UNASSIGNED

CDH3-related hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal-recessive entity characterized by congenital sparse scalp hair and macular dystrophy, leading to severe central visual loss. We report a family with HJMD caused by a novel CDH3 gene mutation and review the mutation spectrum in HJMD. A detailed phenotypic assessment for patients whose molecular results were reported previously is also summarized.

UNASSIGNED

We present a 13-year-old Turkish girl who experienced gradual bilateral visual deterioration with marked hair loss. Hair-pull test results and scalp skin texture were normal. The eyebrows and eyelashes were normal, and no abnormality in the teeth, nails, or limbs was detected. Fundus examination revealed bilateral ring-shaped atrophy of the retinal pigment epithelium with patchy intraretinal pigment clumping at the posterior pole. DNA sequencing analysis detected a novel homozygous deletion (c.447_467del (p.149_156del)) in exon 5 of the CDH3 gene of the patient. Both healthy parents and an older brother were heterozygous for the mutation.

UNASSIGNED

This case of HJMD was related to a novel homozygous mutation, termed c.447_467del (p.149_156del). These findings have significance for the future mutational analysis and genetic counseling of families with HJMD, particularly in our region. The presence of sparse hair in childhood, with or without limb anomalies, should alert clinicians to request an eye consultation. Pediatricians, dermatologists, and ophthalmologists should be aware of the rarely seen entity of juvenile macular dystrophy with hypotrichosis.

Adenomyosis is a prevalent, estrogen-dependent uterine disorder wherein endometrial cells are abnormally present in the myometrium and are surrounded by hyperplastic/hypertrophic smooth muscle. Its etiology is unclear, although endometrial cell invasion into the myometrium has been postulated. RNA methylation, particularly N6-methyladenosine (m⁶A), plays an important role in regulating various physiological processes and invasive disorders. The goal of this in silico and lab-based experimental study was to explore a possible role for m⁶A in adenomyosis. Gene expression profiles of both the endometrium and myometrium of women with adenomyosis (cases) and without disease (controls) were obtained from the publicly available Gene Expression Omnibus (GEO) database. In the endometrium, STRING database analysis revealed that METTL3 functions as a "hub" gene of m⁶A RNA methylation regulators, and the genes involved in m⁶A regulation, including METTL3, FTO, ZC3H13, and YTHDC1 expression, were significantly decreased in cases versus controls. Functional, co-expression, and correlational analyses of endometrium from cases versus controls revealed decreased total m⁶A levels, induced by METTL3, and the downstream elevated insulin-like growth factor-1(IGF1) and D-Dopachrome Tautomerase (DDT), with the latter two having known functions in epithelial proliferation and cell migration, which are important processes in the pathogenesis of adenomyosis in endometrium. m⁶A RNA methylation regulators, including RBM15/15B, ALKBH5, FTO, YTHDF1/2, KIAA1429, HNRNPC, METTL3, ZC3H13, and YTHDC2, were also differentially expressed in the myometrium from cases versus controls. We validated decreased total m⁶A levels and differential expression of m⁶A RNA methylation regulators in the myometrium of patients with adenomyosis using qRT-PCR, immunohistochemistry and tissues available from our biorepository. Possible target genes, including cadherin 3(CDH3), sodium channelβ-subunit 4 (SCN4B), and placenta-specific protein 8 (PLAC8), which are involved in cell adhesion, muscle contraction and immune response in the myometrium of adenomyosis patients were also validated. Thus, through extensive public database mining and validation of select genes, this study, for the first time, implicates m⁶A and its methylation regulators in the pathogenesis of adenomyosis. Follow on functional studies are anticipated to elucidate mechanisms involving m⁶A and its regulators and down-stream effectors in the pathogenesis of this enigmatic reproductive disorder and potentially identify druggable targets to control its associated symptoms.

Keywords: METTL3; adenomyosis; endometrium; in silico; m6A; myometrium.

