Abstract
BACKGROUND: Gastric cancer (GC) is a highly prevalent and lethal malignancy worldwide. Notwithstanding advances in treatment, suboptimal patient outcomes highlight the urgent need for novel therapeutic targets to improve survival. This study aimed to explore the influence of keratin 23 (KRT23) on the proliferation, migration, and invasion of GC cells, as well as its underlying molecular mechanism. METHODS: In this research, the correlation between KRT23 expression and prognosis in GC and the sensitivity analysis of chemotherapy drugs were predicted using bioinformatics methods. The expression pattern of KRT23 in GC samples and cells was examined through immunohistochemistry, quantitative polymerase chain reaction (qPCR), and Western blot. Treatments involving KRT23 knockdown in combination with the PI3K activator (740Y-P) and inhibitor (PI3K-IN-1) were employed. The proliferation, migration, and invasion capabilities of GC cells (MGC803/SGC7901) were analyzed via Cell Counting Kit-8 (CCK-8) and Transwell experiments, and the expression of epithelial-mesenchymal transition (EMT) markers and proteins in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was detected using Western blot. RESULTS: KRT23 was highly expressed in GC. Knockdown of KRT23 significantly inhibited cell proliferation [short hairpin RNA KRT23 (shKRT23) vs. short hairpin RNA normal control (shNC): MGC803, P=0.01; SGC7901, P=0.001; shKRT23 + 740Y-P vs. shKRT23: MGC803, P=0.001; SGC7901, P=0.001], migration (shKRT23 vs. shNC: MGC803 and SGC7901, P<0.001; shKRT23 + 740Y-P vs. shKRT23: MGC803, P=0.007; SGC7901, P=0.004), and invasion [KRT23 overexpression (oeKRT23) vs. KRT23-NC: MGC803, P=0.001; SGC7901, P=0.002] , while the PI3K activator (740Y-P) reversed this effect. Overexpression of KRT23 promoted invasion (oeKRT23 vs. KRT23-NC: MGC803, P=0.001; SGC7901, P=0.002), but the PI3K inhibitor (PI3K-IN-1) counteracted this action (oeKRT23 + PI3K-IN-1 vs. oeKRT23: MGC803, P=0.001; SGC7901, P<0.001). Mechanistically, KRT23 knockdown suppressed the PI3K/AKT/mTOR pathway [decreasing phospho- (p-)PI3K, p-AKT, p-mTOR] and EMT [down-regulating N-cadherin, Snail, Twist1, and up-regulating epithelial cadherin (E-cadherin)], while 740Y-P restored the pathway activity and EMT, and PI3K-IN-1 blocked the effect of oeKRT23. CONCLUSIONS: KRT23 is highly expressed in GC tissues. Knockdown of KRT23 can significantly suppress the proliferation, migration, and invasion of GC cells, and its mechanism might be closely related to the PI3K/AKT/mTOR signaling pathway.