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.
Highlights
Cellular signaling pathways refer to the process of intracellular biochemical effects after extracellular signals act on membranal or intracellular receptors
Wan et al [53] found that tumorassociated macrophages(TAMs) stimulated signal transducer and activator of transcription 3 (STAT3) to promote production of liver cancer stem cells (LCSCs) through the secretion of IL-6; the activation of IL-6/STAT3 signals promotes liver cancer cells to produce LCSC, facilitating the resistance of liver cancer cells to sorafenib [54]. These findings suggest that IL-6/STAT3 signaling pathway is a crucial factor in the occurrence of LCSCs and drug resistance
Effects of IL-6/STAT3 Signaling Pathway on the Expression of p53 and AFP in Hepatocellular carcinoma (HCC) Cells P53 is one of tumor suppressor genes that most widely studied in human cancer, and the activation of p53 mainly leads to the inhibition of cancer cells growth and promotes DNA repair and apoptosis, the role is mainly mediated by its transcriptional activity
Summary
Cellular signaling pathways refer to the process of intracellular biochemical effects after extracellular signals act on membranal or intracellular receptors. Effects of IL-6/STAT3 Signaling Pathway on the Expression of p53 and AFP in HCC Cells P53 is one of tumor suppressor genes that most widely studied in human cancer, and the activation of p53 mainly leads to the inhibition of cancer cells growth and promotes DNA repair and apoptosis, the role is mainly mediated by its transcriptional activity. In HBV-related HCCs, HBx can, by interacting with p53, stimulate the expression of AFP by blocking the inhibitory effect of p53 on the promoter of afp gene [67] These mechanisms may be associated with the promotion of IL-6 secretion and the activation of the IL-6/ STAT3 signaling pathway in HCC cells. The IL-6/STAT3 signaling pathway is closely related to HCC initiation, development, metastasis, and drug resistance, which is continuously activated and overexpressed in a variety of tumor cells and has become a hot spot in cancer treatment. These studies imply that blocking IL-6R is applied to therapeutic of HCC
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