Identification of gene signatures associated with ulcerative colitis and the association with immune infiltrates in colon cancer.

Background: Inflammatory bowel diseases, including ulcerative colitis (UC) and Crohn's disease, are some of the most common inflammatory disorders of the gastrointestinal tract. The dysfunction of the immune system in the intestines is suggested to be the underlying cause of the pathogenesis of UC. However, the mechanisms regulating these dysfunctional immune cells and inflammatory phenotypes are still unclear. Methods: The differential expression analysis on microarray datasets were performed including GSE24287, GSE87466, GSE102133, and GSE107499, including 376 samples. "Gene Ontology" and "Kyoto Encyclopedia of Genes and Genomes" pathway enrichment analyses were conducted to identify the common differentially expressed genes (DEGs) in these datasets and explore their underlying biological mechanisms. Further algorithms like "Cell-type Identification by Estimating Relative Subsets of RNA Transcripts" were used to determine the infiltration status of immune cells in patients with UC. "Cytoscape" and "Gene Set Enrichment Analysis" were used to screen for hub genes and to investigate their biological mechanisms. The Tumor Immune Estimation Resource database was used to study the correlation between hub genes and infiltrating immune cells in patients with UC. A total of three hub genes, CCL3, MMP3, and TIMP1, were identified using Cytoscape. Results: A positive correlation was observed between these hub genes and patients with active UC. These genes served as a biomarker for active UC. Moreover, a decrease in CCL3, MMP3, and TIMP1 expression was observed in the mucosa of the intestine of patients with active UC who responded to Golimumab therapy. In addition, results show a significant positive correlation between CCL3, MMP3, and TIMP1 expression and different immune cell types including dendritic cells, macrophages, CD8+ T cells, and neutrophils in patients with colon cancer. Moreover, CCL3, MMP3, and TIMP1 expression were strongly correlated with different immune cell markers. Conclusion: Study results show the involvement of hub genes like CCL3, MMP3, and TIMP1 in the pathogenesis of UC. These genes could serve as a novel pharmacological regulator of UC. These could be used as a therapeutic target for treating patients with UC and may serve as biomarkers for immune cell infiltration in colon cancer.

The role of hypoxic mesenchymal stem cells in tumor immunity.

The emerging evidence has shown that mesenchymal stem cells (MSCs) not only exert a significant role in the occurrence and development of tumors, but also have immunosuppressive potential in tumor immunity. Hypoxia is a sign of solid tumors, but how functions of hypoxic MSCs alter in the tumor microenvironment (TME) remains less well and comprehensively described. Herein, we mostly describe and investigate recent advances in our comprehension of the emerging effects of different tissue derived MSCs in hypoxia condition on tumor progression and development, as well as bidirectional influence between hypoxic MSCs and immune cells of the TME. Furthermore, we also discuss the potential drug-resistant and therapeutic role of hypoxic MSCs. It can be envisaged that novel and profound insights into the functionality of hypoxic MSCs and the underlying mechanisms in tumor and tumor immunity will promote the meaningful and promising treatment strategies against tumor.

Synergistic reversal effect of epithelial-to-mesenchymal transition by miR-223 inhibitor and genistein in gemcitabine-resistant pancreatic cancer cells.

Emerging studies have demonstrated that EMT phenotype is closely related with tumor progression and drug resistance in a variety of human cancers. Recently, it has been extensively demonstrated that microRNAs (miRNAs) play a pivotal role in regulating EMT. In our previously reports, we have reported that inhibition of miR-223 could reverse EMT phenotype and improve chemotherapeutic drug sensitivity. We also reported that genistein down-regulated miR-223 expression in gemcitabine-resistant (GR) pancreatic cancer cells. Here, we explored whether there was the synergistic effect between miR-223 inhibitor and genistein on cell growth, migration, invasion and reversal of EMT in GR pancreatic cancer. We found that the combination of miR-223 inhibitor and genistein synergistically reduced cell motility and invasion and enhanced gemcitabine sensitivity in GR cells. In addition, we further observed that miR-223 inhibitor and genistein reversed EMT features in GR cells. This study suggests that the combination of miR-223 inhibitor and genistein may be a potential therapeutic strategy for the treatment of pancreatic cancer.

Arsenic trioxide suppresses cell growth and migration via inhibition of miR-27a in breast cancer cells.

