Page 39 - Hormel Report 2023

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PUBLICATION
HIGHTLIGHT:
• Sun, L., Wang, Y., Wang, X., Navarro-Corcuera, A., Ilyas, S., Jalan-Sakrikar, N., Gan, C., Tu, X., Shi, Y., Tu, K., Liu, Q., Lou, Z., Dong, H., Sharpe, A. H., Shah, V. H., & Kang, N. (2022). PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II. Cell Reports, 38(6), 110349.
• Yang, F., Hilakivi-Clarke, L., Shaha, A., Wang, Y., Wang, X., Deng, Y., Lai, J., & Kang, N. (2023). Metabolic reprogramming and its clinical implication for liver cancer. Hepatology.
We found that TGFβ1-stimulated Glut1 PM localization, glycolysis, and HSC activation requires the SH3 domain of Src. Under TGFβ stimulation, The SH3 domain of Src recruits SH3BP5, activator specific for Rab11, onto the endosomes to induce Rab11 activation and Rab11-dependent Glut1 trans- port towards the PM. This study is currently under revision for Hepatology.
Investigate How PKCzeta Regulates Glycolysis for CAF Activation of HSCs.
We also study how Glut1 is anchored to the PM of HSCs and found that TGFβ1 stimulation leads to the formation of a VASP/PKCζ/Glut1 protein complex at the PM that is required for anchoring Glut1 at the PM. We are currently preparing a manuscript of this study for submission.
Determine the Role of CMTM6 in Glut1 Trafficking, Glycolysis, and Colorectal Liver Metastasis.
Funded by the Windfelts Pilot Award, we have tested the hypothesis that CMTM6, a trans-membrane protein, may regulate glycolysis thereby facilitating liver metastasis of colorectal cancer. We found that CMTM6 physically interacts with Glut1 in colorectal cancer cells and CMTM6 knockdown reduces PM Glut1 level, glycolysis, colorectal cancer proliferation and growth in vitro and colorectal liver metastasis in mice.
Explore Epitranscriptomic Regulation of CAF Activation of HSCs.
The N6-adenosine modification (m6A) is a dynamic
reversible process in RNA molecule, which is erased by RNA demethylase ALKBH5 or FTO. Since TGFβ stimulation leads to global transcriptomic changes in HSCs, we are testing the hypothesis that while turning on and off gene transcription
is a major determinant, m6A-mediated epitranscriptomic regulation constitutes a second layer of regulation for the TGFβ transcriptome and CAF activation of HSCs. Our wet-lab experiments and RNA seq/bioinformatics reveal that ALKBH5-mediated RNA demethylation is indeed required
for CAF activation of HSCs induced by TGFβ1. This study is funded by the Paint the Town Pink Pilot Award and Mayo Liver Cancer SPORE DRP Award.
ORCID iD:
https://orcid.org/0000-0002-4565-7976