Molecular alterations that take roles in gastric tumorigenesis and metastasis

Ph.D. ; Background and Aims: Metabolic dysregulation is one of the hallmarks of gastric cancer (GC). In this study, by using Infinium Human Methylation 450K BeadChip array, we identified Calcium Binding Protein 39-Like as a novel tumor suppressor silenced by promoter methylation in GC and aim to elucidate the underlying mechanism. ; Results: Biological studies of cellular functions indicated that CAB39L functions as a tumor suppressor since ectopic expression of CAB39L exhibited suppressive effects on multiple cancerous phenotypes in both GC cell lines and GC orthotopic mouse model, whereas knockdown of CAB39L promoted tumor progression. Mechanistically, CAB39L cooperates with LKB1-STRAD protein complex and induced the phosphorylation of LKB1 which could further activate AMPK pathway. LKB1- AMPK pathway stimulation in GC cell lines are tumor suppressive, as metformin (a well-known AMPK pathway activator) treatment exhibited inhibition on GC cell proliferation. Moreover, LKB1 downregulation by siRNA reversed the inhibitory effect of CAB39L on cell proliferation, suggesting that the suppressive effects of CAB39L is dependent on LKB1-AMPK axis. Transcriptome sequencing and gene set enrichment analysis (GSEA) showed that CAB39L was tightly linked with oxidative phosphorylation and mitochondrial biogenesis. Being consistent, CAB39L-activated phosphorylation of AMPK exhibited elevation in PGC1α phosphorylation and enhanced the expression level of genes involved in mitochondrial respiration complexes. Reasonably, CAB39L reversed Warburg effect in GC cell lines, as validated by increase in oxygen consumption rate (OCR) and decrease in extracellular acidification rate (ECAR). Concomitantly, knockdown of CAB39L stimulated a metabolic transition to Warburg phenotype. In GC patients, the degree of promoter hypermethylation was associated with poor prognosis. ; Conclusion: Our study illustrated that CAB39L functions as a novel tumor suppressor which inhibit tumorigenesis by activating LKB1-AMPK-PGC1α axis, hereafter elicits ...