406947

MIR155

microRNA 155;MIR155;microRNA 155

hsa-mir-155

21q21.3

ncRNA

During breast cancer progression, transforming growth factor-beta (TGF-beta) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBPbeta), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-beta-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBPbeta was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBPbeta potentiated the TGF-beta response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-beta. Furthermore, loss of C/EBPbeta enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBPbeta promoted the TGF-beta response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBPbeta as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBPbeta as a mechanism, which promotes breast cancer progression by shifting the TGF-beta response from growth inhibition to EMT, invasion and metastasis.

OBJECTIVE: to investigate the expression of the hsa-miR-155 in serum of endometrial cancer and its clinical significance. METHODS: collected 44 cases blood specimens before surgery operation from Sep. 2008 to Dec. 2009, and collected 12 cases blood specimens from the health of volunteers in comparison. Real time quantity PCR was used to detect the expression of hsa-miR-155 in those specimens and analyzed clinical pathological with the expression of hsa-mir-155 in endometrial cancer. RESULTS: the expression of hsa-miR-155 was (3.9 +/- 0.7) in endometrial cancer, which was significantly higher than that in control group (P < 0.01). The expressions of hsa-miR-155 were (3.7 +/- 0.6), (3.9 +/- 0.6) and (3.7 +/- 0.6) times in well, moderately and poorly differentiated endometrial cancer, respectively, while there were not significant difference (P > 0.05). The expressions were (3.8 +/- 0.6) and (3.9 +/- 0.6) times between endometrioid adenocarcinoma and non-endometrioid adenocarcinoma, and there were significant difference (P > 0.05). The expressions were (2.1 +/- 0.4) and (5.6 +/- 0.8) times in stage I - II and III - IV endometrial cancer, respectively, in which there were significant difference (P < 0.05). The expressions of hsa-miR-155 were (5.5 +/- 0.5) and (1.9 +/- 0.2) times between lymph node metastasis and without lymph node metastasis in endometrial cancer, in which there were significant difference (P < 0.01). CONCLUSION: Hsa-miR-155 may play an important role in the proliferation, and metastasis of endometrial cancer, which may be a indicator in the diagnosis and prognosis of endometrial cancer and may be used as a predictive biomarker.

The prognosis of gallbladder cancer (GBC) remains poor despite recent advances in diagnostics and therapeutic strategies. Although the role of microRNAs (miRs) in GBC have not been well documented, miR-155 is known to be associated with inflammation-associated carcinogenesis in various types of cancers. The aim of this study was to investigate the clinical significance of miR-155 expression and the biological functions of miR-155 in GBC. The expression levels of miR-155 in surgically resected GBCs and gallbladders with pancreaticobiliary maljunction (PBM) were assessed by quantitative reverse transcription-polymerase chain reaction. The relationship between the expression levels of miR-155 and clinicopathological features of GBCs was analyzed. Human GBC cell lines were transfected with miR-155 inhibitors or mimics, and the effects on proliferation and invasion were assessed. miR-155 was significantly overexpressed in GBCs when compared with that in gallbladders with PBM (p=0.007) and normal gallbladders (p=0.04). The high expression level of miR-155 in GBCs was significantly associated with the presence of lymph node metastasis (p=0.01) and a poor prognosis (p=0.02). In vitro assays showed that aberrant expression of miR-155 significantly enhanced GBC cell proliferation and invasion. In conclusion, high miR-155 expression correlates with the aggressive behavior of GBCs, and miR-155 may become a prognostic marker and therapeutic target for GBC.

microRNA-155 (miR-155), an important multifunctional microRNA, has been implicated in the development of multiple solid tumors, yet, its role in gastric cancer cells has not been fully elucidated. In this study, we find that miR-155 was significantly downregulated in gastric cancer cell lines compared with an immortalized gastric epithelial cell line (GES-1). Overexpression of miR-155 in SGC-7901 and MKN-45 gastric cancer cells dramatically suppressed cell migration, invasion and adhesion in vitro. Overexpression of miR-155 significantly reduced the protein levels of SMAD2 and repressed the activity of a luciferase reporter containing one of the two predicted miR-155 binding sites in SMAD2 3-UTR, indicating that SMAD2 may be a miR-155 target gene. miR-155 expression was also remarkably restored by a DNA demethylating agent (5-Aza-2-deoxycytidine) in SGC-7901 and MKN-45 gastric cancer cells. Taken together, these data suggest that miR-155 may function as a tumor suppressor to regulate gastric cancer cell metastasis by targeting SMAD2, and its downregulation in gastric cancer cells may be partly ascribed to DNA methylation.

Dysregulated miRNAs in gastric cancer are usually screened by miRNA microarray from clinical samples, however, reports have indicated that results of each miRNA microarray screening are considerably different, and dysregulated miRNAs, especially downregulated miRNAs were contradictory. In view of this, the Human cancer pathway Finder miRNA PCR array was applied to compare 7 gastric cancer cell lines AGS, SGC-7901, MKN-45, MKN-28, MGC-803, BCG-823, and HGC-27 with an immortalized normal gastric cell line, GES-1 in cancer pathway-related miRNA expression profile, followed by qPCR verification, the clinical significance of downregulated miRNAs and the Enriched KEGG pathways and GO terms of their target genes were analyzed. Thirty-eight miRNAs were upregulated, and four miRNAs were downregulated in gastric cancer cell lines. Clinical significance of 4 miRNAs including mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p in gastric cancer tissue compared with adjacent non-tumor tissues of 58 patients indicated that the low-expression group of mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p showed more extensive lymph node metastasis, lymphatic invasion, venous invasion, high-stage Borrmann type, lymphatic invasion and poor differentiation than that of the high-expression groups, respectively (P<0.05; chi(2) test). Enriched KEGG pathway analyses showed that most of the targeted genes of the 4 miRNAs concentrated on 37 signaling pathways, and were involved in the same pathways related to cancer. Enriched GO terms showed that targeted genes of the 4 miRNAs concentrated on 339 terms, 24 of 339 terms are associated with cancer tumorigenesis. The Human cancer pathway Finder miRNA PCR array could be used to screen dysregulated miRNAs effectively, and 4 screened miRNAs, mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p were found to be downregulated in gastric cancer. Clinical significance and bioinformatic analysis on the target genes of these 4 miRNAs indicated that they were deeply involved in tumorigenesis, suggesting roles such as miRNA tumor suppressors in gastric cancer tumorigenesis which could be applied in gastric cancer diagnosis and prognosis.