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1:CAS:528:DyaK28XntVynur8%3D. 10.1128/MCB.16.12.6644 12 Zavros Y, Eaton KA, Kang W, Rathinavelu S, Katukuri V, Kao JY, Samuelson LC, Merchant JL. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. 1:CAS:528:DyaK3MXkt1eis7k%3D 10 Merchant JL, Shiotani A, Mortensen ER, Shumaker DK, Abraczinskas DR. 10.1038/s41575-022-00591-0 18 Ding L, Chakrabarti J, Sheriff S, Li Q, Thi Hong HN, Sontz RA, Mendoza ZE, Schreibeis A, Helmrath MA, Zavros Y, Merchant JL. Toll-like Receptor 9 pathway mediates Schlafen+-MDSC polarization during Helicobacter-induced gastric metaplasias. As a woman of color, and as an academic gastroenterologist specializing in molecular mechanisms of gastric and colon cancer, I recently decided to take on a leadership role while still juggling a working molecular biology laboratory and maintaining a small clinical practice. [Extracted from the article]

The absence of a mentor or mentors is a major contribution to the "leaky academic pipeline", leading trainees, and early-career and even mid-tier investigators to "give up", despite outstanding training in the various biomedical disciplines. Since physicians are trained in human pathophysiology, MD-driven research typically involves fundamental, translational, or clinical questions related to disease pathogenesis or clinical applications. With that, it is my hope that one can achieve a productive, creative, and personally satisfying academic biomedical career and become part of the solution to the erosion of the impact of physician-scientists on clinical practice. [Extracted from the article]

Background: Intestinal metaplasia (IM) is a gastric cancer precursor lesion (GCPL) and an extremely high risk factor for progression to gastric cancer (GC). Clinical guidelines recommend that patients with extensive IM undergo a gastroscopy every 3 years. However, protein biomarkers that indicate a transition from IM to GC are lacking. Our group recently identified an interferon-alpha (IFNα)-responsive gene, Schlafen 4 (Slfn4), in immune cells that correlates with metaplastic changes in Helicobacter-infected mice. We therefore tested the hypothesis that a human homolog of Slfn4, namely, Schlafen 5 (SLFN5), correlates with progression of GCPL to GC.Methods: Jurkat T-lymphoid and HL-60 myeloid cell lines were treated with IFNα, and SLFN5 mRNA was quantified by quantitative PCR. SLFN5 protein expression in the inflamed gastric mucosa was co-localized to specific immune cell types by immunohistochemistry using CD20, CD2, and MAC2 antibodies. SLFN5 expression was also determined by immunohistochemistry in formalin-fixed paraffin-embedded samples from individuals with non-atrophic gastritis, atrophic gastritis, complete IM, incomplete IM, and GC, respectively.Results: The IFNα treatment of Jurkat and HL-60 cells induced SLFN5 mRNA. SLFN5 protein was expressed mainly by T lymphocytes in inflamed gastric mucosa. The highest level of SLFN5 expression was observed in patients with IM that progressed to GC. Receiver operating characteristic curves demonstrated that correlating SLFN5 expression with the histologic diagnosis of IM significantly increased the probability of identifying patients who may progress to GC.Conclusion: In this study population, elevated SLFN5 protein expression in patients with IM correlated with progression to GC. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Alterations in 5-hydroxytryptamine (5-HT) signaling have been implicated as a factor contributing to the altered bowel habit of irritable bowel syndrome (IBS) patients. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in enterochromaffin cell 5-HT biosynthesis. We hypothesized that genetic variants affecting TPH1 gene expression might alter intestinal 5-HT bioavailability and subsequently the propensity for distinct bowel habit subtypes in IBS. In this study, we assessed the only common TPH1 proximal promoter variant (−347C/A; rs7130929) and its association with bowel habit predominance in IBS.METHODS:Electrophoretic mobility shift assays were performed to assess whether the −347C/A-allele variant affects the DNA binding of nuclear factors. Genotype distribution was determined for 422 IBS patients subtyped using the Rome III criteria and for 495 healthy controls recruited from two university medical centers. Association with bowel habit was tested using a multinomial logistic regression model controlling for race, anxiety, depression, and study site.RESULTS:Early growth response factor 1 (EGR-1) bound with higher affinity to a site comprising the minor A-allele of single-nucleotide polymorphism (SNP) −347C/A. TPH1 genotype frequencies did not differ between IBS patients and controls overall. The CC genotype was more prevalent in the IBS-D subtype (47%) than in the IBS-C (25%) and IBS-M (37%) subtypes (P=0.039) after adjusting for race and other covariates. Colonic biopsies from a small cohort of IBS patients from one center were tested for higher TPH1 mRNA expression in samples with CC compared with the CA genotype, but the results did not reach statistical significance.CONCLUSIONS:The TPH1 promoter SNP −347C/A differentially binds EGR-1 and correlates with IBS bowel habit subtypes and possibly colonic TPH1 expression consistent with its role in modulating intestinal 5-HT signaling. [ABSTRACT FROM AUTHOR]

Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1. [ABSTRACT FROM AUTHOR]