Characterisation of mouse pluripotent stem cells has revealed two distinct pluripotent states, naive and primed, that maintain characteristics of the pre and post implanted epiblast respectively. Recent studies have developed several culture systems that seek to recapitulate the naive phenomenon in human pluripotent stem cells. Therefore, robust methods to isolate these cells will be fundamental to assess their potential in modelling human development and disease. Here we review current methods for human naive pluripotent culture and collate a list of cell surface antigens that have been identified as markers to differentiate naive from primed human pluripotent stem cells. While these culture systems do display marker variability, and not all antigens mentioned were assessed in all methods, this review provides a resource for researchers of the human naive pluripotent stem cell state. SSEA-4, SSEA-3, CD24, CD75, CD7, CD77, CD130/GP130, CD57, CD90 and NLGN4X were all found to have a +/- expression profile in at least 2 methods, while +/- expression of Tra-1-81, CDH3, CD172a, CD107b, CD229 was reported in one method. Often it was reported that naive and primed cells could be defined using a low/medium/high expression of the following antigens TRA-1-60, PCDH1, GPR64, MHC Class I, however these markers were more likely to display expression pattern differences between methods. Studies using mouse naive cells indicate that they may have benefits over primed cells in modelling development and disease, and while it is yet to be determined if the same can be said about a human naive state, tools to identify this population should greatly further the field.

Mesodermal differentiation of induced pluripotent stem cells (iPSCs) in vitro and subsequent specification into mesodermal derivatives like chondrocytes is currently afflicted with a substantial cell loss that severely limits tissue yield. More knowledge on the key players regulating mesodermal differentiation of iPSCs is currently needed to drive all cells into the desired lineage and to overcome the current need for intermediate cell selection steps to remove misdifferentiated cells. Using two independent human iPSC lines, we here report that a short initial WNT/β-catenin pulse induced by the small molecule CHIR99021 (24 h) enhanced expression of mesodermal markers (PDGFRα, HAND1, KDR, and GATA4), supported the exit from pluripotency (decreased OCT4, SOX2, and LIN28A) and inhibited ectodermal misdifferentiation (reduced PAX6, TUBB3, and NES). Importantly, the initial CHIR pulse increased cell proliferation until day 14 (five-fold), adjusted expression of adhesion-related genes (CDH3 up, CDH6 down) and increased extracellular matrix (ECM)-related gene expression (COL6, COL1, COL3, COL5, DCN, NPNT, LUM, MGP, MATN2, and VTN), thus yielding more matrix-interacting progenitors with a high aggregation capability. Enhanced contribution to chondrogenic pellet formation increased the cell yield after eight weeks 200-fold compared to controls. The collagen type II and proteoglycan-positive area was enlarged in the CHIR group, indicating an increased number of cartilage-forming cells. Conclusively, short initial WNT activation improved mesoderm commitment and our data demonstrated for the first time to our knowledge that, acting via stimulation of cell proliferation, ECM expression and cell aggregation, WNT pulsing is a key step to make cell selection steps before chondrogenesis obsolete. This advanced understanding of the WNT/β-catenin function is a major step toward robust and efficient generation of high-quality mesodermal progenitors from human iPSCs and toward rescuing low tissue yield during subsequent in vitro chondrogenesis, which is highly desired for clinical cartilage regeneration, disease modeling and drug screening.

Keywords: WNT/β-catenin; aggregation; cartilage; cell survival; extracellular matrix; induced pluripotent stem cells.

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.

