Hepatocellular carcinoma (HCC) is a global health problem. Currently, there is no effective therapeutic strategy for HCC. Methyl gallate (MG), from plant-derived phenolic gallic acid, has exhibited antitumor efficacy. However, the effect of MG on HCC is unclear. In vitro growth activity was detected by a sulforhodamine assay. A zebrafish xenotransplantation was applied to evaluate the inhibitory effect of MG. Reactive oxygen species (ROS) production, autophagy, and lysosome formation were detected by specific dyes. Finally, apoptosis was examined using annexin V-FITC/PI staining and western blot was performed to determine the molecular mechanism. It was demonstrated that MG treatment inhibited the proliferation of Hep3B, Mahlavu, and HepJ5 cells. Xenotransplantation also showed that MG inhibited the growth of Hep3B and HepJ5 cells. MG treatment increased cellular levels of superoxide and oxidative stress. Increases in autophagy and lysosome formation were found after MG treatment. The western blot analysis showed that MG activated cleavage of caspase-3 and poly (SDP ribose) polymerase (PARP), modulated levels of the Bcl2, Bax, and Bad ligands, and induced apoptosis. MG induced autophagy with notable activation of beclin-1, autophagy related 5+12 (ATG5+12), and conversion of light chain 3-I (LC3-I) to II. Our study showed that MG exposure inhibited HCC proliferation both in vitro and in vivo. And blocking autophagy enhanced MG-induced cytotoxicity in HCC cells. These findings suggested MG might serve as a powerful therapeutic supplement for human HCC patients.

Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein–protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.

CRC is the second leading cause of cancer-related death. The complex mechanisms of metastatic CRC limit available therapeutic choice. Thus, identifying new CRC therapeutic targets is essential. Moesin (MSN), a member of the ezrin–radixin–moesin family, connects the cell membrane to the actin-based cytoskeleton and regulates cell morphology. We investigated the role of MSN in the progression of CRC. GENT2 and oncomine were used to study MSN expression and CRC patient outcomes. MSN-specific shRNAs or MSN-overexpressed plasmid were used to establish MSN-KD and MSN overexpressed cell lines, respectively. SRB, migration, wound healing, and flow cytometry were used to test cell survival and migration. Propidium iodide and annexin V stain were used to analyze the cell cycle and apoptosis. MSN expression was found to be higher in CRC tissues than in normal tissues. Higher MSN expression is associated with poor overall survival, disease-free survival, and relapse-free survival rates in CRC patients. MSN silencing inhibits cell proliferation, adhesion, migration, and invasion in vitro, whereas MSN overexpression accelerates cell proliferation, adhesion, migration, and invasion. RNA sequencing was used to investigate differentially expressed genes, and RUNX2 was discovered as a possible downstream target for MSN. In CRC patients, RUNX2 expression was significantly correlated with MSN expression. We also found that MSN silencing decreased cytoplasmic and nuclear β-catenin levels. Additionally, pharmacological inhibition of β-catenin in MSN-overexpressed cells led to a reduction of RUNX2, and activating β-catenin signaling by inhibiting GSK3β rescued the RUNX2 downregulation in MSN-KD cells. This confirms that MSN regulates RUNX2 expression via activation of β-catenin signaling. Finally, our result further determined that RUNX2 silencing reduced the ability of MSN overexpression cells to proliferate and migrate. MSN accelerated CRC progression via the β-catenin-RUNX2 axis. As a result, MSN holds the potential to become a new target for CRC treatment.

Colorectal cancer (CRC) ranks among the most prevalent forms of cancer globally, and its late-stage survival outcomes are less than optimal. A more nuanced understanding of the underlying mechanisms behind CRC’s development is crucial for enhancing patient survival rates. Existing research suggests that the expression of Cell Wall Biogenesis 43 C-Terminal Homolog (CWH43) is reduced in CRC. However, the specific role that CWH43 plays in cancer progression remains ambiguous. Our research seeks to elucidate the influence of CWH43 on CRC’s biological behavior and to shed light on its potential as a therapeutic target in CRC management. Utilizing publicly available databases, we examined the expression levels of CWH43 in CRC tissue samples and their adjacent non-cancerous tissues. Our findings indicated lower levels of both mRNA and protein expressions of CWH43 in cancerous tissues. Moreover, we found that a decrease in CWH43 expression correlates with poorer prognoses for CRC patients. In vitro experiments demonstrated that the suppression of CWH43 led to increased cell proliferation, migration, and invasiveness, while its overexpression had inhibitory effects. Further evidence from xenograft models showed enhanced tumor growth upon CWH43 silencing. Leveraging data from The Cancer Genome Atlas (TCGA), our Gene Set Enrichment Analysis (GSEA) indicated a positive relationship between low CWH43 expression and the activation of the epithelial–mesenchymal Transition (EMT) pathway. We conducted RNA sequencing to analyze gene expression changes under both silenced and overexpressed CWH43 conditions. By identifying core genes and executing KEGG pathway analysis, we discovered that CWH43 appears to have regulatory influence over the TTK-mediated cell cycle. Importantly, inhibition of TTK counteracted the tumor-promoting effects caused by CWH43 downregulation. Our findings propose that the decreased expression of CWH43 amplifies TTK-mediated cell cycle activities, thus encouraging tumor growth. This newly identified mechanism offers promising avenues for targeted CRC treatment strategies.

Background: Colorectal cancer (CRC) is highly prevalent and lethal globally, and its prognosis remains unsatisfactory. Drug resistance is regarded as the main cause of treatment failure leading to tumor recurrence and metastasis. The overexpression of fucosylated epitopes, which are usually modifications of glycoproteins, was reported to occur in various epithelial cancers. However, the effects of treatments that target these antigens in colorectal cancer remain unclear. Methods: This study investigated the expression of heavily fucosylated glycans (HFGs) in 30 clinical samples from patients with CRC and other normal human tissues. The complement-dependent cytotoxicity was explored in vitro through treatment with anti-HFG monoclonal antibody (mAb) alone or in combination with chemotherapeutic agents. In vivo inhibitory effects were also examined using a xenograft mouse model. Results: Immunohistochemistry staining and western blotting revealed that HFG expression was higher in human colorectal cancer tissues than in normal tissues. In DLD-1 and SW1116 cells, which overexpress fucosylated epitopes, anti-HFG mAb produced observable cytotoxic effects, especially when it was combined with chemotherapeutic agents. The xenograft model also demonstrated that anti-HFG mAb had potent and dose-dependent inhibitory effects on colorectal tumor growth. Conclusions: As a novel cancer antigen, HFGs are a promising treatment target, and the implementation of anti-HFG mAb treatment for CRC warrants further investigation.