR, and miRNAs related to STAT۳ regulation can be applied to treat cancer.

کلیدواژه ها:

STAT۳ ، Jak/STAT۳ signaling ، interleukin-۶ ، Let-۷ miRNA