Identification Of Sialyltransferase Genes Associated With The Prognosis Of Lung Adenocarcinoma Based On Bioinformatics Technology

Lung cancer is the second most common cancer and the cancer with the highest mortality rate,accounting for about one in ten(11.4%)of diagnosed cancers and one in five(18.0%)of deaths.Clinically,non-small cell lung cancer(NSCLC)accounts for about 85% of lung cancers,Lung adenocarcinoma(LUAD)is the most common type of NSCLC,accounting for the 70% of patients with non-small cell lung cancer.The concept of "oncogene dependence" refers to the dependence of tumor cells on the specific activity of activated or overexpressed oncogenes.In lung cancer,the major oncogenic drivers are EGFR and KRAS mutations and ALK rearrangements,which are most commonly seen in LUAD and provide excellent drug targets for targeted therapy.These treatments have improved the survival rate of some patients,but the overall cure rate of LUAD patients is not optimistic due to tumor heterogeneity and tumor recurrence.Therefore,it is very important to explore new biomarkers and drug targets for LUAD patients.Glycosylation is the most abundant and diverse post-translational modification of proteins in all eukaryotic cells.These monosaccharides or glycans are linked to specific amino acids of proteins and are involved in the regulation of metabolic pathways and important processes within cells,such as cell-cell interactions and cell adhesion.Abnormal glycosylation often occurs in malignant tumors and is involved in tumorigenesis and metastasis.Sialic acid modifications are terminal sugar modifications of negatively charged sialic acids consisting of nine-carbon monosaccharides,primarily linked by sialyltransferases through α2,3-,α2,6-,and α2,8.Sialyltransferases are mainly composed of four families: ST3 GAL,ST6GAL,ST6 GALNAC and ST8 Sia.Among them,the ST3 GAL family members are mainly located in the Golgi apparatus and are responsible for the specific sialyl transfer catalytic reaction of α2,3-linked.Due to different catalytic substrates,it is divided into six members ST3GAL1-6.Highly aberrant sialylation of the glycosyl end of tumor cells contributes to signal transduction and immune evasion.In the tumor microenvironment,highly sialic acid-modified tumor cells can bind to NK or T cells by binding to Siglec receptors on different immune cells.Meanwhile,abnormal sialylation of some key signaling pathway factors such as TNFR1 and TGF-β1 can also promote tumor progression.In addition,the synthesis of Lewis X antibody and Lewis antigen in saliva also promoted tumor invasion and metastasis.However,the regulation of sialylation on tumor progression in lung adenocarcinoma cells is unclear.In our previous study,we found that ST3GAL6 could promote bladder cancer progression.We therefore asked the scientific question whether the ST3 GAL family is involved in the tumor development of lung adenocarcinoma.Here,we systematically investigated the clinical relevance of the expression levels of ST3 GAL family members to LUAD patients in Oncomine,TCGA and GEO databases.Among the six ST3 GAL family members,we found that ST3GAL6 was down-regulated in LUAD samples compared to normal lung tissue in the Oncomine,TCGA-LUAD and GSE68465 datasets.Moreover,the down-regulation of ST3GAL6 was significantly negatively correlated with the grade and histological subtype of LUAD samples,indicating a poor clinical prognosis.Furthermore,we explored the possible working mechanism of ST3GAL6 in the development of LUAD,and found a relationship between ST3GAL6 and EGFR through protein interaction analysis.Through further cellular experiments,the results showed that knockdown of ST3GAL6 promoted the activation of EGFR/MAPK signaling pathway in LUAD cells A549 and HCC827,accompanied by increased expression levels of matrix metalloproteinases 2 and 9,which in turn promoted tumor cell invasion.In addition,the antisense long non-coding RNA of ST3GAL6,ST3GAL6-AS1,positively regulates ST3GAL6 at the m RNA level,which is consistent with ST3GAL6 in predicting the prognosis of LUAD patients,showing that its low expression in lung adenocarcinoma is consistent with LUAD patients.Associated with worse prognosis,it is speculated that ST3GAL6-AS1 may have a regulatory effect on ST3GAL6.Cellular experiments confirmed that the down-regulation of ST3GA6-AS1 also led to the activation of EGFR/MAPK signaling pathway in A549 and HCC827,and promoted the invasiveness of cancer cells,which further proved that ST3GAL6-AS1 positively regulates the expression of ST3GAL6 in LUAD cells.Based on the above results,we believe that the ST3GAL6-AS1-regulated sialyltransferase ST3GAL6 frequently down-regulated in LUAD patients and negatively regulates EGFR/MAPK signaling to promote cancer cell invasion,which may serve as a promising independent prognostic marker in LUAD patients.