Ferrostatin-1 inhibits ferroptosis of vascular smooth muscle cells and alleviates abdominal aortic aneurysm formation through activating the SLC7A11/GPX4 axis.

Ferroptosis, a type of iron-catalyzed necrosis, is responsible for vascular smooth muscle cell (VSMC) death and serves as a potential therapeutic target for alleviating aortic aneurysm. Here, our study explored the underlying mechanism of ferroptosis affecting VSMC functions and the resultant formation of AAA using its inhibitor Ferrostatin-1 (Fer-1). Microarray-based gene expression profiling was employed to identify differentially expressed genes related to AAA and ferroptosis. An AAA model was established by angiotensin II (Ang II) induction in apolipoprotein E-knockout (ApoE-/- ) mice, followed by injection of Fer-1 and RSL-3 (ferroptosis inducer). Then, the role of Fer-1 and RSL-3 in the ferroptosis of VSMCs and AAA formation was analyzed in Ang II-induced mice. Primary mouse VSMCs were cultured in vitro and treated with Ang II, Fer-1, sh-SLC7A11, or sh-GPX4 to assess the effect of Fer-1 via the SLC7A11/GPX axis. Bioinformatics analysis revealed that GPX4 was involved in the fibrosis formation of AAA, and there was an interaction between SLC7A11 and GPX4. In vitro assays showed that Fer-1 alleviated Ang II-induced ferroptosis of VSMCs and retard the consequent AAA formation. The mechanism was associated with activation of the SLC7A11/GPX4 pathway. Silencing of SLC7A11 or GPX4 could inhibit the ameliorating effect of Fer-1 on the ferroptosis of VSMCs. In vivo animal studies further demonstrated that Fer-1 inhibited Ang II-induced ferroptosis and vessel wall structural abnormalities in AAA mouse through activation of the SLC7A11/GPX4 pathway. Fer-1 may prevent AAA formation through activation of the SLC7A11/GPX4 pathway.

Increased plasma renin by vasodilators promotes the progression of abdominal aortic aneurysm.

Background: It is well-accepted that antihypertensive therapy is the cornerstone of treatment for abdominal aortic aneurysm (AAA) patients with hypertension. Direct-acting vasodilators were used in the treatment of hypertension by directly relaxing vascular smooth muscle but may have destructive effects on the aortic wall by activating the renin-angiotensin system axis. Their roles in AAA disease remain to be elucidated. In this study, we used hydralazine and minoxidil, two classical direct-acting vasodilators, to investigate their influence and potential mechanisms on AAA disease. Methods and results: In this study, we investigated the plasma renin level and plasma renin activity in AAA patients. Simultaneously, age and gender ratio-matched patients diagnosed with peripheral artery disease and varicose veins were selected as the control group using a ratio of 1:1:1. Our regression analysis suggested both the plasma renin level and plasma renin activity are positively associated with AAA development. In view of the well-established relationship between direct-acting vasodilators and increased plasma renin concentration, we established a porcine pancreatic elastase-infused AAA mouse model, followed by oral administration of hydralazine (250 mg/L) and minoxidil (120 mg/L) to investigate effects of direct-acting vasodilators on AAA disease. Our results suggested both hydralazine and minoxidil promoted the progression of AAA with increased aortic degeneration. Mechanistically, the vasodilators aggravated aortic inflammation by increased leukocyte infiltration and inflammatory cytokine secretion. Conclusion and relevance: The plasma renin level and plasma renin activity are positively associated with AAA development. Direct vasodilators aggravated experimental AAA progression, which raised cautionary concerns about their applications in AAA disease.

Long non-coding RNA crnde promotes deep vein thrombosis by sequestering miR-181a-5p away from thrombogenic Pcyox1l.

