• BAMBI
• Colorectal cancer
• Metastasis
• SP5
• circSP5

• Animals
• Humans
• Colorectal Neoplasms/genetics
• Disease Models, Animal
• Liver Neoplasms/genetics
• Membrane Proteins
• RNA
• RNA, Circular/genetics

• 82103439 the National Natural Science Foundation of China

Colorectal cancer (CRC) is the third leading cause for cancer related death, in which metastasis exerts a pivotal role. Therefore, we aim to find out the possible mechanism underlying CRC metastasis. We found that the level of miR-125b was elevated in normal, primary CRC, and distant metastasis tissues stepwise, and high level miR-125b was positively correlated with lymph node metastasis and tumor differentiation. In vitro and in vivo assays showed miR-125b significantly promoted CRC migration and invasion. To elucidate the potential mechanism, cystic fibrosis transmembrane conductance regulator (CFTR) and cingulin (CGN) were defined as two target genes of miR-125b. On the one hand, miR-125b promoted epithelial-mesenchymal transition (EMT) and the production and secretion of urokinase plasminogen activator (uPA) by inhibiting CFTR; on the other hand, miR-125b activated Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) signaling by repressing CGN. Therefore, we provided a potential biomarker for CRC prevention and treatment in the future.

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

• colorectal cancer
• invasion
• metastasis
• miRNA
• migration

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/genetics
• Carcinoma, Ovarian Epithelial/genetics
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• MicroRNAs/genetics
• Middle Aged
• Ovarian Neoplasms/genetics
• Prognosis

• The Mermaid Project
• Danish Cancer Research Foundation
• Herlev Hospital Research Council

Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated.

MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on.

MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST.

Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC.

• chemotherapeutic sensitivity
• colorectal cancer
• drug resistance
• miR-125b-2-3p

• Aged
• Animals
• Antineoplastic Agents/therapeutic use
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Cell Proliferation/genetics
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• Epithelial-Mesenchymal Transition/genetics
• Female
• HCT116 Cells
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Neoplasm Metastasis/genetics
• Protein-Tyrosine Kinases/genetics
• Protein-Tyrosine Kinases/metabolism
• RNA, Long Noncoding/metabolism
• Real-Time Polymerase Chain Reaction
• Tumor Stem Cell Assay
• Up-Regulation

Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

Ovarian cancer has a high incidence rate and mortality in gynaecologic malignancies. Epithelial ovarian cancer (EOC) accounts for >95% of ovarian cancer cases. Most of the patients with EOC are difficult to diagnose in early stage. The aim of the present study was to compare the long non-coding (lnc)RNA expression profiles of five ovarian cancer cell lines (IGROV1, A2780, SKOV3, ES2, and Hey) and an ovarian epithelial cell line (IOSE80) in order to identify differentially expressed lncRNAs and their associated microRNAs (miRNAs). The expression profiles of lncRNAs and mRNAs in these cell lines were determined by microarray gene analysis and reverse transcription-quantitative PCR. lncRNA neuropeptides B and W receptor 1–2 (NPBWR1-2) overexpression was induced in the SKOV3 cell line. Cell viability, proliferation, migration, invasion and apoptosis were evaluated using MTT, colony-formation, Transwell and flow cytometry assays, respectively. The microarray results indicated that several lncRNAs were differentially expressed in the five ovarian cancer cell lines compared with the normal ovarian epithelial cell line. Compared with IOSE80, lncRNA NPBWR1-2 was downregulated by more than two-fold in all five ovarian cancer cell lines. Moreover, NPBWR1-2 overexpression in the SKOV3 cell line decreased cell viability, inhibited proliferation, migration and invasion, and promoted apoptosis compared with the control cells. A total of 20 miRNAs, which are involved in tumorigenesis and development, were predicted to be associated with NPBWR1-2 by bioinformatics analysis. The results of the present study suggest that lncRNA NPBWR1-2 affects the occurrence and development of ovarian cancer via multiple miRNAs, providing a theoretical basis for the development of novel clinical treatments.

