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Background and Objective Serine hydroxymethyltransferase 2 (SHMT2) functions as a key enzyme in serine/glycine biosynthesis and one-carbon metabolism. Recent studies have shown that SHMT2 participated in tumor growth and progression in a variety of cancer types. The objective of the present study is to explore the expression of SHMT2 and evaluate its prognostic value in patients with intrahepatic cholangiocarcinoma (iCCA). Patients and Methods We retrospectively investigated the expression of SHMT2 in 100 primary iCCA samples through immunohistochemical (IHC) staining on a tissue array. Results High SHMT2 expression was found in 52 of the 100 specimens. The results indicated that SHMT2 level was upregulated compared to adjacent nontumor intrahepatic bile duct tissue. Furthermore, SHMT2 level was closely associated with tumor T stage (P = 0.017) and tumor TNM stage (P = 0.041) in patients with iCCA, but not with age, gender, tumor size, tumor number, pathological grade, vascular invasion, or N stage. Moreover, Kaplan-Meier analysis suggested that patients with lower SHMT2 level have longer survival rate than those with high expression (45.8 vs 23.1%, P = 0.030). Additionally, the multivariate analysis model indicated SHMT2 is an independent adverse prognosticator in iCCA. Conclusion High SHMT2 level was correlated with poorer overall survival in patients with iCCA. SHMT2 was proved to be a powerful and independent prognostic factor and a potential therapeutic target for patients with iCCA.

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Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of Bifidobacterium, a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as Desulfovibrio, Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.

Activation of p53 may induce apoptosis or cellular senescence in stressed cells. We here report that epidermal growth factor receptor (EGFR) is downregulated by p53 activation in a subset of cancer cell lines, and this EGFR downregulation mediates cellular senescence caused by p53 activation. EGFR confers resistance to senescence by sustaining the ERK signaling. DYRK1A (dual-specificity tyrosine-phosphorylated and tyrosine-regulated kinase 1A), an EGFR-stabilizing kinase, is downregulated by p53 and, when ectopically expressed, can attenuate p53 activation-induced EGFR reduction and cellular senescence. We further showed that the increased degradation of DYRK1A caused by p53 activation was mediated by MDM2. MDM2 was found to physically interact with and ubiquitinate DYRK1A, ultimately leading to its proteosomal degradation. Importantly, administration of Nutlin-3a, which disrupts the binding of MDM2 to p53, but not that of MDM2 to DYRK1A, reduced the levels of DYRK1A and EGFR, induced senescence, and inhibited growth of tumor xenografts formed by U87 glioblastoma cells. Ectopic expression of EGFR in tumor xenografts attenuated senescence and tumor reduction caused by Nultin-3a. Our findings thus established a novel link between p53 and EGFR and may have implications in p53 activation-based therapies.