Isoliquiritigenin (2’-4’-4-trihydroxychalcone, ISL), a flavonoid from the herbal medicine Glycyrrhiza uralensis Fisch, has promising antitumor effects. While ISL has demonstrated anti-cancer potential, its comprehensive molecular mechanism of action in lung cancer remains inadequately explored, particularly in the context of combination therapy with gemcitabine (Gem). This study conducted in vivo and in vitro experiments to investigate the anti-lung cancer effect of ISL (50 mg/kg/d), in combination with Gem (50 mg/kg/3d) (ISL + Gem) and elucidate the molecular mechanism of ISL (25 µM) combined with Gem (1 µM) (ISL + Gem) in inducing apoptosis and inhibiting proliferation of lung cancer cells. The results revealed that ISL + Gem exerted its antitumor effects by promoting apoptosis and inhibiting the proliferation of lung cancer cells as well as their ability to invade and metastasize. It was discovered that long non-coding RNA (lncRNA) -p21 was differentially lowly expressed in human non-small cell lung cancer (NSCLC) tissues. In vitro studies confirmed that combined ISL and Gem treatment increased lncRNA-p21 expression in NSCLC cell lines. Inhibitory effects of proliferation, invasion and migration as well as induction of apoptosis by ISL + Gem can be enhanced by the overexpression of lncRNA-p21 and eliminated by knock-down of lncRNA-p21. Luciferase assays revealed that lncRNA-p21 acts as a competing endogenous RNA (ceRNA) for miR-4534, which was significantly upregulated in NSCLC tissues compared to normal controls. Treatment with ISL, Gem, or their combination effectively suppressed miR-4534 expression in H460 cells. Further studies revealed that ISL + Gem, overexpression of lncRNA-p21 or silencing of miR-4534 inhibited the expression of CXC chemokine ligand-12 (CXCL12), as well as janus kinase 2 and signal transducer activator of transcription 3 (JAK2/STAT3) pathway-related proteins. In contrast, knock-down of lncRNA-p21 or overexpression of miR-4534 reversed the above effects of ISL + Gem. In conclusion, this study showed that ISL combined with Gem could effectively impede the progression of lung cancer partially through inactivating JAK2/STAT3 signaling pathway via lncRNA-p21/miRNA-4534 axis.
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