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MicroRNA 34a (miR-34a) is a tumor suppressor gene, but how it regulates cell proliferation is not completely understood. We now show that the microRNA miR-34a regulates silent information regulator 1 (SIRT1) expression. MiR-34a inhibits SIRT1 expression through a miR-34a-binding site within the 3' UTR of SIRT1. MiR-34 inhibition of SIRT1 leads to an increase in acetylated p53 and expression of p21 and PUMA, transcriptional targets of p53 that regulate the cell cycle and apoptosis, respectively. Furthermore, miR-34 suppression of SIRT1 ultimately leads to apoptosis in WT human colon cancer cells but not in human colon cancer cells lacking p53. Finally, miR-34a itself is a transcriptional target of p53, suggesting a positive feedback loop between p53 and miR-34a. Thus, miR-34a functions as a tumor suppressor, in part, through a SIRT1-p53 pathway.

The detailed mechanism of pulmonary arteriovenous malformations after Glenn surgery (G-PAVMs) in cyanotic congenital heart disease (CHD) remains unclear. Microarray in situ hybridization was performed to assess the miRNA (miRNA) profiles of serum from pediatric patients (0–6 years of age) with G-PAVMs and after the Fontan procedure without G-PAVMs. In addition, we investigated the tube formation, migration, and proliferation of human lung microvascular endothelial cells (HMVEC-L) transfected with miR-25-3p mimic, miR-25-3p inhibitor, or PHLPP2 small interfering RNA, and examined HIF-1α/VEGF-A signaling after hypoxic stimulation. Serum miRNAs that showed ≥ 2-fold higher levels in patients with G-PAVMs than in other patients were selected. MiR-25-3p was significantly upregulated in the pulmonary artery sera of the post-Glenn group than in the post-Fontan group. We identified PHLPP2 as a direct target of miR-25-3p. PHLPP2 expression was significantly decreased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells. HIF-1α and VEGF-A expression levels were increased in HMVEC-L transfected with miR-25-3p mimic compared to the control cells in a PHLPP2/Akt/mTOR signaling-dependent manner after hypoxic stimulation. MiR-25-3p promoted HMVEC-L angiogenesis, proliferation, and migration under hypoxic conditions. MiR-25-3p in the pulmonary arteries may contribute to G-PAVM development.

Adhesion molecules expressed by activated endothelial cells play a key role in regulating leukocyte trafficking to sites of inflammation. Resting endothelial cells normally do not express adhesion molecules, but cytokines activate endothelial cells to express adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), which mediate leukocyte adherence to endothelial cells. We now show that endothelial cells express microRNA 126 (miR-126), which inhibits VCAM-1 expression. Transfection of endothelial cells with an oligonucleotide that decreases miR-126 permits an increase in TNF-α-stimulated VCAM-1 expression. Conversely, overexpression of the precursor to miR-126 increases miR-126 levels and decreases VCAM-1 expression. Additionally, decreasing endogenous miR-126 levels increases leukocyte adherence to endothelial cells. These data suggest that microRNA can regulate adhesion molecule expression and may provide additional control of vascular inflammation.

The acidic tumor microenvironment plays a critical role in the malignant transformation of cancer cells. One mechanism underlying this transformation involves epithelial-mesenchymal transition (EMT). This is induced by prolonged exposure to acidic conditions. EMT is an essential process in cancer progression, with Transforming Growth Factor Beta (TGF-β) playing a central role in its induction. However, little was known about the factors regulating TGF-β under acidic conditions. This study aimed to elucidate the mechanism of EMT under acidic conditions and identify novel therapeutic targets to inhibit cancer cell migration and metastasis. Focusing on lung cancer, we explored microRNAs associated with EMT that were differentially expressed under acidic conditions in A549 cells and identified miR-193b-3p as a novel candidate. Under acidic conditions, miR-193b-3p expression decreased around days 3–14. Downregulation of miR-193b-3p promoted increased TGFβ2 expression, resulting in EMT changes in A549 cells. Our study suggests that the interaction between miR-193b-3p, TGFβ2, and the acidic tumor microenvironment promotes cancer EMT change. Understanding these interactions may not only enhance our biological comprehension of cancer, but also pave the way for the development of targeted therapies to inhibit cancer metastasis.

The pathway involving the tumor suppressor gene TP53 can regulate tumor angiogenesis by unclear mechanisms. Here we show that p53 regulates hypoxic signaling through the transcriptional regulation of microRNA-107 (miR-107). We found that miR-107 is a microRNA expressed by human colon cancer specimens and regulated by p53. miR-107 decreases hypoxia signaling by suppressing expression of hypoxia inducible factor-1β (HIF-1β). Knockdown of endogenous miR-107 enhances HIF-1β expression and hypoxic signaling in human colon cancer cells. Conversely, overexpression of miR-107 inhibits HIF-1β expression and hypoxic signaling. Furthermore, overexpression of miR-107 in tumor cells suppresses tumor angiogenesis, tumor growth, and tumor VEGF expression in mice. Finally, in human colon cancer specimens, expression of miR-107 is inversely associated with expression of HIF-1β. Taken together these data suggest that miR-107 can mediate p53 regulation of hypoxic signaling and tumor angiogenesis.