• lncRNA
• miRNA
• microarray
• neuropeptides B and W receptor 1–2
• ovarian cancer

• apoptosis
• miR-1179
• microRNA
• ovarian cancer

Glioblastoma multiforme (GBM) is one of the most malignant types of glioma known for its reduced survival rate and rapid relapse. Previous studies have shown that the expression patterns of different microRNAs (miRNA/miR) play a crucial role in the development and progression of GBM. In order to identify potential miRNA signatures of GBM for prognostic and therapeutic purposes, we downloaded and analyzed two expression data sets from Gene Expression Omnibus profiling miRNA patterns of GBM compared with normal brain tissues. Validated targets of the deregulated miRNAs were identified using MirTarBase, and were mapped to Search Tool for the Retrieval of Interacting Genes/Proteins, Database for Annotation, Visualization and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes databases in order to construct interaction networks and identify enriched pathways of target genes. A total of 6 miRNAs were found to be deregulated in both expression datasets studied. Pathway analysis demonstrated that most of the target genes were enriched in signaling cascades connected to cancer development, such as ‘Pathways in cancer’, ‘Focal adhesion’ and ‘PI3K-Akt signaling pathway’. Of the five target genes that were enriched in the glioblastoma pathway, in the WikiPathway database, both HRas proto-oncogene, GTPase and MET proto-oncogene, receptor tyrosine kinase target genes of hsa-miR-139-5p, were found to be significantly associated with patient survival. The present study may thus form the basis for further exploration of hsa-miR-139-5p, not only as a therapeutic agent, but also as a diagnostic biomarker for GBM as well as a predictive marker for patient survival.

• GEO2R
• gene expression omnibus
• glioblastoma multiforme
• microRNA
• pathway analysis

MicroRNA-335 (miR-335) was reported to suppress cell proliferation in prostate cancer (PC), a common malignancy in males. The expression of early growth response 3 (EGR3) was determined to be elevated in human PC tissues; however, the possible effects and underlying mechanism of miR-335 on PC remains unknown. In the present study, miR-335 mimics and miR-335 inhibitors were respectively transfected into DU145 cells. Stable silencing of EGR3 was observed in DU145 cells following transfection with small interfering RNA. We also used Cell Counting Kit-8 and in vitro angiogenesis assays to determine the viability and revascularization potential of DU145 cells. The expression levels of EGR and caspase-3 activity were analyzed by immunohistochemistry and immunocytochemistry, respectively. We predicted the target of miR-335 by bioinformatics analysis and a dual-luciferase reporter gene assay. Western blot and quantitative real-time polymerase chain reaction analyses were performed to determine the protein and mRNA expression of molecules. miR-335 expression was downregulated in PC tissues and cell lines. Overexpression of miR-335 significantly reduced the viability and the formation of regenerative tubes of DU145 cells, and inhibited the expression of inflammatory factors. EGR3 was proposed as a possible target of miR-335, and was negatively regulated by miR-335. Silencing EGR3 suppressed the viability and angiogenesis of DU145 cells, and reduced the activity of caspase-3 and inflammatory factor expression. miR-335 inhibition along with EGR3 silencing EGR3 inhibited the cell proliferation. Furthermore, miR-335 inhibited the formation of a PC solid tumor xenograft in vivo. Thus, miR-335 may exert an antitumor effect on DU145 cells by regulating the expression of EGR3. The findings of the present study may provide insight into a novel therapeutic strategy for the treatment of prostatic carcinoma.

• Colorectal carcinoma, KRAS mutation, miR-425-5p expression levels, DICER1 gene, TNFRSF10B gene
• PTEN gene.

Ovarian cancer is the leading cause of death by gynecologic cancers in the Western world. The aim of the study was to identify microRNAs (miRNAs) associated with prognosis and/or resistance to chemotherapy among patients with epithelial ovarian cancer.

Using information from the Pelvic Mass Study we identified a cohort of women with epithelial ovarian cancer. Tumor tissues were then collected and analyzed by global miRNA microarrays. MiRNA profiling was then linked to survival and time to progression using Cox proportional-hazards regression models. Logistic regression models were used for the analysis of resistance to chemotherapy. Our results were validated using external datasets retrieved from the NCBI Gene Expression Omnibus database.

