• Diagnosis
• Epithelial-mesenchymal transition
• Metastasis
• MicroRNA
• Pancreatic cancer

• Hepatocellular carcinoma
• MHCC-97H
• Metastasis
• miR-661

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• MicroRNAs/genetics
• Humans
• Neoplasm Metastasis/genetics
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic

• Breast cancer
• Non-coding RNAs
• Organs
• Pathways
• Subtypes
• Tumor cells
• Tumor microenvironment

• Humans
• Female
• Breast Neoplasms/pathology
• Tumor Microenvironment/genetics
• Melanoma
• Tropism
• Neoplasm Metastasis
• Melanoma, Cutaneous Malignant

• Cancer Stem Cells
• Cancer heterogeneity
• Cancer plasticity
• Cancer therapy
• Epithelial-Mesenchymal Transition
• Therapy resistance
• Tumor microenvironment

• head and neck neoplasms
• immunity, innate
• macrophages
• tumor microenvironment

Consistently, the high metastasis of cancer cells is the bottleneck in the process of tumor treatment. In this process of metastasis, a pivotal role is executed by epithelial–mesenchymal transition (EMT). The epithelial-to-mesenchymal transformation was first proposed to occur during embryonic development. Later, its important role in explaining embryonic developmental processes was widely reported. Recently, EMT and its intermediate state were also identified as crucial drivers in tumor progression with the gradual deepening of research. To gain insights into the potential mechanism, increasing attention has been focused on the EMT-related transcription factors. Correspondingly, miRNAs target transcription factors to control the EMT process of tumor cells in different types of cancers, while there are still many exciting and challenging questions about the phenomenon of microRNA regulation of cancer EMT. We describe the relevant mechanisms of miRNAs regulating EMT, and trace the regulatory roles and functions of major EMT-related transcription factors, including Snail, Twist, zinc finger E-box-binding homeobox (ZEB), and other families. In addition, on the basis of the complex regulatory network, we hope that the exploration of the regulatory relationship of non-transcription factors will provide a better understanding of EMT and cancer metastasis. The identification of the mechanism leading to the activation of EMT programs during diverse disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Here, we summarize the recent progress in this direction, with a promising path for further insight into this fast-moving field.

• Aquaporins
• Embryo implantation
• Endometrium
• Growth factors
• MicroRNAs
• Steroids
• Transcription factors
• Trophoblast

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in Egypt. A deep understanding of the molecular events occurring in HCC can facilitate the development of novel diagnostic and/or therapeutic approaches. In the present study, we describe a novel axis of hsa-circ-0000221–miR-661–PTPN11 mRNA proposed by in silico and in vitro analysis and its role in HCC pathogenesis. We observe a reduction in the expression levels of hsa-circ-0000221 and PTPN11 mRNA in HCC patients’ sera tested compared with control subjects. The reduction occurs with a concomitant increase in the expression of miR-661. Furthermore, the introduction of exogenous hsa-circ-0000221 into Hep-G2 or SNU449 cell lines results in detectable decrease in cellular viability and an increase in apoptotic manifestations that is associated with G1 accumulation and CCDN1 overexpression. Altogether, these findings indicate the tumor-suppressive role of hsa-circ-0000221 in HCC, which acts through miR-661 inhibition, along with a subsequent PTPN11 mRNA increase, where PTPN11 is known to inhibit cell proliferation in many forms of cancer. Our study encourages further investigation of the role of circRNAs in cancer and their potential use as molecular biomarkers.

• PTPN11
• hepatocellular carcinoma
• hsa-circ-0000221
• miR-661

• Diabetes type II
• Foot ulcer
• miR-571
• miR-661
• miR-770-5p

• Adult
• Aged
• Biomarkers/blood
• Case-Control Studies
• Diabetes Complications/genetics
• Diabetes Mellitus, Type 2/genetics
• Diabetic Foot/genetics
• Female
• Gene Expression/genetics
• Humans
• Iran/epidemiology
• Male
• MicroRNAs/blood
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Transcriptome/genetics

Recent studies comparing canine mammary tumors (CMTs) and human breast cancers have revealed remarkable tumor similarities, identifying shared expression profiles and acquired mutations. CMTs can also provide a model of inherited breast cancer susceptibility in humans; thus, we investigated breed-specific whole genome sequencing (WGS) data in search for novel CMT risk factors that could subsequently explain inherited breast cancer risk in humans.