Keywords: ABCA3, ATP-binding cassette transporter A3; APCs, antigen-presenting cells; Biomarkers; CAFs, cancer-associated fibroblasts; CCRCC, clear-cell renal cell carcinoma; CD-UPRT, cytosine deaminase-uracil phosphoribosyltransferase; CDH3, cadherin 3; CRC, colorectal cancer; DC, dendritic cells; DEXs, DC-derived exosomes; DLBCL, diffuse large B-cell lymphoma; DNM3, dynamin 3; Del-1, developmental endothelial locus-1; Drug delivery; Drug resistance; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; ESCRT, endosomal sorting complex required for transport; Exosomes; GPC1, glypican-1; HA, hyaluronic acid; HCC, hepatocellular carcinoma; HIF1, hypoxia-inducible factor 1; HTR, hormone therapy-resistant; HUVECs, human umbilical vein endothelial cells; ILVs, intraluminal vesicles; MDSCs, myeloid-derived suppressor cells; MIF, migration inhibitory factor; MSC, mesenchymal stem cells; MVB, multivesicular body; NKEXOs, natural killer cell-derived exosomes; NNs, nanoparticles; NSCLC, non-small cell lung cancer; PA, phosphatidic acid; PCC, pheochromocytoma; PD-L1, programmed cell death receptor ligand 1; PDAC, pancreatic ductal adenocarcinoma; PGL, paraganglioma; PI, phosphatidylinositol; PS, phosphatidylserine; PTRF, polymerase I and transcript release factor; RCC, renal cell carcinoma; SM, sphingomyelin; SNARE, soluble NSF-attachment protein receptor; TEX, tumor-derived exosomes; TSG101, tumor susceptibility gene 101; Tumor immunity; Tumor metastasis; circRNAs, circular RNAs; dsDNA, double stranded DNA; hTERT, human telomerase reverse transcriptase; lamp2b, lysosome-associated membrane glycoprotein 2b; lncRNAs, long non-coding RNAs; miRNA, microRNA; mtDNA, mitochondrial DNA; ncRNA, non-coding RNAs.

Breast cancer arising in female BRCA1 mutation carriers is characterized by an aggressive phenotype and early age of onset. We performed tandem mass spectrometry-based proteomics of secretomes and exosome-like extracellular vesicles from BRCA1-deficient and BRCA1-proficient murine breast tumor models to identify extracellular protein biomarkers, which can be used as an adjunct to current diagnostic modalities in patients with BRCA1-deficient breast cancer. We identified 2,107 proteins, of which 215 were highly enriched in the BRCA1-deficient secretome. We demonstrated that BRCA1-deficient secretome proteins could cluster most human BRCA1- and BRCA2-related breast carcinomas at the transcriptome level. Topoisomerase I (TOP1) and P-cadherin (CDH3) expression was investigated by immunohistochemistry on tissue microarrays of a large panel of 253 human breast carcinomas with and without BRCA1/2 mutations. We showed that expression of TOP1 and CDH3 was significantly increased in human BRCA1-related breast carcinomas relative to sporadic cases (p = 0.002 and p < 0.001, respectively). Multiple logistic regression showed that TOP1 (adjusted odds ratio [OR] 3.75; 95% confidence interval [95% CI], 1.85 - 7.71, p < 0.001) as well as CDH3 positivity (adjusted OR 2.45; 95% CI, 1.08 - 5.49, p = 0.032) were associated with BRCA1/2-related breast carcinomas after adjustment for triple-negative phenotype and age. In conclusion, proteome profiling of secretome using murine breast tumor models is a powerful strategy to identify non-invasive candidate biomarkers of BRCA1-deficient breast cancer. We demonstrate that TOP1 and CDH3 are closely associated to BRCA1-deficient breast cancer. These data merit further investigation for early detection of tumors arising in BRCA1 mutation carriers.

UNASSIGNED

To investigate biomarkers for predicting papillary thyroid cancer outcomes.

UNASSIGNED

The expression of biomarkers (ITGA2, SYT12 and CDH3) was studied in a prospective cohort of patients with papillary thyroid cancer. Three outcomes of initial metastases, baseline status and longitudinal status were analyzed and correlated with the biomarkers.

UNASSIGNED

SYT12 provided the best prediction of initial metastasis (sensitivity: 72%; specificity: 54%). SYT12 had the highest accuracy for predicting longitudinal status (sensitivity: 100%; specificity: 47%). The best performance for longitudinal status resulted from combining SYT12 with American Thyroid Association risk stratification, with sensitivity and specificity of 88 and 73%, respectively.

UNASSIGNED

SYT12 has some prognostic significance in papillary thyroid cancer. Further validation studies in larger populations are warranted.

