Regulation Of Epithelial Cell Differentiation Research Articles

Selective signatures in composite MONTANA TROPICAL beef cattle reveal potential genomic regions for tropical adaptation.

Genomic regions related to tropical adaptability are of paramount importance for animal breeding nowadays, especially in the context of global climate change. Moreover, understanding the genomic architecture of these regions may be very relevant for aiding breeding programs in choosing the best selection scheme for tropical adaptation and/or implementing a crossbreeding scheme. The composite MONTANA TROPICAL® population was developed by crossing cattle of four different biological types to improve production in harsh environments. Pedigree and genotype data (51962 SNPs) from 3215 MONTANA TROPICAL® cattle were used to i) characterize the population structure; ii) identify signatures of selection with complementary approaches, i.e. Integrated Haplotype Score (iHS) and Runs of Homozygosity (ROH); and iii) understand genes and traits related to each selected region. The population structure based on principal components had a weak relationship with the genetic contribution of the different biological types. Clustering analyses (ADMIXTURE) showed different clusters according to the number of generations within the composite population. Considering results of both selection signatures approaches, we identified only one consensus region on chromosome 20 (35399405-40329703 bp). Genes in this region are related to immune function, regulation of epithelial cell differentiation, and cell response to ionizing radiation. This region harbors the slick locus which is related to slick hair and epidermis anatomy, both of which are related to heat stress adaptation. Also, QTLs in this region were related to feed intake, milk yield, mastitis, reproduction, and slick hair coat. The signatures of selection detected here arose in a few generations after crossbreeding between contrasting breeds. Therefore, it shows how important this genomic region may be for these animals to thrive in tropical conditions. Further investigations on sequencing this region can identify candidate genes for animal breeding and/or gene editing to tackle the challenges of climate change.

Abstract 7305: Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium

Abstract Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. CRC usually develops from adenomas (CRC precursors) after a long latency period. Prevention is crucial in reducing CRC incidence and progression to cancer. Among several prevention options, calcium has been a widely considered chemo-preventative agent. Aims: Calcium plays a vital role in the regulation of epithelial cell differentiation, which is essential for epithelial growth control. Epidemiological studies have demonstrated that adequate calcium intake is crucial for protection against colonic polyp formation and colorectal cancer. However, recent interventional trials with calcium have had only modest and mixed results, and the question is how to improve efficacy. One potential strategy is to use calcium in combination with additional minerals and trace elements. Results: Our preclinical studies employing monolayer cultures with CRC cell lines and colon organoids cultures from colon polyps have shown that a calcium-rich mineral combination derived from fossilized red algae (Aquamin) is more effective than calcium alone in inducing differentiation, suppressing growth and upregulation of calcium-sensing receptor. When colonic adenomas in culture were subjected to differential proteomic analysis, Aquamin upregulated several proteins involved in proliferation suppression, DNA mismatch repair and inducing differentiation, and apoptosis. Two long-term mouse studies have demonstrated that Aquamin is more effective in suppressing polyp & CRC incidence compared to calcium alone. Based on these findings, we conducted a 90-day FDA-approved trial (a pilot study with ten subjects per arm) comparing the two interventions in human subjects at risk for CRC. Results showed that Aquamin treatment reduced proliferation and increased cell differentiation observed by immunohistochemistry. Proteomic analysis also revealed that the minerals upregulated several proteins related to growth suppression, inducing differentiation and those contributing to cell-cell and cell-matrix adhesion functions and downregulated proteins involved in proliferation and nucleic acid metabolism. Conclusion: These results provide convincing evidence that a multi-mineral combination derived from red algae can provide benefits in preventing CRC that are not seen with calcium alone. Further studies, such as a polyp-prevention trial in human subjects, are warranted to advance these CRC prevention efforts. Citation Format: Isabelle Harber, Shannon McClintock, James Varani, Muhammad N. Aslam. Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7305.

Regulation of epithelial cell differentiation by the Ubiquitous expressed transcript isoform 1 in ulcerative colitis.