BACKGROUND: Deep vein thrombosis (DVT) is an interplay of genetic and acquired risk factors, where functional interactions in lncRNA-miRNA-mRNA ceRNA networks contribute to disease pathogenesis. Based on the high-throughput transcriptome sequencing prediction, we have assessed the contribution of lncRNA Crnde/miR-181a-5p/Pcyox1l axis to thrombus formation. METHODS: DVT was modeled in mice by inferior vena cava stenosis, and inferior vena cava tissues were harvested for high-throughput transcriptome sequencing to screen differentially expressed lncRNAs and mRNAs. The key miRNA binding to Crnde and Pcyox1l was obtained through searching the RNAInter and mirWalk databases. The binding affinity between Crnde, miR-181a-5p, and Pcyox1l was examined by FISH, dual luciferase reporter gene, RNA pull-down, and RIP assays. Functional experiments were conducted in DVT mouse models to assess thrombus formation and inflammatory injury in inferior vena cava. RESULTS: It was noted that Crnde and Pcyox1l were upregulated in the blood of DVT mice. Crnde competitively bound to miR-181a-5p and inhibited miR-181a-5p expression, and Pcyox1l was the downstream target gene of miR-181a-5p. Silencing of Crnde or restoration of miR-181a-5p reduced inflammatory injury in the inferior vena cava, thus curtailing thrombus formation in mice. Ectopic expression of Pcyox1l counterweighed the inhibitory effect of Crnde silencing. CONCLUSIONS: Therefore, Crnde sequesters miR-181a-5p to release Pcyox1l expression via ceRNA mechanism, thus aggravating thrombus formation in DVT.

Comparison of efficiency and safety of open surgery, hybrid surgery and endovascular repair for the treatment of thoracoabdominal aneurysms: a systemic review and network meta-analysis.

Objective: The objective of this study was to perform a network meta-analysis (NMA) to assess the efficacy and safety of three different surgical interventions- open surgical repair (OSR), hybrid surgical repair (HSR), and endovascular repair (EVAR)- for the treatment of thoracoabdominal aortic aneurysms (TAAAs). Methods: Electronic repositories like PubMed, Embase, Web of Science, Scopus, ScienceDirect, the Cochrane library, Clinical trial, and China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies that compared the efficacy of OSR, HSR, and EVAR with endografts for the treatment of TAAAs until December 24th, 2022. Random-effects and fixed-effects models were employed to analyze the data gathered in a network meta-analysis. The study's primary outcomes of interest encompassed in-hospital mortality, long-term survival rate, and postoperative complications. Results: Eleven comparative studies meet inclusion criterias. There were 2,222 patients in OSR, 1,574 patients in EVAR and 537 patients in HSR. EVAR has lower one-month mortality than OSR (RR: 0.31; 95% CI: 0.17-0.70) and HSR (RR: 0.37; 95% CI: 0.22-0.71), and lower incident rate of renal complications than HSR (RR: 0.20; 95% CI: 0.08-0.43) and OSR (RR: 0.34; 95% CI: 0.16-0.65). Nonetheless, there was no noteworthy discrepancy identified in the long-term survival rates of these procedures. Conclusions: As compared with OSR, HSR, and EVAR, EVER has lower one-month mortality, and lower incident rates of complications. Systematic review registration: PROSPERO (CRD42022313829).

Management of Patients with Uncomplicated Symptomatic Isolated Mesenteric Artery Dissection: a Multicentre Experience.

