• PDAC
• apoptosis
• cell cycle
• microRNA (miRNA)
• pancreatic cancer
• proliferation
• signaling pathways

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

• long non-coding RNA
• microRNA
• microbiome
• pancreatic ductal adenocarcinoma

• Canada Excellence Research Chairs, Government of Canada

• cachexia
• endocrine organ-like tumour (EOLT)
• muscle wasting
• pancreatic ductal adenocarcinoma (PDAC)
• tissue wasting

• National Health Research Institutes

• Carcinogenesis
• Metabolic diseases
• Targeted therapy
• Tissue development
• Transcriptional repressor GATA binding 1
• Tricho-rhino-phalangeal syndrome

• National Key Research and Development Program of China

• immune evasion
• molecular mechanism
• pancreatic cancer
• platelet
• targeted therapy

• Clinical trial
• PDGF/PDGFR signaling
• Platelet-derived growth factor
• Small molecule inhibitor
• Tumor therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types with a limited overall survival rate due to the asymptomatic progression of symptoms in metastatic stages of the malignancy and the lack of an early reliable diagnostic biomarker. MicroRNAs (miRs/miRNAs) are small (~18–24 nucleotides), endogenous, non-coding RNAs, which are closely linked to the development of numerous malignancies comprising PDAC. Recent studies have described the role of environmental pollutants such as nickel (Ni) in PDAC, but the mechanisms of Ni-mediated toxicity in cancer are still not completely understood. Specifically, Ni has been found to alter the expression and function of miRs in several malignancies, leading to changes in target gene expression. In this study, we found that levels of Ni were significantly higher in cancerous tissue, thus implicating Ni in pancreatic carcinogenesis. Hence, in vitro studies followed by using both normal and pancreatic tumor cell lines and increasing Ni concentration increased lethality. Comparing LC50 values, Ni-acetate groups demonstrated lower values needed than in NiCl₂ groups, suggesting greater Ni-acetate. Panc-10.05 cell line appeared the most sensitive to Ni compounds. Exposure to Ni-acetate resulted in an increased phospho-AKT, and decreased FOXO1 expression in Panc-10.05 cells, while NiCl₂ also increased PTEN expression in Panc-10.05 cells. Specifically, following NiCl₂ exposure to PDAC cells, the expression levels of miR-221 and miR-155 were significantly upregulated, while the expression levels of miR-126 were significantly decreased. Hence, our study has suggested pilot insights to indicate that the environmental pollutant Ni plays an important role in the progression of PDAC by promoting an association between miRs and Ni exposure during PDAC pathogenesis.

• apoptosis
• environmental toxins
• microRNAs
• nickel
• non-coding RNAs
• pancreatic ductal adenocarcinoma

• Electrophysiology
• GSK-3β
• Next Generation Sequencing
• miRNA

• Animals
• Glycogen Synthase Kinase 3 beta/metabolism
• Hippocampus/metabolism
• Mice
• MicroRNAs/metabolism
• Neuronal Plasticity
• Neurons/metabolism

• Apoptosis
• Cadmium
• EMT
• LC50
• Non-coding RNAs
• Pancreatic ductal adenocarcinoma
• microRNAs

• Cadmium Chloride/toxicity
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/pathology
• Cell Line, Tumor
• Disease Progression
• Environmental Pollutants/toxicity
• Epithelial-Mesenchymal Transition/drug effects
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology

• OVPR Pilot Grant
• University of Westminster

• cancer stem cells
• epithelial–mesenchymal transition
• metastasis
• microRNAs
• non-coding RNAs
• pancreatic ductal adenocarcinoma

Multi-walled carbon nanotube (MWCNT) is one of the most widely used manufactured nanomaterials, however, its potential harmful effect on human health is of great concern. Previously we have shown the acute and chronic exposure to MWCNT induced different responses in human mesothelial MeT-5A cells. In the current study, MeT-5A cells were continuously subjected to MWCNT exposure at 10 μg/cm² for 48 h per passage, up to a whole year, to further clarify the carcinogesis and its potential mechanisms of MWCNT.