Mucosal healing has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Healing of mucosal wounds involves epithelial cell proliferation and differentiation, and Y-box transcription factor ZONAB has recently been identified as the key modulator of intestinal epithelial restitution. We studied the characteristics of UXT-V1 expression in UC patients using immunohistochemistry and qPCR. The functional role of UXT-V1 in the colonic epithelium was investigated using lentivirus-mediated shRNA in vitro and ex vivo. Through endogenous Co-immunoprecipitation and LC-MS/MS, we identified ZONAB as a UXT-V1-interactive protein. Herein, we report that UXT-V1 promotes differentiation of intestinal epithelial cells by regulating the nuclear translocation of ZONAB. UXT-V1 was upregulated in the intestinal epithelia of UC patients compared with that of healthy controls. Knocking down UXT-V1 in NCM-460 cells led to the enrichment of pathways associated with proliferation and differentiation. Furthermore, the absence of UXT-V1 in cultured intestinal epithelial cells and colonic organoids inhibited differentiation to the goblet cell phenotype. Mechanistically, the loss of UXT-V1 in the intestinal epithelial cells allowed nuclear translocation of ZONAB, wherein it regulated the transcription of differentiation-related genes, including AML1 and KLF4. Taken together, our study reveals a potential role of UXT-V1 in regulating epithelial cell differentiation, proving a molecular basis for mucosal healing in UC.

Comparison of gene expression profiles in healthy individuals and people with lung cancer using the meta-analysis method.

Advances in the early detection of cancer are a way for treatment to be effective. However, due to the inability of early diagnose and treatment for lung cancer, the death rate of this type of cancer is high. Usually, a high percentage of patients are diagnosed at a stage where they are not able to receive treatment. The purpose of this study was the comparison of gene expression profiles in healthy individuals and people with lung cancer. The raw data sets GSE10072 and GSE19804 were taken from the GEO online database. Differentially expressed genes (DEGs) were identified between the non-tumor and tumor tissue samples using a meta-analysis investigation. Then, gene ontology and biological pathway analysis were performed with the Enrichr online server. The protein-protein interaction network of genes obtained from the meta-analysis investigation was drawn and analyzed using the String Online database and Cytoscape Software. Meta-analysis results showed a total of 515 differentially expressed genes. The results of the functional processes and biological pathway revealed that differentially expressed genes were mainly enriched in positive regulation of cell differentiation, regulation of cell population proliferation, regulation of epithelial cell differentiation, positive regulation of epithelial cell proliferation, response to growth factor, defense response to the tumor cell, cellular response to UV, regulation of cell cycle process, cell adhesion molecules, PPAR signaling pathway, TNF signaling pathway, ECM-receptor interaction, p53 signaling pathway, PI3K-Akt signaling pathway, and Cell cycle. Finally, key genes related to lung cancer, including IL6, MMP9, VWF, PECAM1, FOS, and CAV1 were identified. In conclusion, comparisons of gene expression profiles in healthy individuals and people with lung cancer identified some key genes that can act as lung cancer markers and can be used to predict new findings on cancer. These genes can play an important role in diagnosis and early cancer treatment.

Exploring Relevant mRNAs and miRNAs in Injured Urethral Tissues of Rats with High-Throughput Sequencing.

Acute urethral injuries caused by urethral endoscopy and other mechanical injuries are the main reasons for secondary infection and late urethral stricture. However, there are no studies to explore the transcriptomic changes in urethral injury and the molecular mechanism of urethral injury, which is important for the treatment and cure of urethral injury. Therefore, we used RNA-seq and sRNA-seq profiles from normal and injured urethral tissues to identify and characterize differentially expressed mRNAs and miRNAs. In total, we found 166 differentially expressed mRNAs, of which 69 were upregulated, and 97 were downregulated in injured urethral tissues. The differentially expressed mRNAs were mainly involved in the positive regulation of epithelial cell differentiation, focal adhesion, cell adhesion molecules, protein activation cascade, complement activation, complement and coagulation cascades, and chemokine-mediated signaling pathway. Additionally, we found six upregulated and four downregulated miRNAs, respectively, in the injured urethral tissues. Notably, their target genes were involved in the vascular endothelial growth factor receptor 2 binding, PI3k-Akt signaling pathway, and Notch signaling pathway. In summary, our results suggest that the cell damage response induced by mechanical injury activates the pathological immune response in a variety of ways in injured urethral tissues.