OBJECTIVE: Isolated mesenteric artery dissection (IMAD) is an increasingly diagnosed disease. However, multicentre studies to support clinical decision making are limited. This multicentre retrospective study aimed to investigate the characteristics, treatment options, and outcomes of IMAD. METHODS: Data from consecutively enrolled patients with IMAD between October 2009 and May 2021 at three hospitals were collected retrospectively. One hundred and ninety uncomplicated symptomatic IMAD patients were divided into two groups: conservative (n = 141) and operative (n = 49). The costs, length of hospital stay, factors affecting outcomes, symptom relief, and complete remodelling of superior mesenteric artery (SMA) were analysed between the two groups. RESULTS: Compared with patients who received operative treatment, patients receiving conservative treatment had shorter hospital stays (8.2 ± 4.6 vs. 11.9 ± 6.4 day, p < .020) and lower hospital costs (14 900 ± 1 048 vs. 60 400 ± 7 733 yuan, p < .001). In contrast, patients receiving operative treatment showed higher complete SMA remodelling (95.9% vs. 51.8%, p < .001). The cumulative rate of symptom relief was similar between the groups (p = .71). The rates were 78% vs. 79%, 87% vs. 87%, 89% vs. 87% at one, 12, and 60 months in the conservative and operative groups, respectively. Further subgroup analysis showed that endovascular treatment of IMAD had the advantage of shorter hospital stays than open surgery (10.7 ± 4.5 vs. 25.2 ± 9.4 days, p < .010). Univariable analysis showed that Sakamoto type II was associated with failed complete SMA remodelling (odds ratio 0.34; 95% confidence intervals 0.13 - 0.91; p = .031). CONCLUSION: IMAD patients achieved good long term survival and symptom relief regardless of the treatment. Sakamoto type II IMAD is a risk factor for failed complete SMA remodelling. Although endovascular treatment provided a higher rate of complete SMA remodelling, the conservative group had statistically significantly shorter hospital stays, lower hospital costs, and similar cumulative rates of symptom relief. Therefore, this study supports conservative treatment as the main strategy for uncomplicated symptomatic IMAD patients.

Akkermansia muciniphila Alters Gut Microbiota and Immune System to Improve Cardiovascular Diseases in Murine Model.

The gut microbiota plays an important role in a variety of cardiovascular diseases. The probiotics screened based on microbiota can effectively improve metabolism and immune function of the body, which is of great value in the field of cardiovascular disease treatment. Abdominal aortic aneurysms (AAA) refer to the lesion or injury of the abdominal aortic wall resulting in a localized bulge, which is one of the cardiovascular diseases with pulsing mass as the main clinical symptom. Previous studies have confirmed that A. muciniphila was depleted in the guts of AAA patients or mice. A. muciniphila is a potential probiotic for the treatment of intestinal microbiome-related diseases. Therefore, this study aims to investigate the effects of A. muciniphila on gut microbiota and disease-related biomarkers in AAA mice. C57BL/6J mice were used to construct the AAA model and treated with A. muciniphila. Aortic aneurysm formation in the AAA group is associated with the increased diameter of the abdominal aorta and inflammatory infiltration. A. muciniphila inhibited the formation of AAA and repaired tissue damage. The number of gut microbiota and α diversity index were decreased in the model group. A. muciniphila increased the number of gut microbiota and α diversity in AAA mice. The abundance of uncultured bacterium and Lactobacillus were increased, while the abundance of the Lachnospiraceae NK4A136 group was reduced in the AAA group. Compared with the control group, the levels of MMP-1, MMP-9, IL-33, CTSB, and CTSL in tissue and the levels of IL-6, IFN-γ, and CRP in blood were significantly increased, and the levels of IL-4, IL-10, and IL-17A in blood were significantly decreased in the AAA group. The intervention of A. muciniphila reversed these changes. The gut microbiota function prediction showed changes in E. coli, Clostridium, and Lactobacillus metabolism-related functional pathways. Akkermansia was negatively correlated with Helicobacter and Lactobacillus and positively correlated with Clostridium_sensu_stricto_1 and Escherichia shigella at the genus level. In conclusion, A. muciniphila inhibited the formation of AAA by restoring gut microbiota diversity, altering the expression of peripheral immune factors, and the functions of E. coli, Clostridium, and Lactobacillus, which may provide a new theoretical basis for the application of probiotics in cardiovascular diseases.

D-Dimer Is a Diagnostic Biomarker of Abdominal Aortic Aneurysm in Patients With Peripheral Artery Disease.