After one-year MWCNT treatment, MeT-5A cells exhibited neoplastic-like properties, including morphological changes, anchorage-independent growth, increased cell proliferation and cell migration. Further examination revealed the expression of microRNA 221 (miR221) was gradually decreased, while the annexin a1 expression was increased at both the mRNA and protein level during the exposure. Bioinformatic analysis indicated that annexin a1 is a target for miR221 regulation, and it was confirmed by transfecting cells with miR221 mimics, which resulted in the downregulation of annexin a1. Detailed analyses demonstrated miR221 was involved in the regulation of cell migration, e.g., downregulation of miR221 or overexpression of ANNEXIN A1, contributed to the increased cell migration. In contrast, overexpression of miR221 or downregulation of ANNEXIN A1 slowed cell migration.

Taken together, these results point to a neoplastic-transforming property of MWCNT, and the miR221-annexin a1 axis is involved in the regulation of cell migration in the transformed cells.

The online version contains supplementary material available at 10.1186/s41021-021-00209-y.

• Annexin a1
• Long-term exposure
• Multi-walled carbon nanotubes (MWCNT)
• Neoplastic-like transformation

In this study, we determined the involvement of SOX2 and its downstream signaling molecules in hepatocellular carcinoma (HCC) progression. We carried out lentiviral transfection in HepG2 cells to determine the roles of SOX2, CCAT1, EGFR, miR-222-5p, and CYLD in HepG2 cells. We first determined the interaction between SOX2 and CCAT1 and that between miR-222-5p and CYLD and their effect on tumor growth in vivo was analyzed in HCC-xenograft bearing nude mice xenografts. SOX2 and CCAT1 were highly expressed in HCC tissues and HepG2 cells. SOX2 bound to the regulatory site of CCAT1. Silencing of SOX2 or CCAT1 inhibited HepG2 cell proliferation, migration, and invasion as well as decreased the expression of CCAT1 and EGFR. CCAT1 silencing reduced EGFR expression, but EGFR expression was increased in HCC tissues and HepG2 cells, which promoted proliferation, migration, and invasion in vitro. EGFR upregulated miR-222-5p, leading to downregulation of CYLD. miR-222-5p inhibition or CYLD overexpression repressed cell functions in HepG2 cells. SOX2 silencing decreased CCAT1, EGFR, and miR-222-5p expression but increased CYLD expression. Loss of SOX2 also reduced the growth rate of tumor xenografts. In summary, SOX2-mediated HCC progression through an axis involving CCAT1, EGFR, and miR-222-5p upregulation and CYLD downregulation.