Potential Impact of Cancer Susceptibility Genes on Lung Cancer Metastasis.

Background Studies of prognosis-related molecular markers are an important tool to uncover the mechanism of tumour metastasis. Cancer susceptibility gene testing is an important tool for genetic counselling of cancer risk. However, the impact of lung cancer susceptibility genes (LCSGs) on lung cancer metastasis and prognosis has not been well studied. Methods The list of lung cancer susceptibility genes was retrospectively analysed and updated. After expression profiling and functional analysis, LCSG-based signatures for prognosis were identified by Cox regression and LASSO regression analyses. For translational purposes, nomograms integrating LCSGs and clinical characteristics were constructed. Results A total of 301 LCSGs were employed for modelling. For lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), 10-gene and 7-gene signatures were created and independently validated. The LCSG-based risk score could stratify LUAD survival (univariate: hazard ratio (HR) = 1.076, 95% confidence interval (CI) = 1.049–1.103, P < 0.001; multivariate: HR = 1.066, 95% CI = 1.037–1.095, P < 0.001) and LUSC survival (univariate: HR = 1.149, 95% CI = 1.066−1.239, P < 0.001; multivariate: HR = 1.129, 95% CI = 1.038−1.228, P = 0.005). One of the processes affected by differentially expressed genes in both LUAD and LUSC was the negative regulation of epithelial cell differentiation. Conclusions Overall, novel LCSG-based gene signatures for LUAD and LUSC were constructed. These findings could expand the understanding of the impact of LCSG expression on cancer metastasis and prognosis.

Mitochondrially localized MPZL3 emerges as a signaling hub of mammalian physiology.

MPZL3 is a nuclear-encoded, mitochondrially localized, immunoglobulin-like V-type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling hub that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology.

Exploring the Potential Key IncRNAs with Endometriosis by Construction of a ceRNA Network.

PurposeThe etiology and pathophysiology of endometriosis remain unclear. Current research indicates long noncoding RNA (lncRNA) may play an important role in the pathogenesis and development of endometriosis. However, the molecular mechanism of lncRNA in endometriosis is far from clear.Patients and MethodsThe lncRNA and mRNA expression of 8 patients with ovarian endometriosis were determined by high-throughput RNA sequencing (8 ectopic endometria samples vs 8 eutopic endometria samples), and miRNA expression profiles were obtained from our previous study. Then a lncRNA-associated competing endogenous RNA (ceRNA) network was constructed by combining the regulatory interaction and negative co-expression interaction between the differentially expressed lncRNAs/mRNAs and miRNAs by different rules.ResultsThe constructed lncRNA-related ceRNA network was composed of two separate networks, network 1 including 14,137 dysregulated lncRNA–mRNA interactions, referring to 242 lncRNAs, 55 miRNAs and 1600 mRNAs, network 2 including 4459 dysregulated lncRNA–mRNA interactions, referring to 111 lncRNAs, 39 miRNAs and 1151 mRNAs. The top six hub lncRNAs (LINC01140, MSC-AS1, HAGLR, CKMT2-AS1, JAKMIP2-AS1, AL365361.1) in the significant ternary relationship of mRNA–miRNA–lncRNA in network 1, and the top six hub lncRNAs (PAX8-AS1, MIR17HC, PART1, HOXA-AS3, PLAC4, LINC00511) in the significant ternary relationship of mRNA–miRNA–lncRNA in network 2 were selected. Functional enrichment analysis of these lncRNA-related mRNAs indicated that the lncRNAs in network 1 mainly take part in positive regulation of phagocytosis, myeloid leukocyte activation, and tissue remodeling, while the lncRNAs in network 2 mainly take part in negative regulation of cell proliferation, blood vessel development and regulation of epithelial cell differentiation, which is consistent with the results obtained from the different rules to construct the networks.ConclusionlncRNA-related ceRNA network analysis recognized key lncRNAs related to the development of endometriosis.

