STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a major global health problem and its treatment options have been limited. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor important for various cellular processes. Overexpression and constitutive activation of STAT3 have been frequently found in HCC and associated with poor prognosis. Ample evidence has shown that STAT3 plays pivotal roles in the initiation, progression, metastasis and immune suppression of HCC. Thus, STAT3 has attracted attention as a novel therapeutic target in HCC. Clinical trials have investigated STAT3-targeted therapeutics either as monotherapy or in combination with chemotherapeutic agents, immune checkpoint inhibitors and alternative targeted drugs. Some of these studies have yielded encouraging results. Particularly, napabucasin-a cancer stemness inhibitor targeting STAT3-driven gene transcription-has stood out with its promising clinical efficacy and safety profile. Nonetheless, clinical investigations of STAT3-targeted therapies in HCC are limited and more efforts are strongly urged to evaluate their clinical performance in HCC. Here, we provide a comprehensive review of the roles of STAT3 in HCC and follow by comprehensive analysis of STAT3 targeted strategies.

Keywords: STAT3; combination therapy; hepatocellular carcinoma; targeted therapy; transcription factor.

Figure 1

The STAT3 signaling pathway and its crosstalk with NF-kB. STAT3 is activated primarily by cytokines and growth factors, in addition to other signaling molecules. Canonically, ligand binding to receptors triggers phosphorylation of tyrosine kinases and subsequently STAT3 at Y705, followed by STAT3 dimerization and translocation to the nucleus where it drives transcription of target genes involved in cell survival and proliferation. Non-canonically, STAT3 can also be phosphorylated at S727, translocate to the mitochondrion, as well as autoregulate its own transcription to produce u-STAT3. Under normal conditions, STAT3 activation is under tight negative regulation by SOCS, PTP and PIAS members. Remarkably, STAT3 is involved in extensive crosstalk with the inflammatory NF-kB pathway. Activated NF-kB has been reported to either activate or inhibit STAT3 signaling, respectively by producing various cytokines including the major STAT3-inducing cytokine IL-6 and preventing reactive oxygen species (ROS) accumulation responsible for oxidizing negative regulators of STAT3. In return, STAT3 may sustain NF-kB activation via p300-mediated acetylation. Moreover, u-STAT3 and u-NF-kB can work in concert to coregulate another set of genes.

Figure 2

STAT3-mediated oncogenesis in hepatocellular carcinoma (HCC). IL-6 and IL-22 are major stimuli that activate STAT3 signaling in HCC cells. Activated STAT3 promotes HCC cell proliferation, anti-apoptosis, migration, invasion, angiogenesis and stemness properties via transcriptional regulation of target genes, cooperation with NF-kB and epigenetic regulation involving miRNA. A paracrine STAT3 activation loop between tumor and stromal cells also exerts suppressive effects in various immune cells in the HCC tumor microenvironment.