title: Overexpression of hyaluronan-binding protein 1 (HABP1/p32/gC1qR) in HepG2 cells leads to increased hyaluronan synthesis and cell proliferation by up-regulation of cyclin D1 in AKT-dependent pathway.
abstract: Overexpression of the mature form of hyaluronan-binding protein 1 (HABP1/gC1qR/p32), a ubiquitous multifunctional protein involved in cellular signaling, in normal murine fibroblast cells leads to enhanced generation of reactive oxygen species (ROS), mitochondrial dysfunction, and ultimately apoptosis with the release of cytochrome c. In the present study, human liver cancer cell line HepG2, having high intracellular antioxidant levels was chosen for stable overexpression of HABP1. The stable transformant of HepG2, overexpressing HABP1 does not lead to ROS generation, cellular stress, and apoptosis, rather it induced enhanced cell growth and proliferation over longer periods. Phenotypic changes in the stable transformant were associated with the increased "HA pool," formation of the "HA cable" structure, up-regulation of HA synthase-2, and CD44, a receptor for HA. Enhanced cell survival was further supported by activation of MAP kinase and AKT-mediated cell survival pathways, which leads to an increase in CYCLIN D1 promoter activity. Compared with its parent counterpart HepG2, the stable transformant showed enhanced tumorigenicity as evident by its sustained growth in low serum conditions, formation of the HA cable structure, increased anchorage-independent growth, and cell-cell adhesion. This study suggests that overexpression of HABP1 in HepG2 cells leads to enhanced cell survival and tumorigenicity by activating HA-mediated cell survival pathways.
authors.affiliation: Biochemistry Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Rachna
authors.initials: R
authors.lastname: Kaul
authors.forename: Paramita
authors.initials: P
authors.lastname: Saha
authors.forename: Mallampati
authors.initials: M
authors.lastname: Saradhi
authors.forename: Ramachandra L A
authors.initials: RL
authors.lastname: Prasad
authors.forename: Soumya
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Ilora
authors.initials: I
authors.lastname: Ghosh
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Tyagi
authors.forename: Kasturi
authors.initials: K
authors.lastname: Datta
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D015854:Up-Regulation / Q000235:genetics
chemical_list: C087299:C1QBP protein, human; C530104:CCND1 protein, human; C497483:CD44 protein, human; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D019938:Cyclin D1; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D051057:Proto-Oncogene Proteins c-akt