The expression of seven key genes can predict distant metastasis of colorectal cancer to the liver or lung.

OBJECTIVE: It is unclear how primary colorectal cancer (CRC) cells select to metastasize to the liver or lungs, the most frequent distant metastasis of CRC. We aimed to identify the key genes and pathways that may predict the distant metastasis of CRC to these sites. METHODS: Three gene expression array datasets from the Gene Expression Omnibus were analyzed. Protein-protein network analyses, best subsets regressions and backward stepwise regression analyses were used to screen the key genes and their expressions were used to construct a predictive logistic regression model. Expression data from local clinical samples were used as a validation dataset. The receiver operating characteristic (ROC) curve was used to test the performance of the predictive model. RESULTS: In total, 59 differentially expressed genes (DEG) related to liver-metastasis, 90 related to lung metastasis and 45 related to both liver and lung metastasis were identified. The KEGG pathways and gene oncology (GO) terms that were enriched in liver and lung metastasis were identified. A predictive logistic regression model consisted of SPARC, COL1A2, MMP9, COL11A1, COL3A1, CXCL12 and THBS2 was established. The area under the ROC curve reached 0.839 in predicting liver and lung metastasis, using our clinical samples as the validation dataset. CONCLUSIONS: Seven key genes capable of predicting liver and lung metastasis of colorectal cancer were identified, which provides clues for exploring the mechanism of selecting target organs during the metastatic process in CRC and inspires the researches for new potential targets for therapy to inhibit metastasis.

Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner.

Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays an important pathogenic role. However, the current drugs for IBD treatment are far from optimal. Previous researches indicated that parthenolide (PTL) had not only anti-cancer properties but also strong anti-inflammatory activities. Rationale: To investigate the protective effect of PTL on colon inflammation and demonstrate the underlying gut microbiota-dependent mechanism. Methods: Colon inflammation severity in mouse model was measured by body weight change, mortality, colon length, disease activity index (DAI) score, H&E staining and colonoscopy evaluation. Gut microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA sequencing and targeted metabolomics. Luminex cytokine microarray and Enzyme-linked immunosorbent assay (ELISA) were conducted to measure the colon cytokines profile. The frequency of immune cells in lamina propria (LP) and spleen were phenotyped by flow cytometry. Results: The PTL-treated mice showed significantly relieved colon inflammation, as evidenced by a reduction in body weight loss, survival rate, shortening of colon length, DAI score, histology score and colonoscopy score. Notably, when the gut microbiota was depleted using antibiotic cocktails, the protective effect of PTL on colon inflammation disappeared. PTL treatment downregulated the level of proinflammatory cytokines, including IL-1ß, TNF-α, IL-6, and IL-17A and upregulated the immunosuppressive cytokine IL-10 in colon tissue. 16S rRNA sequencing indicated that PTL-treated mice exhibited much more abundant gut microbial diversity and flora composition. Targeted metabolomics analysis manifested the increased SCFAs production in PTL-treated mice. Additionally, PTL administration selectively upregulated the frequency of colonic regulatory T (Treg) cells as well as downregulated the ratio of colonic T helper type 17 (Th17) cells, improving the Treg/Th17 balance to maintain intestinal homeostasis. Gut microbiota depletion and fecal microbiota transplantation (FMT) was performed to confirm this gut microbiota-dependent mechanism. Conclusions: PTL ameliorated colon inflammation in a gut microbiota-dependent manner. The underlying protective mechanism was associated with the improved Treg/Th17 balance in intestinal mucosa mediated through the increased microbiota-derived SCFAs production. Collectively, our results demonstrated the role of PTL as a potential gut microbiota modulator to prevent and treat IBD.