WGS was carried out on five CMT-affected Gold Retrievers from a large pedigree of 18 CMT-affected dogs. Protein truncating variants (PTVs) detected in all five samples (within human orthlogs) were validated and then genotyped in the 13 remaining CMT-affected Golden Retrievers. Allele frequencies were compared to canine controls. Subsequently, human blood-derived exomes from The Cancer Genome Atlas breast cancer cases were analyzed and allele frequencies were compared to Exome Variant Server ethnic-matched controls.

Carcinoembryonic Antigen-related Cell Adhesion Molecule 24 (CEACAM24) c.247dupG;p.(Val83Glyfs^∗48) was the only validated variant and had a frequency of 66.7% amongst the 18 Golden Retrievers with CMT. This was significant compared to the European Variation Archive (p-value 1.52 × 10^–8) and non-Golden Retriever American Kennel Club breeds (p-value 2.48 × 10^–5). With no direct ortholog of CEACAM24 in humans but high homology to all CEACAM gene family proteins, all human CEACAM genes were investigated for PTVs. A total of six and sixteen rare PTVs were identified in African and European American breast cancer cases, respectively. Single variant assessment revealed five PTVs associated with breast cancer risk. Gene-based aggregation analyses revealed that rare PTVs in CEACAM6, CEACAM7, and CEACAM8 are associated with European American breast cancer risk, and rare PTVs in CEACAM7 are associated with breast cancer risk in African Americans. Ultimately, rare PTVs in the entire CEACAM gene family are associated with breast cancer risk in both European and African Americans with respective p-values of 1.75 × 10^–13 and 1.87 × 10^–04.

This study reports the first association of inherited CEACAM mutations and breast cancer risk, and potentially implicates the whole gene family in genetic risk. Precisely how these mutations contribute to breast cancer needs to be determined; especially considering our current knowledge on the role that the CEACAM gene family plays in tumor development, progression, and metastasis.

• CEACAM
• breast cancer
• canine mammary tumor
• comparative oncology
• inherited risk
• rare protein truncating variants
• splice mutations
• whole genome sequencing

• EMT
• SNAI1
• SNAI2
• chondrogenesis
• epigenetic modulation
• osteogenesis
• zinc finger protein

• Cancer
• Epithelial cells
• Mesenchymal cells
• miRNA

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial–mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.

• drug resistance
• epi-drugs
• epigenetics
• epithelial–mesenchymal transition
• liquid biopsy
• pancreatic ductal adenocarcinoma

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor
• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/metabolism
• Cell Line, Tumor
• Drug Resistance, Neoplasm/genetics
• Early Detection of Cancer
• Epigenesis, Genetic
• Epigenomics/methods
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Genetic Heterogeneity
• Histones/metabolism
• Humans
• Liquid Biopsy
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism

• cancer metastasis
• long non-coding RNA
• metabolic reprogramming
• microRNA
• non-coding RNA

• Lipid trafficking
• Metabolism
• START domain

• Animals
• Biological Transport/genetics
• Carrier Proteins/chemistry
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Carrier Proteins/physiology
• Humans
• Intracellular Space/metabolism
• Lipid Metabolism/genetics
• Membrane Transport Proteins/chemistry
• Membrane Transport Proteins/genetics
• Membrane Transport Proteins/metabolism
• Membrane Transport Proteins/physiology
• Mice
• Mice, Knockout
• Phosphoproteins/chemistry
• Phosphoproteins/genetics
• Phosphoproteins/physiology

