How perceived threat of COVID-19 related to aggressive tendencies during the pandemic in Hubei Province and other regions of China: Mediators and moderators.

During the COVID-19 pandemic in early 2020, domestic violence, interpersonal conflicts, and cyberbullying have risen sharply in China. We speculate that the perceived threat of COVID-19 is related to a general, non-target-specific aggressive tendency during the pandemic. We surveyed 1556 Chinese people in April 2020 (757 people in Hubei Province, the pandemic epicenter in China, and 799 in other regions of China where the pandemic is relatively not severe). A multiple-group structural equation modeling analysis found significant total effects between perceived threat of COVID-19 and aggressive tendencies during the pandemic in both regional groups, and the effect between them was mainly achieved through the mediating roles of sense of control and powerlessness during the pandemic. For all participants, negative coping strategies significantly aggravated the association between perceived threat of COVID-19 and aggressive tendencies during the pandemic, but the buffers were different across regions of outbreak severity. For participants in other regions where the pandemic is relatively not severe, positive coping strategies could mitigate the association between perceived threat of COVID-19 and aggressions. However, for participants in Hubei Province, the epicenter of China's pandemic, higher life satisfaction was more effective in buffering. These findings extend the possible consequences of the perceived COVID-19 threat and suggest that improving the life satisfaction of residents in areas with severe outbreaks is more effective in mitigating the adverse effects of COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-021-01792-7.

Increased plasma genistein after bariatric surgery could promote remission of NAFLD in patients with obesity.

Background: Bariatric surgery is associated with a positive effect on the progress of non-alcoholic associated fatty liver disease (NAFLD). Although weight loss is the obvious mechanism, there are also weight-independent mechanisms. Methods: We collected blood samples from 5 patients with obesity before and 3 months after surgery and performed an LC-MS-based untargeted metabolomics test to detect potential systemic changes. We also constructed sleeve gastrectomy (SG) mice models. The plasma, liver and intestine samples were collected and analyzed by qPCR, ELISA and HPLC. Cohousing experiments and feces transplantation experiments were performed on mice to study the effect of gut microbiota. Genistein administration experiments were used to study the in vivo function of the metabolites. Results: Plasma genistein (GE) was identified to be elevated after surgery. Both clinical data and rodent models suggested that plasma GE is negatively related to the degree of NAFLD. We fed diet-induced obese (DIO) mice with GE, and we found that there was significant remission of NAFLD. Both in vivo and in vitro experiments showed that GE could restrict the inflammation state in the liver and thus relieve NAFLD. Finally, we used co-housing experiments to alter the gut microbiota in mice, and it was identified that sleeve gastrectomy (SG) mice had a special gut microbiota phenotype, which could result in higher plasma GE levels. By feces transplantation experiment (FMT), we found that only feces from the SG mice (and not from other lean mice) could induce higher plasma GE levels. Conclusion: Our studies showed that SG but not calorie restriction could induce higher plasma GE levels by altering the gut microbiota. This change could promote NAFLD remission. Our study provides new insights into the systemic effects of bariatric surgery. Bariatric surgery could affect remote organs via altered metabolites from the gut microbiota. Our study also identified that additional supplement of GE after surgery could be a therapy for NAFLD.

Perceived Severity of COVID-19 and Post-pandemic Consumption Willingness: The Roles of Boredom and Sensation-Seeking.

The COVID-19 pandemic restricts people's activities and makes consumer businesses suffered. This study explored the relationship between the perceived severity of COVID-19 and the post-pandemic consumption willingness. Study 1 surveyed 1464 Chinese people in March 2020, found the perceived severity of COVID-19 during the pandemic significantly increased the willingness to consume post-pandemic, and boredom stemming from limited activities and sensation-seeking expressions mediated this effect. Study 2 conducted an experiment with 174 participants in August 2020, found a high level of perceived severity of COVID-19 and the experience of life tedium during the pandemic significantly increased individuals' impulsive buying tendencies after the pandemic. The results suggested the level of perceived severity of COVID-19 may influence people's post-pandemic consumption patterns.

Nutrient Stress-Dysregulated Antisense lncRNA GLS-AS Impairs GLS-Mediated Metabolism and Represses Pancreatic Cancer Progression.

