Single-step genomic prediction of fruit-quality traits using phenotypic records of non-genotyped relatives in citrus.

The potential of genomic selection (GS) is currently being evaluated for fruit breeding. GS models are usually constructed based on information from both the genotype and phenotype of population. However, information from phenotyped but non-genotyped relatives can also be used to construct GS models, and this additional information can improve their accuracy.

A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors.

Background: Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs.

Runx3 regulates folliculogenesis and steroidogenesis in granulosa cells of immature mice.

We previously demonstrated that female Runx3 knockout (Runx3) mice were anovulatory and their uteri were atrophic and that Runx3 mRNA was expressed in granulosa cells. To clarify how Runx3 regulates folliculogenesis and ovulation, we examine the effects of Runx3 knockout on the gene expression of growth factors associated with folliculogenesis and enzymes associated with steroidogenesis. In Runx3 mouse ovaries, the numbers of primary and antral follicles were lower than those in wild-type (wt) mice at 3 weeks of age, indicating that the loss of Runx3 affects folliculogenesis.

Predicting segregation of multiple fruit-quality traits by using accumulated phenotypic records in citrus breeding.

In the breeding of citrus (Citrus spp.), suitable fruit quality is essential for consumer acceptance of new cultivars. To identify parental combinations producing F1 progeny with fruit-quality traits exceeding certain selection criteria, we developed a simple and practical method for predicting multiple-trait segregation in an F1 progeny population.

Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models.

Background: Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells.

Runx3 transcription factor regulates ovarian functions and ovulation in female mice.

We previously demonstrated that the Runx3 transcription factor is expressed in the hypothalami, pituitaries, and ovaries of mice, and that Runx3 knockout (Runx3) mice are anovulatory and their uteri are atrophic. Runx3 mRNA expression was detected in the granulosa cells of ovarian follicles, and in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). In the present study, we examined the effects of Runx3 knockout on the gene expression of enzymes associated with steroidogenesis.

Proteasome activity is required for the initiation of precancerous pancreatic lesions.

Proteasome activity is significantly increased in advanced cancers, but its role in cancer initiation is not clear, due to difficulties in monitoring this process in vivo. We established a line of transgenic mice that carried the ZsGreen-degron(ODC) (Gdeg) proteasome reporter to monitor the proteasome activity. In combination with Pdx-1-Cre;LSL-Kras(G12D) model, proteasome activity was investigated in the initiation of precancerous pancreatic lesions (PanINs).

CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells.

Identification and purification of cancer stem cells (CSCs) lead to the discovery of novel therapeutic targets; however, there has been no study on isolation of the CSC population among pancreatic neuroendocrine tumors (pNETs). This study aimed to identify pNET CSCs and to characterize a therapeutic candidate for pNET CSCs. We identified CSCs by aldehyde dehydrogenase (ALDH) activity in pNET clinical specimens and cell lines.

Activin A regulates growth of gastro-intestinal epithelial cells by mediating epithelial-mesenchymal interaction.

The importance of epithelial-mesenchymal interaction on the development of gastro-intestinal (GI) organs has been repeatedly reported, but its molecular mechanism has not been fully understood though several factors including hepatocyte growth factor and endothelin-3 have been shown to mediate it. Activins have been demonstrated to play important roles in the regulation of organogenesis in vertebrates, but their roles in the regulation of growth and differentiation of GI organs remain to be solved. In the present study, we examined expression of activins in developing rat GI tract, and found that inhibin bA encoding activin A was specifically expressed by GI mesenchymes, while inhibin bB encoding activin B was expressed by both epithelial and mesenchymal components.

CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors.

Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49f(high) cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49f(low) cells did not when subcutaneously injected into immunodeficient mice.

A patient-derived xenograft mouse model generated from primary cultured cells recapitulates patient tumors phenotypically and genetically.

Background: Preclinical trials of cancer therapeutics require both in vitro and in vivo evaluations. Recently, a patient-derived xenograft model in immunodeficient mice has been reported as a valuable in vivo evaluation system. In our current study, we aimed to establish a more efficient and accurate system for preclinical trials by generating primary cancer cells from patients and performing xenograft transfers of these cells into mice.

Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity.

The transcription factor RUNX3 functions as a tumor suppressor in the gastrointestinal epithelium, where its loss is an early event in carcinogenesis. While RUNX3 acts concurrently as a mediator of TGF-β signaling and an antagonist of Wnt, the cellular changes that follow its loss and their contribution to tumorigenicity are not fully understood. Here, we report that the loss of Runx3 in gastric epithelial cells results in spontaneous epithelial-mesenchymal transition (EMT).

Runx3 expression and its roles in mouse endometrial cells.

Runx3 is a transcription factor that belongs to the Runx family. We studied the localization of Runx3 mRNA in the mouse uterus, and its function in the mouse endometrium using Runx3 knockout (Runx3(-/-)) mice. Runx3 mRNA was detected in the endometrial luminal epithelial cells, glandular epithelial cells and stromal cells below the epithelial cell layer on the luminal side.

Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer.

Background: Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGC, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGC. Genetic alterations of TP53 are also frequently found in DGC.