Cancer statistics in 2018 highlight an 8.6 million incidence in female cancers, and 4.2 million cancer deaths globally. Moreover, breast cancer is the most frequent malignancy in females and twenty percent of these develop metastasis. This provides only a small chance for successful therapy, and identification of new molecular markers for the diagnosis and prognostic prediction of metastatic disease and development of innovative therapeutic molecules are therefore urgently required. Differentially expressed microRNAs (miRNAs) in cancers cause multiple changes in the expression of the tumorigenesis-promoting genes which have mostly been investigated in breast cancers. Herein, we summarize recent data on breast cancer-specific miRNA expression profiles and their participation in regulating invasive processes, in association with changes in cytoskeletal structure, cell-cell adhesion junctions, cancer cell-extracellular matrix interactions, tumor microenvironments, epithelial-to-mesenchymal transitions and cancer cell stem abilities. We then focused on the epigenetic regulation of individual miRNAs and their modified interactions with other regulatory genes, and reviewed the function of miRNA isoforms and exosome-mediated miRNA transfer in cancer invasiveness. Although research into miRNA’s function in cancer is still ongoing, results herein contribute to improved metastatic cancer management.

• breast cancer
• epigenetic regulation
• female cancer
• invasiveness
• metastasis
• miRNA expression
• miRNA target genes

HIV remains incurable because of viral persistence in latent reservoirs that are inaccessible to antiretroviral therapy. A potential curative strategy is to reactivate viral gene expression in latently infected cells. However, no drug so far has proven to be successful in vivo in reducing the reservoir, and therefore new anti-latency compounds are needed. We explored the role of microRNAs (miRNAs) in latency maintenance and their modulation as a potential anti-latency strategy. Latency models based on treating resting CD4 T cells with chemokine (C-C motif) ligand 19 (CCL19) or interleukin-7 (IL7) before HIV infection and next-generation sequencing were used to identify the miRNAs involved in HIV latency. We detected four upregulated miRNAs (miRNA-98, miRNA-4516, miRNA-4488, and miRNA-7974). Individual or combined inhibition of these miRNAs was performed by transfection into cells latently infected with HIV. Viral replication, assessed 72 h after transfection, did not increase after miRNA modulation, despite miRNA inhibition and lack of toxicity. Furthermore, the combined modulation of five miRNAs previously associated with HIV latency was not effective in these models. Our results do not support the modulation of miRNAs as a useful strategy for the reversal of HIV latency. As shown with other drugs, the potential of miRNA modulation as an HIV reactivation strategy could be dependent on the latency model used.

• CCL19
• HIV latency
• HIV latency model
• IL-7
• LRA
• latency-reversing agent
• miRNA modulation

• C-phosphate-G islands
• Sinonasal inverted papilloma
• epigenetics
• methylation
• squamous cell carcinoma

• Cancer stem cells
• Colorectal cancer
• Immunotherapy
• Nectin-1

• RRBS method
• TCGA data
• clinical implication
• expression
• miRNA methylome
• oral cancer
• pathway analysis
• survival analysis
• tobacco marker

Deregulation of microRNA (miRNA/miR) expression has been implicated in the development of pancreatic ductal adenocarcinoma (PDAC). However, the role of miR-661 in PDAC remains unknown. In the present study, it was revealed that miR-661 expression was significantly upregulated in PDAC tissues compared with that in adjacent normal tissues by using reverse transcription-quantitative polymerase chain reaction assays. Higher miR-661 expression revealed a positive association with lymph node metastasis, an advanced T stage and a poor prognosis in patients with PDAC. Furthermore, ectopic expression of miR-661 significantly promoted the cell proliferation ability in PDAC cell lines, and simultaneously promoted Wnt signaling pathway-related protein expression of β-catenin, transcription factor 4 and cyclin D1 in vitro. However, the downregulation of miR-661 revealed reverse effects. Thus, the results of the present study indicated that miR-661 may function as a prognostic marker and provide insight for pancreatic cancer treatment.