A total of 197 patients with epithelial ovarian cancer were included for miRNA microarray analysis. In multivariate analyses we identified a number of miRNAs significantly correlated with overall survival (miR-1183 (HR: 1.42, 95% CI:1.17–1.74, p = 0.0005), miR-126-3p (HR: 1.38, 95% CI:1.11–1.71, p = 0.0036), time to progression (miR-139-3p (HR: 1.48, 95% CI: 1.13–1.94, p = 0.0047), miR-802 (HR: 0.48, 95% CI: 0.29–0.78, p = 0.0035)), progression free survival (miR-23a-5p (HR:1.32, 95% CI:1.09–1.61, p = 0.004), miR-23a-3p (HR:1.70, 95% CI:1.15–2.51, p = 0.0074), miR-802 (HR: 0.48, 95% CI: 0.29–0.80, p = 0.0048)), and resistance to chemotherapy (miR-1234 (HR: 0.26, 95% CI: 0.11–0.64, p = 0.003)). A few miRNAs identified in our training cohort, were validated in external cohorts with similar results.

Eight miRNAs were identified as significant predictors of overall survival, progression free survival, time to progression, and chemotherapy resistance. A number of these miRNAs were significantly validated using external datasets. Inter-platform and inter-laboratory variations may have influence on the ability to compare and reproduce miRNA results. The use of miRNAs as potential markers of relapse and survival in ovarian cancer warrants further investigation.

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Ovarian Epithelial/genetics
• Carcinoma, Ovarian Epithelial/metabolism
• Carcinoma, Ovarian Epithelial/mortality
• Carcinoma, Ovarian Epithelial/pathology
• Databases, Nucleic Acid
• Disease-Free Survival
• Female
• Gene Expression Profiling
• Humans
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/mortality
• Ovarian Neoplasms/pathology
• RNA, Neoplasm/biosynthesis
• RNA, Neoplasm/genetics
• Survival Rate

Liver metastasis is a primary factor of prognosis and long-term survival for patients diagnosed with colorectal cancer (CRC). Colorectal cancer liver metastasis (CRCLM), is a complex biological process involving multiple factors and steps, and its mechanisms are yet to be discovered. In recent years, small noncoding RNAs, especially microRNAs (miRNAs) have been proven to play an important role in tumorigenesis, progression and metastasis in a variety of cancers, including CRC. Increasing evidence suggests that miRNAs, including those from exosomes secreted by tumor cells in circulation, could be used as promising biomarkers in early cancer detection, treatment, and prognosis. In this review, we focus on the functional roles and clinical applications of miRNAs, especially those from circulating exosomes secreted by tumor cells related to CRCLM.

• Colorectal cancer (CRC)
• exosome
• liver metastasis
• miRNAs

• Humans
• MicroRNAs/metabolism
• Neoplasms/drug therapy
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Mas

• 18052 Cancer Research UK

Aberrant levels of circulating microRNAs are potential biomarkers for the early detection of colorectal cancer. The aim of this study was to study miR-139-3p and miR-622 in serum as a non-invasive biomarker for colorectal cancer diagnosis. We applied quantitative polymerase chain reaction to determine the levels of miR-139-3p and miR-622 in 42 pairs of tumor and adjacent non-tumor tissues, and in serum samples of 117 patients and 90 control subjects. Our results showed that miR-139-3p was silenced whereas miR-622 was overexpressed in colorectal cancer. Similarly, serum miR-139-3p level was significantly lower in colorectal cancer patients than in control subjects whereas miR-622 was more frequently detectable in patients. ROC analysis showed that AUC of miR-139-3p was 0.9935, with a sensitivity of 96.6% and specificity of 97.8%. Serum miR-139-3p level showed high sensitivity and specificity for both early and late stage CRCs and proximal and distal CRCs. Detectable serum miR-622 showed a sensitivity of 87.5% and specificity of 63.5% for discriminating CRC patients, but the sensitivity dropped for late stage patients (72.7%). We also included analyses of the blood CEA level for comparing the diagnostic performance of these blood-based biomarkers. The median level in CRC patients (3.6 ng/ml) was significantly higher than that in control (1.8 ng/ml). The AUC value of CEA in diagnosing CRC patients was 0.7515. CEA showed a positive correlation with tumor stage and age of patients and its level was higher in male. Collectively, serum miR-139-3p has strong potential as a promising non-invasive biomarker in colorectal cancer detection.