Molecular subtypes of urothelial carcinoma may be divided into luminal and nonluminal tumors. Nonluminal tumors are composed of cases with basal/squamous-like or small cell/neuroendocrine features, with a consensus on the molecular characteristics of the respective subtype. In contrast, luminal tumors are more disparate with three to five suggested subtypes and with definitions that do not always cohere. To resolve some of these disparities we assembled a cohort of 344 luminal tumors classified as urothelial-like (Uro), with the subtypes UroA, UroAp, UroB, and UroC, or genomically unstable (GU) according to the LundTax system. Cases were systematically analyzed by immunohistochemistry using antibodies for proteins representing important biological processes or cellular states: KRT5, EGFR, and CDH3 for the integrity of a basal cell layer; CCNB1, Ki67, and FOXM1 for proliferation; FGFR3 and ERBB2 for receptor tyrosine kinase status; CCND1, CDKN2A(p16), RB1, and E2F3 for cell cycle regulation; PPARG, GATA3, and TP63 for the differentiation regulatory system; and KRT20 and UPK3 for the differentiation readout. We show that Uro tumors form one, albeit heterogenous, group characterized by FGFR3, CCND1, and RB1 expression, but low or absence of CDKN2A(p16) and ERBB2 expression. The opposite expression pattern is observed in GU cases. Furthermore, Uro tumors are distinguished from GU tumors by showing a high RB1/p16 expression ratio. Class defining characteristics were independent of pathological stage and growth pattern, and thus intrinsic. In Uro tumors, proliferation was limited to a well-defined single layer of basal-like cells in UroA tumors but occurred throughout the tumor parenchyma, independent of the basal layer, in the more progressed UroAp and UroC tumors. A similar change in proliferation topology was not observed in GU. We conclude that luminal urothelial carcinomas consist, at the molecular pathology level, of two major subtypes, the larger heterogenous Uro and the biologically distinct GU subtype. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Ventral incisional hernia is the most common long-term complication after an abdominal operation. Among newly diagnosed colorectal cancer patients, we screened the preoperative plasma proteome to explore predictive markers for the development of an incisional hernia.

We utilized preoperative plasma samples of 72 newly diagnosed colorectal cancer patients who underwent midline incision for tumor resection between 2010 and 2013. A total of 21 patients with incisional hernia occurrence were matched with 51 patients with at least 18 months follow-up without an incisional hernia by sex, age, and body mass index. To assess predictive markers of incisional hernia risk, we screened the plasma proteome for >2,000 distinct proteins using a well-validated antibody microarray test. Paired t tests were used to compare protein levels between cases and controls. A gene-set-enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) was applied to test for differences in signaling pathways between the 2 groups.

The proteome screen identified 25 proteins that showed elevated or reduced plasma levels in the hernia group compared to the control group (nominal P values < .05). Several proteins were in pathways associated with wound healing (CCL21, SHBG, BRF2) or cell adhesion (PCDH15, CDH3, EPCAM).

Our study shows that there are multiple individual and groups of plasma proteins that could feasibly predict the personal hernia risk prior to undergoing an operation. Further investigations in larger, independent sample sets are warranted to replicate findings and validate clinical utility of potential biomarkers. After validation, such a biomarker could be incorporated into a multifactorial risk model to guide clinical decision-making.

Hypotrichosis with juvenile macular dystrophy is a rare congenital disease mainly found in the Druze population of Northern Israel. This disorder is caused by the CDH3 mutation encoding P-cadherin, which is expressed in retinal pigment epithelium and hair follicles. An 11-year-old girl who was born to related Portuguese parents, had hypotrichosis since birth and macular dystrophy diagnosed at age 5. Fundus examination and fluorescein angiography revealed located macular pigmentary abnormalities. No molecular analysis was done. A fundus examination should be considered mandatory in the assessment of congenital hypotrichosis.

