Abstract
This present study centers hepatocellular adenomas (IHCAs) and its effect due to gp130 mutations based on evolutionary relationship as well as literature survey involving wet-laboratory experiments. Generally, IL6 family of cytokines interacts with their respective IL6 receptors and gp130, which in turn induces JAK/STAT pathway to activate pro-inflammatory STAT3 target genes. The activation of this signaling pathway poses a paramount impact in tumor development. Several mutations in gp130 were studied through evolutionary relatedness which aggravates the tumorigenesis. Mutations in IL6Rα binding domain region (positions: 131–218 of human gp130) from MSA were also studied. A point mutation: A200V in Otolemur garnettii showed the deleterious effect. Further, the deleterious effect upon proteins’ functionality was also examined and seven mutations were responsible for it. V189G showed the highest destabilizing effect. Unstable conformation shifts were also observed in the proteins due to their respective mutations. Change in the transmembrane region, change in gp130s’ ordered interface, loss of sulfation at Y186, lesser relative solvent accessibility, change in protein stability and metal binding properties were also observed in several mutations. These mutations might be responsible for changing the activity of the IL6Rα binding domain region of human gp130 protein triggering hepatocellular adenomas. Therefore, targeting gp130 and its mutations would serve as an important therapeutic target to cause apoptosis of the tumor cells. Interaction studies within the three proteins for the respective mutations could also to be in the future pathway of research. It would also aim to instigate the drug discovery for the same.
Shreya Bhattacharya, Debina Basu, Ritika Nandy, and Arundhati Banerjee are equally contributed to this work.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Rooks J (1979) Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA: J Am Med Assoc 242:644–648
Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, Izard T, Balabaud C, Bioulac-Sage P, Zucman-Rossi J (2008) Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457:200–204
Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspect Biol 6:a016295–a016295
Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809
Tebbutt N, Giraud A, Inglese M, Jenkins B, Waring P, Clay F, Malki S, Alderman B, Grail D, Hollande F, Heath J, Ernst M (2002) Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8:1089–1097
Poussin K, Pilati C, Couchy G, Calderaro J, Bioulac-Sage P, Bacq Y, Paradis V, Leteurtre E, Sturm N, Ramos J, Guettier C, Bardier-Dupas A, Boulai A, Wendum D, Selves J, Izard T, Nault J, Zucman-Rossi J (2013) Biochemical and functional analyses of gp130 mutants unveil JAK1 as a novel therapeutic target in human inflammatory hepatocellular adenoma. OncoImmunology. 2:e27090
Schütt A, Zacharias M, Schneider N, Horn S, Grötzinger J, Rose-John S, Schmidt-Arras D (2013) gp130 activation is regulated by D2–D3 interdomain connectivity. Biochem J 450:487–496
Johnson D, O’Keefe R, Grandis J (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15:234–248
Altschul S (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402
El-Gebali S, Mistry J, Bateman A, Eddy S, Luciani A, Potter S, Qureshi M, Richardson L, Salazar G, Smart A, Sonnhammer E, Hirsh L, Paladin L, Piovesan D, Tosatto S, Finn R (2018) The Pfam protein families database in 2019. Nucl Acids Res 47:D427–D432
Sievers F, Higgins D (2017) Clustal Omega for making accurate alignments of many protein sequences. Protein Sci 27:135–145
Choi Y, Chan A (2015) PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31:2745–2747
Cheng J, Randall A, Baldi P (2005) Prediction of protein stability changes for single-site mutations using support vector machines. Proteins: Struct Funct Bioinf 62:1125–1132
Garnier J, Gibrat J, Robson B (1996) GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 32:540–553
Li B, Krishnan V, Mort M, Xin F, Kamati K, Cooper D, Mooney S, Radivojac P (2009) Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25:2744–2750
George RA et al (2002) An analysis of protein domain linkers: their classification and role in protein folding. Protein Eng 15(11):871–879
Xiang C et al (2019) Blocking IL-6/GP130 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity in human pancreatic cancer cells. Curr Cancer Drug Targets 19:417. https://doi.org/10.2174/1568009618666180430123939
Ling M et al (2019) Bazedoxifene as a novel GP130 inhibitor for colon cancer therapy. J Exp Clin Cancer Res 38:63
Banerjee A, Dasgupta R, Ray S (2019) Residual participation and thermodynamic stability due to molecular interactions in IL11, IL11Rα and Gp130 from Homo sapiens: an in silico outlook for IL11 as a therapeutic remedy. Int J Pept Res Ther 1–12. doi: https://doi.org/10.1007/s10989-019-09996-z
Acknowledgements
Authors are thankful to ICMR Project (ID: 2019-3336) for the funding of the project.
Puja Ghosh from Department of Biotechnology, Pondicherry University, Puducherry, is also acknowledged for her support. Authors are also grateful to the Department of Biotechnology, Amity University, Kolkata, for the cooperation. Authors are also grateful to the Department of Biosciences and Bioengineering, IIT, Guwahati, for the cooperation and support as well. Authors are also grateful to Dr. Rakhi Dasgupta from Department of Biochemistry and Biophysics, University of Kalyani, for the support.
Conflicts of Interest
None.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this paper
Cite this paper
Bhattacharya, S., Basu, D., Nandy, R., Banerjee, A., Ray, S. (2021). A Limelight on Human Gp130 and Its Deleterious Mutations: A Computational Sequence Level Approach for Hepatocellular Carcinomas. In: Maji, A.K., Saha, G., Das, S., Basu, S., Tavares, J.M.R.S. (eds) Proceedings of the International Conference on Computing and Communication Systems. Lecture Notes in Networks and Systems, vol 170. Springer, Singapore. https://doi.org/10.1007/978-981-33-4084-8_42
Download citation
DOI: https://doi.org/10.1007/978-981-33-4084-8_42
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-33-4083-1
Online ISBN: 978-981-33-4084-8
eBook Packages: Intelligent Technologies and RoboticsIntelligent Technologies and Robotics (R0)