MicroRNAs (miRNAs) are a group of small non-coding RNA molecules predicted to control the activity of about 30 % of all protein-coding genes in mammals. The expression of microRNA-424-5p (miR-424-5p) has been shown to vary in multiple hematological and solid organ malignancies, such as pancreatic cancer. This study aimed to characterize the function of upregulated miR-424-5p in pancreatic cancer and show how downstream suppressor of cytokine-induced signaling 6 (SOCS6) is negatively regulated by miR-424-5p. MiR-424-5p and SOCS6 expression was detected using quantitative real-time PCR (qRT-PCR) in pancreatic cancer tissues and adjacent non-tumorous ductal epithelium tissues. Luciferase reporter assays were used to assess SOCS6 as a target of miR-424-5p. The downstream effect of SOCS6 was measured by qRT-PCR after miR-424-5p inhibition and SOCS6 upregulation. The functions of miR-424-5p in vitro in pancreatic cancer cells were measured by migration and invasion assays and flow cytometry. Results suggested miR-424-5p was significantly upregulated in pancreatic cancer and suppress the expression of SOCS6, and miR-424-5p increased proliferation, migration and invasion of pancreatic cancer cells, while inhibited cell apoptosis. It was concluded that miR-424-5p is frequently upregulated in pancreatic cancer and modulates ERK1/2 signaling pathway by negatively regulating SOCS6.

Background/Aims: Ischemic stroke is still one of the leading debilitating diseases with high morbidity and mortality. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) play an important role in cerebral ischemia/reperfusion (I/R) injury. However, the mechanism underlying the regulation of ROS generation is still not fully elucidated. This study aims to explore the role of transforming growth beta (TGF-β) signals in ROS generation. Methods: Sprague–Dawley rats were subjected to I/R injury, and PC-12 cells were challenged by hypoxia/reoxygenation (H/R) and/or treated with activin receptor-like kinase (ALK5) inhibitor Sb505124 or siRNA against ALK5. Brain damage was evaluated using neurological scoring, triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, infarct volume measurement, TUNEL staining, and caspase-3 activity measurement. Expression of TGF-β and oxidative stress-related genes was analyzed by real-time polymerase chain reaction and Western blot; NOX activity and ROS level were measured using spectrophotometry and fluorescence microscopy, respectively. Results: I/R contributed to severe brain damage (impaired neurological function, brain infarction, tissue edema, apoptosis), TGF-β signaling activation (upregulation of ALK5, phosphorylation of SMAD2/3) and oxidative stress (upregulation of NOX2/4, rapid release of ROS [oxidative burst]). However, Sb505124 significantly reversed these alterations and protected rats against I/R injury. As in the animal results, H/R also contributed to TGF-β signaling activation and oxidative stress. Likewise, the inhibition of ALK5 or ALK5 knockdown significantly reversed these alterations in PC-12 cells. Other than ALK5 knockdown, ALK5 inhibition had no effect on the expression of ALK5 in PC-12 cells. Conclusions: Our studies demonstrated that TGF-β signaling activation is involved in the regulation of NOX2/NOX4 expression and exacerbates cerebral I/R injury.

GPC-1 is significantly related to the perineural invasion of pancreatic cancer, holding some prognostic significance in patients with pancreatic cancer.

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(1) IP can protect the rat liver from normothermic IR injury by modulation of the expression of apoptosis-regulating genes C-jun and Bcl-XL; (2) IR injury may activate the apoptosis of hepatocytes by increasing the expression of apoptosis-inducing gene C-jun; (3) IP may prohibit the apoptosis of hepatocytes by increasing the expression of apoptosis-inhibitory gene Bcl-XL.