Cancer cells are known to undergo metabolic reprogramming, such as glycolysis and glutamine addiction, to sustain rapid proliferation and metastasis. It remains undefined whether long noncoding RNAs (lncRNA) coordinate the metabolic switch in pancreatic cancer. Here we identify a nuclear-enriched antisense lncRNA of glutaminase (GLS-AS) as a critical regulator involved in pancreatic cancer metabolism. GLS-AS was downregulated in pancreatic cancer tissues compared with noncancerous peritumor tissues. Depletion of GLS-AS promoted proliferation and invasion of pancreatic cancer cells both in vitro and in xenograft tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via formation of double stranded RNA with GLS pre-mRNA through ADAR/Dicer-dependent RNA interference. GLS-AS expression was transcriptionally downregulated by nutrient stress-induced Myc. Conversely, GLS-AS decreased Myc expression by impairing the GLS-mediated stability of Myc protein. These results imply a reciprocal feedback loop wherein Myc and GLS-AS regulate GLS overexpression during nutrient stress. Ectopic overexpression of GLS-AS inhibited proliferation and invasion of pancreatic cancer cells by repressing the Myc/GLS pathway. Moreover, expression of GLS-AS and GLS was inversely correlated in clinical samples of pancreatic cancer, while low expression of GLS-AS was associated with poor clinical outcomes. Collectively, our study implicates a novel lncRNA-mediated Myc/GLS pathway, which may serve as a metabolic target for pancreatic cancer therapy, and advances our understanding of the coupling role of lncRNA in nutrition stress and tumorigenesis.Significance: These findings show that lncRNA GLS-AS mediates a feedback loop of Myc and GLS, providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1.large.jpg.See related commentary by Mafra and Dias, p. 1302.

Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription.

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.

Reciprocal loop of hypoxia-inducible factor-1α (HIF-1α) and metastasis-associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E-cadherin transcription.

Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1α (HIF-1α) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1α recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1α, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer.

Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.

The responsively decreased PKM2 facilitates the survival of pancreatic cancer cells in hypoglucose.

Cancer cells predominantly produce energy at a high rate of glycolysis even in aerobic environment. It is termed as Warburg effect and is necessary for the tumorigenesis. Studies showed pyruvate kinase M2 (PKM2), a key regulator of the Warburg effect, is overexpressed and involved in numerous cancers. However, the expression and function of PKM2 in pancreatic cancer (PC) remain undefined. Our results showed that PKM2 is overexpressed in the PC tissue compared to the peritumoral tissue. Unexpected, the downregulation of PKM2 did not affect the proliferation, invasion, and chemoresistance of PC cells. Since pancreatic cancer is a hypovascular tumor with comparably insufficient energy supply, we further investigate the relationship between PKM2 and hypoglucose. Interestingly, we further discovered that decreased expression of PKM2 was detected in PC samples with lower microvessel density as well as in PC cells treated with hypoglucose condition (0.5 mM). Furthermore, the downregulation of PKM2 facilitated, while the upregulation of PKM2 inhibited, PC cells survival during hypoglucose. We further revealed that the repressed PKM2 induced autophagy, high NADPH/NADP ratio, and biomacromolecule production, but reduced ROS accumulation. Moreover, AMPKα1 knockdown repressed the autophagy and survival of PC cells during hypoglucose, which were promoted by PKM2 knockdown. Collectively, our study indicates that decreased PKM2 diverts glucose metabolism to biomacromolecule accumulation and antioxidants generation during glucose deprivation. This metabolism alteration elevates AMPKα1-dependent autophagy, which facilitates PC cell survival during glucose deprivation. Therefore, functions of PKM2 are complicated and cannot be defined as oversimplified promoter or inhibitor in PC.

ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca2+/RhoA pathway.

Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. This study reports that ASIC1 and ASIC3 are mainly expressed on membrane of pancreatic cancer cells and upregulated in pancreatic cancer tissues. ASIC1 and ASIC3 are responsible for an acidity-induced inward current, which is required for elevation of intracellular Ca2+ concentration ([Ca2+]i). Inhibition of ASIC1 and ASIC3 with siRNA or pharmacological inhibitor significantly decreased [Ca2+]i and its downstream RhoA during acidity and, thus, suppressed acidity-induced epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. Meanwhile, downregulating [Ca2+]i with calcium chelating agent BAPTA-AM or knockdown of RhoA with siRNA also significantly repressed acidity-induced EMT of pancreatic cancer cells. Significantly, although without obvious effect on proliferation, knockdown of ASIC1 and ASIC3 in pancreatic cancer cells significantly suppresses liver and lung metastasis in xenograft model. In addition, ASIC1 and ASIC3 are positively correlated with expression of mesenchymal marker vimentin, but inversely correlated with epithelial marker E-cadherin in pancreatic cancer cells. In conclusion, this study indicates that ASICs are master regulator of acidity-induced EMT. In addition, the data demonstrate a functional link between ASICs and [Ca2+]i/RhoA pathway, which contributes to the acidity-induced EMT.