Transcriptomic analysis reveals essential microRNAs after peripheral nerve injury.

Studies have shown that microRNAs (miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages (acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs (miR-21, let-7, miR-223, miR-10b, miR-132, miR-15b, miR-127, miR-29a, miR-29b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29a, and miR-29b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs (i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China (approval No. 20190303-18) on March 3, 2019.

VIRdb: a comprehensive database for interactive analysis of genes/proteins involved in the pathogenesis of vitiligo.

Vitiligo is a chronic asymptomatic disorder affecting melanocytes from the basal layer of the epidermis which leads to a patchy loss of skin color. Even though it is one of the neglected disease conditions, people suffering from vitiligo are more prone to psychological disorders. As of now, various studies have been done in order to project auto-immune implications as the root cause. To understand the complexity of vitiligo, we propose the Vitiligo Information Resource (VIRdb) that integrates both the drug-target and systems approach to produce a comprehensive repository entirely devoted to vitiligo, along with curated information at both protein level and gene level along with potential therapeutics leads. These 25,041 natural compounds are curated from Natural Product Activity and Species Source Database. VIRdb is an attempt to accelerate the drug discovery process and laboratory trials for vitiligo through the computationally derived potential drugs. It is an exhaustive resource consisting of 129 differentially expressed genes, which are validated through gene ontology and pathway enrichment analysis. We also report 22 genes through enrichment analysis which are involved in the regulation of epithelial cell differentiation. At the protein level, 40 curated protein target molecules along with their natural hits that are derived through virtual screening. We also demonstrate the utility of the VIRdb by exploring the Protein–Protein Interaction Network and Gene–Gene Interaction Network of the target proteins and differentially expressed genes. For maintaining the quality and standard of the data in the VIRdb, the gold standard in bioinformatics toolkits like Cytoscape, Schrödinger’s GLIDE, along with the server installation of MATLAB, are used for generating results. VIRdb can be accessed through “http://www.vitiligoinfores.com/”.

Regulation of bone morphogenetic protein 4 on epithelial tissue.

Epithelial tissues provide tissue barriers and specialize in organs and glands. When epithelial homeostasis is physiologically or pathologically stimulated, epithelial cells produce mesenchymal cells through the epithelial-mesenchymal transition, forming new tissues, promoting the cure of diseases or leading to illness. A variety of cytokines are involved in the regulation of epithelial cell differentiation. Bone morphogenetic proteins (BMPs), especially the bone morphogenetic protein 4 (BMP4) has a variety of biological functions and plays a prominent role in the regulation of epithelial cell differentiation. BMP4 is an important regulatory factor of a series of life activities in vertebrates, which is also related to cell proliferation, differentiation and mobility, it also has relation with tumor development. This paper mainly reviews the mechanism of BMP4's regulation on epithelial tissues, as well as its effect on the growth, differentiation, benign lesions and malignant lesions of epithelial tissues, and expounds the function of BMP4 in epithelial tissues, to provide theoretical support for the research on reducing epithelial diseases.

Analysis of expression of p53, p63 and proliferating cell nuclear antigen proteins in odontogenic keratocyst: An immunohistochemical study.

