Page 41 - Hormel Report 2021

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Current research projects:
1) The role of PD-L1 in activation of hepatic stellate cells into tumor-promoting myofibroblasts.
2) Src regulation of glycolysis of hepatic stellate cells.
3) The role of PKCzeta in glycolysis of hepatic
stellate cells.
Publications:
• Gao J, Wei B, Liu M, Hirsova P, Sehrawat TS, Cao S, Hu X, Xue
F, Yaqoob U, Kang N, Kostallari
E, Shah VH. Endothelial p300 promotes portal hypertension and hepatic fibrosis through CCL2-mediated angiocrine signaling. Hepatology. 2020 Nov 7. doi: 10.1002/hep.31617. Online ahead of print. PMID: 33159815
• Xia Qian, Wei Zhang, Alireza Shams, Kahee Mohammed, Alex S Befeler, Ningling Kang, Jinping ali Lai. Yes-associated protein-1 may serve as a diagnostic marker
and therapeutic target for residual/recurrent hepatocellular carcinoma post-transarterial chemoembolization. Liver Res. 2020 Dec;4(4):212-217. doi: 10.1016/j.livres.2020.11.002. Epub 2020 Nov 8. PMID: 33520338
• Xia Qian, Wei Zhang, Hua Yang, Lanjing Zhang, Ningling Kang, Jinping Lai. Role of Yes-associated protein-1 in gastrointestinal cancers and hepatocellular carcinomas. Exploratory Research and Hypothesis in Medicine (DOI: 10.14218/ ERHM.2021.00017)
activity, contributing to immune escape of cancer. Since the role of PD-L1 in hepatic stellate cells (HSCs) remains unknown, we studied PD-L1 expression in HSCs. We found that PD-L1 expression is induced
by TGFβ stimulation and that PD-L1 is required for activation/differentiation of HSCs into myofibroblasts induced by TGFβ. Mechanistic studies revealed
that PD-L1 stabilizes TGFβ receptor I and II by two distinct mechanisms thereby promoting myofibro- blastic activation of HSCs. The extracellular domain of PD-L1 binds to TβRII protein and protects it from lysosome-mediated degradation whereas a C-termi- nal 260-RLRKGR-265 motif on PD-L1 binds to TβRI mRNA and protects it from degradation by the RNA exosome complex. Moreover, PD-L1 is required for
HSC expression and release of tumor-promoting factors and targeting HSC PD-L1 suppresses tumor-promoting effect of HSCs in vitro and in vivo. A manuscript of this study is currently under revision for Cell Report.
The other two projects are related to mechanisms that fuel the process of myofibroblastic activation of HSCs. We found that the TGFβ-stimulated HSC activation/ differentiation process is dependent upon breakdown of glucose (glycolysis) and that TGFβ stimulation promotes glucose transport into HSCs, a process mediated by glucose transporter 1 (Glut1) on the plasma membrane. One project in my lab is therefore focused on Glut1 trafficking induced by TGFβ and another is investigating how TGFβ promotes glucose transport into HSCs.