• Wnt signaling pathway
• microRNA-661
• microRNAs
• pancreatic ductal adenocarcinoma
• tumor prognosis

• Metastasis
• cancer
• epithelial-to-mesenchymal transition
• microRNA-10b

• R01 CA163461 NCI NIH HHS
• R25 CA174650 NCI NIH HHS
• R01 CA221771 NCI NIH HHS
• R01 CA135650 NCI NIH HHS
• R56 CA214464 NCI NIH HHS

Emodin has a direct inhibitory effect on the growth and metastasis of a variety of malignant tumor cells. MicroRNA-1271 (miR-1271) has an extensive tumor-suppression effect by inhibiting epithelial mesenchymal transition (EMT) in tumor cells and induces tumor cell apoptosis. Proceeding with the EMT regulatory mechanism of pancreatic carcinoma, the present study aimed to examine the inhibitory effect of miR-1271 and emodin against invasion and metastasis of pancreatic carcinoma. The expression of EMT-related markers (E-cadherin, ZEB1 and TWIST1) was analyzed by western blotting. mRNA levels of miR-1271, E-cadherin, ZEB1 and TWIST1 in pancreatic tumor cells (SW1990) were measured through reverse transcription-quantitative polymerase chain reaction and cell invasiveness was detected using Transwell assays. In addition, a liver metastatic model was established with an implantation of pancreatic tumor tissue into the spleens of nude mice to study the effect of emodin on pancreatic cancer liver metastasis. In the present study, it was demonstrated that miR-1271 significantly decreased in pancreatic cancer cells and tissues. Twist1 may be a target gene of miR-1271. Emodin could inhibit the proliferation ability of pancreatic cancer cells and increased miR-1271 expression level. Further, we found that miR-1271 significantly inhibited SW1990 cell EMT and invasive ability. We also provided the evidence that emodin inhibited SW1990 cell EMT by raising the level of miR-1271. Moreover, the in vivo experiments have verified the inhibiting effect of emodin against liver metastasis of pancreatic cancer. The data in the present study indicated that emodin inhibited pancreatic cancer EMT and invasion by increasing the content of miR-1271.

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is involved in tumor development. However, how ADAMTS6 influences cancer remains unknown. We investigated the biological function and clinical implications of ADAMTs6 in breast cancer (BC). Its functional significance in BC cell lines was confirmed by ADAMTs6 overexpression or downregulation both in vitro and in vivo studies. Enhanced ADAMTS6 expression suppressed cell migration, invasion, and tumorigenesis, whereas knockdown promoted these characteristics. The extracellular signal-regulated kinase (ERK) pathway was partially involved in ADAMTS6-mediated inhibition of BC development, and miR-221-3p was identified as a predicted target for ADAMTS6. Results from the luciferase assay confirmed that miR-221-3p directly inhibited ADAMTS6 expression by binding its 3′-untranslated region. In addition, immunohistochemistry data from specimens from 182 BC patients showed that high ADAMTS6 expression was significantly correlated with favorable disease-free survival (DFS, p = 0.045). Subgroup analysis of patients with ER positive, PR positive or HER-2 negative tumors revealed that high ADAMTS6 expression more strongly extended DFS compared to low expression (p = 0.004, p = 0.009, p = 0.017). Multivariate analyses confirmed that ADAMTS6 expression was an independent risk factor for DFS (p = 0.011). Together, these data demonstrate that ADAMTS6 inhibits tumor development by regulating the ERK pathway via binding of miR-221-3p. Thus, its expression may be a potential prognostic biomarker for BC.

• ADAMTS6
• ERK pathway
• breast cancer
• prognosis
• tumor suppressor

• Antimetabolites, Antineoplastic
• Capecitabine
• Chemoradiotherapy, Adjuvant/adverse effects
• Chemoradiotherapy, Adjuvant/methods
• Dermatitis/genetics
• Diarrhea/genetics
• Disease-Free Survival
• Female
• Genetic Variation
• Genotype
• Humans
• Kaplan-Meier Estimate
• Leukopenia/genetics
• Male
• MicroRNAs/genetics
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• Postoperative Care
• Rectal Neoplasms/genetics
• Rectal Neoplasms/mortality
• Rectal Neoplasms/therapy