Mesh fixation with glue versus suture for chronic pain and recurrence in Lichtenstein inguinal hernioplasty.

BACKGROUND: Chronic pain following mesh-based inguinal hernia repair is frequently reported, and has a significant impact on quality of life. Whether mesh fixation with glue can reduce chronic pain without increasing the recurrence rate is still controversial. OBJECTIVES: To determine whether tissue adhesives can reduce postoperative complications, especially chronic pain, with no increase in recurrence rate, compared with sutures for mesh fixation in Lichtenstein hernia repair. SEARCH METHODS: We searched the following electronic databases with no language restrictions: the Cochrane Central Register of Controlled Trials (CENTRAL; issue 4, 2016) in the Cochrane Library (searched 11 May 2016), MEDLINE Ovid (1986 to 11 May 2016), Embase Ovid (1986 to 11 May 2016), Science Citation Index (Web of Science) (1986 to 11 May 2016), CBM (Chinese Biomedical Database), CNKI (China National Knowledge Infrastructure), VIP (a full-text database in China), Wanfang databases. We also checked reference lists of identified papers (included studies and relevant reviews). SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials comparing glue versus sutures for mesh fixation in Lichtenstein hernia repair. Cluster-RCTs were also eligible. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed the risk of bias independently. Dichotomous outcomes were expressed as odds ratio (OR) with 95% confidence intervals (CI). Continuous outcomes were expressed as mean differences (MD) with 95% CIs. MAIN RESULTS: Twelve trials with a total of 1932 participants were included in this review. The overall postoperative chronic pain in the glue group was reduced by 37% (OR 0.63, 95% CI 0.44 to 0.91; 10 studies, 1418 participants, low-quality evidence) compared with the suture group. However, the results changed when we conducted subgroup analysis with regard to the type of mesh. Subgroup analysis of included studies using lightweight mesh showed the reduction of chronic pain was less profound and insignificant (OR 0.77, 95% CI 0.50 to 1.17). Subgroup analysis of included studies using heavyweight mesh resulted in a significant benefit from the fixation with glue (OR 0.38, 95% CI 0.17 to 0.82).Hernia recurrence was similar between the two groups (OR 1.44, 95% CI 0.63 to 3.28; 12 studies, 1932 participants, low-quality evidence). Fixation with glue was superior to suture regarding duration of the operation (MD -3.13, 95% CI -4.48 to -1.78; 9 studies, 1790 participants, low-quality evidence); haematoma (OR 0.52, 95% CI 0.31 to 0.86; 10 studies, 1384 participants, moderate-quality evidence); and recovery time to daily activities (MD -1.26, 95% CI -1.89 to -0.63; 3 studies, 403 participants, low-quality evidence).We also investigated adverse events. There were no significant differences between the two groups. For superficial wound infection pooled analyses showed OR 1.23, 95% CI 0.37 to 4.11; 7 studies, 763 participants (low-quality evidence); for mesh/deep infection OR 0.67, 95% CI 0.16 to 2.83; 8 studies, 1393 participants (low-quality evidence). Furthermore, we investigated seroma (a postoperative swelling caused by fluid) (OR 0.83, 95% CI 0.51 to 1.33); and persisting numbness (OR 0.81, 95% CI 0.57 to 1.14).Finally, six trials involving 1009 participants reported postoperative length of stay, resulting in non-significant difference between the two groups (MD -0.12, 95% CI: -0.35 to 0.10)Due to the lack of data, it was impossible to draw any distinction between synthetic glue and biological glue.Eight out of 12 trials showed high risk of bias in at least one of the investigated domains. Two studies were quasi-randomised controlled trials and the allocation sequence of one trial was not concealed. Nearly half of the included trials either did not provide adequate information or had high risk of bias regarding blinding processes. The risk of bias for incomplete outcome data of all the included studies varied from low to high risk of bias. Two trials did not report on some important outcomes. One study was funded by the manufacturer producing the fibrin sealant. Therefore, according to the 'Summary of findings' tables, the quality of the evidence (GRADE) for the outcomes is moderate to low. AUTHORS' CONCLUSIONS: Based on the short-term results, glue may reduce postoperative chronic pain and not simultaneously increase the recurrence rate, compared with sutures for mesh fixation in Lichtenstein hernia repair. Glue may therefore be a sensible alternative to suture for mesh fixation in Lichtenstein repair. Larger trials with longer follow-up and high quality are warranted. The difference between synthetic glue and biological glue should also be assessed in the future.