ZNF148 (ZBP-89, Zfp148) is a multifunctional transcription factor expressed at low levels in most tissues. When overexpressed in gastrointestinal cancer cell lines, ZNF148 inhibits cellular proliferation and induces apoptosis. We sought to determine whether intestinal ZNF148 overexpression would abrogate adenoma development in the ApcMin/+ mouse, i.e., whether ZNF148 is a tumor suppressor. The 13-kb villin promoter was spliced upstream of the ZNF148 cDNA to generate transgenic villin-ZNF148 (ZNF148TgVZ) mice. Intestinal mucosal ZNF148 expression was elevated in four of five ZNF148TgVZ lineages and correlated with increased caspase-3 expression and activation. In addition, DNA fragmentation was increased in ZNF148TgVZ mice relative to wild-type littermates. These results suggested that increased intestinal ZNF148 expression induces apoptosis. ZNF148TgVZ mice were crossed with ApcMin/+ mice to assess the biological significance of intestinal ZNF148 overexpression. The presence of the ZNF148TgVZ allele in ApcMin/+ mice correlated with reduced gastrointestinal bleeding at 5 weeks, a 50% reduction in adenoma burden at 20–22 weeks, and prolonged survival (median survival of 33.5 days vs. 21.5 days), relative to nontransgenic littermates. These data suggest that enhanced ZNF148 expression activates intestinal apoptosis and thereby mitigates disease burden in ApcMin/+ mice. They also suggest that ZNF148 is a therapeutic target to inhibit colon cancer development. [ABSTRACT FROM AUTHOR]

The current study tests the hypothesis that chronic atrophic gastritis from hypochlorhydria in the gastrin-deficient mouse predisposes the stomach to gastric cancer. Gross morphology and histology of 12-month-old wild-type (WT), gastrin-deficient (G-/-) and somatostatin-deficient (SOM-/-) mice were examined. Parietal and G cells, Ki67, TUNEL, villin and MUC2 expression were analysed by immunohistochemistry. RUNX3 and STAT3 expression was analysed by Western blot. Anchorage-independent growth was determined by cell cluster formation in soft agar. Compared to the WT and SOM-/-mice, hypochlorhydric G-/-mice developed parietal cell atrophy, significant antral inflammation and intestinal metaplasia. Areas of metaplasia within the G-/-mouse stomach showed decreased RUNX3 expression with elevated MUC2 and villin expression. Cells isolated from the tumor grew in soft agar. However, the cells isolated from WT, nontransformed G-/-and SOM-/-gastric tissue did not form colonies in soft agar. Consistent with elevated antral proliferation, tumor tissue isolated from the G-/-mice showed elevated phosphorylated STAT3 expression. We then examined the mechanism by which STAT3 was constitutively expressed in the tumor tissue of the G-/-mice. We found that IFN?expression was also significantly higher in the tumor tissue of G-/-mice compared to WT and SOM-/-animals. To determine whether STAT3 was regulated by IFN?, MKN45 cells were cocultured with IFN?or gastrin. IFN?significantly stimulated phosphorylation of STAT3 in the MKN45 cell line, but not gastrin. Therefore, we show here that in the hypochlorhydric mouse stomach, the chronic gastritis, atrophy, metaplasia, dysplasia paradigm can be recapitulated in mice. Moreover, neoplastic transformation of the antral gastric mucosa does not require gastrin.Oncogene (2005) 24, 2354-2366. doi:10.1038/sj.onc.1208407 Published online 14 February 2005 [ABSTRACT FROM AUTHOR]

BACKGROUND: The absence of sonic hedgehog (Shh) correlates with the development of intestinal metaplasia (IM) suggesting the possibility of an association between Shh expression and neoplastic transformation.AIM: To examine Shh expression in the noncancerous mucosa of patients with gastric cancer and compare it to Shh expression inHelicobater pylori-infected and uninfected controls. We also assessed the relationship between the type of IM and Shh expression.METHODS: Fifty-three patients with endoscopic mucosal resection (EMR) for early gastric cancer and 48 sex- and age-matched controls were studied. Two specimens each were obtained from the greater and lesser curves of the corpus and from the greater curve of the antrum. The histopathological grading used was the updated Sydney System. IM was categorized by staining with Alcian blue/high iron diamine. Expression of Shh was evaluated by immunostaining.RESULTS: The Shh immunostaining in the corpus lesser curve significantly correlated with the scores of atrophy and IM. Shh staining in the antrum was significantly higher inH. pylori-negative controls than those inH. pylori-positive controls as well as in patients without IM compared to those with IM (p<0.001). The Shh staining in the corpus lesser curve decreased inH. pylori-negative controls, -positive controls and the cancer group respectively (p= 0.003), and was significantly higher (p= 0.006) in the complete IM group compared to those in the incomplete IM group.CONCLUSIONS: Loss of Shh is an early change that occurs in the mucosa prior to neoplastic transformation. Its loss correlates with the type of IM and may play a role in carcinogenesis.(Am J Gastroenterol 2005;100:581–587) [ABSTRACT FROM AUTHOR]