Accumulating evidence has demonstrated that arsenic trioxide (ATO) exhibits its anti-cancer activities in a variety of human malignancies. Recent studies have revealed that ATO regulated multiple microRNAs (miRNAs) in human cancers. However, the exact mechanism of ATO-mediated tumor suppressive function has not been fully elucidated. In the present study, we explore whether ATO governed oncogenic miR-27a in breast cancer cells by multiple methods such as MTT assay, RT-PCR, Wound healing assay, Western blotting analysis, migration, Transwell invasion assay, and transfection. Our results showed that ATO inhibited cell growth, migration, invasion, and induced cell apoptosis in breast cancer cells. Further molecular analysis dissected that ATO inhibited miR-27a expression in breast cancer cells. Moreover, inhibition of miR-27a suppressed cell growth, migration, invasion, and trigged cell apoptosis, whereas overexpression of miR-27a enhanced cell growth, motility, and inhibited apoptosis in breast cancer cells. Notably, we found that miR-27a inhibitor treatment potentiates ATO-induced breast cancer cell growth inhibition, apoptosis and motility inhibition. However, overexpression of miR-27a partly abrogated ATO-mediated anti-tumor activity. Our findings provide a novel anti-tumor mechanism of ATO involved in miR-27a for the treatment of breast cancer.

[Proanthocyanidins inhibit pancreatic cancer AsPC-1 cell growth and migration through up-regulation of let-7a].

OBJECTIVE: To ascertain whether proanthocyanidins inhibit cell growth and migration by increasing let-7a expression in pancreatic cancer AsPC-1 cells. METHODS: The proliferation rate, cell apoptosis rate and cell migration ability of AsPC-1 cells treated with proanthocyanidins were measured by MTT assay, Annexin V-FITC/PI staining, and Transwell migration assay, respectively. The expression of let-7a AsPC cells was detected by miRNA real-time RT-PCR after proanthocyanidins treatment. The changes in the biological behaviors of AsPC-1 cells were evaluated after transfection with let-7a mimics. RESULTS: Compared with the control group, proanthocyanidins treatment caused dose-dependent decrements of the proliferation rate and migration ability and increased the apoptosis rate in AsPC-1 cells. AsPC-1 cells with proanthocyanidins treatment showed increased expression of let-7a. Transfection with let-7a mimics resulted in obvious decreases in the cell growth rate and migration ability, and proanthocyanidins treatment significantly enhanced the inhibitory effect of let-7a mimics. CONCLUSION: Proanthocyanidins-induced cell growth and migration inhibition are partially mediated by up-regulation of let-7a expression in AsPC-1 cells.

[Grape seed proanthocyanidins extract inhibits pancreatic cancer cell growth through down-regulation of miR-27a expression].

OBJECTIVE: To explore the eff ect of grape seed proanthocyanidins extract (GSPE) on the growth of pancreatic cancer cells and the underlying mechanisms. METHODS: The pancreatic cancer AsPC-1 cells were cultured in vitro. The effects of GSPE on cell proliferation, apoptosis and migration were analyzed by MTT, Annexin V-FITC/PI and Transwell migration assay, respectively. The expression of miR-27a and FOXO1 in AsPC-1 cells was determined by real-time RT-PCR and Western blot, respectively. The miR-27a inhibitors were applied to verify the role of miR-27a in mediation of GSPE effects. RESULTS: GSPE inhibited cell growth in a dose-dependent manner. This inhibitory effect was significant when the dosage of GSPE was more than 50 µg/mL (P<0.05 vs control). GSPE also could induce apoptosis and inhibit cell migration. MiR-27a expression was notably down-regulated when the dosage of GSPE was 75 µg/mL (P<0.01 vs control). Compared with the control group, cell proliferation inhibition was significantly increased in the miR-27a inhibitor group, the GSPE group and the miR-27a inhibitor plus GSPE group (P<0.01), while cell migration was significantly decreased (P<0.01). Compared with the GSPE or the miR-27a inhibitor group, the growth and migration inhibitory effects in the miR-27a inhibitor plus GSPE group were more obviously (P<0.01). Both GSPE and miR-27a inhibitor alone could up-regulate FOXO1 expression. But these effects were more apparent when they are applied in combination. CONCLUSION: GSPE inhibites AsPC-1 cells' growth and migration partly through down-regulation of miR-27a expression.