Background:Odontogenic keratocyst (OKC) is a benign intraosseous lesions (within the jaw bone) of odontogenic origin that account for about 10% of jaw cysts. They are characterized by an aggressive behavior with a relatively high recurrence rate. Early diagnosis and follow-up of the patient with OKC is important because the possibility of such patient there is develop to other features of Nevoid basal cell carcinoma syndrome in future. Considering the roles and effects of p53, p63 and proliferating cell nuclear antigen (PCNA) in cells proliferation, this study was designed.Objectives:To understand the behavior of epithelial cells in pathogenesis and biological aspects of OKC in diagnosis.Materials and Methods:Immunohistochemical (IHC)technique was performed in 21 cases of OKCs.Results:Immunological stained p53 cells were mainly located in the suprabasal layers. p63 and PCNA-positive cells were found throughout the lining epithelium including basal and suprabasal cell layers. The intensity of staining was more in p63 and PCNA than the p53 expression of the cystic epithelial lining.Conclusions:It is possible that the biological behavior of OKCs may be related to the suprabasal proliferative compartment in the cystic epithelium as observed. These proteins may participate in the regulation of epithelial cell differentiation. Taken together, these data may favor tumerigenesis on OKCs.

Deep RNA sequencing analysis of syncytialization-related genes during BeWo cell fusion.

The syncytiotrophoblast (STB) plays a key role in maintaining the function of the placenta during human pregnancy. However, the molecular network that orchestrates STB development remains elusive. The aim of this study was to obtain broad and deep insight into human STB formation via transcriptomics. We adopted RNA sequencing (RNA-Seq) to investigate genes and isoforms involved in forskolin (FSK)-induced fusion of BeWo cells. BeWo cells were treated with 50 μM FSK or dimethylsulfoxide (DMSO) as a vehicle control for 24 and 48 h, and the mRNAs at 0, 24 and 48 h was sequenced. We detected 28,633 expressed genes and identified 1,902 differentially expressed genes (DEGs) after FSK treatment for 24 and 48 h. Among the 1,902 DEGs, 461 were increased and 395 were decreased at 24 h, while 879 were up-regulated and 763 were down-regulated at 48 h. When the 856 DEGs identified at 24 h were traced individually at 48 h, they separated into 6 dynamic patterns via a K-means algorithm, and most were enriched in down-even and up-even patterns. Moreover, the Gene Ontology (GO) terms syncytium formation, cell junction assembly, cell fate commitment, calcium ion transport, regulation of epithelial cell differentiation and cell morphogenesis involved in differentiation were clustered, and the MAPK pathway was most significantly regulated. Analyses of alternative splicing isoforms detected 123,200 isoforms, of which 1,376 were differentially expressed. The present deep analysis of the RNA-Seq data of BeWo cell fusion provides important clues for understanding the mechanisms underlying human STB formation.

Integrins regulate epithelial cell differentiation by modulating Notch activity.

Coordinating exit from the cell cycle with differentiation is crucial for proper development and tissue homeostasis. Failure to do so can lead to aberrant organogenesis and tumorigenesis. However, little is known about the developmental signals that regulate the switch from cell cycle exit to differentiation. Signals downstream of two key developmental pathways, Notch and Salvador-Warts-Hippo (SWH), and signals downstream of myosin activity regulate this switch during the development of the follicle cell epithelium of the Drosophila ovary. Here, we have identified a fourth player, the integrin signaling pathway. Elimination of integrin function blocks the mitosis-to-endocycle switch and differentiation in posterior follicle cells (PFCs), by regulation of the cyclin-dependent kinase inhibitor (CKI) dacapo. In addition, integrin-mutant PFCs show defective Notch signaling and endocytosis. Furthermore, integrins act in PFCs by modulating the activity of the Notch pathway, as reducing the amount of Hairless, the major antagonist of Notch, or misexpressing Notch intracellular domain rescues the cell cycle and differentiation defects. Taken together, our findings reveal a direct involvement of integrin signaling on the spatial and temporal regulation of epithelial cell differentiation during development.

Abstract 441: Identification of genes with differential expression in induced radio-resistant human colorectal cancer cell lines.

