A full spectrum of metabolic aberrations that are directly linked to colorectal cancer (CRC) at early curable stages is critical for developing and deploying molecular diagnostic and therapeutic approaches that will significantly improve patient survival. We have recently reported a urinary metabonomic profiling study on CRC subjects (n = 60) and health controls (n = 63), in which a panel of urinary metabolite markers was identified. Here, we report a second urinary metabonomic study on a larger cohort of CRC (n = 101) and healthy subjects (n = 103), using gas chromatography time-of-flight mass spectrometry and ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry. Consistent with our previous findings, we observed a number of dysregulated metabolic pathways, such as glycolysis, TCA cycle, urea cycle, pyrimidine metabolism, tryptophan metabolism, polyamine metabolism, as well as gut microbial-host co-metabolism in CRC subjects. Our findings confirm distinct urinary metabolic footprints of CRC patients characterized by altered levels of metabolites derived from gut microbial-host co-metabolism. A panel of metabolite markers composed of citrate, hippurate, p-cresol, 2-aminobutyrate, myristate, putrescine, and kynurenate was selected, which was able to discriminate CRC subjects from their healthy counterparts. A receiver operating characteristic curve (ROC) analysis of these markers resulted in an area under the receiver operating characteristic curve (AUC) of 0.993 and 0.998 for the training set and the testing set, respectively. These potential metabolite markers provide a novel and promising molecular diagnostic approach for the early detection of CRC.

Recent studies suggest that biofluid-based metabonomics may identify metabolite markers promising for colorectal cancer (CRC) diagnosis. We report here a follow-up replication study, after a previous CRC metabonomics study, aiming to identify a distinct serum metabolic signature of CRC with diagnostic potential. Serum metabolites from newly diagnosed CRC patients (N = 101) and healthy subjects (N = 102) were profiled using gas chromatography time-of-flight mass spectrometry (GC–TOFMS) and ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC–QTOFMS). Differential metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (VIP > 1) and the Mann–Whitney U test (p < 0.05). With a total of 249 annotated serum metabolites, we were able to differentiate CRC patients from the healthy controls using an orthogonal partial least-squares-discriminant analysis (OPLS-DA) in a learning sample set of 62 CRC patients and 62 matched healthy controls. This established model was able to correctly assign the rest of the samples to the CRC or control groups in a validation set of 39 CRC patients and 40 healthy controls. Consistent with our findings from the previous study, we observed a distinct metabolic signature in CRC patients including tricarboxylic acid (TCA) cycle, urea cycle, glutamine, fatty acids, and gut flora metabolism. Our results demonstrated that a panel of serum metabolite markers is of great potential as a noninvasive diagnostic method for the detection of CRC.

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This study demonstrates the ability of salinomycin to selectively target "CD133+" cell subpopulations and decrease the malignant traits in colorectal cancer lines.

MicroRNAs (miRNAs) have emerged as critical epigenetic regulators involved in cancer progression. miR-320a has been identified to be a novel tumour suppressive miRNA in colorectal cancer (CRC). However, the detailed molecular mechanisms are not fully understood. Here, we reported that miR-320a inversely associated with CRC aggressiveness in both cell lines and clinical specimens. Functional studies demonstrated that miR-320a significantly decreased the capability of cell migration/invasion and induced G0/G1 growth arrest in vitro and in vivo. Furthermore, Rac1 was identified as one of the direct downstream targets of miR-320a and miR-320a specifically binds to the conserved 8-mer at position 1140-1147 of Rac1 3'-untranslated region to regulate Rac1 protein expression. Over-expression of miR-320a in SW620 cells inhibited Rac1 expression, whereas reduction of miR-320a by anti-miR-320a in SW480 cells enhanced Rac1 expression. Re-expression of Rac1 in the SW620/miR-320a cells restored the cell migration/invasion inhibited by miR-320a, whereas knockdown of Rac1 in the SW480/anti-miR-320a cells repressed these cellular functions elevated by anti-miR-320a. Conclusively, our results demonstrate that miR-320a functions as a tumour-suppressive miRNA through targeting Rac1 in CRC.

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Emodin (EMO) has been shown to possess pleiotropic anticancer capabilities in many types of cancer, including epithelial ovarian cancer (EOC). Inhibitory efficacy of EMO on EOC invasion and migration was previously observed, however, the underlying mechanisms have not been completely elucidated. The present study is aimed to explore the mechanisms. Transwell assay demonstrated that EMO significantly inhibited A2780 and SK-OV-3 cell invasion. Western blot analysis was performed to detect the expression levels of epithelial to mesenchymal transition (EMT)-related markers. We found that EMO treatment dose-dependently upregulated E-cadherin, keratin and downregulated N-cadherin, vimentin, matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) to repress EMT. Mechanistically, EMO could inhibit glycogen synthase kinase 3β (GSK-3β) phosphorylation, decrease total β-catenin protein levels and subsequently downregulate transcription factor zinc finger E-box binding homeobox 1 (ZEB1) expression. These effects of EMO were weakened when the cells were pretreated with SB216763, an inhibitor of GSK-3β kinase. Besides, we utilized small interfering RNA (siRNA) to downregulate ZEB1 expression. We found that treatment of ZEB1-knockdown cells with EMO, ZEB1 levels were lowest and cell invasion was weakest but ZEB1 knockdown had no effect on the expression of phospho-Ser9-GSK-3β (p-GSK-3βSer9), β-catenin. In conclusion, our results suggested that EMO inhibited EOC cell invasion by regulation of GSK-3β/β-catenin/ZEB1 signaling pathway to suppress EMT in vitro.

This study demonstrated that nigericin could partly reverse the EMT process during cell invasion and metastasis.