• CRC
• biomarker
• miR-139-3p
• miR-622
• miRNA

Tumour stroma has important roles in the development of colorectal cancer (CRC) metastasis. We aimed to clarify the roles of microRNAs (miRNAs) and their target genes in CRC stroma in the development of liver metastasis.

Tumour stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by laser capture microdissection, and miRNA expression was analysed using TaqMan miRNA arrays.

Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumour stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of tenascin C in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P<0.001). Univariate and multivariate analyses revealed that the tenascin C staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128).

Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate tenascin C to promote liver metastasis. Tenascin C in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis.

• miR-718; MicroRNA; Early growth response protein 3 (EGR3); Hepatocellular carcinoma (HCC); Malignant phenotype

• Adenomas
• Colon cancer
• Serum miRNAs

• Adenoma/blood
• Adenoma/metabolism
• Aged
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Colonic Neoplasms/blood
• Colonic Neoplasms/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• MicroRNAs/blood
• MicroRNAs/genetics
• Middle Aged

• Nanjing Medical Science and Technology Development Project
• Nanjing Medical Science and Technology Development Project

• G-CSF
• MCL1
• colorectal cancer
• metastasis
• microRNA-125b

• Genetic polymorphisms
• Hepatocellular carcinoma
• Survival
• miRNA

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Female
• Genetic Predisposition to Disease/genetics
• Genotype
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Male
• MicroRNAs/genetics
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• Prognosis
• Risk Factors
• Young Adult

• Cluster
• Colorectal cancer
• MicroRNA
• Target
• Transcription factor

• DNA damage
• comet assay
• exosome
• high-throughput screening
• lead sulfide quantum dots (PbS QDs)
• nanoparticle toxicity

• 3-Mercaptopropionic Acid/chemistry
• Biomarkers, Tumor/metabolism
• Carcinogens/chemistry
• Carcinogens/toxicity
• Chemokine CXCL5/genetics
• Chemokine CXCL5/metabolism
• Coated Materials, Biocompatible/chemistry
• Coated Materials, Biocompatible/pharmacology
• Comet Assay
• DNA Damage/drug effects
• Exosomes/chemistry
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Interleukin-8/genetics
• Interleukin-8/metabolism
• Lead/chemistry
• Lead/toxicity
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Proteomics
• Quantum Dots/chemistry
• Quantum Dots/toxicity
• Sulfides/chemistry
• Sulfides/toxicity
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• microrna
• ptpn18
• mir-125a-5p
• gastrointestinal stromal tumours
• imatinib
• resistance
• sarcoma
• prognosis

• Antineoplastic Agents/therapeutic use
• Benzamides/therapeutic use
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/mortality
• Gastrointestinal Stromal Tumors/drug therapy
• Gastrointestinal Stromal Tumors/genetics
• Gastrointestinal Stromal Tumors/mortality
• Humans
• Imatinib Mesylate
• MicroRNAs/physiology
• Mutation
• Piperazines/therapeutic use
• Protein Tyrosine Phosphatases, Non-Receptor/genetics
• Protein Tyrosine Phosphatases, Non-Receptor/physiology
• Proto-Oncogene Proteins c-kit/genetics
• Pyrimidines/therapeutic use
• Receptor, Platelet-Derived Growth Factor alpha/genetics

• adenoma
• biomarker
• blood
• colorectal cancer
• diagnosis
• feces
• miRNA
• prediction
• prognosis

• Adenomatous Polyps/genetics
• Biomarkers, Tumor
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy
• Early Detection of Cancer
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Neoplasm Metastasis
• Neoplasm Staging
• Prognosis
• Treatment Outcome