Background: Etiology and risk factors of peripheral artery disease (PAD) include age, smoking, and hypertension, etc. , which are shared by an abdominal aortic aneurysm (AAA). Concomitance with AAA in patients with PAD is not rare but is easily overlooked in the clinical situation, though management strategies are altered totally. This study aims to investigate diagnostic biomarkers for the prediction of AAA in patients with PAD. Methods: A total of 684 patients diagnosed with AAA and/or PAD were enrolled and analyzed retrospectively. Each patient with PAD and AAA was gender and age-matched. Demographic data, medical history, and serum laboratory test profiles were obtained. Statistical analysis was performed to determine diagnostic biomarkers of AAA in patients with PAD. Results: Firstly, 320 patients with PAD-only and 320 patients with AAA-only were compared. Levels of bilirubin and D-Dimer were decreased, while the incidence of diabetes mellitus, levels of fibrinogen, and platelet count were increased significantly in patients with PAD-only compared with those in patients with AAA-only (P < 0.001). Next, 364 patients with PAD (44 patients with AAA) and 364 patients with AAA (44 patients with PAD) were compared. Multivariate logistic regression analysis confirmed the differential distribution of bilirubin, D-dimer, fibrinogen, and platelet count between patients with AAA and patients with PAD (P < 0.05). Receiver operator curves (ROC) showed that the area under the curve (AUC) of total bilirubin, direct bilirubin, D-dimer, fibrinogen, and platelet count was 0.6113, 0.5849, 0.7034, 0.6473, and 0.6785, respectively. Finally, to further validate the predictive efficacy of mentioned markers, a multivariable logistics regression analysis was performed between the PAD only group and the PAD with AAA group. The results suggested increased levels of D-dimer in the PAD with AAA group compared to the PAD only group (OR: 2.630, 95% CI:1.639-4.221; P < 0.001). In particular, the Youden index suggested that the cut-off value of D-dimer for predicting AAA in patients with PAD was 0.675 mg/L with a sensitivity of 76.9% and a specificity of 84.9% (AUC = 0.8673; 95% CI, 0.8106-0.9240, P < 0.001). In all 364 patients with PAD, 41.46% patients were diagnosed AAA when D-dimer is >0.675 mg/L, while only 3.55% patients were diagnosed AAA when D-dimer ≤ 0.675 mg/L. Conclusions: PAD and AAA exert different clinical and serum profiles; D-dimer (>0.675 mg/L) is a reliable biomarker for the prediction of AAA in patients with PAD.

Linear ubiquitination modification of NR6A1 by LUBAC inhibits RIPK3 kinase activity and attenuates apoptosis of vascular smooth muscle cells.

Nuclear receptor subfamily 6 group A member 1 (NR6A1) is involved in promoting the apoptotic process of vascular smooth muscle cells (VSMCs) which is a critical process involved in atherosclerosis, but the action mechanism remains to be determined. Therefore, we studied the underlying mechanisms by which NR6A1 accelerated VSMC apoptosis in atherosclerosis. An atherosclerosis model has been established in apolipoprotein E-deficient rats with a high-fat diet for 12 weeks, which was characterized by pathological aortic plaques, increased lipid deposition and collagen content in aortic tissues, and high cholesterol and triglycerides levels in the serum. NR6A1 was experimentally shown to increase at protein level rather than messenger RNA level in atherosclerotic rats. Immunofluorescence exhibited the main location of NR6A1 in the cell nucleus of rat aortic tissues. By performing ectopic expression experiments, NR6A1 was demonstrated to suppress the viability and expedite the apoptosis of VSMCs, corresponding to augmented caspase-3, caspase-8, and caspase-9 activities. It was further unraveled that NR6A1 could activate receptor-interacting serine/threonine-protein kinase 3 (RIPK3) by inducing its phosphorylation. Conversely, RIPK3 inhibitor GSK872 undermined the proapoptotic effect of NR6A1 on VSMCs. The co-immunoprecipitation assay identified that linear ubiquitin chain assembly complex (LUBAC) can be pulled down by NR6A1. Furthermore. LUBAC inhibited the expression of NR6A1 by promoting its linear ubiquitination, thereby dephosphorylating RIPK3 and consequently inhibiting the VSMC apoptosis. Overall, LUBAC-induced linear ubiquitination of NR6A1 can potentially arrest the apoptosis of VSMCs in atherosclerosis by downregulating RIPK3 and attenuating caspase activity. This finding suggests promising athero-protective targets by limiting VSMC apoptosis.