Abstract Colorectal cancer (CRC) is the third most common type of cancer in developed countries. Proper radiotherapy with chemotherapy is the worldwide treatment for CRC patients. It has been reported that chemoradiotherapy is related to chemical and radiation resistance and may cause local recurrence. To investigate features in resistant tumors, various cancer cell lines that have resistance to chemo and radiotherapy have been established. In this study, three radio-resistant human colorectal cancer cell lines (SNU-61R80GY, SNU-283R80GY, and SNU-503R80GY) were induced by exposing them to a total of 80 greys of Cs-137 to define their characteristics compared to their parental cell lines (SNU-61, SNU-283, and SNU-503). In order to explain cellular properties of parental and induced radio-resistant cell lines, cell proliferation assay, soft agar colony forming assay, cell cycle analysis, and apoptotic assay were performed. Interestingly, remarkable increases of cell proliferation and colony forming abilities on the induced radio-resistant cell line (SNU-503R80GY) were observed compared to the parental cell line (SNU-503) without irradiation although there was no significant change with cell cycle and apoptotic assay using FACS and western blot analysis. Gene expression microarray analysis was then conducted to identify genetic differences between the induced radio-resistant cell lines and the parental cell lines and thirty-three genes with more than 2-fold up-regulated upon induced radio-resistant cell lines were analyzed. According to the gene ontology analysis of these genes, most of them were associated with responses to hypoxia and oxygen levels, oxidation reduction, regulation of epithelial cell differentiation, and cell-cell adhesion. Five genes with more than 3-fold up-regulated upon all three induced radio-resistant cell lines were also sorted out as candidate marker genes for radio-resistance. Furthermore, various genes that are related with cell migration, growth, differentiation, adhesion, and ERBB signaling pathways were screened by RT-PCR. In conclusion, induced radio-resistant human colorectal cancer cell lines have different features such as differential gene expression patterns, and a great ability of cell proliferation, and colony forming compared to the parental cell lines. These results suggest that the induced radio-resistant cell lines are more tumorigenic than the parental cell lines. These cellular and genetic characteristics on the induced radio-resistant cell lines could be considered markers for radio-resistance. The genes that were 3-fold up-regulated on the induced radio-resistant cell lines could be also regarded as candidate markers for radio-resistance. In order to verify our hypothesis, we are in the process of performing the same experiments using other human colorectal cancer cell lines. Citation Format: Ye-Ah Kim, Sang-Geun Jang, Young-Kyoung Shin, Ja-Lok Ku. Identification of genes with differential expression in induced radio-resistant human colorectal cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 441. doi:10.1158/1538-7445.AM2013-441

A tale of two collagen receptors, integrin β1 and discoidin domain receptor 1, in epithelial cell differentiation

As increase in collagen deposition is no longer taken as simply a consequence but, rather, an inducer of disease progression; therefore, the understanding of collagen signal transduction is fundamentally important. Cells contain at least two types of collagen receptors: integrins and discoidin domain receptors (DDRs). The integrin heterodimers α(1)β(1), α(2)β(1), α(10)β(1), and α(11)β(1) are recognized as the non-tyrosine kinase collagen receptors. DDR1 and 2, the tyrosine kinase receptors of collagen, are specifically expressed in epithelium and mesenchyme, respectively. While integrin β(1) and DDR1 are both required for cell adhesion on collagen, their roles in epithelial cell differentiation during development and disease progression seem to counteract each other, with integrin β(1) favoring epithelium mesenchyme transition (EMT) and DDR1 inducing epithelial cell differentiation. The in vitro evidence shows that the integrin β(1) and DDR1 exert opposing actions in regulation of membrane stability of E-cadherin, which itself is a critical regulator of epithelial cell differentiation. Here, we review the functional roles of integrin β(1) and DDR1 in regulation of epithelial cell differentiation during development and disease progression, and explore the underlining mechanisms regarding to the regulation of membrane stability of E-cadherin.