• R01 CA72851 NCI NIH HHS
• CA181572 NCI NIH HHS
• R01 CA184792 NCI NIH HHS
• CA184792 NCI NIH HHS
• R01 CA181572 NCI NIH HHS
• R01 CA072851 NCI NIH HHS

• Colorectal cancer
• Invasion
• Metastasis
• microRNA-320a
• microRNA-320b

Colorectal cancer is the third most common cancer worldwide. Metastasis is a major cause of colorectal cancer-related death. Mechanisms of metastasis remain largely obscure. MicroRNA is one of the most important epigenetic regulators by targeting mRNAs post-transcriptionally. Accumulated evidence has supported its significant role in the metastasis of colorectal cancer, including epithelial-mesenchymal transition and angiogenesis. Dissecting microRNAome potentially identifies specific microRNAs as biomarkers of colorectal cancer metastasis. Better understanding of the complex network of microRNAs in colorectal cancer metastasis provide new insights in the biological process of metastasis and in the potential targets for colorectal cancer therapies and for diagnosis of recurrent and metastatic colorectal cancer.

• MicroRNAs
• Colorectal neoplasms
• Neoplasm metastasis

• K23 CA148964 NCI NIH HHS
• P50 CA062924 NCI NIH HHS

miRNAs are proved to have causal roles in tumorgenesis involving various types of human cancers, but the mechanism is not clear. We aimed to explore the effect of miRNAs on the development of ovarian cancer and the underlying mechanism.

The miRNA expression profile GSE31801 was downloaded from GEO (Gene Expression Omnibus) database. Firstly, the differentially expressed miRNAs were screened. Target genes of the miRNAs were collected from TargetScan, PicTar, miRanda, and DIANA-microT database, then the miRNA-miRNA co-regulating network was constructed using miRNA pairs with common regulated target genes. Next, the functional modules in the network were studied, the miRNA pairs regulated at least one modules were enriched to form the miRNA functional synergistic network (MFSN).

Risk miRNA were selected in MFSN according to the topological structure. Transcript factors (TFs) in MFSN were identified, followed by the miRNA-transcript factor networks construction. Totally, 42 up- and 61 down-regulated differentially expressed miRNAs were identified, of which 68 formed 2292 miRNA pairs in the miRNA-miRNA co-regulating network. GO: 0007268 (synaptic transmission) and GO: 0019226 (transmission of nerve impulse) were the two common functions of miRNAs in MFSN, and hsa-miR-579 (36), hsa-miR-942 (31), hsa-miR-105 (31), hsa-miR-150 (34), and hsa-miR-27a* (32) were selected as the hub nodes in MFSN.

In all, 17 TFs, including CREM, ERG, and CREB1 were screened as the cancer related TFs in MFSN. Other TFs, such as BIN1, FOXN3, FOXK1, FOXP2, and ESRRG with high degrees may be inhibited in ovarian cancer. MFSN gave us a new shed light on the mechanism studies in ovarian cancer.

• Adult
• Carcinoma/genetics
• Carcinoma/metabolism
• Carcinoma/mortality
• Carcinoma, Papillary
• Carcinoma, Papillary, Follicular/genetics
• Carcinoma, Papillary, Follicular/metabolism
• Carcinoma, Papillary, Follicular/mortality
• Disease-Free Survival
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Gene Expression Regulation
• Humans
• Male
• MicroRNAs/metabolism
• Middle Aged
• Multivariate Analysis
• Oligonucleotide Array Sequence Analysis
• Predictive Value of Tests
• Proportional Hazards Models
• Thyroid Cancer, Papillary
• Thyroid Gland/metabolism
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/metabolism
• Thyroid Neoplasms/mortality
• Treatment Outcome

