IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 (IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.

Activated TAZ induces liver cancer in collaboration with EGFR/HER2 signaling pathways

“…[ 45 ]. The signaling pathway is a significant contributor to liver cancer development and targeting the JAK/STAT3 signaling pathway is proposed as a promising therapy for HCC [ 46 , 47 ].…”

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.…”

Roles of Interleukin-6-mediated immunometabolic reprogramming in COVID-19 and other viral infection-associated diseases

“…It has been demonstrated that IL-6 initiates transcription of various downstream genes involved in liver development and metabolism. IL-6 can activate STAT3, promote proliferation, angiogenesis and anti-apoptotic genes, and inhibit pro-apoptotic genes, thus facilitating the proliferation and migration of HepG2 cells both in vivo and in vitro [99] , [100] , [101] ( Fig. 5 ).…”

“…5 ). While ATF3-mediated up-regulation of IL-6Rα promotes the drug resistance to sorafenib and regofinib in HCC, targeting IL-6R could increase the therapeutic efficacy of sorafenib/regofinib in advanced HCC [100] , [102] . IL-6 can upregulate the inhibitor of differentiation 1 (Id1) from bone marrow-derived myeloid cells, which is contributed to shifting dendritic cell differentiation toward myeloid-derived suppressor cells [103] .…”

“…IL-6 can upregulate the inhibitor of differentiation 1 (Id1) from bone marrow-derived myeloid cells, which is contributed to shifting dendritic cell differentiation toward myeloid-derived suppressor cells [103] . Moreover, cancer-related fibroblasts (CAFs) highly expressing IL-6 exert a powerful immunosuppressive effect in HCC microenvironment by recruiting bone marrow derived immunosuppressive cells [100] . Furthermore, IL-6 disrupt the function of tumor infiltrating T cells through up-regulating inhibitory immune checkpoints.…”