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Background: Lung cancer is a malignant tumor with one of the highest rates of cancer-related morbidity and mortality worldwide. Non-small cell lung cancer (NSCLC) account for 85% of all lung cancers and have a poor prognosis. Proanthocyanidins (PCs) are polyphenolic compounds that are found widely in natural plants. The present study aimed to determine the effects of PC on lung cancer and identify its possible mechanism.Methods: A cell growth assay was used to detect the cell growth ability of A549 cancer cells, and a clonal formation assay was used to detect the cloning ability of A549 cancer cells. Flow cytometry was used to detect the effect of PCs on apoptosis and the cell cycle. The wound healing test, Transwell migration, and invasion test were used to detect the migration and invasion of human NSCLC A549 cells. Western blotting was utilized to detect the expression levels of N-cadherin, E-cadherin, vimentin, Janus kinase 2 (JAK2), p-signal transducer and activator of transcription 3 (p-STAT3), STAT3, matrix metalloproteinase 2 (MMP-2), MMP-9, and the apoptosis-related proteins, B-cell lymphoma-2 (Bcl-2) and BCL2-associated X (Bax). Cell immunofluorescence was used to detect the expression levels of the p-STAT3 primary antibody.Results: PCs reduced the proliferation and cloning ability of A549 cells and significantly inhibited the migration and invasion of A549 cells in a dose-dependent manner. At the same time, PCs induced apoptosis in A549 cells and G2/M cell cycle arrest. PCs increased the pro-apoptotic protein expression, Bax, and down-regulated the anti-apoptotic protein expression, Bcl-2. PCs also inhibited the epithelial-mesothermal transition (EMT) process of A549 cells. We also found that the JAK2/STAT3 signaling pathway inhibitor, AG490, cooperated with PCs to inhibit A549 cell invasion and migration. Our results demonstrated that PCs could mediate the antitumor effect of NSCLC via the JAK2/STAT3 pathway. Conclusions: PCs can inhibit NSCLC A549 cell proliferation, invasion, metastasis, clone formation, EMT, and induced apoptosis and G2/M cell cycle arrest. They work by inhibiting the JAK2/STAT3 signaling pathway. As a novel antitumor drug, PCs have broad application prospects for the treatment of NSCLC.

Minichromosome maintenance protein 5 (MCM5) is a critical cell cycle regulator; its role in DNA replication is well known, but whether it is involved in the regulation of organogenesis in a cell cycle-independent way, is far from clear. In this study, we found that a loss of mcm5 function resulted in a mildly smaller liver, but that mcm5 overexpression led to liver bifida. Further, the data showed that mcm5 overexpression delayed endodermal migration in the ventral–dorsal axis and induced the liver bifida. Cell cycle analysis showed that a loss of mcm5 function, but not overexpression, resulted in cell cycle delay and increased cell apoptosis during gastrulation, implying that liver bifida was not the result of a cell cycle defect. In terms of its mechanism, our data proves that mcm5 represses the expression of cxcr4a, which sequentially causes a decrease in the expression of itgb1b during gastrulation. The downregulation of the cxcr4a-itgb1b cascade leads to an endodermal migration delay during gastrulation, as well as to the subsequent liver bifida during liver morphogenesis. In conclusion, our results suggest that in a cell cycle-independent way, mcm5 works as a gene expression regulator, either partially and directly, or indirectly repressing the expression of cxcr4a and the downstream gene itgb1b, to coordinate endodermal migration during gastrulation and liver location during liver organogenesis.

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