Colorectal cancer (CRC) is one of the leading causes of cancer related deaths and the search for prognostic biomarkers that might improve treatment decisions is warranted. MicroRNAs (miRNAs) are short non-coding RNA molecules involved in regulating gene expression and have been proposed as possible biomarkers in CRC. In order to characterize the miRNA transcriptome, a large cohort including 88 CRC tumors with long-term follow-up was deep sequenced. 523 mature miRNAs were expressed in our cohort, and they exhibited largely uniform expression patterns across tumor samples. Few associations were found between clinical parameters and miRNA expression, among them, low expression of miR-592 and high expression of miR-10b-5p and miR-615-3p were associated with tumors located in the right colon relative to the left colon and rectum. High expression of miR-615-3p was also associated with poorly differentiated tumors. No prognostic biomarker candidates for overall and metastasis-free survival were identified by applying the LASSO method in a Cox proportional hazards model or univariate Cox. Examination of the five most abundantly expressed miRNAs in the cohort (miR-10a-5p, miR-21-5p, miR-22-3p, miR-143-3p and miR-192-5p) revealed that their collective expression represented 54% of the detected miRNA sequences. Pathway analysis of the target genes regulated by the five most highly expressed miRNAs uncovered a significant number of genes involved in the CRC pathway, including APC, TGFβ and PI3K, thus suggesting that these miRNAs are relevant in CRC.

• Biomarkers, Tumor/genetics
• Cluster Analysis
• Colorectal Neoplasms/genetics
• Female
• High-Throughput Nucleotide Sequencing/methods
• Humans
• Male
• MicroRNAs/genetics
• Prognosis
• Proportional Hazards Models
• Real-Time Polymerase Chain Reaction
• Transcriptome

MicroRNAs have been implicated in many critical cellular processes including apoptosis. We have previously found that apoptosis in pancreatic cancer cells was induced by adamantyl retinoid-related (ARR) molecule 3-Cl-AHPC. Here we report that 3-Cl-AHPC-dependent apoptosis involves regulating a number of microRNAs including miR-150* and miR-630. 3-Cl-AHPC stimulated miR-150* expression and caused decreased expression of c-Myb and IGF-1R in the pancreatic cancer cells. 3-Cl-AHPC-mediated reduction of c-Myb resulted in diminished binding of c-Myb with IGF-1R and Bcl-2 promoters, thereby causing repression of their transcription and protein expression. Over-expression of miR-150* also resulted in diminished levels of c-Myb and Bcl-2 proteins. Furthermore, the addition of the miRNA inhibitor 2′-O-methylated miR-150 blocked 3-Cl-AHPC-mediated increase in miR-150* levels and abrogated loss of c-Myb protein. Knockdown of c-Myb in PANC-1 cells resulted in enhanced apoptosis both in the presence or absence of 3-Cl-AHPC confirming the anti-apoptotic property of c-Myb. Overexpression of miR-630 also induced apoptosis in the pancreatic cancer cells and inhibited target protein IGF-1R mRNA and protein expression. Together these results implicate key roles for miR-150* and miR-630 and their targeting of IGF-1R to promote apoptosis in pancreatic cancer cells.

• Adamantane/analogs & derivatives
• Adamantane/pharmacology
• Apoptosis/genetics
• CD24 Antigen/metabolism
• Cell Line, Tumor
• Cinnamates/pharmacology
• Gene Expression
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Knockdown Techniques
• Genes, bcl-2
• Humans
• Hyaluronan Receptors/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplastic Stem Cells/metabolism
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins c-myb/genetics
• Proto-Oncogene Proteins c-myb/metabolism
• Receptor, IGF Type 1/genetics
• Receptor, IGF Type 1/metabolism
• Spheroids, Cellular
• Tumor Cells, Cultured

• Aged
• Aged, 80 and over
• Calcium Channels/genetics
• Calcium Channels/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Disease-Free Survival
• Female
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/secondary
• Male
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Middle Aged
• Neoplasm Metastasis
• TRPV Cation Channels/genetics
• TRPV Cation Channels/metabolism

AIM: To investigate the regulative effect of miRNA-338-3p (miR-338-3p) on cell growth in colorectal carcinoma (CRC).

