LSP1 Involved in Liver Regeneration Termination, Deleted in 50 Percent of Human Liver Cancer and Major Determinant of Response to Sorafenib
Abstract
Our studies on LSP1 and its role in hepatocyte signaling pathways aimed at control of growth and hepatocyte differentiation, started in 2011, with a paper unexpectedly demonstrating that LSP1 protein carboxyterminal was deleted in approximately 46 percent of hepatocellular carcinomas (HCC) and amplified in 5 percent of HCC, with the latter amplification acting as a dominant negative to eliminate the effects of the normal protein. While there was abundant literature on LSP1 in leucocytes and lymphocytes, there was no literature whatsoever to link it to hepatocyte growth and function. In a subsequent paper published in 2014, we demonstrated that upregulation of LSP1in an HCC cell line dramatically suppressed cell proliferation while downregulation in an HCC cell line expressing LSP1 increased cell proliferation and cell migration. Forced expression of LSP1 in mouse liver also decreased liver regeneration after partial hepatectomy. The data obtained supported the hypothesis that LSP1 overall is a growth suppressor for normal hepatocytes and HCC. In a subsequent paper published in 2018, we published some of the data generated by the current DoD award. (Please note: We gave credit to the DoD award for support of the part of the research published in that paper by acknowledging DoD and stating the CDMRP Log Number: CA160119). We used mice with transgenic overexpression of LSP1 (LSP1 TG) and genomic deletion knockout of LSP1 (LSP1 KO), and showed that the TG mice had suppressed liver regeneration whereas the KO mice had enhanced regeneration. In the latter paper, we showed that LSP1 controls a very important signaling pathway, RAF/MEK/ERK, which is held together by the scaffolding protein KSR. That pathway receives signaling from many upstream proteins and regulates phosphorylation of ERK1 and ERK2, important components of optimization and regulation of many cellular pathways in all cell types, including cell growth and differentiation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1117701
Entities
People
- George K. Michalopoulos
Organizations
- University of Pittsburgh