STMN1 is a cytosolic phosphoprotein that not only participates in cell division, but also plays an important role in other microtubule-dependent processes, such as cell motility. Furthermore, STMN1 acts as a "relay protein" in several intracellular signaling pathways that influence cell growth and differentiation. Thus, STMN1 is likely to support cellular processes essential for tumor progression: survival and migration. Indeed, elevated STMN1 expression has been reported in various types of human malignancies and is correlated with poor prognosis in these human malignancies. However, the clinical and prognostic significance of STMN1 in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, we assessed STMN1 in PDAC in this retrospective study. We first examined STMN1 expression in PDAC tissues from 27 cases and matched adjacent non-cancerous tissues by quantitative polymerase chain reaction (PCR) and western blot analyses. Next, immunohistochemistry was used to evaluate STMN1 expression in 87 archived paraffin-embedded PDAC specimens. STMN1 mRNA and protein expression levels were to a large extent up-regulated in PDAC tissue compared with their adjacent non-cancerous tissues. Moreover, STMN1 expression was closely correlated with histological differentiation, lymphatic metastasis, and TNM stage (P = 0.023, 0.047, and 0.014, respectively). In addition, PDAC patients with higher STMN1 expression died sooner than those with lower STMN1 expression (P < 0.01). Multivariate analysis demonstrated that STMN1 expression was an independent prognostic factor for PDAC patients (P < 0.01). Herein, we provide the first evidence that up-regulated STMN1 may contribute to tumor progression and poor prognosis in PDAC patients and may serve as a novel prognostic marker.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide, and microRNAs (miRs) are considered to serve important functions in the pathogenesis of HCC by regulating the expression of specific target genes. The present study was conducted to investigate the role of miR-199 and its putative target X-box binding protein 1 (XBP1) in HCC, as well as of the downstream gene cyclin D. The expression levels of miR-199, XBP1 and cyclin D were detected in clinical HCC specimens. The effect of miR-199 on the regulation of HCC cell proliferation and its underlying mechanism were examined in Hep3B2.1–7 cells, through expression assays and measurement of cell proliferation (via Cell Counting Kit-8, and 5-ethynyl-2′-deoxyuridine and DAPI double-staining assays) coupled with gain- and lose- of function experiments. The expression of XBP1 and cyclin D was significantly increased in HCC tissues when compared with adjacent non-HCC tissues, while the expression of miR-199 was decreased. Exogenous miR-199 significantly suppressed the expression of XBP1 and cyclin D in Hep3B2.1–7 cells. However, the expression of XBP1 and cyclin D significantly increased on treatment with miR-199 inhibitor. Consistently, Hep3B2.1–7 cells co-transfected with a wild type reporter plasmid [XBP1-3′untranslated region (UTR)-WT] and exogenous miR-199 exhibited lower relative luciferase enzyme activity than cells co-transfected with negative control miRNA and XBP1-3′UTR-WT, while cells co-transfected with mutated plasmid (XBP1-3′UTR-MU) and miR-199 exhibited no change. It was further observed that knockdown of XBP1 by small interfering RNA significantly decreased the expression of cyclin D in Hep3B2.1–7 cells. Additionally, exogenous miR-199 decreased the proliferation of Hep3B2.1–7 cells, which was contrary to the effect of miR-199 inhibitor. In conclusion, it was demonstrated that miR-199 negatively regulated the expression of XBP1 by directly binding to its 3′UTR and that XBP1 impacted cyclin D expression, which was associated with the cell cycle regulation in Hep3B2.1–7 cells. These findings suggested that a miR-199/XBP1/cyclin D axis may serve an important role in the pathogenesis of HCC.

MicroRNAs (miRNAs, miR) play a fundamental role in cerebral ischemia/reperfusion (I/R) injury. However, the role of miRNAs in toxic aldehyde and tyrosine accumulation is not fully elucidated. We constructed a cerebral I/R rat model and found that overexpression of miR-193 was associated with the accumulation of 4-Hydroxynonenal (4-HNE), Malondialdehyde (MDA), and tyrosine, and with the decrease of aldehyde dehydrogenase (ALDH2), tyrosine hydroxylase (TH), and dopamine. To unveil the molecular mechanism of the miR-193-mediated phenotype in I/R injury as described above, we performed bioinformatic analysis and found that ALDH2 was a potential target of miR-193. Through in vitro experiments (such as miR-193 mimic/inhibitor transfection, luciferase reporter gene plasmid transfection, and 4-HNE exposure) and in vivo infusion of miR-193 agomir, we demonstrated that miR-193 directly suppressed the expression of ALDH2 and led to toxic aldehyde accumulation, resulting in dysfunction of tyrosine hydroxylase. The present study suggests that the overexpression of miR-193 in a rat model exacerbated brain injury due to the following sequential process: targeted suppression of ALDH2, aldehyde accumulation, and tyrosine hydroxylase dysfunction, leading to tyrosine accumulation and insufficiency of dopamine synthesis.