To elucidate the role of a type II transmembrane serine protease, ST14/Prss14, during breast cancer progression, we utilized publically accessible databases including TCGA, GEO, NCI-60, and CCLE. Survival of breast cancer patients with high ST14/Prss14 expression is significantly poor in estrogen receptor (ER) negative populations regardless of the ratios of ST14/Prss14 to its inhibitors, SPINT1 or SPINT2. In a clustering of 1085 selected EMT signature genes, ST14/Prss14 is located in the same cluster with CDH3, and closer to post-EMT markers, CDH2, VIM, and FN1 than to the pre-EMT marker, CDH1. Coexpression analyses of known ST14/Prss14 substrates and transcription factors revealed context dependent action. In cell lines, paradoxically, ST14/Prss14 expression is higher in the ER positive group and located closer to CDH1 in clustering. This apparent contradiction is not likely due to ST14/Prss14 expression in a cancer microenvironment, nor due to negative regulation by ER. Genes consistently coexpressed with ST14/Prss14 include transcription factors, ELF5, GRHL1, VGLL1, suggesting currently unknown mechanisms for regulation. Here, we report that ST14/Prss14 is an emerging therapeutic target for breast cancer where HER2 is not applicable. In addition we suggest that careful conclusions should be drawn not exclusively from the cell line studies for target development.

OBJECTIVE

Pancreatic cancer is one of the most aggressive tumors in mankind. Its aggressiveness is only due to the biological progressive characteristics but also the difficulty for clinical early detection which urges us to find diagnostic tools for early diagnosis. Biomarkers are a developing tool used to measure molecules such as proteins, DNA, or RNAs in blood samples or suspected tumor tissues. The molecular dysregulation is believed to play major roles in tumorigenesis or a result after the tumor formation and can be used as a biomarker for tumor detection.

METHODS

In this paper, we studied the gene expression profiles using tissues from pancreatic cancer patients.

RESULTS

We observed dysregulation of gene expression profiles using high-throughput sequencing technique and verified three-gene upregulation, REG4, CDH3 and S100P both in pancreatic cell lines and carcinoma tissues by RT-PCR and Northern Blot. A detailed description of the genes involved is listed within this article.

CONCLUSIONS

We believe that by unraveling the gene dysregulation profiles in pancreatic tumor tissues can we achieve an early and precise diagnosis of pancreatic cancer. Moreover, these newly found genes, due to their functions involved in cell migration and mitosis, may play major roles in tumorigensis.

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by sparse scalp hair caused by hair follicle abnormalities as well as progressive retinal degeneration leading to blindness in the second or third decade of life. It is associated with mutations of the cadherin 3 (CDH3) gene, which result in abnormal expression of P-cadherin. Mutations in CDH3 are related to ectodermal dysplasia, ectrodactyly, and macular dystrophy. In this report, we describe an 11-year-old Iranian boy born with a missing left index fingernail and sparse scalp hair who later displayed macular pigmentary changes. Genetic testing of the CDH3 gene revealed a homozygous gene variant at exon 6 (640A>T). This novel in-frame mutation converts a lysine to a premature stop codon, altering synthesis of P-cadherin on chromosome 16q22.

Purpose: To find underlying mutations causing highly-activated Wnt activity in mammary tumor cell lines associated with rounded morphology indicative of stemness/EMT. Methods: Stemness of high Wnt cell lines was confirmed using qPCR on selected genes and microRNA profiling, followed by whole-exome sequencing of 3 high Wnt canine mammary tumor cell lines and 5 low/absent Wnt cell lines. Candidate genes were identified and their involvement in Wnt activity investigated using siRNA silencing. Results: The high Wnt cell lines had morphological and gene expression characteristics reminiscent of stemness. All individual cell lines had about 4000 mutations in the exome in comparison to the reference canine genome. The three high basal Wnt cell lines had 167 unique exome mutations. Seven of these mutations resulted in a SIFT score <0.2 of proteins related to Wnt signaling. However, gene silencing did not change the Wnt pathway activation. Renewed analysis with respect to putative relations to Wnt signaling revealed that P-cadherin (CDH3) had three mutations in the coding region of the extracellular domain and was associated with high Wnt signaling. Silencing by siRNA not only in lowered Wnt activity, but also decreased levels of phosphorylated cSRC and sP-cad, and changed cell morphology towards spindle cell appearance. Conclusion: It is concluded that expression of mutated CDH3 is associated with activation of cSRC, stabilization of ß-catenin and a rounded morphology related to a stemness/EMT phenotype. A decreased Wnt activity can be found also by cSRC inhibition, but CDH3 silencing has an additional effect on morphology indicating reversal of EMT.