Knockdown of long noncoding RNA GAS5 reduces vascular smooth muscle cell apoptosis by inactivating EZH2-mediated RIG-I signaling pathway in abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA), an irreversible cardiovascular disease prevalent in the artery, causes the increase of the aneurysm diameter over time, and is a fatal phenomenon inducing sidewall rupture. Long noncoding RNAs (lncRNAs) serve as promising biomarkers for AAA. In the present study, we sought to define the role of lncRNA growth-arrest-specific transcript 5 (GAS5) in growth of smooth muscle cells (SMC) and progression of AAA. METHODS: Initially, we established angiotensin II (Ang II)-induced AAA mouse models and Ang II-treated vascular SMC model. RT-qPCR and Western blot analysis were adopted to determine expression of GAS5 and zeste homolog 2 (EZH2). After ectopic expression and depletion experiments in Ang II-treated mice and vascular SMCs, cell apoptosis was detected in SMCs using flow cytometry and in mice using TUNEL staining. The binding of GAS5 and EZH2 was evaluated using RNA binding protein immunoprecipitation (RIP) and Co-IP assays. RESULTS: Increased GAS5 and RIG-I but decreased EZH2 were found in aortic tissues of AAA mice. EZH2 overexpression inhibited AAA formation and suppressed SMC apoptosis. Functionally, EZH2 blocked the RIG-I signaling pathway and consequently inhibited SMC apoptosis. GAS5 regulated EZH2 transcription in a negative manner in SMCs. Knockdown of GAS5 attenuated SMC apoptosis, which was reversed by EZH2 inhibition or RIG-I overexpression. CONCLUSIONS: The current study demonstrated that GAS5 induced SMC apoptosis and subsequent AAA onset by activating EZH2-mediated RIG-I signaling pathway, highlighting GAS5 as a novel biomarker for AAA.

"Ring on Anastomosis" for Avoidance of Acute Proximal Anastomotic Leak after Open Surgical Repair of Abdominal Aortic Aneurysm.

BACKGROUND: Acute proximal anastomotic leak is among severe complications after open surgical repair (OSR) of abdominal aortic aneurysm. We have proposed an approach of "ring on anastomosis" (ROA) as a technical improvement of conventional OSR to reinforce proximal anastomotic section. METHODS: One hundred and nineteen abdominal aortic aneurysm patients admitted to Xiangya Hospital, Central South University were enrolled. Patients were randomly divided into conventional group (n = 54) and ROA group (n = 65). The ring is prepared by cutting out a 2-cm circle from the graft. Operative time, intraoperative blood loss, perioperative mortality, and retroperitoneal hematoma were recorded. Poisson distribution analysis was used between two groups. All methods were carried out in accordance with Declaration of Helsinki. RESULTS: No obvious difference in operative time or intraoperative blood loss was identified [(205.5 ± 6.535) versus (195.6 ± 6.034) minutes, P > 0.05; (756 ± 98.22) versus (673.1 ± 98.93) ml, P > 0.05, respectively]. Two patients in conventional group (2/54, 3.7%) died while no dead case was reported in ROA group (P = 0.047). Three cases in conventional group experienced retroperitoneal hematoma while none was witnessed in ROA group (P = 0.027). An average of 18 months of follow-up was obtained in all patients, and no proximal anastomotic stenosis was reported. CONCLUSIONS: As a technical improvement of conventional OSR, ROA reinforces aorta graft anastomotic section and diminishes anastomotic leak as well as perioperative death without extra cost of time and money.

Elevated STMN1 Expression Correlates with Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma.

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.

miR-193b directly targets STMN1 and uPA genes and suppresses tumor growth and metastasis in pancreatic cancer.

