The normal expression of human  globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with ␣-globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing -globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the -globin 3 untranslated region (3UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by ␣CP/hnRNP-E, a factor that plays a critical role in stabilizing human ␣-globin mRNA. Mutations within the new determinant destabilize -globin mRNA in intact cells while also ablating its 3UTR-specific interaction with the polyfunctional RNA-binding factor nucleolin. We speculate that 3UTR-bound nucleolin enhances mRNA stability by optimizing ␣CP access to its functional binding site. This model is favored by in vitro evidence that ␣CP binding is enhanced both by cis-acting stem-destabilizing mutations and by the trans-acting effects of supplemental nucleolin. These studies suggest a mechanism for -globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human ␣-globin mRNA.Erythroid cells accumulate hemoglobin through a process that is critically dependent upon the high stabilities of mRNAs that encode their constituent ␣-and -globin subunits (10, 64). In vivo analyses estimate a half-life for human ␣-globin mRNA of between 24 and 60 h (47,62,63,74), while similar studies with cultured NIH 3T3 and murine erythroleukemia (MEL) cells (2, 36, 42), primary mouse hematopoietic cells (4), and human erythroid progenitors (62, 63) suggest a half-life value for human -globin mRNA that exceeds 16 to 20 h. Globin mRNAs survive, and continue to translate at high levels, for as long as a week following nuclear condensation and extrusion in transcriptionally silent erythroid progenitor cells. As might be anticipated, mutations that impair the normal stabilities of globin mRNAs can severely impact the levels of their encoded proteins. For example, an mRNA-destabilizing mutation reduces the expression of ␣ Constant Spring to less than 2% of normal levels (45,51,80), resulting in a clinically important form of thalassemia characterized by a substantial imbalance in ␣-and -globin chain accumulation (10, 64).The cis-acting determinants and trans-acting factors that participate in regulating ␣-globin mRNA stability have recently been identified, and the relevant molecular mechanisms have been described in detail. Mutational analyses carried out with cultured cells (80, 81) and with animal models (52, 66) clearly demonstrate the importance of the 3Ј untranslated region (3ЈUTR) to the constitutively high stability of ␣-globin mRNA (45). Other studies have mapped this characteristic to a phylogenically conserved, 16-nucleotide (nt) C/U-rich element in this region (39,75,76). The cis-acting pyrimidine-rich element (PRE) assembles an mRNP "␣-complex" that compri...
Recent studies have shown that circulating microRNAs are potential biomarkers for various types of malignancies. The aim of this study was to investigate the feasibility of using serum exosomal microRNAs (miRNAs) as novel serological biomarkers for hepatocellular carcinoma (HCC) diagnosis and prognosis. Exosomes are small membranous vesicles (30–100 nm). Exosomal miR-665 levels in HCC patients were significantly higher than those in healthy subjects (P < 0.05), and exosomal miR-665 levels were significantly upregulated in tumours larger in size (> 5 cm), in tumours with local invasion and in those at an advanced clinical stage (stage III/IV) of HCC (P = 0.0042, 0.0197, and 0.0276, respectively). The survival time of the exosomal miR-665 high-expression group (n = 17) was significantly shorter than that of the low-expression group (n = 13) (P = 0.036). In addition, we found that HCC cell-derived exosomes promoted hepatoma cell proliferation and upregulated the expression level of proteins in the MAPK/ERK pathway in vitro and in vivo. This study suggests that serum exosomal miR-665 may be a novel minimally invasive biomarker for HCC diagnosis and prognosis.
The lack of sensitive and specific biomarkers hinders pathological diagnosis and prognosis for hepatocellular carcinoma (HCC). Since glutaminolysis plays a crucial role in carcinogenesis and progression, we sought to determine if the expression of kidney-type and liver-type glutaminases (GLS1 and GLS2) were informative for pathological diagnosis and prognosis of HCC. We compared the expression of GLS1 and GLS2 in a large set of clinical samples including HCC, normal liver, and other liver diseases. We found that GLS1 was highly expressed in HCC; whereas, expression of GLS2 was mainly confined to non-tumor hepatocytes. The sensitivity and specificity of GLS1 for HCC were 96.51% and 75.21%, respectively. A metabolic switch from GLS2 to GLS1 was observed in a series of tissues representing progressive pathologic states mimicking HCC oncogenic transformation, including normal liver, fibrotic liver, dysplasia nodule, and HCC. We found that high expression of GLS1 and low expression of GLS2 in HCC correlated with survival time of HCC patients. Expression of GLS1 and GLS2 were independent indexes for survival time; however, prognosis was predominantly determined by the level of GLS1 expression. These findings indicate that GLS1 expression is a sensitive and specific biomarker for pathological diagnosis and prognosis of HCC.
Background and Aim:Long noncoding RNA-plasmacytoma variant translocation 1 is identified to be highly expressed and exhibits oncogenic activity in a variety of human malignancies, including pancreatic cancer. However, little is known about the overall biological role and mechanism of plasmacytoma variant translocation 1 in pancreatic cancer so far. In this study, we investigated the effect of plasmacytoma variant translocation 1 on pancreatic cancer cell proliferation and migration as well as epithelial–mesenchymal transition.Methods:Pancreatic cancer tissue specimens and cell line were used in this study, with normal tissue and cell line acting as control.Results:It showed that plasmacytoma variant translocation 1 expression was significantly upregulated in pancreatic cancer tissues or cell line compared to normal groups. Plasmacytoma variant translocation 1 downregulation significantly inhibited zinc finger E-box-binding protein 1/Snail expression but promoted p21 expression, and it also inhibited the cell proliferation and migration. Additionally, p21 downregulation enhanced, and p21 overexpression repressed, zinc finger E-box-binding protein 1/Snail expression and cells proliferation in PANC-1 cells. However, p21 downregulation reversed the effect of plasmacytoma variant translocation 1 downregulation on zinc finger E-box-binding protein 1/Snail expression and cell proliferation and migration.Conclusion:Plasmacytoma variant translocation 1 promoted epithelial–mesenchymal transition and cell proliferation and migration through downregulating p21 in pancreatic cancer cells.
Pancreatic cancer is one of the most deadly cancers with a poor prognosis. Although microRNAs are involving in the carcinogenesis and development of pancreatic cancer, little information is known regarding the role of miR-663b in pancreatic cancer. In this study, the expression of miR-663b in pancreatic cancer cells was down-regulated by hypermethylation in its putative promoter region, and overexpression of miR-663b repressed cell proliferation, invasion and migration, and induced apoptosis in pancreatic cancer cells. Bioinformatics analysis, luciferase report assay and rescue experiments showed that insulin-like growth factor 2 (IGF2) was a direct target of miR-663b. Results from clinical samples showed that the expression level of miR-663b correlated with the pathological grading, and the expression of miR-663b was down-regulated and was inversely correlated with IGF2 expression level in pancreatic cancer tissues. More importantly, the long non-coding RNA, HOX transcript antisense RNA (HOTAIR), was up-regulated in both pancreatic cancer cells and tissues, and HOTAIR suppressed the expression of miR-663b in pancreatic cancer by histone modification on H3K4me3 and H3K27me3 on miR-663b promoter. Further in vivo studies demonstrated that the stable overexpression of miR-663b or knock-down of HOTAIR inhibited tumor growth and was associated with IGF2 expression. In summary, our studies demonstrated that miR-663b is epigenetically repressed by HOTAIR and exerts its tumor-suppressive function via targeting IGF2 in pancreatic cancer.
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