OBJECTIVE

The goal of the study was to evaluate changes in lung status due to spaceflight stressors that include radiation above levels found on Earth.

METHODS

Within hours after return from a 13-day mission in space onboard the Space Shuttle Atlantis, C57BL/6 mice (FLT group) were euthanized; mice housed on the ground in similar animal enclosure modules served as controls (AEM group). Lung tissue was collected to evaluate the expression of genes related to extracellular matrix (ECM)/adhesion and stem cell signaling. Pathway analysis was also performed. In addition, immunohistochemistry for stem cell antigen-1 (SCA-1), the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay for apoptosis, and staining for histological characteristics were performed.

RESULTS

There were 18/168 genes significantly modulated in lungs from the FLT group (p<0.05 vs. AEM); 17 of these were up-regulated and one was down-regulated. The greatest effect, namely a 5.14-fold increase, was observed on Spock1 (also known as Spark/osteonectin), encoding a multi-functional protein that has anti-adhesive effects, inhibits cell proliferation and regulates activity of certain growth factors. Additional genes with increased expression were cadherin 3 (Cdh3), collagen, type V, alpha 1 (Col5a1), integrin alpha 5 (Itga5), laminin, gamma 1 (Lamc1), matrix metallopeptidase 14 (Mmp14), neural cell adhesion molecule 1 (Ncam1), transforming growth factor, beta induced (Tgfbi), thrombospondin 1 (Thbs1), Thbs2, versican (Vcan), fibroblast growth factor receptor 1 (Fgfr1), frizzled homolog 6 (Fzd6), nicastrin (Ncstn), nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4 (Nfatc4), notch gene homolog 4 (Notch4) and vang-like 2 (Vangl2). The down-regulated gene was Mmp13. Staining for SCA-1 protein showed strong signal intensity in bronchiolar epithelial cells of FLT mice (p<0.05 vs. AEM). TUNEL positivity was also significantly higher in the FLT mice (p<0.05 vs. AEM), but no consistent histological differences were noted.

CONCLUSIONS

The results demonstrate that spaceflight-related stress had a significant impact on lung integrity, indicative of tissue injury and remodeling.

BACKGROUND

Genetic background of Riedel's thyroiditis remains unknown. Herein, we describe our results of studies on genes expression levels in Riedel's thyroiditis.

UNASSIGNED

We report the case of 48-year old woman with Riedel's thyroiditis who has presented unusual course of disease with non-specific cervical discomfort, though as with no pain and/or no compression symptoms. After surgery, thyroid specimens were quantitatively evaluated, regarding PIK3CA, PIK3CD, PIK3CG, Tg, TGFB1, THRB, COL1, CDKN1C, CDH3 and CACNA2D2 genes expression levels, by real-time PCR in the ABI PRISM® 7500 Sequence Detection System. Out of 10 above genes, in 2 cases the expression was higher than in respective Controls of unchanged thyroid tissue. In the remaining 8 cases, expression in question became comparable or lower as in Controls.

CONCLUSIONS

The association between increased expression levels of PIK3CA and CDH3 genes and Riedel's thyroiditis is not well-defined. However, the increased expression of PIK3CA and CDH3 genes in our case report and in previous studies of other authors on various malignancies may suggest possible molecular relation between Riedel's thyroiditis and certain neoplastic processes, the relation of which requires further genetic evaluation. It is to be stressed that gene expression studies in Riedel's thyroiditis are difficult to perform, mainly due to fibrosis, resulting in scarce thyroid specimens and - in consequence - small amount of genetic material.

BACKGROUND

Cadherins (CDHs) have been reported to be associated with cancer. However, the clinical significance of CDH gene methylation in hepatocellular carcinoma (HCC) remains unclear.

