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Previous reports have suggested that some probiotics inhibit tumorigenesis and cancer progression. However, the molecules involved have not yet been identified. Here, we show that the culture supernatant of Lactobacillus casei ATCC334 has a strong tumour-suppressive effect on colon cancer cells. Using mass spectrometry, we identify ferrichrome as a tumour-suppressive molecule produced by L. casei ATCC334. The tumour-suppressive effect of ferrichrome is greater than that of cisplatin and 5-fluorouracil, and ferrichrome has less of an effect on non-cancerous intestinal cells than either of those agents. A transcriptome analysis reveals that ferrichrome treatment induces apoptosis, which is mediated by the activation of c-jun N-terminal kinase (JNK). Western blotting indicates that the induction of apoptosis by ferrichrome is reduced by the inhibition of the JNK signalling pathway. This we demonstrate that probiotic-derived ferrichrome exerts a tumour-suppressive effect via the JNK signalling pathway.

BackgroundPancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers.MethodsThe ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction.ResultsThe expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5–20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022).ConclusionsThe level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4006-5) contains supplementary material, which is available to authorized users.

Background & Aims Little is known about the genetic factors that contribute to development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS, via inactivation of tumor suppressor pathways. We investigated whether individuals with multiple SSAs carry germline loss-of-function mutations (nonsense and splice-site) in genes that regulate OIS – the p16–Rb and ATM–ATR DNA damage response pathways. Methods Through bioinformatic analysis of the literature, we identified a set of genes that function at main nodes of the p16–Rb and ATM–ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated individuals with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 individuals, matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms. Results We identified mutations in genes that regulate senescence (ATM, PIF1, TELO2, XAF1, and RBL1) in 5/20 individuals with multiple SSAs (odds ratio [OR]=3.0; 95% confidence interval [CI], 0.9–8.9; P=.04). In 2 individuals, we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (OR=460; 95% CI, 23.1– 16384; P=6.8×10−5). In knockdown experiments with pancreatic duct cells exposed to ultraviolet light, RNF43 appeared to function as a regulator of ATM–ATR DNA damage response. Conclusions We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs. We identified RNF43 as a regulator of the DNA damage response, and associated nonsense variants in this gene with high risk of developing SSAs.