Triple Negative Breast Cancer (TNBC), a clinically aggressive subtype of breast cancer, disproportionately affects African American (AA) women when compared to non-Hispanic Whites (NHW). MiRNAs(miRNAs) play a critical role in these tumors, through the regulation of cancer driver genes. In this study, our goal was to characterize and compare the patterns of miRNA expression in TNBC of AA (n = 27) and NHW women (n = 30). A total of 256 miRNAs were differentially expressed between these groups, and distinct from the ones observed in their respective non-TNBC subtypes. Fifty-five of these miRNAs were mapped in cytobands carrying copy number alterations (CNAs); 26 of them presented expression levels concordant with the observed CNAs. Receiving operating characteristic (ROC) analysis showed a good power (AUC ≥ 0.80; 95% CI) for over 65% of the individual miRNAs and a high combined power with superior sensitivity and specificity (AUC = 0.88 (0.78−0.99); 95% CI) of the 26 miRNA panel in discriminating TNBC between these populations. Subsequent miRNA target analysis revealed their involvement in the interconnected PI3K/AKT, MAPK and insulin signaling pathways. Additionally, three miRNAs of this panel were associated with early age at diagnosis. Altogether, these findings indicated that there are different patterns of miRNA expression between TNBC of AA and NHW women and that their mapping in genomic regions with high levels of CNAs is not merely physical, but biologically relevant to the TNBC phenotype. Once validated in distinct cohorts of AA women, this panel can potentially represent their intrinsic TNBC genome signature.

• African American
• copy number
• microRNA
• non-Hispanic white
• triple negative breast cancer

• ATG-4B
• bioinformatics
• biomarkers
• hepatocellular carcinoma
• miR-661
• prognosis

Pancreatic cancer is characterized by chemoresistance after several cycles of chemotherapy, which is a major issue responsible for treatment failure of pancreatic cancer. Therefore, it is necessary to explore the specific mechanism underlying chemotherapeutic resistance to overcome this issue. Here we report that miR-1266 is dramatically elevated and correlates with poor survival and chemotherapy response in pancreatic cancer patients. Upregulation of miR-1266 enhanced the chemoresistance of pancreatic cancer cells to gemcitabine (GEM) in vitro and in vivo; conversely, inhibition of miR-1266 yielded the opposite effect. Importantly, silencing of miR-1266 restored the sensitivity of pancreatic cancer cells to GEM in a dose-dependent manner in vivo. Furthermore, our results demonstrate that miR-1266 promotes resistance of pancreatic cancer cells to GEM by targeting multiple negative regulators of the STAT3 and NF-κB pathways, including SOCS3, PTPN11, ITCH, and TNIP1, leading to constitutive activation of STAT3 and NF-κB signaling. Thus, our findings clarify a novel mechanism by which miR-1266 induces chemotherapeutic resistance in pancreatic cancer, indicating that miR-1266 may be used as chemotherapeutic response indicator. Antagomir-1266 as a chemotherapeutic sensitizer, in combination with GEM, may serve as a rational regimen in the treatment of chemotherapy-resistant pancreatic cancer.

• NF-kB signaling
• STAT3 signaling
• chemotherapeutic resistance
• miR-1266
• pancreatic cancer

• EMT
• breast cancer metastasis
• claudin
• miR-30a
• slug

Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA‐661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non‐metastatic human CC cells induces an epithelial‐to‐mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose‐6‐phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage‐II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.

• bioenergetics
• colon cancer
• metabolomics
• miR
• oxidative stress

• ESRP1
• TGF-β1
• epithelial-mesenchymal transition (EMT)
• microRNA-23a (miR-23a)
• pancreatic cancer

Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular aggregates (MCAs), adhesion to and disruption of the mesothelial lining of the peritoneum, and submesothelial matrix anchoring and proliferation to generate widely disseminated metastases. This exceptional microenvironment is highly permissive for phenotypic plasticity, enabling mesenchymal-to-epithelial (MET) and epithelial-to-mesenchymal (EMT) transitions. In this review, we summarize current knowledge on EOC heterogeneity in an EMT context, outline major regulators of EMT in ovarian cancer, address controversies in EMT and EOC chemoresistance, and highlight computational modeling approaches toward understanding EMT/MET in EOC.