METHODS

Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, available studies were identified from online electronic database. The overall odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated and analyzed.

RESULTS

A total of 29 eligible studies with 2562 HCC samples and 1685 controls were included. E-cadherin (CDH1) hypermethylation was observed to be significantly higher in HCC than in benign, adjacent, or normal samples. Moreover, CDH1 hypermethylation was not associated with gender, tumor grade, clinical stage, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection in HCC patients. H-cadherin (CDH13), protocadherin-10 (PCDH10), P-cadherin (CDH3), and M-cadherin (CDH15) methylation may have an increased risk of HCC in fewer than 4 studies, and methylated cadherin 8, type 2 (CDH8) and OB-cadherin (CDH11) had a similar OR in HCC and adjacent samples. When HCC samples were compared with normal samples, the analysis of sample type revealed a significantly higher OR in normal blood samples than in normal tissues for hypermethylated CDH1 (50.82 vs 4.44).

CONCLUSIONS

CDH1 hypermethylation may play a key role in the carcinogenesis of HCC. However, CDH1 hypermethylation was not correlated with clinicopathological features. Methylated CDH13, PCDH10, CDH3, and CDH15, but not methylated CDH8 or CDH11, may lead to an increased risk of HCC. Hypermethylated CDH1 may become a noninvasive blood biomarker. Further studies with more data are necessary.

Copy number variation (CNV) is crucial for gene regulation in humans. A number of studies have revealed that CNV contributes to the initiation and progression of cancer. In this study, we analysed four breast cancer cell lines and six fresh frozen tissues from patients to evaluate the CNV present in the genome using microarray-based comparative genomic hybridization (aCGH). Six genes located at 16q22.1 were analysed by real-time PCR. The real-time PCR analysis revealed that the loss of CDH1/E2F4 may be associated with worse clinical and pathological findings. Interestingly, covariation of CDH1, CDH3, CTCF and E2F4 was found to be associated with triple negative breast cancer and HER-2 receptor status. In conclusion, our study supports the idea that CNV at 16q22.1 in breast cancer is a frequent event; furthermore, it reveals the covariation of CDH1, CDH3, CTCF and E2F4. The role of the covariation is more complex than a simple additive effect of these four separate genes, which may provide a novel target for breast cancer.

Background: Placental-Cadherin (CDH3), a cell adhesion molecule, is associated with the function of cells to bind with other cells and the extracellular matrix (ECM). CDH3 is highly expressed in many malignancies, and has been proved it could be a serum marker to monitor colorectal cancer, but the CDH3 expression levels in thyroid cancer is still not clear. In this article, we will illuminate the correlation between CDHs expression and thyroid cancer.

Materials and methods: We analyzed the level of CDH3 expression in 60 pair of tissue samples (contrast thyroid cancer tissues with adjacent normal thyroid tissues) by Real-time PCR, and TCGA data portal. After that, we transfected small interfering RNA to silence CDH3 in thyroid cancer cell lines (KTC-1 and BCPAP) and confirmed the function of CDH3 by performed colony formation, migration, invasion, cell counting kit-8 and apoptosis assays.

Results: CDH3 was upregulated in thyroid cancer tissues compared to the adjacent normal tissues (T:N=71.87±39.88:5.35±5.91, P<0.0001) and TCGA (T:N=19.43±13.82:1.22±1.33, P<0.0001). In thyroid cell lines (KTC-1 and BCPAP) experiments showed that downregulated CDH3 inhibited proliferation, migration, and invasion. Meanwhile, inhibited CDH3 expression could upregulate E-cadherin, downregulated N-cadherin, which may control invasion and migration.

Conclusion: Thyroid cancer cells CDH3 expression levels is a correlation with its ability to grow, migrate and invade.