Down-regulation of miR-223 reverses epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells.

Recent studies have demonstrated that acquisition of epithelial-to-mesenchymal transition (EMT) is associated with drug resistance in pancreatic cancer cells; however, the underlying mechanisms are not fully elucidated. Emerging evidence suggests that microRNAs play a crucial role in controlling EMT. The aims of this study were to explore the potential role of miR-223 in governing EMT in gemcitabine-resistant (GR) pancreatic cancer cells. To achieve this goal, real-time reverse transcription-PCR and western blot analysis were used to validate whether GR cells acquired EMT in AsPC-1 and PANC-1 cells. Invasion, migration, and detachment assays were performed to further identify the EMT characteristics in GR cells. The miR-223 inhibitor was used to determine its role in GR-induced EMT. We found that GR cells acquired EMT features, which obtained elongated fibroblastoid morphology, decreased expression of epithelial marker E-cadherin, and up-regulation of mesenchymal markers. Furthermore, we observed that GR cells are associated with high expression of miR-223. Notably, inhibition of miR-223 led to the reversal of EMT phenotype. More importantly, miR-223 governs GR-induced EMT in part due to down-regulation of its target Fbw7 and subsequent upregulation of Notch-1 in pancreatic cancer. Our study implied that down-regulation of miR-223 could be a novel therapy for pancreatic cancer.

Curcumin inhibits cell growth and invasion through up-regulation of miR-7 in pancreatic cancer cells.

Accumulating evidence has revealed that a natural compound curcumin exerts its anti-tumor activity in pancreatic cancer. However, the underlying molecular mechanism remains elusive. Recently, miRNAs have been demonstrated to play a crucial role in tumorigenesis, suggesting that targeting miRNAs could be a promising approach for the treatment of human cancers. In this study, we explored whether curcumin regulates miR-7, leading to the inhibition of cell growth, migration and invasion in pancreatic cancer cells. We observed that curcumin suppressed cell growth, migration and invasion, and induced cell apoptosis, which is associated with increased expression of miR-7 and subsequently decreased expression of SET8, one of the miR-7 targets. These findings demonstrated that targeting miR-7 by curcumin could be a novel strategy for the treatment of pancreatic cancer.

Genistein inhibits cell growth and invasion through regulation of miR-27a in pancreatic cancer cells.

BACKGROUND: Although genistein has been reported to exert its anti-tumor activity, the exact mechanism of its action is poorly elucidated. Recently, it has been found that genistein could regulate the expression of microRNAs. Therefore, our aim in the present study was to find whether genistein regulates specific miR-27a in pancreatic cancer cells. METHODS: We performed our studies using multiple methods including MTT assay, RT-PCR, Western blotting analysis, migration, invasion assay, and transfection. RESULTS: We observed that genistein significantly inhibited the expression of miR-27a in pancreatic cancer cells. Moreover, inhibition of miR-27a suppressed cell growth and induced apoptosis as well as inhibited invasion in pancreatic cancer cells. Furthermore, we found a synergy effect between miR-27a and genistein on cell growth inhibition, apoptosis, and invasion, suggesting that targeting miR-27a may represent a potential strategy for treatment of pancreatic cancer. CONCLUSIONS: Our findings demonstrated that genistein plays a tumor suppressor role in part through inhibition of miR-27a in pancreatic cancer cells.

Genistein down-regulates miR-223 expression in pancreatic cancer cells.

Although genistein has been shown to inhibit tumorigenesis in a variety of human cancers including pancreatic cancer (PC), the exact molecular mechanism of its anti-cancer effects has not yet been fully elucidated. Recently, microRNAs (miRNAs) have been reported to regulate multiple aspects of tumor development and progression, indicating that targeting miRNAs could be a novel strategy to treat human cancers. In the current study, we investigated whether a natural compound genistein could down-regulate onco-miR-223, resulting in the inhibition of cell growth and invasion, and induction of apoptosis in PC cells. We found that genistein treatment significantly inhibited miR-223 expression and up-regulated Fbw7, one of the targets of miR-223. Moreover, down-regulation of miR-223 inhibited cell growth and induced apoptosis in PC cells. These findings suggest that genistein exerts its anti-tumor activity partly through downregulation of miR-223 in PC cells.