STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma

Abstract

Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) are key transcription factors activated by pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6 (IL-6). In this study, we combined in vitro cell culture experiments and immunohistochemical analyses of human HCC (N = 124) and CCA (N = 138) specimens. We observed that in the absence of STAT3, IL-6 induced the activation of STAT1 and its target genes suggesting that IL-6 derived from the tumor microenvironment may activate both STAT1 and STAT3 target genes in HCC tumor cells. In addition, STAT1 and STAT3 were highly activated in a subset of HCC, which exhibited a high degree of infiltrating CD8- and FOXP3-positive immune cells and PD-L1 expression. Our results demonstrate that STAT1 and STAT3 are expressed and activated in HCC and tumor infiltrating immune cells. In addition, HCC cases with high STAT1 and STAT3 expression also exhibited a high degree of immune cell infiltration, suggesting increased immunological tolerance.

Nucleus‐localized circSLC39A5 suppresses hepatocellular carcinoma development by binding to STAT1 to regulate TDG transcription

“…60,61 There is evidence that STAT1 has a two-sided effect on tumorigenesis in different types of cancer. [62][63][64][65][66][67] In this study, STAT1 was proved to bind to the promoter regions of TDG, SRRM3, and PPP1R7. TDG is a crucial enzyme that mainly affects the cell cycle, inhibits tumor development, 68,69 and interacts with the PCNA.…”

“…STAT1 is a transducer protein that acts as a transcription factor in the nucleus to regulate the transcription of target genes 60,61 . There is evidence that STAT1 has a two‐sided effect on tumorigenesis in different types of cancer 62–67 . In this study, STAT1 was proved to bind to the promoter regions of TDG, SRRM3, and PPP1R7.…”

HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling

“…In this study, M2 and preS2 deletion significantly enhanced the retention of HBsAg in ER, compared to the WT counterpart. Sustained activation of ER stress endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity [32]. The ER stress sensors, PERK and XBP1, were both reported to promote the survival capacity of cells by activating STAT3 [33,34].…”

Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis

“…Taking into account the results obtained in the combination experiments that showed a potentiation of sorafenib cytotoxicity by caryophyllane sesquiterpenes, especially βcaryophyllene oxide, and the recognized involvement of ABC-transporters and STAT3 signaling in the progression and chemoresistance of hepato-biliary-pancreatic cancers [27][28][29][30][31][32][33], a possible modulation by treatments of this cascade in Bx-PC3, associated with the observed changes in MDR1 and MRPs pumps, was also evaluated (Figure 11). Activation of STAT3 by phosphorylation at tyrosine 705 (phospho(Tyr705)-STAT3), which is known to play an important role in the control of cell survival, proliferation, and apoptosis [34], has been measured.…”