METHODS: The lentiviral vector pLV-THM-miR-338-3p and pLV-THM-miR-338-3p-inhibitor were constructed. The recombinant viral vector encoding the pre-miR-338-3p or miR-338-3p-inhibitor and the two packaging plasmids psPAX2 and pMD2.G were cotransfected into human embryonic kidney 293T cells to package lentivirus. The supernatant containing the lentivirus particles was harvested to determine the viral titer, and this supernatant was then used to transduce CRC-derived cell line, SW-620. Flow cytometry was utilized for sorting the green fluorescent protein (GFP)⁺ cells to establish the SW-620 cell line stably expressing pre-miR-338-3p or miR-338-3p-inhibitor. Moreover, the expression of miR-338-3p was determined by real-time reverse transcriptase polymerase chain reaction, and Western blotting was used to detect the expression of the smoothened (SMO, the possible target of miR-338-3p) protein in SW-620 cells. Furthermore, the status of CRC cell proliferation and apoptosis were detected by 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry, respectively.

RESULTS: Restriction enzyme digestion and DNA sequencing demonstrated that the lentiviral vector pLV-THM-miR-338-3p and pLV-THM-miR-338-3p-inhibitor were constructed successfully. GFP was expressed after the SW-620 cells were transduced by the lentivirus. Expression of miR-338-3p in SW-620 cells transduced with the lentivirus pLV-THM-miR-338-3p was significantly increased (relative expression 3.91 ± 0.51 vs 2.36 ± 0.44, P < 0.01). Furthermore, overexpression of miR-338-3p inhibited the expression of SMO protein in SW-620 cells, which showed obviously suppressed proliferation ability [cellular proliferation inhibition rate (CPIR) 61.9% ± 5.2% vs 41.6% ± 4.8%, P < 0.01]. Expression of miR-338-3p in SW-620 cells transduced with the lentivirus pLV-THM-miR-338-3p-inhibitor was significantly decreased (relative expression 0.92 ± 0.29 vs 2.36 ± 0.44, P < 0.01). Moreover, the downregulated expression of miR-338-3p caused upregulated expression of the SMO protein in SW-620 cells, which showed significantly enhanced proliferation ability (CPIR 19.2% ± 3.8% vs 41.6% ± 4.8%, P < 0.01). However, anti-SMO-siRNA largely, but not completely, reversed the effects induced by blockage of miR-338-3p, suggesting that the regulative effect of miR-338-3p on CRC cell growth was indeed mediated by SMO.

CONCLUSION: miR-338-3p could suppress CRC growth by inhibiting SMO protein expression.

• Colorectal carcinoma
• Hsa-miRNA-338-3p
• Smoothened
• Lentivirus

• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Genetic Vectors
• HEK293 Cells
• Humans
• Lentivirus/genetics
• MicroRNAs/metabolism
• RNA Interference
• Receptors, G-Protein-Coupled/genetics
• Receptors, G-Protein-Coupled/metabolism
• Signal Transduction
• Smoothened Receptor
• Transduction, Genetic
• Transfection
• Up-Regulation

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Carcinoma, Non-Small-Cell Lung/blood
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Female
• Humans
• Lung Neoplasms/blood
• Lung Neoplasms/diagnosis
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Male
• MicroRNAs/blood
• MicroRNAs/genetics
• Middle Aged
• Pilot Projects
• Prognosis
• Sensitivity and Specificity

• brain metastasis
• colorectal cancer
• microarray
• microrna

Ovarian cancer is a common cause of cancer mortality in women with limited treatment effectiveness in advanced stages. The limitation to treatment is largely the result of high rates of cancer recurrence despite chemotherapy and eventual resistance to existing chemotherapeutic agents. The objective of this paper is to review current concepts of ovarian carcinogenesis. We will review existing hypotheses of tumor origin from ovarian epithelial cells, Fallopian tube, and endometrium. We will also review the molecular pathogenesis of ovarian cancer which results in two specific pathways of carcinogenesis: (1) type I low-grade tumor and (2) type II high-grade tumor. Improved understanding of the molecular basis of ovarian carcinogenesis has opened new opportunities for targeted therapy. This paper will also review these potential therapeutic targets and will explore new agents that are currently being investigated.

• 3' Untranslated Regions
• Animals
• Base Sequence
• Blotting, Western
• Cell Division/physiology
• Cell Line, Tumor
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• MicroRNAs/physiology
• Mucin-4/metabolism
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• RNA Processing, Post-Transcriptional
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction

• CA137513 NCI NIH HHS