Molecular Characterization of Advanced Colorectal Cancer Using Serum Proteomics and Metabolomics.

Colorectal cancer (CRC) is a growing public health concern due to its high mortality rate. Currently, there is a lack of valid diagnostic biomarkers and few therapeutic strategies are available for CRC treatment, especially for advanced CRC whose underlying pathogenic mechanisms remain poorly understood. In the present study, we investigated the serum samples from 20 patients with stage III or IV advanced CRC using data-independent acquisition (DIA)-based proteomics and ultra-performance liquid chromatography coupled to time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS) metabolomics techniques. Overall, 551 proteins and 719 metabolites were identified. Hierarchical clustering analysis revealed that the serum proteomes of advanced CRC are more diversified than the metabolomes. Ten biochemical pathways associated with cancer cell metabolism were enriched in the detected proteins and metabolites, including glycolysis/gluconeogenesis, biosynthesis of amino acids, glutathione metabolism, and arachidonic acid metabolism, etc. A protein-protein interaction network in advanced CRC serum was constructed with 80 proteins and 21 related metabolites. Correlation analysis revealed conserved roles of lipids and lipid-like molecules in a regulatory network of advanced CRC. Three metabolites (hydroquinone, leucenol and sphingomyelin) and two proteins (coagulation factor XIII A chain and plasma kallikrein) were selected to be potential biomarkers for advanced CRC, which are positively and significantly correlated with CEA and/or CA 19-9. Altogether, the results expanded our understanding of the physiopathology of advanced CRC and discovered novel potential biomarkers for further validation and application to improve the diagnosis and monitoring of advanced CRC.

Peiminine inhibits colorectal cancer cell proliferation by inducing apoptosis and autophagy and modulating key metabolic pathways.

Peiminine, a compound extracted from the bulbs of Fritillaria thunbergii and traditionally used as a medication in China and other Asian countries, was reported to inhibit colorectal cancer cell proliferation and tumor growth by inducing autophagic cell death. However, its mechanism of anticancer action is not well understood, especially at the metabolic level, which was thought to primarily account for peiminine's efficacy against cancer. Using an established metabolomic profiling platform combining ultra-performance liquid chromatography/tandem mass spectrometry with gas chromatography/mass spectrometry, we identified metabolic alterations in colorectal cancer cell line HCT-116 after peiminine treatment. Among the identified 236 metabolites, the levels of 57 of them were significantly (p < 0.05) different between peiminine-treated and -untreated cells in which 45 metabolites were increased and the other 12 metabolites were decreased. Several of the affected metabolites, including glucose, glutamine, oleate (18:1n9), and lignocerate (24:0), may be involved in regulation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway and in the oxidative stress response upon peiminine exposure. Peiminine predominantly modulated the pathways responsible for metabolism of amino acids, carbohydrates, and lipids. Collectively, these results provide new insights into the mechanisms by which peiminine modulates metabolic pathways to inhibit colorectal cancer cell growth, supporting further exploration of peiminine as a potential new strategy for treating colorectal cancer.

Estrogen Receptors in Regulating Cell Proliferation of Esophageal Squamous Cell Carcinoma: Involvement of Intracellular Ca2+ Signaling.

Esophageal cancer is a deadly disease in the esophagus with a poor prognosis. Over 90 % of esophageal cancer is esophageal squamous cell carcinoma (ESCC) and its pathogenic mechanisms remain unclear. Epidemiology study found a strong gender difference with a sex ratio of 8-9:1 in favor of males, but the molecular mechanisms for so striking gender difference are poorly understood so far. In the present study, we demonstrated the expression of estrogen receptors in human ESCC cells. 17ß-E2 but not 17α-E2 was found to dose-dependently suppress the cell proliferation of human ESCC cells, which was attenuated by estrogen receptor antagonist ICI1 82,780. Furthermore, 17ß -E2 but not 17α-E2 10 nM markedly induced both intracellular Ca2+ release and extracellular Ca2+ entry into ESCC cells, which was again attenuated by estrogen receptor antagonist ICI182,780. Taken together, our data clearly demonstrate that estrogen exerts anti-proliferative action on human ESCC cells likely through estrogen receptor-Ca2+ signaling pathway, which may provide a reasonable explanation on the striking male predominance of ESCC.