Pancreatic cancer has the poorest prognosis among all cancer types, due to its late diagnosis and the lack of effective therapies. Therefore, identification of novel gene targets, which are differentially expressed in pancreatic cancer and functionally involved in the malignant phenotype, is critical to achieve early diagnosis and develop effective therapeutic strategies. microRNAs (miRNAs) are small non-coding RNAs, which negatively regulate the expression of their targets. Due to their various targets, miRNAs play a key role in a number of physiological processes and in oncogenesis. Therefore, investigating the role of miRNAs in tumor may contribute to the development of new diagnostic and therapeutic tools for various types of cancer, including pancreatic cancer. Here, we investigated the role of miR-193b in pancreatic cancer. Our data showed that the expression of miR-193b is markedly decreased in pancreatic cancer tissues compared to adjacent healthy tissues. The Panc-1 cell line transfected with the miR­193b exhibited significantly decreased proliferative, migratory, and invasive ability compared to untransfected cells. Moreover, miR-193b inhibited the expression of stathmin 1 (STMN1) and urokinase-type plasminogen activator (uPA) in Panc-1 cells. These data suggest that miR-193b acts as a tumor suppressor in pancreatic cancer. Therefore, miR-193b may constitute a promising therapeutic agent for the suppression of pancreatic cancer cell growth and metastasis.

Resveratrol attenuates morphine antinociceptive tolerance via SIRT1 regulation in the rat spinal cord.

In recent years, researchers have begun to pay more attention to the role of Sirtuin 1 (SIRT1, a class III histone deacetylase) in pain. However, little research has been conducted examining the involvement of SIRT1 in chronic morphine tolerance. The aim of this study was to investigate the role of spinal SIRT1 and acetyl-histone H3(Ac-H3) in chronic morphine tolerance in rats. Chronic morphine tolerance was induced by twice-daily intrathecal (i.t.) injections of morphine (10µg) for 6 days. Control rats received normal saline (NS). Resveratrol (Res, a SIRT1 stimulant, 30µg i.t.) or dimethyl sulfoxide (DMSO, 10µl i.t.) was then injected on days 7-13. The thermal paw withdrawal threshold was assessed to determine the analgesic effects of morphine (10µg). qRT-PCR, western blotting and immunohistochemistry were used to detect the expression of SIRT1 and global Ac-H3. Administration of morphine for 6 days induced a stabilized antinociceptive tolerance, down-regulated SIRT1 expression and up-regulated Ac-H3 expression in the spinal dorsal horn. Resveratrol treatment from day 7 to 13 increased SIRT1 expression, suppressed global Ac-H3 expression compared to the morphine tolerance (MT) group, and significantly reversed morphine antinociceptive tolerance. These results suggest that resveratrol reversed morphine tolerance by upregulating the expression of SIRT1 in the spinal dorsal horn. SIRT1 and global Ac-H3 in the spinal cord may play an important role in the mechanisms of chronic morphine tolerance.

MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer.

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.

Overexpression of MMSET is correlation with poor prognosis in hepatocellular carcinoma.

The multiple myeloma SET domain (MMSET) involved in the t(4;14)(p16;q32) chromosomal translocation encodes a histone lysine methyltransferase. High expression of MMSET is common translocation in multiple myeloma (MM) and is associated with the worst prognosis. Recent studies have shown that overexpression of MMSET is significant in other tumor types compared to their normal tissues. However, little is known about its role in hepatocellular carcinoma (HCC). In these study we investigate the expression of MMSET in HCC and to make correlations with clinicopathologic features. Twenty-eight pairs of HCC and adjacent non-tumor tissues, and eight normal liver tissues were collected for MMSET detection by western blotting and real time-PCR analysis. Immunohistochemistry was used to determine the expression of MMSET in HCC and adjacent non-tumor tissues from 103 patients. Overexpression of MMSET was significantly associated with Edmondson stage, vascular invasion. Moreover, Kaplan-Meier curves showed that MMSET upregulated was associated with shorter overall survival and disease-free survival in HCC patient. In conclusion, our study demonstrates for the first time that overexpression of MMSET is an independent prognostic factor and is correlated with poor survival in HCC patients.

miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway.