MicroRNAs (MiRNAs) are short, non-coding RNA that regulate a variety of cellular functions by suppressing target protein expression. We hypothesized that a set of microRNA regulate tumor responses to hypoxia by inhibiting components of the hypoxia signaling pathway. We found that miR-22 expression in human colon cancer is lower than in normal colon tissue. We also found that miR-22 controls hypoxia inducible factor 1α (HIF-1α) expression in the HCT116 colon cancer cell line. Over-expression of miR-22 inhibits HIF-1α expression, repressing vascular endothelial growth factor (VEGF) production during hypoxia. Conversely, knockdown of endogenous miR-22 enhances hypoxia induced expression of HIF-1α and VEGF. The conditioned media from cells over-expressing miR-22 contain less VEGF protein than control cells, and also induce less endothelial cell growth and invasion, suggesting miR-22 in adjacent cells influences endothelial cell function. Taken together, our data suggest that miR-22 might have an anti-angiogenic effect in colon cancer.

Endothelial exocytosis regulates vascular thrombosis and inflammation. The trafficking and release of endothelial vesicles is mediated by SNARE (Soluble NSF Attachment protein REceptors) molecules, but the exact identity of endothelial SNAREs has been unclear. Three SNARE molecules form a ternary complex, including isoforms of the syntaxin (STX), vesicle-associated membrane protein (VAMP), and synaptosomal-associated protein (SNAP) families. We now identify SNAP23 as the predominant endothelial SNAP isoform that mediates endothelial exocytosis of von Willebrand Factor (VWF). SNAP23 was localized to the plasma membrane. Knockdown of SNAP23 decreased endothelial exocytosis, suggesting it is important for endothelial exocytosis. SNAP23 interacted with the endothelial exocytic machinery, and formed complexes with other known endothelial SNARE molecules. Taken together, these data suggest that SNAP23 is a key component of the endothelial SNARE machinery that mediates endothelial exocytosis.

Vascular endothelial growth factor A (VEGF-A) plays pivotal roles in regulating tumor angiogenesis as well as physiological vascular function. The major VEGF-A isoforms, VEGF-A121 and VEGF-A165, in serum, plasma, and platelets have not been exactly evaluated due to the lack of the appropriate assay system. Antibodies against human VEGF-A121 and VEGF-A165 (hVEGF-A121 and hVEGF-A165) were successfully produced and Enzyme-Linked ImmunoSorbent Assay (ELISA) for hVEGF-A121 and hVEGF-A165 were separately created by these monoclonal antibodies. The measurement of recombinant hVEGF-A121 and hVEGF-A165 by the created ELISA showed no cross-reaction between hVEGF-A121 and hVEGF-A165 in conditioned media from HEK293 cells transfected with either hVEGF-A121 or hVEGF-A165 expression vector. The levels of VEGF-A121 and VEGF-A165 in serum, plasma, and platelets from 59 healthy volunteers proved that VEGF-A121 level was higher than VEGF-A165 in both plasma and serum in all the cases. VEGF-A121 or VEGF-A165 in serum represented higher level than that in plasma. In contrast, the level of VEGF-A165 was higher than VEGF-A121 in platelets. The newly developed ELISAs for hVEGF-A121 and hVEGF-A165 revealed different ratios of VEGF isoforms in serum, plasma, and platelets. Measuring these isoforms in combination provides useful information as biomarkers for diseases involving VEGF-A121 and VEGF-A165.

We present a mechanistic mathematical model of the basal state for type 2 diabetes mellitus (T2DM) in an analytical form and illustrate its use for in silico basal-state and dynamic studies. At the core of the basal-state model is a quartic equation that expresses the basal plasma glucose concentration solely in terms of model parameters. This analytical model avoids a computationally intensive numerical solver and is illustrated by an investigation of how glucose-utilization parameters impact basal glucose, insulin, insulin-dependent utilization, and hepatic extraction, leveraging median parameter values of early-stage T2DM. Furthermore, the presented basal-state model ensures accurate execution of the corresponding dynamic model, which contains basal quantities within its derivative functions; erroneous, unintended dynamics in plasma glucose, insulin, and C-peptide are illustrated using an incorrect basal glucose value. The presented basal model enables efficient and accurate basal-state and dynamic studies, facilitating the understanding of T2DM pathophysiology and the development of T2DM diagnosis, treatment, and management strategies.

VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment. An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165-the major isoforms of VEGF-A-and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy. The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of -73.8 pg/mL, 95% CI [-149.4, -10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood. The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care.