• CCAT1
• CYLD
• EGFR
• SOX2
• miR-222-5p

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with limited survival rate. Roles for peptidylarginine deiminases (PADs) have been studied in relation to a range of cancers with roles in epigenetic regulation (including histone modification and microRNA regulation), cancer invasion, and extracellular vesicle (EV) release. Hitherto though, knowledge on PADs in PDAC is limited. In the current study, two PDAC cell lines (Panc-1 and MiaPaCa-2) were treated with pan-PAD inhibitor Cl-amidine as well as PAD2, PAD3, and PAD4 isozyme-specific inhibitors. Effects were assessed on changes in EV signatures, including EV microRNA cargo (miR-21, miR-126, and miR-221), on changes in cellular protein expression relevant for pancreatic cancer progression and invasion (moesin), for mitochondrial housekeeping (prohibitin, PHB), and gene regulation (deiminated histone H3, citH3). The two pancreatic cancer cell lines were found to predominantly express PAD2 and PAD3, which were furthermore expressed at higher levels in Panc-1, compared with MiaPaCa-2 cells. PAD2 isozyme-specific inhibitor had the strongest effects on reducing Panc-1 cell invasion capability, which was accompanied by an increase in moesin expression, which in pancreatic cancer is found to be reduced and associated with pancreatic cancer aggressiveness. Some reduction, but not significant, was also found on PHB levels while effects on histone H3 deimination were variable. EV signatures were modulated in response to PAD inhibitor treatment, with the strongest effects observed for PAD2 inhibitor, followed by PAD3 inhibitor, showing significant reduction in pro-oncogenic EV microRNA cargo (miR-21, miR-221) and increase in anti-oncogenic microRNA cargo (miR-126). While PAD2 inhibitor, followed by PAD3 inhibitor, had most effects on reducing cancer cell invasion, elevating moesin expression, and modulating EV signatures, PAD4 inhibitor had negligible effects and pan-PAD inhibitor Cl-amidine was also less effective. Compared with MiaPaCa-2 cells, stronger modulatory effects for the PAD inhibitors were observed in Panc-1 cells, which importantly also showed strong response to PAD3 inhibitor, correlating with previous observations that Panc-1 cells display neuronal/stem-like properties. Our findings report novel PAD isozyme regulatory roles in PDAC, highlighting roles for PAD isozyme-specific treatment, depending on cancer type and cancer subtypes, including in PDAC.

• deiminated histone H3 (citH3)
• extracellular vesicles (EVs)
• miR-126)
• miR-221
• microRNA (miR-21
• moesin
• pancreatic ductal adenocarcinoma (PDAC)
• peptidylarginine deiminases (PADs)
• prohibitin (PHB)
• protein deimination

• cell migration
• epithelial–mesenchymal transition
• metastasis
• miRNA
• oncomiR
• tumor invasiveness
• tumor suppressor miR

Radiotherapy is the major approach and is well tolerated in locally advanced esophageal squamous cell carcinoma (ESCC). And nowadays, no effective biological markers have been identified for predicting the prognosis of patients with ESCC. Platelet-derived growth factor (PDGF) is associated with a poor prognosis of various malignancies. The present study aimed to assess the effect of PDGF-BB on radiotherapeutic responses of ESCC and the underlying mechanisms of its roles in ESCC. Serum from 68 cases that received neoadjuvant or radical radiotherapy was obtained before and during radiotherapy. Gene expression analyses were validated by enzyme linked immunosorbent assay. The prognosis of patients with significantly reduced PDGF-BB was probably better than that of the others found in the progression-free survival and overall survival groups. Depletion of PDGFB significantly suppressed the proliferation, invasion and migration of cancer cells. Inhibiting PDGFB induced cellular apoptosis and promoted the sensitivity to ionizing radiation (IR). Furthermore, IR inhibited PDGF-BB-induced migration by blocking the PI3K/AKT pathway in ESCC cells. We found that the expression of PDGF-BB provided a possible model for predicting ESCC radiotherapy. It can also be used as a prognostic indicator for locally advanced ESCC that was treated by radiotherapy.

• chemoradiotherapy
• curative effect prediction
• esophageal squamous cell carcinoma
• gene expression
• serum biomarkers

• diagnosis
• microRNA
• pancreatic cancer
• potential therapeutic targets
• prognosis

• Animals
• Biomarkers, Tumor/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/therapy
• RNAi Therapeutics/methods

The comprehensive screening of intracellular and extracellular microRNAs was performed to identify novel tumor suppressors. We found that miR-8073 was present in exosome and predominantly exported from colorectal cancer cells. Treatment with a synthetic miR-8073 mimic resulted in a dramatic decrease in the proliferation of various types of cancer cells, which was not observed in similarly treated normal cells. As little is known about the biological functions of miR-8073, its target mRNAs were analyzed by both mRNA expression and in silico sequence analyses, leading to five probable target candidates (FOXM1, MBD3, CCND1, KLK10, and CASP2) that enhance survival during the regulation of the cell cycle, cell proliferation, and apoptosis. We experimentally confirmed that miR-8073 binds the 3’-UTR of each of these mRNA target candidates and that the introduction of a synthetic miR-8073 mimic into cancer cells reduced levels of protein expression. Finally, the antiproliferative effects of miR-8073 were validated in vivo: the subcutaneous injection of a synthetic miR-8073 mimic suppressed colorectal tumor volume to 43% in tumor-bearing xenografted mice. These results suggest that because miR-8073 binds, and thus reduces the levels of, these oncogenic targets, cancer cells must actively downregulate miR-8073 as a survival mechanism. The introduction of miR-8073 into tumors could thus inhibit tumor growth, indicating its great potential for cancer therapeutics.