Analysis of microRNA expression in organ of Corti in neonatal and adult rats

ObjectiveTo characterize microRNA (miRNA) expression profile in microdissected auditory epithelia from the Corti’s Organ in new born and adult rats. MethodsThe TaqMan® MicroRNA Arrays were used to identify expression of microRNA in the new born and adult groups. GO analysis was applied to analyze the main function of the differential expression genes according to the Gene Ontology which is the key functional classification of NCBI. Similarly, Pathway analysis was used to find out the significant pathway of the differential genes according to KEGG, Biocarta and Reatome. ResultsIncreased expression was seen in 16 miRNAs in mature rat compared to new born rats, with increased folding ranging from 17 to 600 folds. Expression levels in 2 miRNAs were reduced in mature rats, namely rno–miR–29c and rno–miR–29a. The high–enrichment GOs targeted by over–expressed miRNAs were negative regulation of epithelial cell differentiation, common–partner SMAD protein phosphorylation, mesenchymal–epithelial cell signaling, regulation of transforming growth factor beta2 production, etc. Functional analysis of miRNAs by KEGG revealed that 19 signal transduction pathways were upregulated and 14 were downregulated. ConclusionsThe difference in miRNA expression patterns in the organ of Corti between neonatal and adult rats may be closely related to maturation of the organ of Corti and loss of proliferative capacity of inner ear hair cells, and TGFß signaling may play an important role in hair cells regeneration.

Expression of Ki-67, p53 and p63 proteins in keratocyst odontogenic tumours: an immunohistochemical study

To investigate the immunohistochemical expression of Ki-67, p53 and p63 in Keratocyst Odontogenic Tumours (KOTs) in order to contribute to the biological profile of this tumor. Immunohistochemical technique was performed using the EnVision System in 37 cases of KOTs. Ki-67- and p53-immunostained cells were mainly located in the suprabasal layers. p63-positive cells were found throughout the lining cystic epithelium. No difference in the immunostaining for these proteins was observed between primary and recurrent KOTs (Ki-67: P = 0.5591; p53: P = 0.9847; p63: P = 0.9127), or between KOTs associated with Nevoid Basal Cell Carcinoma Syndrome (NBCCS) and sporadic KOTs (Ki-67: P = 0.7013; p53: P = 0.3197; p63: P = 0.2427). It is possible that biological behavior of KOTs may be related to suprabasal proliferative compartment in the cystic epithelium as observed by high levels of Ki-67, p53 and p63. In addition, p63 immunostaining may represent immaturity of keratinocytes in KOTs, and suggests that this protein may participate in the regulation of epithelial cell differentiation. Taken together, these data may favor tumorigenesis on KOTs.

Regulation of epithelial cell differentiation and regeneration in IBD

Regulation of epithelial cell differentiation and regeneration in IBD

Retinoic Acid and Histone Deacetylase Inhibitor BML‐210 Inhibit Proliferation of Human Cervical Cancer HeLa Cells

Human papillomavirus (HPV) infection is believed to be the central cause of cervical cancer. The viral proteins E6 and E7 from high-risk HPV types prevent cells from differentiating apoptosis and inducing hyperproliferative lesions. Human cervical carcinoma HeLa cells contain integrated human papillomavirus type 18 (HPV-18). Retinoic acid (RA) is a key regulator of epithelial cell differentiation and a growth inhibitor in vitro of HeLa cervical carcinoma cells. Cellular responses to RA are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors. On the other hand, histone deacetylase inhibitors have been shown to be chemopreventive agents for the treatment of cancer cells. In this article, we have examined the antiproliferative effect of RA and histone deacetylase inhibitor BML-210 on HeLa cells, and particularly the effects on protein expression that may be involved in the cell cycle control and apoptosis. Our data suggest that a combination of RA and BML-210 leads to cell growth inhibition with subsequent apoptosis in a treatment time-dependent manner. We confirm that BML-210 alone or in combination with RA causes a marked increase in the level of p21. The changes in the p53 level are under the influence of p38 phosphorylation. We also discovered that the histone deacetylase inhibitor BML-210 causes increased levels of anti-apoptotic protein Bcl-2 and phosphorylated p38 MAP Kinase; the latter link in cell cycle arrest with response to extracellular stimuli. Our results suggest that RA and BML-210 are involved in different signaling pathways that regulate cell cycle arrest and lead to apoptosis of HeLa cells.