STAT3 Gene Editing    

Signal Transducer and Activator of Transcription (STAT) factors become activated downstream of both intrinsic and extrinsic signals by phosphorylation on a conserved tyrosine residue mainly accomplished by receptor-associated JAK kinases. Tyrosine-phosphorylated (YP)-STATs form active dimers that concentrate in the nucleus to regulate the expression of target genes. The family member STAT3 is canonically activated by YP downstream of many cytokines, growth factors and oncogenes, and is therefore constitutively active in a high percentage of tumors and tumor-derived cell lines of both liquid and solid origin, which often become STAT3 addicted. Accordingly, STAT3 is widely considered as an oncogene and a good target for anti-cancer therapy. Besides its known roles in promoting tumor cell proliferation, survival, angiogenesis, tumor invasion, and immunosuppression, JAK–STAT3 signaling has recently been shown to have important roles in inflammation-mediated cancer, obesity and/or metabolism, cancer stem cells (CSCs) and pre-metastatic niche formation.

STAT3 is activated by the binding of cytokines or growth factors to cell surface receptors. Cytokines such as the interleukins IL-6, IL-10, and IL-11, as well as growth factors such as EGF, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), can activate the tyrosine phosphorylation cascade. Transcriptional activity of STAT3 also depends on the binding of coactivators such as APE/ref-1, CBP/p300, and NCOA/SRC1a. STAT3 regulates gene expression involved in cell cycle (c-Myc and cyclin D1), antiapoptosis (Bcl-2, Bcl-xL, and survivin), angiogenesis (IL-8 and VEGF), and invasion/migration (MMP-2 and MMP-9). Apart from JAKs, STAT3 can be activated by nonreceptor tyrosine kinases such as ABL and Src.

Figure 1. Signaling cascade for STAT3 activity. (Furtek S L, et al. 2016)

Role of STAT3 in Tumorigenesis

STAT3 activity is a double-edged sword whose activity is involved in both embryonic development and oncogenesis. Despite its importance in embryonic development, cumulative data in postnatal mice show that STAT3 may be dispensable for the function of normal cells and tissues. Among all STAT family members, STAT3 is most often correlated to tumorigenesis, and is considered as an oncogene as it is the point of convergence of numerous signaling pathways triggered by cytokines, growth factors and oncogenes. Accumulating evidence strongly implicates the crucial role of aberrant STAT3 activation in malignant transformation and tumorigenesis. On the contrary, abrogation of the STAT3 signaling cascade has been found to cause growth inhibition, apoptosis, and impair tumor growth in mouse xenograft models. Besides, inflated levels of STAT3 have been associated with a poor prognosis in many cancers such as gastric cancer, colorectal cancer, and ovarian cancer. Also, the silencing of the STAT3 signaling cascade has led to a significant reversal of drug resistance and also enhanced chemo-sensitivity in diverse tumor cells. The key role of STAT3 in oncogenesis and chemoresistance development highlights the urgent need to develop novel anti-cancer therapeutics that can negatively regulate STAT3 mediated signaling events.

STAT3 Inhibitors as Potential Cancer Preventive Agents

As mentioned, STAT3 regulates the expression of various genes involved in proliferation, apoptosis, angiogenesis, invasion, and metastasis. Skin carcinogenesis studies with STAT3-deficient mice suggested that STAT3 activation is required for both the initiation and promotion stages. Thus, inhibition of STAT3 provides a rational strategy to block carcinogenesis at the early stage of cancer development. Two major strategies are used to inhibit the STAT3 signaling pathway: (1) Direct inhibition of STAT3 protein with inhibitors targeting one of three structural domains of STAT3, namely SH2 domain, DNA binding domain, and N-terminal domain, which suppresses processes related to STAT3 signaling and functional role through blocking phosphorylation, dimerization, nuclear translocation and DNA binding; or (2) Indirect blocking the upstream regulators of STAT3 pathway. The design and discovery of truly specific and potent STAT3 inhibitors is a challenging process. So far, many laboratories have worked on numerous naturally derived compounds and indicated that these natural STAT3 inhibitors possess efficacious anti-cancer properties. The most important hurdle for the development of a STAT3 inhibitor as potential therapeutics will be the demonstration of their anti-tumor efficacy in in vivo systems and lack of toxicity in relevant animal models of human cancer.

STAT3 Gene Editing Service

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control STAT3 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.