CD133 is a marker of gland-forming cells in gastric tumors and Sox17 is involved in its regulation.

CD133 is a universal marker of tissue stem/progenitor cells as well as cancer stem cells, but its physiological significance remains to be elucidated. Here we examined the relationship between expression of CD133 and features of gastric epithelial cells, and found that CD133-positive (CD133[+]) tumor cell lines formed well-differentiated tumors while CD133-negative (CD133[-]) lines formed poorly differentiated ones when subcutaneously injected into nude mice. We also found that CD133(+) and CD133(-) cell populations co-existed in some cell lines.

Loss of Runx3 is a key event in inducing precancerous state of the stomach.

Background & Aims: RUNX3 is a tumor suppressor originally identified in gastric cancer. The mutation R122C in RUNX3 promotes gastric carcinogenesis by unclear mechanisms. We investigated how Runx3-deficiency contributes to distinct changes in the gastric epithelium that precede neoplasia.

Loss of E-cadherin in mouse gastric epithelial cells induces signet ring-like cells, a possible precursor lesion of diffuse gastric cancer.

Alterations in the E-cadherin gene are associated with sporadic and hereditary diffuse-type gastric cancer. To determine how the loss of function of E-cadherin affects gastric epithelial cell phenotypes, we generated transgenic mice using the Cre-loxP system in which the E-cadherin gene is specifically knocked out in the parietal cell lineage. In the transgenic mice, expression of E-cadherin was lost or reduced in proton pump-expressing parietal cells, which became round in shape and were pushed out of the glands to accumulate in the stromal area.

miR-212 is downregulated and suppresses methyl-CpG-binding protein MeCP2 in human gastric cancer.

To clarify the role of micro (mi) RNAs in gastric carcinogenesis, we studied the expression and function of miRNAs in gastric carcinoma (GC) cells. Initially, we performed microarray analysis using total RNA from 3 human GC cell lines and noncancerous gastric tissue. Among the downregulated miRNAs in GC cells, miR-212 expression was decreased in all 8 GC cell lines examined and a significant decrease of miR-212 expression in human primary GC tissues was also observed in 6 of 11 cases.

Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells.

Background & Aims: The transcription factor RUNX3 is a gastric tumor suppressor. Tumorigenic Runx3(-/-) gastric epithelial cells attach weakly to each other, compared with nontumorigenic Runx3(+/+) cells. We aimed to identify RUNX3 target genes that promote cell-cell contact to improve our understanding of RUNX3's role in suppressing gastric carcinogenesis.

RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis.

In intestinal epithelial cells, inactivation of APC, a key regulator of the Wnt pathway, activates beta-catenin to initiate tumorigenesis. However, other alterations may be involved in intestinal tumorigenesis. Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex with beta-catenin/TCF4 and attenuates Wnt signaling activity.

In vitro differentiation of Runx3-/- p53-/- gastric epithelial cells into intestinal type cells.

We have reported that a lack of RUNX3 function is causally associated with gastric carcinogenesis. We have also presented evidence that loss of Runx3 may be related to the genesis of intestinal metaplasia because expression of RUNX3 is reduced in some intestinal metaplasias, and some Runx3(-/-)p53(-/-) gastric epithelial cells differentiate into intestinal type cells in vivo. Recently several reports have indicated that blood cells play important roles in the gastric carcinogenesis.

Loss of Runx3 affects ovulation and estrogen-induced endometrial cell proliferation in female mice.

Runx3 is a transcription factor that belongs to the Runx family. We studied the function of Runx3 in the mouse ovary and uterus using the Runx3 knockout (Runx3(-/-)) mouse. Ovaries were collected from 8-week-old wild type (wt) and Runx3(-/-) mice.

Developmentally regulated expression of matrix metalloproteinases during fetal rat colon morphogenesis.

To investigate the role of matrix metalloproteinases (MMPs) during gastrointestinal tract development, the expression of gelatinases (MMP-2 and MMP-9) was investigated during fetal rat colon morphogenesis. Fetal rat colons were separated into epithelial and mesenchymal fractions without cross contamination using a chelating agent and a dissecting microscope. Gelatinase activity measured using fluorescently labeled gelatin was higher in the mesenchymal than in the epithelial fraction; the developmental profile revealed that, in both fractions, gelatinase activity was enhanced during colon morphogenesis.

Human G(salpha) mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle.

Pseudohypoparathyroidism type Ia (PHP-Ia) results from the loss of one allele of G(salpha), causing resistance to parathyroid hormone and other hormones that transduce signals via G(s). Most G(salpha)mutations cause the complete loss of protein expression, but some cause loss of function only, and these have provided valuable insights into the normal function of G proteins. Here we have analyzed a mutant G(salpha) (alphas-AVDT) harboring AVDT amino acid repeats within its GDP/GTP binding site, which was identified in unique patients with PHP-Ia accompanied by neonatal diarrhea.

IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells.

Invasion and metastases of cancer cells are the main causes of treatment failure in cancer. IQ motif-containing GTPase activating protein 1 (IQGAP1), plays pivotal roles in intercellular adhesion, migration, invasion and metastases in various cancer cells. However, the role of another family member, IQGAP2, in carcinogenesis remains unknown.