ABSTRACT
Aberrant activation of Hedgehog-Gli1 signaling and accumulation of Gli1 in hepatocellular carcinoma (HCC) are frequently observed. However, the mechanisms leading to the overactivation of this signaling pathway are not fully understood. In this study, we show that the short isoform of PHD finger protein 19 (PHF19) interacts with ß-TrCP, the E3 ligase of Gli1, and that knocking down PHF19 promotes the ubiquitination of Gli1. In a biological function study, PHF19 was found to promote the growth of HCC cells both in liquid culture and in soft agar. Moreover, knocking out PHF19 in a HCC mouse model (MycF/F) using the hydrodynamic method inhibited tumorigenesis and improved survival. Taken together, these results demonstrate that PHF19 promotes the growth of HCC cells by activating the Hedgehog signaling pathway.
Subject(s)
Carcinoma, Hepatocellular/genetics , DNA-Binding Proteins/genetics , Hedgehog Proteins/genetics , Liver Neoplasms/genetics , Signal Transduction/genetics , Transcription Factors/genetics , Zinc Finger Protein GLI1/genetics , Animals , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Cell Movement , Cell Proliferation , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Forkhead Box Protein M1/genetics , Forkhead Box Protein M1/metabolism , Gene Expression Regulation, Neoplastic , Hedgehog Proteins/metabolism , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Mice , Patched-1 Receptor/genetics , Patched-1 Receptor/metabolism , Protein Processing, Post-Translational , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Survival Analysis , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Tumor Burden , Ubiquitination , Xenograft Model Antitumor Assays , Zinc Finger Protein GLI1/metabolismABSTRACT
The coronavirus disease 2019 (COVID-19) has caused global public health and economic crises. Thus, new therapeutic strategies and effective vaccines are urgently needed to cope with this severe pandemic. The development of a broadly neutralizing antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the attractive treatment strategies for COVID-19. Currently, the receptor-binding domain (RBD) of the spike (S) protein is the main target of neutralizing antibodies when SARS-CoV-2 enters human cells through an interaction between the S protein and the angiotensin-converting enzyme 2 expressed on various human cells. A single monoclonal antibody (mAb) treatment is prone to selective pressure due to increased possibility of targeted epitope mutation, leading to viral escape. In addition, the antibody-dependent enhancement effect is a potential risk of enhancing the viral infection. These risks can be reduced using multiple mAbs that target nonoverlapping epitopes. Thus, a cocktail therapy combining two or more antibodies that recognize different regions of the viral surface may be the most effective therapeutic strategy.
Subject(s)
Humans , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, CoronavirusABSTRACT
Communion is an important way to study.Interaction is the most notable character of network.This paper introduces some experience on how to bring net interaction into play in the network-based medical teaching.