PAX6 contributes to the activation and proliferation of hepatic stellate cells via activating Hedgehog/GLI1 pathway. 2020

Can Li, and Yue Hao Tan, and Jing Sun, and Feng Mei Deng, and Yi Lun Liu
School of Basic Medical Science, Chengdu Medical College, Chengdu, 610500, China; Sichuan Clinical Research Center for Geriatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.

Aberrant activation of Hedgehog signaling is considered as the key player in hepatic stellate cell (HSC) activation involved in liver fibrosis (LF). The glioma-associated protein gene (GLI) has a predicted paired box 6 (PAX6)-binding site within its transcribed region. Therefore, this study aimed to investigate the relationship between PAX6 and GLI and their contribution to HSC activation and proliferation. PAX6 expression was upregulated in platelet-derived growth factor-BB (PDGF-BB)-induced LX-2 cells. The activation and proliferation of HSC were inhibited by interference of PAX6 with short hairpin RNA (shPAX6) via curbing Hedgehog signaling. Notably, PAX6 directly bound to the promoter sequence of GLI1 independent of the PTCH/SMO axis. Therefore, we propose that PAX6 upregulation induces HSC activation and proliferation through crosstalk with GLI1 signaling. Thus, these novel mechanistic insights involving the PAX6-mediated regulation of the activation and proliferation of HSC may provide a new therapeutic target for LF.

UI MeSH Term Description Entries
D008103 Liver Cirrhosis Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. Cirrhosis, Liver,Fibrosis, Liver,Hepatic Cirrhosis,Liver Fibrosis,Cirrhosis, Hepatic
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071676 Zinc Finger Protein GLI1 A transcriptional activator and oncogene protein that contains two CYS2-HIS2 ZINC FINGERS. Two isoforms are expressed; both regulate the expression of specific genes during development of craniofacial features, digits, the CENTRAL NERVOUS SYSTEM; and the GASTROINTESTINAL TRACT. They also regulate SONIC HEDGEHOG PROTEIN signaling and cell proliferation. Gli Protein,Gli1 Protein,Glioma-Associated Oncogene Protein,Oncogene GLI Protein,GLI Protein, Oncogene,Glioma Associated Oncogene Protein,Oncogene Protein, Glioma-Associated
D000071841 PAX6 Transcription Factor A paired box transcription factor that has important functions in the development of the eye, nose, central nervous system and pancreas. Mutations in the PAX6 gene are associated with ocular disorders such as ANIRIDIA. Aniridia Type II Protein,Oculorhombin,PAX6 Protein,Paired Box Gene 6 Protein,Paired Box Protein Pax-6,Paired Box Transcription Factor 6,Pax-6 Protein,Pax6.1 Protein,Pax6.2 Protein,Transcription Factor PAX6,Factor PAX6, Transcription,Factor, PAX6 Transcription,PAX6, Transcription Factor,Paired Box Protein Pax 6,Pax 6 Protein,Protein, PAX6,Protein, Pax-6,Protein, Pax6.1,Protein, Pax6.2,Transcription Factor, PAX6
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D053823 Hedgehog Proteins A family of intercellular signaling proteins that play an important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action. Hedgehog Protein,Hedgehog Protein, Vertebrate,Banded Hedgehog Protein,Desert Hedgehog Protein,Indian Hedgehog Protein,Sonic Hedgehog Protein,Vertebrate Hedgehog Protein,Hedgehog Protein, Banded,Hedgehog Protein, Desert,Hedgehog Protein, Indian,Hedgehog Protein, Sonic,Protein, Hedgehog
D055166 Hepatic Stellate Cells Perisinusoidal cells of the liver, located in the space of Disse between HEPATOCYTES and sinusoidal endothelial cells. Ito Cells,Cell, Hepatic Stellate,Cells, Hepatic Stellate,Cells, Ito,Hepatic Stellate Cell,Stellate Cell, Hepatic,Stellate Cells, Hepatic

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