Mechanistic insights into FEN1-mediated drug sensitivity and risk signature in colon cancer: An integrative bioinformatics study.

The overexpression of Flap endonuclease 1 (FEN1) has been implicated in drug resistance and prognosis across various cancer types. However, the precise role of FEN1 in colon cancer remains to be fully elucidated. In this study, we employed comprehensive datasets from The Cancer Genome Atlas, Gene Expression Omnibus, and Human Protein Atlas to examine FEN1 expression and assess its correlation with clinical pathology and prognosis in colon cancer. We utilized the pRRophetic algorithm to evaluate drug sensitivity and performed differential expression analysis to identify genes associated with FEN1-mediated drug sensitivity. Gene set enrichment analysis was conducted to further investigate these genes. Additionally, single-cell sequencing analysis was employed to explore the relationship between FEN1 expression and functional states. Cox regression analysis was implemented to construct a prognostic model, and a nomogram for prognosis was developed. Our analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets revealed a significant upregulation of FEN1 in colon cancer. However, while FEN1 expression showed no notable correlation with prognosis, it displayed associations with metastasis. Single-cell sequencing analysis further confirmed a positive correlation between FEN1 expression and colon cancer metastasis. Furthermore, we detected marked discrepancies in drug responsiveness between the High_FEN1 and Low_FEN1 groups, identifying 342 differentially expressed genes. Enrichment analysis showed significant suppression in processes related to DNA replication, spliceosome, and cell cycle pathways in the Low_FEN1 group, while the calcium signaling pathway, cAMP signaling pathway, and other pathways were activated. Of the 197 genes differentially expressed and strongly linked to FEN1 expression, 39 were significantly implicated in colon cancer prognosis. Finally, we constructed a risk signature consisting of 5 genes, which, when combined with drug treatment and pathological staging, significantly improved the prediction of colon cancer prognosis. This study offers novel insights into the interplay among FEN1 expression levels, colon cancer metastatic potential, and sensitivity to therapeutic agents. Furthermore, we successfully developed a multi-gene prognostic risk signature derived from FEN1.

Luteolin suppresses colorectal cancer cell metastasis via regulation of the miR­384/pleiotrophin axis.

Luteolin (3,4,5,7­tetrahydroxyflavone) is a natural flavonoid that has been found to exhibit anticancer properties in certain types of cancers. In the present study, the role of luteolin and its underlying mechanisms were explored in colorectal cancer (CRC) cells. First, the effects of luteolin on CRC cells proliferation, migration and invasion were examined by CCK­8, wound healing and Transwell assays, respectively. It was demonstrated that luteolin had no effects on CRC cells proliferation while inhibited cells migration and invasion both in vitro and in vivo. Then, expression of pleiotrophin (PTN) and miR­384 was detected in cells and CRC tissues by qPCR. Luteolin was found to upregulate miR­384 and downregulate PTN expressions both in CRC cells and tissues. miR­384 inhibition and PTN overexpression partially reversed the inhibition of HT­29 cells migration and invasion induced by luteolin. Target analysis revealed that miR­384 directly regulates PTN expression. The correlation analysis between PTN expression and clinical characteristics revealed that PTN expression was positively related to cancer progression. The present study demonstrated that luteolin exerts anticancer effects against CRC cells by modulating PTN via miR­384 expression suggested that PTN may serve as a promising candidate for therapeutic applications in CRC treatment.

25-HC decreases the sensitivity of human gastric cancer cells to 5-fluorouracil and promotes cells invasion via the TLR2/NF-κB signaling pathway.

Hyperlipidemia is associated with metastasis in patients with gastric cancer (GC). 25­Hydroxycholesterol (25­HC) is a type of oxysterol which is synthesized from cholesterol and is involved in a number of processes, including inflammation, immune responses and cancer development. However, the role of 25­HC in gastric cancer remains unknown. In the present study, we demonstrated that 25­HC had no effects on GC cell proliferation and apoptosis, whereas it decreased the sensitivity of GC cells to 5­fluorouracil (5­FU), as demonstrated by the increased cell proliferation and the decreased cell apoptosis. On the other hand, exposure to 2.5­10 µM of 25­HC significantly promoted GC invasion, both in vitro (using AGS and MGC­803 GC cell lines) and in vivo (in an animal model), accompanied by the upregulation of the expression levels of matrix metalloproteinases (MMPs). Further investigations revealed that the promotion of GC invasion was, at least in part due to the activation of Toll­like receptor 2 (TLR2)/nuclear factor (NF)­κB signaling. Our results demonstrated that 25­HC promoted GC cells invasion by upregulating TLR2/NF­κB­mediated MMP expression. Thus, on the whole, the findings of this study suggest a novel mechanism of hyperlipidemia­induced GC progression.