MiR-548an, Transcriptionally Downregulated by HIF1α/HDAC1, Suppresses Tumorigenesis of Pancreatic Cancer by Targeting Vimentin Expression.

Hypoxic microenvironments contribute to the tumorigenesis of numerous cancers by regulating the expression of a subset of miRNAs called "hypoxiamiRs." However, the function and mechanism of these deregulated miRNAs in hypoxic microenvironments within pancreatic cancers remain undefined. This study demonstrates that miR-548an is significantly downregulated in pancreatic cancer tissues and correlates with increased tumor size, advanced TNM stage, distant metastasis, and poor prognosis. Moreover, the overexpression of miR-548an significantly inhibited the proliferation and invasion of pancreatic cancer cells in vitro and in vivo We further revealed that hypoxia-induced factor-1α (HIF-1α) induces the downregulation of miR-548an in pancreatic cancer cells during hypoxia. Our co-IP and ChIP assays revealed that HIF-1α and histone deacetylase 1 (HDAC1) form a complex and bind to the hypoxia response elements (HRE) on the miR-548an promoter. In addition, inhibition of HDAC1 with trichostatin A antagonizes the suppression of miR-548 by hypoxia. Our dual luciferase assay validated that miR-548an directly binds to the 3' untranslated region of vimentin mRNA. The downregulation of vimentin suppresses the proliferation and invasion of pancreatic cancer cells in vitro and in vivo In addition, vimentin was inversely correlated with miR-548an expression in pancreatic cancer samples. In conclusion, our findings suggest that the HIF-1α-HDAC1 complex transcriptionally inhibits miR-548an expression during hypoxia, resulting in the upregulation of vimentin that facilitates the pancreatic tumorigenesis. Mol Cancer Ther; 15(9); 2209-19. ©2016 AACR.

Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway.

Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in numerous cancers, while their function in pancreatic cancer is rarely elucidated. The present study identifies a functional lncRNA and its potential role in tumorigenesis of pancreatic cancer. Microarray co-assay for lncRNAs and mRNAs demonstrates that lncRNA-NUTF2P3-001 is remarkably overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS mRNA expression. After downregulating lncRNA-NUTF2P3-001, the proliferation and invasion of pancreatic cancer cell are significantly inhibited both in vitro and vivo, accompanying with decreased KRAS expression. The dual-luciferase reporter assay further validates that lncRNA-NUTF2P3-001 and 3'UTR of KRAS mRNA competitively bind with miR-3923. Furthermore, miR-3923 overexpression simulates the inhibiting effects of lncRNA-NUTF2P3-001-siRNA on pancreatic cancer cell, which is rescued by miR-3923 inhibitor. Specifically, the present study further reveals that lncRNA-NUTF2P3-001 is upregulated in pancreatic cancer cells under hypoxia and CoCl2 treatment, which is attributed to the binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the upstream of KRAS promoter. Data from pancreatic cancer patients show a positive correlation between lncRNA-NUTF2P3-001 and KRAS, which is associated with advanced tumor stage and worse prognosis. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumor oncogene KRAS and implicate that lncRNA-NUTF2P3-001 and miR-3923 can be applied as novel predictors and therapeutic targets for pancreatic cancer.

MiR-652 inhibits acidic microenvironment-induced epithelial-mesenchymal transition of pancreatic cancer cells by targeting ZEB1.