• cadherins
• computational modeling of EMT
• epithelial-to-mesenchymal transition (EMT)
• heterogeneity
• intraperitoneal metastasis
• intraperitoneal tumor microenvironment
• mesenchymal-to-epithelial transition (MET)
• ovarian cancer

• R01 CA086984 NCI NIH HHS
• R01 CA109545 NCI NIH HHS

The dysregulation of microRNAs (miRNAs) alters expression level of pro-oncogenic or tumor suppressive mRNAs in breast cancer, and in the long run, causes multiple biological abnormalities. Identification of such interactions of miRNA-mRNA requires integrative analysis of miRNA-mRNA expression profile data. However, current approaches have limitations to consider the regulatory relationship between miRNAs and mRNAs and to implicate the relationship with phenotypic abnormality and cancer pathogenesis.

We modeled causal relationships between genomic expression and clinical data using a Bayesian Network (BN), with the goal of discovering miRNA-mRNA interactions that are associated with cancer pathogenesis. The Multiple Beam Search (MBS) algorithm learned interactions from data and discovered that hsa-miR-21, hsa-miR-10b, hsa-miR-448, and hsa-miR-96 interact with oncogenes, such as, CCND2, ESR1, MET, NOTCH1, TGFBR2 and TGFB1 that promote tumor metastasis, invasion, and cell proliferation. We also calculated Bayesian network posterior probability (BNPP) for the models discovered by the MBS algorithm to validate true models with high likelihood.

The MBS algorithm successfully learned miRNA and mRNA expression profile data using a BN, and identified miRNA-mRNA interactions that probabilistically affect breast cancer pathogenesis. The MBS algorithm is a potentially useful tool for identifying interacting gene pairs implicated by the deregulation of expression.

• E2F1
• Metastasis
• Non small cell lung cancer
• RB
• miR-661

• Cadherins
• Cyclosporine
• Epithelial-mesenchymal transition
• Gingival overgrowth
• Transforming growth factor beta1

• Breast cancer
• Chemotherapy
• Docetaxel
• STARD10
• miR-638

• cell biology
• epithelial
• microarrays
• pulmonary
• toxicology

• Breast
• Drug resistance
• Metastasis
• microRNA

MicroRNAs (miRNAs) are 22- to 24-nucleotide, small, non-coding RNAs that bind to the 3′UTR of target genes to control gene expression. Consequently, their dysregulation contributes to many diseases, including diabetes and cancer. miR-22 is up-regulated in numerous metastatic cancers and recent studies have suggested a role for miR-22 in promoting stemness and metastasis. TIP60 is a lysine acetyl-transferase reported to be down-regulated in cancer but the molecular mechanism of this reduction is still unclear. In this study, we identify TIP60 as a target of miR-22. We show a negative correlation in the expression of TIP60 and miR-22 in breast cancer patients, and show that low levels of TIP60 and high levels of miR-22 are associated with poor overall survival. Furthermore, pathway analysis using high miR-22/low TIP60 and low miR-22/high TIP60 breast cancer patient datasets suggests association of TIP60/miR-22 with epithelial-mesenchymal transition (EMT), a key alteration in progression of cancer cells. We show that blocking endogenous miR-22 can restore TIP60 levels, which in turn decreases the migration and invasion capacity of metastatic breast cancer cell line. These results provide mechanistic insight into TIP60 regulation and evidence for the utility of the combination of TIP60 and miR-22 as prognostic indicator of breast cancer progression.

• EMT
• KAT5
• TIP60
• cancer
• miR-22

Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.

• Pancreatic cancer
• Cancer stem cells
• Stem cell markers
• Exosomes
• Crosstalk

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Exosomes/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplastic Stem Cells/metabolism
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism

• Cancer
• EMT
• miRNAs