• Biomarker
• Bladder cancer
• Circular RNA
• Epithelial-to-mesenchymal transition
• Metastasis

• Cardiac progenitor cells
• Cardiac repair
• Epicardium
• Epithelial-to-mesenchymal transition
• Myocardial infarction

Supplemental Digital Content is available in the text.

MicroRNA-22 (miR-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury.

We applied a wire-injury mouse model, and local delivery of AgomiR-22 or miR-22 inhibitor, as well, to explore the therapeutic potential of miR-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested, and various in vivo, ex vivo, and in vitro models of VSMC phenotype switching were conducted to examine miR-22 expression during VSMC phenotype switching.

Expression of miR-22 was closely regulated during VSMC phenotypic modulation. miR-22 overexpression significantly increased expression of VSMC marker genes and inhibited VSMC proliferation and migration, whereas the opposite effect was observed when endogenous miR-22 was knocked down. As expected, 2 previously reported miR-22 target genes, MECP2 (methyl-CpG binding protein 2) and histone deacetylase 4, exhibited a regulatory role in VSMC phenotypic modulation. A transcriptional regulator and oncoprotein, EVI1 (ecotropic virus integration site 1 protein homolog), has been identified as a novel miR-22 target gene in VSMC phenotypic modulation. It is noteworthy that overexpression of miR-22 in the injured vessels significantly reduced the expression of its target genes, decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries, whereas the opposite effect was observed with local application of a miR-22 inhibitor to injured arteries. We next examined the clinical relevance of miR-22 expression and its target genes in human femoral arteries. We found that miR-22 expression was significantly reduced, whereas MECP2 and EVI1 expression levels were dramatically increased, in diseased in comparison with healthy femoral human arteries. This inverse relationship between miR-22 and MECP2 and EVI1 was evident in both healthy and diseased human femoral arteries.

Our data demonstrate that miR-22 and EVI1 are novel regulators of VSMC function, specifically during neointima hyperplasia, offering a novel therapeutic opportunity for treating vascular diseases.

• MDS1 and EVI1 complex locus protein
• atherosclerosis
• cell movement
• cell proliferation
• methyl-CpG-binding protein 2
• microRNAs
• neointima

• Sp1
• VSMC phenotype switch
• miR-124
• proliferation

• 3' Untranslated Regions
• Adult
• Aortic Dissection/genetics
• Aortic Dissection/metabolism
• Aortic Dissection/pathology
• Aortic Aneurysm/genetics
• Aortic Aneurysm/metabolism
• Aortic Aneurysm/pathology
• Binding Sites
• Case-Control Studies
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• Down-Regulation
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/pathology
• Myocytes, Smooth Muscle/metabolism
• Myocytes, Smooth Muscle/pathology
• Phenotype
• Signal Transduction
• Sp1 Transcription Factor/genetics
• Sp1 Transcription Factor/metabolism
• Time Factors
• Transfection

• HPASMC
• PDGF-BB
• cJUN
• miRNA
• proliferation

The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era.

• hepatocellular carcinoma (HCC)
• microRNA
• p53

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• DNA Methylation/genetics
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• MicroRNAs/metabolism
• Molecular Targeted Therapy
• Tumor Suppressor Protein p53/metabolism

Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin.

HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells.

Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy.