Recent evidences suggest that the acidic microenvironment might facilitate epithelial mesenchymal transition (EMT) of tumor cells, while the effects of acidity on EMT of pancreatic cancer (PC) remain undefined. The present study demonstrated that acidity suppressed miR-652 expression, which further promoted EMT process by absenting inhibition on the transcriptional factor ZEB1 expression. At first, we found that acidity remarkably enhanced invasion ability of PC cells accompanying with increased mesenchymal and decreased epithelial markers. Meanwhile, miRNAs-microarray showed that miR-652, the potential regulator of ZEB1, was distinctly decreased in acidity-treated PC cells. Furthermore, restoration of miR-652 reversed acidity-induced EMT by inhibiting ZEB1 expression, while miR-652 inhibitor induced EMT in normal PC cells through promoting ZEB1 expression. Nevertheless, knockdown of ZEB1 significantly suppressed acidity-induced EMT in PC cells, but ZEB1 overexpression rescued the EMT which was inhibited by miR-652 overexpression. The in vivo results showed that the tumor growth and liver metastasis were remarkably retarded by both miR-652 overexpression and ZEB1 knockdown. The clinical samples further revealed that miR-652 was decreased in PC tissues and antagonistically correlated with ZEB1 expression, associating with late tumor stage, lymphatic invasion and metastasis. In conclusion, our study indicated a novel acidity/miR-652/ZEB1/EMT axis in the tumorigenesis of PC.

Chronic pancreatitis and pancreatic cancer demonstrate active epithelial-mesenchymal transition profile, regulated by miR-217-SIRT1 pathway.

Epithelial-mesenchymal transition (EMT) is supposed to be an inflammation induced response which may take a central role in tumorigenesis. Since recent evidence indicates that microRNAs may be involved in EMT, the present study set out to reveal the miRNA which might regulate the EMT in CP (chronic pancreatitis) and PC (pancreatic cancer) and its potential mechanism. Firstly, we provided evidence that both CP and PC tissues demonstrated active EMT profile. Consistently, miR-217 was obviously down-regulated in CP, PC and TGF-ß1 treated PC cells, while negatively correlated to its direct target SIRT1. Moreover, either ectopic expression of miR-217 or inhibition of SIRT1 remarkably induced mesenchymal to epithelial transition (MET) in TGF-ß1 treated PC cells. On the contrary, miR-217 inhibitor promoted EMT in PC cells but not in SIRT-knockdown PC cells. Clinical information from a cohort of 54 PC patients demonstrated that down-regulated miR-217 was positively correlated with late tumor stage, lymphatic invasion, vascular infiltration and distant metastasis. These results suggest that the overexpressed TGF-ß1 in inflammation triggers the deregulation of the miR-217-SIRT1 pathway and then promotes the EMT process, which might be involved in the tumorigenesis of PC. Additionally, miR-217 may function as a novel target and predictor for PC prevention and therapy.

miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4.

miRNAs are associated with various types of cancer due to their ability to affect expression of genes that modulate tumorigenesis. In this study, we explored the role of miR-141 in pancreatic cancer. The analysis of clinical characteristics showed that miR-141 was significantly downregulated in tissues and cell lines of pancreatic cancer. Moreover, the decreased miR-141 level was significantly associated with tumor size and TNM stage, as well as lymph node and distant metastasis. Meanwhile, both Kaplan-Meier and multivariate survival analysis showed decreased miR-141 were associated with overall survival. Overexpression of miR-141 in pancreatic cancer cells inhibited cell proliferation, clonogenicity, and invasion; induced G1 arrest and apoptosis; and enhanced chemosensitivity. To understand how miR-141 mediates the phenotype of pancreatic cancer cells, a bioinformatics tool was used to identify MAP4K4 as a potential target of miR-141. The Dual-Luciferase reporter gene assay showed that miR-141 binds directly to the 3'-untranslated region (3'UTR) of MAP4K4 to inhibit MAP4K4 expression. Western blot and quantitative real-time PCR (qRT-PCR) analyses revealed that MAP4K4 expression was inversely correlated with miR-141 expression both in pancreatic cancer samples and cell lines. Knockdown of MAP4K4 inhibited cell proliferation, clonogenicity, and invasion, induced G1 arrest and apoptosis, and enhanced chemosensitivity. In a nude mouse xenograft model, both overexpression of miR-141 and knockdown of MAP4K4 significantly repressed pancreatic cancer cell growth. Therefore, we conclude that miR-141 targets MAP4K4, acts as a tumor suppressor in pancreatic cancer cells, and may serve as a novel therapeutic agent for miRNA-based pancreatic cancer therapy.

MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3.

Accumulating evidence indicates that microRNAs (miRNAs) are aberrantly expressed in human cancer and contribute to the tumorigenesis, but their roles in pancreatic cancer are still largely unknown. In this study, our data showed that miR-130b was significantly downregulated in 52 pairs of pancreatic cancer tissues and five cell lines. Furthermore, the deregulated miR-130b was correlated with worse prognosis, increased tumor size, late TNM stage, lymphatic invasion and distant metastasis. Multivariate analysis showed that miR-130b expression was a significant and independent prognostic predictor for pancreatic cancer patients. Functional studies indicated that the overexpression of miR-130b dramatically suppressed the proliferation of pancreatic cancer cells both in vitro and in vivo, which could be attributed to the induction of apoptosis and cell cycle arrest at S phase. Meanwhile, an overexpressed miR-130b remarkably inhibited the invasive ability of pancreatic cancer cells. Moreover, the dual luciferase assay revealed that STAT3 was directly targeted by miR-130b, which was further confirmed by the inverse expression of miR-130b and STAT3 in pancreatic cancer samples. Our findings suggested that miR-130b might have a considerable potential in prognosis identification and application of therapy for pancreatic cancer.

Nicotinamide prohibits proliferation and enhances chemosensitivity of pancreatic cancer cells through deregulating SIRT1 and Ras/Akt pathways.

BACKGROUND: Nicotinamide (NAM), the precursor for the synthesis of NAD(+) and also an inhibitor of SIRT1, has been discovered to inhibit some types of cancer. However, little is known about the effects of NAM on pancreatic cancer cells. Since previous research showed that SIRT1 and K-Ras/Akt signaling acted as a promoter in tumorigenesis of pancreatic cancer, our present research set out to explore whether NAM inhibits proliferation and facilitates chemosensitivity in pancreatic cancer cells as well as the potential mechanisms involving SIRT1 and K-Ras/Akt pathway. METHODS: Cell viability was assessed by MTT assay, and apoptosis and cell cycle were measured by flow cytometry. Cell invasive ability was evaluated by matrigel invasion assays. The activity of SIRT1 was measured by the Fluor de Lys deacetylation assay. Expression levels of SIRT1, K-Ras, Phosphated Akt (P-Akt, Ser-473) and Akt were measured using western blot. In vivo tumor growth was performed in pancreatic cancer cells xenografts. RESULTS: NAM inhibited the proliferation of pancreatic cancer cells in a dose-dependent manner, and significantly induced apoptosis and cell cycle arrest in G2/M phase. Moreover, NAM obviously restrained cell invasive ability and increased the chemosensitivity. NAM significantly inhibited the activity of SIRT1 and decreased expression of SIRT1, K-Ras and P-Akt. Further, NAM prohibited proliferation and enhanced GEM antitumor activity in vivo. CONCLUSIONS: Our results implied that NAM might be a potential therapeutic agent for human pancreatic cancer treatment through downregulating SIRT1, K-Ras and P-Akt expression.

Effects of different resuscitation fluid on severe acute pancreatitis.