Keywords: CDH3; Placental-Cadherin; Thyroid cancer; cell adhesion molecule.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. PTC is typically curable with an excellent survival rate; however, some patients experience disease recurrence or death. This study aimed to discover potential key genes and signaling pathways of PTC, which could provide new insights for thyroid lesions. Four GEO microarray datasets were integrated to screen for candidate genes involved in PTC progression. A total of 164 upregulated and 168 downregulated differentially expressed genes (DEGs) were screened. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes were used in pathway enrichment analyses for DEGs. A protein-protein interaction network was then built and analyzed utilizing STRING and Cytoscape, followed by the identification of 13 hub genes by cytoHubba. CDH3, CTGF, CYR61, OGN, FGF13, and CHRDL1 were selected through survival analyses. Furthermore, immune infiltration, mutations and methylation analysis indicated that these six hub genes played vital roles in immune surveillance and tumor progression. ROC and K-M plots showed that these genes had good prognostic values for PTC which was validated by TCGA dataset. Finally, GSEA for a single hub gene revealed that each candidate hub gene had close associations with PTC development. These findings provided new insights into PTC pathogenesis and identified six candidate gene prognosis signature for PTC.

Keywords: bioinformatics; hub genes; papillary thyroid cancer; signaling pathways; tumor infiltrating.

BACKGROUND Pancreatic cancer (PAC) is a lethal cancer and it is essential to develop accurate diagnostic and prognostic biomarkers for PAC. MATERIAL AND METHODS An integrated microarray analysis of PAC was conducted to identify differentially expressed genes (DEGs) between PAC and non-tumor controls. Expression of DEGs were further confirmed by The Cancer Genome Atlas and the Genotype-Tissue Expression. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and protein-protein integration network construction were performed to further research the biological functions of DEGs. Receiver-operating characteristic analysis and survival analysis were used to evaluate the diagnostic and prognostic value of DEGs for PAC. RESULTS Seventeen microarray datasets were downloaded from Gene Expression Omnibus to conduct the integrated microarray analysis. A total of 1136 DEGs (596 upregulated and 540 downregulated DEGs) in PAC tissues compared with non-tumor controls were identified. Pancreatic secretion (Kegg: 04972), insulin signaling pathway (Kegg: 04910), and several cancer-related pathways including pathways in cancer (Kegg: 05200), MAPK signaling pathway (Kegg: 04010), and pancreatic cancer (Kegg: 05212) were enriched for DEGs in PAC. Seven DEGs (AHNAK2, CDH3, IFI27, ITGA2, LAMB3, SLC6A14, and TMPRSS4) were found to have both great diagnostic and prognostic value for PAC. High expression of these 7 DEGs were significantly associated with poor prognosis of patients with PAC. CONCLUSIONS These 7 DEGs might be potential diagnostic and prognostic biomarkers for PAC and help uncovering the mechanism of PAC.

Esophageal cancer is one of the most common cancer with limited therapeutic strategies, thus it is important to develop more effective strategies to against it. Sulforaphene (SFE), an isothiocyanate isolated from radish seeds, was proved to inhibit esophageal cancer progression in the current study. Flow cytometric analysis showed SFE induced cell apoptosis and cycle arrest in G2/M phase. Also, scrape motility and transwell assays presented SFE reduced esophageal cancer cell metastasis. Microarray results showed the influence of SFE on esophageal cancer cells was related with stearoyl-CoA desaturase (SCD), cadherin 3 (CDH3), mitogen-activated protein kinase kinase 3 (MAP2K3) and growth arrest and DNA damage inducible beta (GADD45B). SCD and CDH3 could promote esophageal cancer metastasis via activating the Wnt pathway, while the latter one was involved in a positive feedback loop, GADD45B-MAP2K3-p38-p53, to suppress esophageal cancer growth. GADD45B was known to be the target gene of p53, and we proved in this study, it could increase the phosphorylation level of MAP2K3 in esophageal cancer cells, activating p38 and p53 in turn. SFE treatment elevated MAP2K3 and GADD45B expression and further stimulated this feedback loop to better exert antitumor effect. In summary, these results demonstrated that SFE had the potential for developing as a chemotherapeutic agent because of its inhibitory effects on esophageal cancer metastasis and proliferation.