• DNA repair
• fractionated ionizing radiation
• heat shock protein-90
• lung adenocarcinoma
• radioresistance mechanisms

• PASMCs
• PDGF pathway
• PIM-1
• miR-328

• 3' Untranslated Regions/genetics
• Adolescent
• Adult
• Angiogenesis Inducing Agents/pharmacology
• Becaplermin
• Cell Movement/genetics
• Cell Proliferation/genetics
• Cells, Cultured
• Child, Preschool
• Gene Expression Regulation/drug effects
• HEK293 Cells
• Heart Defects, Congenital/blood
• Heart Defects, Congenital/genetics
• Humans
• MicroRNAs/blood
• MicroRNAs/genetics
• Middle Aged
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/metabolism
• Proto-Oncogene Proteins c-pim-1/genetics
• Proto-Oncogene Proteins c-pim-1/metabolism
• Proto-Oncogene Proteins c-sis/pharmacology
• Pulmonary Artery/cytology
• RNA Interference
• Young Adult

• Endothelial-to-mesenchymal transition
• Neprilysin
• PDGF-B
• Pulmonary artery remodeling
• TGF-β1

• OncomiR
• PanIN
• TS-miR
• cancer stem cells
• epithelial to mesenchymal transition
• microRNA
• pancreatic cancer
• tumor suppressor

• Biomarkers, Tumor/genetics
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/pathology
• Cell Cycle
• Cell Differentiation
• Cell Movement
• Cell Proliferation
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Molecular Targeted Therapy
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Prognosis
• Survival Rate

• I01 BX001002 BLRD VA
• I01 BX001989 BLRD VA

Pancreatic cancer is an aggressive disease and the fourth most lethal cancer in developed countries. Despite all progress in medicine and in understanding the molecular mechanisms of carcinogenesis, pancreatic cancer still has a poor prognosis, the median survival after diagnosis being around 3 to 6 months and the survival rate of 5 years being less than 4%. For pancreatic ductal adenocarcinoma (PDAC), which represents more than 90% of new pancreatic cancer cases, the prognosis is worse than for the other cancers with a patient mortality of approximately 99%. Therefore, there is a pressing need for developing new and efficient therapeutic strategies for pancreatic cancer. In this regard, microRNAs not only have been seen as potential diagnostic and prognostic molecular markers but also as promising therapeutic agents. In this context, this review provides an examination of the most frequently deregulated microRNAs (miRNAs) in PDAC and their putative molecular targets involved in the signaling pathways of pancreatic
carcinogenesis. Additionally, it is presented a summary of gene therapy clinical trials involving miRNAs and it is illustrated the therapeutic potential associated to these small non-coding RNAs, for PDAC treatment. The facts presented here constitute a strong evidence of the remarkable opportunity associated to the application of microRNA-based therapeutic strategies as a novel approach for cancer therapy.

• gene therapy
• microRNA-based therapeutics
• microRNAs
• pancreatic cancer
• pancreatic ductal adenocarcinoma

Patients exhibiting pancreatic cancer possess poor rates of survival. Therefore, the identification of a biomarker that can be measured non-invasively and be used to predict patient outcomes is required for the successful treatment of pancreatic cancer. The present study evaluated serum microRNA (miRNA/miR) profiles in patients exhibiting pancreatic cancer, who were treated with lapatinib and capecitabine in a phase II trial. Serum samples were collected for the measurement of a panel of miRNAs (miR-21, miR-210, miR-221 and miR-7) associated with the epidermal growth factor receptor (EGFR)1 and human epidermal growth factor receptor (HER)2 pathways. Preclinically, human pancreatic cancer PANC-1, MIA PaCa-2 and BXCP-3 cell lines were utilized for miRNA and drug resistance studies. In total, 6/17 patients treated experienced disease progression following 2 cycles of treatment [non-responders (NRS)], while another 6/17 patients exhibited a stable disease state and received >4 cycles of treatment [responders (RS); range, 4–22 cycles]. Five patients withdrew from the study due to severe toxicity or mortality. The mean overall survival time was 6.5 vs. 10.4 months for NRS and RS, respectively. Significant upregulation of serum miRNAs at earlier time points (3–6 weeks) was observed in NRS. miRNA levels increased with cancer progression, and lapatinib and 5-fluorouracil (5-FU; the active form of capecitabine) treatment increased the miRNA levels (specifically miR-210 and miR-221) in the treatment-resistant pancreatic cancer PANC-1 and MIA PaCa-2 cell lines. However, lapatinib and 5-FU treatment did not increase the miRNA levels in the treatment-sensitive BXPC-3 cell line. Inhibition of miR-221 increased the sensitivity of the PANC-1 cells to treatment. In conclusion, an increase in specific serum miRNAs was associated with resistance to lapatinib and capecitabine treatment. Additional investigation is required with regard to the application of the miRNA panel investigated in the present study as a potential predictor of patient responses to anti-EGFR/HER2 treatment.

