Q2. What are the contributions in "Potential role of signal transducer and activator of transcription (stat)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma" ?
Subramaniam et al. this paper showed that the potential role of signal transducer and activator of transcription ( STAT ) 3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma.
Q3. What future works have the authors mentioned in the paper "Potential role of signal transducer and activator of transcription (stat)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma" ?
A variety of animal models have been used to study the role of STAT3 signaling cascades in HCC development. Hence, the knowledge gained about STAT3 in HCC will depend on solutions to these potential problems. However, appropriate human studies are required to validate the promising results obtained in mice and move the STAT3 inhibitors from the bench side to the bed for the treatment of HCC patients.
Q4. What are the main factors that increase hepatic tumor development in animals?
Sex hormones, such as estrogens, progesterone, and oral contraceptives have been shown to increase hepatic tumor development in animals.
Q5. What is the role of the JAKs in the activation of STAT3?
The JAKs in turn phosphorylate the specific tyrosines in the intracellular domain of gp130, providing docking sites for the Src homology 2 (SH2) domain of signaling molecules of STAT3.
Q6. What is the role of JAKs in cytokine signaling?
JAKs can either bind to intracellular domains of cytokine receptor signaling chains or catalyze ligand-induced phosphorylation of intracellular tyrosine residues on the receptor [140].
Q7. What is the role of STAT3 in tumor angiogenesis?
Activated STAT3 affects tumor angiogenesis by regulating the expression of multiple pro-angiogenic molecules in tumor cells and by participating in the signal transduction of angiogenic molecule receptors in tumor endothelial cells.
Q8. What is the role of IL-6 in phosphorylation of gp130?
When IL-6 binds to its specific receptor subunit, it can induce dimerization of gp130 receptor and activation of the gp130-associated JAK [52,139].
Q9. What is the role of STAT3 in the development of hepatocytes?
In addition to being associated with cell growth, STAT3 activation has been found to be critical for differentiation of keratinocytes [152], and myeloid cells [153], and plays an important role in mediating the formation of epithelial tubules in response to hepatocyte growth factor [154].
Q10. What is the role of STAT3 in the metastatic potential of HCC?
The amelioration of the malignant behaviors of HCCLM3 following orthotopic implantation, included impeded migration, hampered neovascularization, inhibited local metastasis, and reduced lung metastasis, indicating that STAT3 also mediates the metastatic potential of HCCLM3, a highly malignant variant of HCC [195].
Q11. What is the role of the N-terminal domain in the transcription of STATs?
The tetramerization of STATs contributes to stability of the STAT-DNA binding by means of the interaction with randomly arranged low-affinity STAT binding sites, thus increasing transcriptional activity [83].
Q12. What are the main roles of STAT proteins in cytokine signaling?
STAT proteins have been shown to play pivotal roles in cytokine signaling pathways, which are involved in regulating cell growth and differentiation in systems ranging from Dictyostelium to mammals [38].
Q13. What is the role of cyclin D1 in the development of hepatocytes?
Recent studies have indicated that inappropriate expression of cell cycle-related proteins, such as cyclin D1, cyclin-dependent kinase 4 (Cdk4), cyclin E, cyclin A, p16 and p27, as one of the major factors contributing to HCC initiation and development [225–227].
Q14. What is the role of STAT3 in cell growth and survival?
In fact, loss of STAT3 is lethal even to embryonic stem cells [148] indicating a key role for STAT3 in cell growth and/or survival.
Q15. What are other physiological negative protein modulators of the STAT3 signaling pathway?
Other physiological negative protein modulators of the STAT3 signaling pathway also involving negative regulation include the JAK binding protein (JAB) and STAT-induced STAT inhibitor [163].
Q16. What is the role of STAT3 in the migration of epidermal cells?
In-vitro studies on keratinocytes have shown that STAT3 plays an important role in the migration of epidermal cells, and is essential for skin renovation [156].
Q17. What is the role of the SH3 domain in the regulation of cytokine activity?
The SH3 domain contributes to substrate recruitment [110,111] and is critical for the regulation of kinase activity [112–114], (Fig. 4).
Q18. What is the role of cyclin D1 in liver development?
it is likely that STAT3 can act as a potential negative regulator of cyclinD1 transcription during fetal liver development, whereas it positively regulates cyclin D1 expression in hepatoma cells and at the initial phase of liver regeneration.
Q19. What is the significance of STAT3 deletion in HCC?
While safety remains a point of concern, given the fact that STAT3-null mice are embryonically lethal, tissue-specific STAT3 deletion experiments have indicated that STAT3 may not be essential for the survival of normal differentiated cells.
Q20. What is the role of the SH2 domain in the development of anticancer agents?
Targeting the SH2 domain would uncouple STAT3 from the growth and survival signaling pathways and is a reasonable approach for the development of anticancer agents [270,271].
Q21. What is the binding affinity of a specific STAT dimer for a single target DNA?
The observed variation in the binding affinity of a particular activated STAT dimer for a single target DNA sequence is determined by differences in the nucleotide sequence [140].