Jun 17, 2022
RPG Seminar (2022-06-17)
Date: Friday, 17 June 2022
Time: 5:00 p.m. - 6:00 p.m.
Meeting ID: 977 4164 3394
Presenter: Miss Huajian YU, PhD candidate
Primary Supervisor: Dr. Stephanie MA
Presentation Title: TCF7L2-driven SERPINA12 upregulation promotes the tumorigenic capacity of hepatocellular carcinoma stem cells
Abstract: Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. Understanding the mechanisms that drive cancer stemness, which we now know is the root cause of therapy failure and tumor recurrence, is fundamental for designing improved therapeutic strategies. The aim of this study is to identify molecular players specific to CD133+ HCC to better design drugs that can precisely interfere with cancer stem cells (CSCs) but not normal stem cell function. Transcriptome profiling of epithelial-specific ‘normal’ CD133+ cells isolated from fetal and regenerating liver against ‘HCC’ CD133+ cells isolated from proto-oncogene driven and inflammation-associated HCC revealed preferential overexpression of SERPINA12 in HCC but not fetal and regenerating liver cells. SERPINA12 upregulation in HCC is tightly associated with aggressive clinical and stemness features. Upstream, CD133 bound to and interacted with p85 to promote the activation of PI3K/AKT/β-catenin signaling, a well-known upstream regulator of TCF7L2, which was shown to bind to the promoter of SERPINA12 to promote its transcriptional activity. Functional characterization of SERPINA12 demonstrated the promotion of self-renewal, therapy resistance and metastatic abilities. Mechanistically, SERPINA12 functioned through a hyperactivated AKT/β-catenin signaling cascade, forming a positive feed-forward loop. Intravenous administration of rAVV8-shSERPINA12 sensitized HCC cells to sorafenib and impeded the CSC subset in an immunocompetent HCC mouse model. Our findings revealed that SERPINA12 is preferentially overexpressed in epithelial HCC CD133+ cells and is a key contributor to HCC initiation and progression by driving an AKT/β-catenin feed-forward loop.
Presenter: Mr. Xin ZHANG, PhD candidate
Primary Supervisor: Prof. Quan HAO
Presentation Title: Using Prediction Models for X-ray Protein Structure Determination
Abstract: The 14th edition of Critical Assessment of Structure Prediction (CASP14) showed that accurate in silico models of protein structure domains are on the horizon. As more accurate models become available, the utilization of these models for X-ray crystallographic phasing by molecular replacement (MR) has been verified. However, for the models with high root-mean-square deviation (r.m.s.d.), the popular MR program Phaser may not obtain a solution, which also impacts the downstream model building and refinement procedure. FSEARCH is a procedure to utilize the low-resolution molecular shape for crystallographic phasing and can tolerate relatively high initial errors in the search model. The Iterative Protein Crystal structure Automatic Solution (IPCAS) pipeline is an automatic direct-methods-aided dual-space iterative phasing and model-building procedure. This study presents a combination method of FSEARCH and IPCAS to help with structure determination. Two cases have been tested for the method, and almost complete models have been generated for both cases with reasonable Rwork/Rfree. Therefore, the combination method provides a good tool for X-ray structure determination using protein structure prediction models with high r.m.s.d.
ALL ARE WELCOME
Should you have any enquiries, please feel free to contact Miss Cynthia Cheung at 3917 9748.