• biomarker
• lapatinib
• microRNA-221
• pancreatic cancer
• predict

• EMT
• Liver
• Microarray
• PFOS
• miRNA

• Alkanesulfonic Acids/adverse effects
• Animals
• Fluorocarbons/adverse effects
• Gene Expression Regulation/drug effects
• Gene Regulatory Networks/drug effects
• Homeostasis/drug effects
• Liver/chemistry
• Liver/drug effects
• Male
• MicroRNAs/genetics
• Potassium, Dietary/adverse effects
• Rats
• Rats, Sprague-Dawley
• Thyroid Hormones/blood
• Transcriptome/drug effects

Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data.

• animal models
• bile ductular reaction
• epithelial to mesenchymal transition
• hepatic fibrosis
• hepatic progenitor cells
• myofibroblasts
• renal fibrosis

• Biomarkers, Tumor/metabolism
• Evidence-Based Medicine
• Feasibility Studies
• Humans
• Image Interpretation, Computer-Assisted/methods
• Magnetic Resonance Imaging/methods
• Molecular Imaging/methods
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/metabolism
• Prognosis
• Reproducibility of Results
• Sensitivity and Specificity

• colorectal cancer
• hepatocellular carcinoma
• microRNA
• pancreatic cancer

The eukaryotic cell cycle is controlled by a complex regulatory network, which is still poorly understood. Here we demonstrate that TRPS1, an atypical GATA factor, modulates cell proliferation and controls cell cycle progression. Silencing TRPS1 had a differential effect on the expression of nine key cell cycle-related genes. Eight of these genes are known to be involved in the regulation of the G2 phase and the G2/M transition of the cell cycle. Using cell synchronization studies, we confirmed that TRPS1 plays an important role in the control of cells in these phases of the cell cycle. We also show that silencing TRPS1 controls the expression of 53BP1, but not TP53. TRPS1 silencing also decreases the expression of two histone deacetylases, HDAC2 and HDAC4, as well as the overall HDAC activity in the cells, and leads to the subsequent increase in the acetylation of histone4 K16 but not of histone3 K9 or K18. Finally, we demonstrate that TRPS1 expression is elevated in luminal breast cancer cells and luminal breast cancer tissues as compared with other breast cancer subtypes. Overall, our study proposes that TRPS1 acts as a central hub in the control of cell cycle and proliferation during cancer development.

