Upregulated β-galactoside α2,6-sialyltransferase I (ST6Gal-I) expression reportedly occurs in many cancers and is correlated with metastasis and poor prognosis. However, the mechanisms by which ST6Gal‑I facilitates gastric cancer progression remain poorly understood. Trastuzumab is exclusively used in human epidermal growth factor receptor 2 (HER2)+ gastric cancers; however, most advanced HER2+ gastric cancers develop trastuzumab resistance. Herein, we identified HER2 as an ST6Gal‑I substrate and showed that HER2 α2,6 sialylation confers protection against trastuzumab‑mediated apoptosis. SGC7901 cancer cell models in which ST6Gal‑I was overexpressed or knocked down were constructed, revealing that ST6Gal‑I overexpression induced high HER2 sialylation levels and increased cell viability and invasion compared to those in the vector cell line under serum starvation; ST6Gal‑I knockdown had the opposite effects. ST6Gal‑I overexpression also potentiated cell cycle arrest in the G2/S phase to reduce drug sensitivity. In addition, FACS analysis revealed that high ST6Gal‑I levels increased resistance to trastuzumab‑induced apoptosis, accompanied by decreased caspase‑3 levels. However, the ST6Gal‑I knockdown cell line revealed increased caspase‑3 levels and evident apoptosis compared with those in the vector cell line. Although ST6Gal‑I overexpression increased HER2 sialylation, corresponding to decreased HER2 phosphorylation, high α2,6‑sialylation enhanced Akt and ERK phosphorylation levels compared to those in the vector cell line; ST6Gal‑I knockdown had the opposite effects. Collectively, these results implicated a functional role of ST6Gal‑I in promoting tumor cell progression and trastuzumab resistance.

Recent studies have identified pleiotropic roles of methyltransferase-like 3 (METTL3) in tumor progression. However, the roles of METTL3 in esophageal squamous cell carcinoma (ESCC) are still unclear. Here, we investigated the function and mechanism of METTL3 in ESCC tumorigenesis. We reported that higher METTL3 expression was found in ESCC tissues and was markedly associated with depth of invasion and poor prognosis. Loss- and gain-of function studies showed that METTL3 promoted the migration and invasion of ESCC cells in vitro. Integrated methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) analysis first demonstrated that glutaminase 2 (GLS2) was regulated by METTL3 via m6A modification. Our findings identified METTL3/GLS2 signaling as a potential therapeutic target in antimetastatic strategies against ESCC.

No abstract

Fibroblast growth factor receptors (FGFrs) have been implicated in the malignant transformation and chemoresistance of epithelial ovarian cancer; however, the underlying molecular mechanisms are poorly understood. increased sialyltransferase activity that enhances protein sialylation is an important post-translational process promoting cancer progression and malignancy. in the present study, α2,6-sialyltransferase (ST6Gal-i) overexpression or knockdown cell lines were developed, and FGFr1 was examined to understand the effect of sialylation on migration and drug resistance, and the underlying mechanisms. it was identified that cells with ST6Gal-I overexpression had increased cell viability and migratory ability upon serum deprivation. Moreover, ST6Gal-i overexpression cells had strong resistance to paclitaxel, as demonstrated by low growth inhibition rate and cell apoptosis level. a mechanistic study showed that ST6Gal-i overexpression induced high α2,6-sialylation of FGFr1 and increased the expression of phospho-erK1/2 and phospho-focal adhesion kinase. Further study demonstrated that the FGFr1 inhibitor Pd173047 reduced cell viability and induced apoptosis; however, ST6Gal-i overexpression decreased the anticancer effect of Pd173047. in addition, ST6Gal-i overexpression attenuated the effect of adriamycin on cancer cells. collectively, these results suggested that FGFr1 sialylation plays an important role in cell migration and drug chemoresistance in ovarian cancer cells.

Background The aim of present study was to screen the novel and promising targets of curcumin in hepatocellular carcinoma diagnosis and chemotherapy. Methods Potential targets of curcumin were screened from SwissTargetPrediction, ParmMapper and drugbank databases. Potential aberrant genes of hepatocellular carcinoma were screened from Genecards databases. Fifty paired hepatocellular carcinoma patients’ gene expression profiles from the GEO database were used to test potential targets of curcumin. Besides, GO analysis, KEGG pathway enrichment analysis and PPI network construction were used to explore the underlying mechanism of candidate hub genes. ROC analysis and Kaplan-Meier analysis were used to evaluate the diagnostic and prognostic value of candidate hub genes, respectively. Real-time PCR was used to verify the results of bioinformatics analysis. Results Bioinformatics analysis results suggested that AURKA, CDK1, CCNB1, TOP2A, CYP2B6, CYP2C9, and CYP3A4 genes served as candidate hub genes. AURKA, CDK1, CCNB1 and TOP2A were significantly upregulated and correlated with poor prognosis in hepatocellular carcinoma, AUC values of which were 95.7, 96.9, 98.1 and 96.1% respectively. There was not significant correlation between the expression of CYP2B6 and prognosis of hepatocellular carcinoma, while CYP2C9 and CYP3A4 genes were significantly downregulated and correlated with poor prognosis in hepatocellular carcinoma. AUC values of CYP2B6, CYP2C9, and CYP3A4 were 96.0, 97.0 and 88.0% respectively. In vitro, we further confirmed that curcumin significantly downregulated the expression of AURKA, CDK1, and TOP2A genes, while significantly upregulated the expression of CYP2B6, CYP2C9, and CYP3A4 genes. Conclusions Our results provided a novel panel of AURKA, CDK1, TOP2A, CYP2C9, and CYP3A4 candidate genes for curcumin related chemotherapy of hepatocellular carcinoma.