Correction:Kinome-wide analysis of the effect of statins in colorectal cancer (British Journal of Cancer, (2021), 124, 12, (1978-1987), 10.1038/s41416-021-01318-9)

The original version of this article unfortunately contained a mistake in an author name. Lucas J. A. C. Hawinkels should be Lukas J. A. C. Hawinkels. The authors apologize for the oversight. The original article has been corrected

Kinome-wide analysis of the effect of statins in colorectal cancer

Background Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. Methods CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. Results Kinome analysis can distinguish between non-specific, toxic effects caused by 10 mu M of Lovastatin and specific effects on cell signalling caused by 2 mu M Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. Conclusions Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC

The role of EZH2 and DNA methylation in the silencing of the tumour suppressor RUNX3 in colorectal cancer

In gastric cancer, a new epigenetic mechanism of tumour suppressor loss has been suggested where the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is responsible for loss of expression of RUNX3. This is consistent with EZH2 upregulation in multiple cancer types being associated with poor prognosis. We investigated whether EZH2 influences the expression of RUNX3 in colorectal cancer (CRC) and whether this is independent of methylation. We determined protein and messenger RNA (mRNA) levels of EZH2 and RUNX3 and assessed RUNX3 methylation with methylation-specific polymerase chain reaction using 72 human CRCs and 8 CRC cell lines. We assessed the effect of efficient RNA interference-mediated knockdown of EZH2 on RUNX3 levels, cell viability and H3K27 trimethylation of the RUNX3 promoter using chromatin immunoprecipitation. Despite higher levels of EZH2 and lower levels of RUNX3 in CRC specimens in general, no inverse correlation between EZH2 and RUNX3 in paired samples was found arguing against a major role for histone methylation in silencing RUNX3 in CRC. Conversely, downregulation of RUNX3 mRNA in the same tumours was associated with RUNX3 DNA methylation (P < 0.05). In cell lines, knockdown of EZH2 removed the repressive chromatin marks from RUNX3 but did not result in RUNX3 re-expression. However, it prevented the re-silencing of RUNX3 after the removal of demethylating agents. In conclusion, DNA methylation is primarily responsible for the transcriptional silencing of RUNX3 in CRC, but EZH2 and histone methylation are necessary for its methylation-dependent re-silencing after the removal of demethylating agents. These results would predict that inhibitors of EZH2 and histone methylation would enhance the effects of demethylating agents in cancer therapy

Epithelial endoplasmic reticulum stress orchestrates a protective IgA response.

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.Wellcome Trust Senior Investigator Award 106260/Z/14/Z HORIZON2020/European Research Council Consolidator Grant 64888

Intestinal Tumorigenesis Is Not Affected by Progesterone Signaling in Rodent Models

Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the ApcMin/+ mouse, a model for spontaneous intestinal polyposis. PRKO-ApcMin/+mice exhibited no change in polyp number, size or localization compared to ApcMin/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis

The concerted action of oncogenic driver mutations directs global translation in intestinal epithelial cells

Oncogenic transformation of colorectal cancer cells is driven by a set of mutations that cause aberrant signaling of growth factor–receptor pathways. Using organoids, we demonstrate that the most frequent driver mutations in APC, KRAS, SMAD4, and TP53 are enhancers of the global mRNA translational capacity, which is linked to intestinal cell growth in an mTOR-dependent manner

Use of Rome II criteria in childhood defecation disorders: Applicability in clinical and research practice

Objectives To evaluate the prevalence of pediatric functional gastrointestinal disorders with the use of the Rome II criteria and to compare these data with the classic Iowa criteria. Study design Patients recorded defecation and encopresis frequency. A standard history was taken and a physical examination including a rectal examination was done. The prevalence of both criteria was assessed and compared. Results One hundred ninety-eight consecutive patients (age, 0.66 to 15.76 years; 131 male subjects) were included. According to the Rome II criteria, 64%, 18%. and 21% of patients fulfilled the criteria for functional constipation, functional fecal retention, and functional nonretentive fecal soiling, respectively. Using the classic criteria, 74% and 18% of patients fulfilled the criteria for pediatric constipation and solitary encopresis, respectively; 16% of the patients fulfilling the pediatric constipation criteria were not recognized by the Rome II constipation criteria. Fair agreement was found between functional nonretentive fecal soiling and solitary encopresis. Encopresis was present in 79% of constipated children. Conclusions The Rome criteria are restrictive and exclude several children with constipation. We recommend including encopresis and rectal digital examination and excluding arbitrary age limits and retentive behavior in the revision of the Rome criteri