Pancreatic cancer remains difficult to treat and has a high mortality rate. It is difficult to diagnose early, mainly due to the lack of screening imaging modalities and specific biomarkers. Consequently, it is important to develop biomarkers that enable the detection of early stage tumors. Emerging evidence is accumulating that tumor cells release substantial amounts of RNA into the bloodstream that strongly resist RNases in the blood and are present at sufficient levels for quantitative analyses. These circulating RNAs are upregulated in the serum and plasma of cancer patients, including those with pancreatic cancer, compared with healthy controls. The majority of RNA biomarker studies have assessed circulating microRNAs (miRs), which are often tissue-specific. There are few reports of the tumor-specific upregulation of other types of small non-coding RNAs (ncRNAs), such as small nucleolar RNAs and Piwi-interacting RNAs. Long ncRNAs (lncRNAs), such as HOTAIR and MALAT1, in the serum/plasma of pancreatic cancer patients have also been reported as diagnostic and prognostic markers. Among tissue-derived RNAs, some miRs show increased expression even in pre-cancerous tissues, and their expression profiles may allow for the discrimination between a chronic inflammatory state and carcinoma. Additionally, some miRs and lncRNAs have been reported with significant alterations in expression according to disease progression, and they may thus represent potential candidate diagnostic or prognostic biomarkers that may be used to evaluate patients once detection methods in peripheral blood are well established. Furthermore, recent innovations in high-throughput sequencing techniques have enabled the discovery of unannotated tumor-associated ncRNAs and tumor-specific alternative splicing as novel and specific biomarkers of cancers. Although much work is required to clarify the release mechanism, origin of tumor-specific circulating RNAs, and selectivity of carrier complexes, and technical advances must also be achieved, such as creating a consensus normalization protocol for quantitative data analysis, circulating RNAs are largely unexplored and might represent novel clinical biomarkers.

• MicroRNA
• Non-coding RNA
• Pancreatic cancer
• Biomarkers
• Early detection

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Early Detection of Cancer/methods
• Humans
• Molecular Diagnostic Techniques
• Pancreatic Neoplasms/blood
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Predictive Value of Tests
• Prognosis
• RNA/blood
• RNA/genetics
• RNA, Messenger/blood
• RNA, Messenger/genetics
• RNA, Untranslated/blood
• RNA, Untranslated/genetics

To investigate the role(s) of Trps1 in non-anastomotic biliary stricture (NABS) following liver transplantation.

Immunohistochemical and histological techniques were used to detect Trps1, E-cadherin, CK19, vimentin, α-SMA, and collagen deposition. Human intrahepatic biliary epithelial cells (HIBECs) were infected with a Trps1 adenovirus, or transfected with Trps1 short-interfering RNAs (siRNAs). Reverse transcription polymerase chain reaction (RT-PCR) assays and western blotting were used to determine expression levels of epithelial and mesenchymal markers, and Trps1 in HIBECs.

Expression of Trps1 and epithelial markers was down-regulated or absent in NABS liver samples. Mesenchymal markers were seen in biliary epithelial cells (BECs), with collagen deposited around the bile duct. Trps1 expression positively correlated with epithelial markers. Expression of epithelial marker mRNAs and proteins in HIBECs decreased with prolonged cold preservation (CP), while mesenchymal marker expression increased. A 12-h CP period led to increased Trps1 mRNA and protein levels. Expression of E-cadherin was increased in HIBECs following Trps1 adenovirus infection and CP/reperfusion injury (CPRI), with vimentin expression levels reduced and CPRI-mediated epithelial-mesenchymal transition (EMT) inhibited. Transfection of HIBECs with Trps1 siRNAs in conjunction with CPRI revealed that E-cadherin expression was decreased, vimentin expression was increased, and CPRI-mediated EMT was promoted.

Trps1 is involved in NABS pathogenesis following liver transplantation and negatively correlates with BEC EMT and biliary fibrosis in liver grafts. Trps1 demonstrates antagonistic effects that could reverse EMT.

• Adult
• Bile Ducts/metabolism
• Bile Ducts/pathology
• Cadherins/metabolism
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Epithelial-Mesenchymal Transition/physiology
• Female
• Fibrosis/metabolism
• Fibrosis/pathology
• Humans
• Liver Diseases/metabolism
• Liver Diseases/pathology
• Liver Diseases/surgery
• Liver Transplantation
• Male
• Middle Aged
• Repressor Proteins
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Vimentin/metabolism

• MicroRNA
• growth
• human non-small cell lung cancer

• Diagnosis
• Pancreatic cancer
• Pathogenesis
• Therapy
• miRNA