Pancreatic cancer is characterized by early metastasis and high mortality. In this study, the role of miR-143 in invasion and metastasis was investigated in pancreatic cancer cells. miR-143 expression was established by an adenovirus-carried miR-143 expression cassette. mRNA and protein levels of gene expression were examined by RT-PCR and Western blot assay, respectively. Rho GTPases activity was measured by the pull down assay. The role of miR-143 in migration and invasion of Panc-1 cells was tested in vitro. The antimetastatic effect of miR-143 was tested in a liver metastasis model, while its antitumor growth effect was tested in a xenograft Panc-1 tumor model. Results demonstrated that ARHGEF1 (GEF1), ARHGEF2 (GEF2), and K-RAS genes are the targets of miR-143. miR-143 expression significantly decreased mRNA and protein levels of GEF1, GEF2, and K-RAS genes; lowered the constitutive activities of RhoA, Rac1, and Cdc42 GTPases; decreased the protein levels of MMP-2 and MMP-9; but significantly increased the protein level of E-cadherin. miR-143 expression also significantly inhibited the migration and invasion of Panc-1 cells in vitro, liver metastasis, and xenograft tumor growth in vivo. Our study suggested that miR-143 plays a central role in the invasion and metastasis of pancreatic cancer and miR-143 is a potential target for pancreatic cancer therapy.

miR-301a is a candidate oncogene that targets the homeobox gene Gax in human hepatocellular carcinoma.

BACKGROUND: MicroRNAs (miRNA) are a group of noncoding small RNAs that repress mRNA expression or induce mRNA degradation by binding to the 3'-untranslated regions of mRNAs. MiRNAs have been connected closely with the development of cancers such as hepatocellular carcinoma (HCC). However, the overexpression of microRNA-301a (miR-301a) has seldom been connected with tumorigenesis in HCC. AIMS: This study aims to characterize the function of upregulated miR-301a in HCC and show how the downstream growth arrest-specific homeobox (Gax) is negatively regulated by miR-301a. METHODS: The expression of miR-301a and Gax was detected using real-time PCR on HCC tissues and adjacent non-tumorous tissues. The luciferase reporter assay was used to assess Gax as a target of miR-301a. The nuclear factor κB (NF-κB) was measured by western blot after inhibiting miR-301a and enhancing Gax. The functions of miR-301a in vivo in HCC cells were measured by migration and invasion assays and flow cytometry. RESULTS: MiR-301a was significantly upregulated and Gax was downregulated in HCC samples compared with in the matching nontumoral tissues. Inhibiting miR-301a expression caused the upregulation of Gax and repressed NF-κB expression. We have shown that miR-301a plays an important role in increasing proliferation, migration and invasion and in inhibiting apoptosis of HCC cells. CONCLUSIONS: miR-301a is frequently upregulated in HCC and modulates NF-κB expression by negatively regulating Gax.

Growth of vertically aligned InGaN nanorod arrays on p-type Si substrates for heterojunction diodes.

InGaN nanorod arrays have been grown by molecular beam epitaxy on bare and high-temperature AIN-buffered Si(111) substrates. It has been found that well vertically aligned InGaN nanorod arrays can be grown by using the high-temperature AIN buffer layer. On bare Si substrate, high-resolution transmission electron microscopy revealed an amorphous SiNx layer generated at the interface, and the thickness and flatness of the SiNx layer may affect the relative alignment of the nanorods with the substrate. By using the high-temperature AIN buffer layer, the interface quality was improved, and uniform InGaN nanorods could be grown. N-InGaN nanorods/p-Si heterostructure diodes were fabricated, which exhibit well rectifying behavior with a low turn on voltage of 1.2 eV and an on/off ratio of 7.2 at 2.5 V.