ABSTRACT
Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.
Subject(s)
Hydrolases , Virus Diseases , Humans , Hydrolases/metabolism , Mannosephosphates/analysis , Mannosephosphates/chemistry , Mannosephosphates/metabolism , Virus Diseases/metabolism , Lysosomes/metabolismABSTRACT
Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.
Subject(s)
Adaptor Proteins, Signal Transducing , Apoptosis Regulatory Proteins , Colorectal Neoplasms , Intracellular Signaling Peptides and Proteins , Humans , Adaptor Proteins, Signal Transducing/metabolism , Apoptosis , Apoptosis Regulatory Proteins/metabolism , Colorectal Neoplasms/genetics , gamma Catenin/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Neoplasm Proteins/metabolism , Valosin Containing Protein/genetics , Valosin Containing Protein/metabolismABSTRACT
OBJECTIVES: Circular RNAs (circRNAs) can interact with microRNAs (miRNAs) to regulate gene expression in cancer cells. However, the roles of competitive endogenous RNA (ceRNA) networks consisting of differentially expressed circRNAs (DECs), miRNAs, and messenger RNAs (mRNAs) in stomach adenocarcinoma (STAD) remain unclear. This study was performed to explore novel regulatory networks in STAD. METHODS: The circRNA expression profiles, as well as miRNA and mRNA sequence data of STAD, were retrieved from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Candidates were identified to construct a network through a comprehensive bioinformatics strategy. The expression of hub-genes identified by protein-protein interactions (PPI) was validated by quantitative reverse transcription (RT) polymerase chain reaction. RESULTS: A total of 51 DECs were identified in the GSE83521 and GSE89143 datasets of GEO. A total of 11 448 differentially expressed mRNAs (DEMs) and 458 differentially expressed miRNAs (DEMIs) were obtained by RNA sequencing of TCGA-STAD. Prediction by using five online databases (Cancer-Specific CircRNA, CircInteractome, miRTarBase, miRDB, and TargetScan) resulted in the selection of 6 DECs, 6 DEMIs, and 36 DEMs to establish a circRNA-miRNA-mRNA regulatory network based on the interactions of circRNA-miRNA and miRNA-mRNA. Through PPI analysis, four hub-genes (COL10A1, COL5A2, COL4A1, and COL3A1) were discovered. Moreover, overexpressions of COL10A1, COL5A1, and COL4A1 were associated with a poor overall survival rate of patients with STAD. On the basis of TNM staging, we found that the expressions of COL10A1, COL5A2, and COL3A1 in T2, T3, and T4 was significantly higher than in T1. Hub-genes expressions were validated in STAD tissues and cell lines. CONCLUSIONS: Our study provides a novel perspective on the regulatory mechanism of STAD involving ceRNAs including DECs, DEMIs, and DEMs.
Subject(s)
Adenocarcinoma , Gene Regulatory Networks , MicroRNAs , RNA, Circular , RNA, Messenger , RNA, Neoplasm , Stomach Neoplasms , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Databases, Nucleic Acid , Humans , MicroRNAs/genetics , RNA, Circular/genetics , RNA, Circular/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolismABSTRACT
Hepatocellular carcinoma (HCC) is highly resistant to traditional chemotherapeutic approaches, which causes difficulty in the development of effective drugs for the treatment of HCC. Berberine, a major ingredient of Rhizoma coptidis, is a natural alkaloid used in traditional Chinese medicine. Berberine exhibits potent antitumor activity against HCC due to its high efficiency and low toxicity. In the present study, we found that berberine sensitized HepG cells to NF-κB-mediated apoptosis. Berberine exhibited a significant antiproliferation effect on the HepG2 cells and promoted apoptosis. Both qRT-PCR and immunofluorescence staining revealed that berberine reduced the NF-κB p65 levels in HepG2 cells. Moreover, p65 overexpression rescued berberine-induced cell proliferation and prevented HepG2 cells from undergoing apoptosis. These results suggest that berberine inhibits the growth of HepG2 cells by promoting apoptosis through the NF-κB p65 pathway.
Subject(s)
Apoptosis/physiology , Berberine/pharmacology , Carcinoma, Hepatocellular/metabolism , Down-Regulation/physiology , Liver Neoplasms/metabolism , NF-kappa B/metabolism , Apoptosis/drug effects , Berberine/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/physiology , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , NF-kappa B/antagonists & inhibitorsABSTRACT
Hepatocellular carcinoma (HCC) has frequent incidence and the third highest mortality rate among cancers in the world. This study aimed to clarify the roles of miR-217 and metadherin (MTDH) in HCC. First, we identified that miR-217 expression was downregulated and MTDH expression was upregulated in the HCC tissues. Functional studies revealed that miR-217 negatively regulated MTDH expression via binding to the 3'-untranslated region of MTDH mRNA in the HCC cells. In our further studies, the miR-217 overexpression resulted in downregulation of MTDH expression in HCC cells. The miR-217 overexpression in HCC cells suppressed proliferation, migration, and invasion inducing apoptosis. Taken together, our study provides the initial evidence that the increase of MTDH expression is associated with the decrease of miR-217 expression in HCC. This study also suggests that miR-217 inhibits malignant progression of HCC in vitro and may be used for miRNA-based therapy, possibly via directly targeting MTDH.