AIM: To compare effects of different resuscitation fluid on microcirculation, inflammation, intestinal barrier and clinical results in severe acute pancreatitis (SAP). METHODS: One hundred and twenty patients with SAP were enrolled at the Pancreatic Disease Institute between January 2007 and March 2010. The patients were randomly treated with normal saline (NS group), combination of normal saline and hydroxyethyl starch (HES) (SH group), combination of normal saline, hydroxyethyl starch and glutamine (SHG group) in resuscitation. The ratio of normal saline to HES in the SH and SHG groups was 3:1. The glutamine (20% glutamine dipeptide, 100 mL/d) was supplemented into the resuscitation liquid in the SHG group. Complications and outcomes including respiratory and abdominal infection, sepsis, abdominal hemorrhage, intra-abdominal hypertension, abdominal compartment syndrome (ACS), renal failure, acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), operation intervention, length of intensive care unit stay, length of hospital stay, and mortality at 60 d were compared. Moreover, blood oxygen saturation (SpO2), gastric intramucosal pH value (pHi), intra-abdominal pressure (IAP), inflammation cytokines, urine lactulose/mannitol (L/M) ratio, and serum endotoxin were investigated to evaluate the inflammatory reaction and gut barrier. RESULTS: Compared to the NS group, patients in the SH and SHG groups accessed the endpoint more quickly (3.9 ± 0.23 d and 4.1 ± 0.21 d vs 5.8 ± 0.25 d, P < 0.05) with less fluid volume (67.26 ± 28.53 mL/kg/d, 61.79 ± 27.61 mL/kg per day vs 85.23 ± 21.27 mL/kg per day, P < 0.05). Compared to the NS group, incidence of renal dysfunction, ARDS, MODS and ACS in the SH and SHG groups was obviously lower. Furthermore, incidence of respiratory and abdominal infection was significantly decreased in the SH and SHG groups, while no significant difference in sepsis was seen. Moreover, less operation time was needed in the SH and SHG group than the NS group, but the difference was not significant. The mortality did not differ significantly among these groups. Blood SpO2 and gastric mucosal pHi in the SH and SHG groups increased more quickly than in the NS group, while IAP was significantly decreased in the SH and SHG group. Moreover, the serum tumor necrosis factor-α, interleukin-8 and C-reactive protein levels in the SH and SHG groups were obviously lower than in the NS group at each time point. Furthermore, urine L/M ratio and serum endotoxin were significantly lower in the SH group and further decreased in the SHG group. CONCLUSION: Results indicated that combination of normal saline, HES and glutamine are more efficient in resuscitation of SAP by relieving inflammation and sustaining the intestinal barrier.

Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer.

BACKGROUND: DNA hypermethylation is proved to be involved in carcinogenesis. Because chronic pancreatitis (CP) is a consistent risk factor for pancreatic cancer, the possible alteration and tumor contribute effects of hypermethylated in cancer-1 (HIC1) promoter methylation in CP was investigated. METHODS: Methylation of HIC1 promoter HIC1 and SIRT1 expression were detected in human normal pancreas (NP), CP and pancreatic adenocarcinoma tissues. Furthermore, HIC1/SIRT1 pathway was regulated by demethylating reagent and exogenous expression in PANC-1, BxPC-3 and AsPC-1 cell lines, cell biology behavior including proliferation, apoptosis, cell cycle and senescence were detected. RESULTS: The methylation of HIC1 promoter was demonstrated in 70.3 % pancreatic carcinoma (45 of 64), 47.5 % CP (19 of 40) and 11.4 % NP tissues (4 of 35). Moreover, hypermethylation of HIC1 promoter and deregulation of HIC1 expression in pancreatic cancer were significantly related to high-stage tumor and older patient age. HIC1 promoter hypermethylation was also observed in pancreatic cancer cell lines including PANC-1, BxPC-3 and AsPC-1. Restoration of HIC1 function with 5-aza-dC treatment or pCDNA3FlagHIC1 plasmid transfection leaded to a reduction in cell proliferation, obvious cell senescence, cell cycle arrest and apoptosis, accompanied with acetylated p53 and p21(WAF1 of Cip1) upregulation. While after further transfected with pCDNA3FlagSIRT1 plasmid, the growth inhibition, senescence and cycle arrest without apoptosis were partially rescued with deregulated acetylated p53 and p21(WAF1 of Cip1). CONCLUSIONS: Our results indicate that hypermethylation of HIC1 promoter in CP may contribute to the aberrant expression of HIC1/SIRT1 pathway and then involve in the pancreatic carcinogenesis.

miR-148b functions as a tumor suppressor in pancreatic cancer by targeting AMPKα1.

miRNAs are small noncoding RNAs that participate in a variety of biologic processes, and dysregulation of miRNA is always associated with cancer development and progression. Aberrant expression of miR-148b has been found in some types of cancer, but its expression and potential biologic role in pancreatic cancer are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 48 pairs of human pancreatic cancer tissues and five cell lines. Furthermore, the deregulated miR-148b was correlated with increased tumor size, late tumor-node-metastasis stage, lymphatic invasion, distant metastasis, and worse prognosis in pancreatic cancer. Functional studies indicated overexpression of miR-148b dramatically suppressed the growth of cancer cells, attributable to induction of apoptosis and cell-cycle arrest at S-phase. Meanwhile, miR-148b remarkably inhibited invasion and enhanced chemosensitivity of pancreatic cancer cells. Moreover, ectopic expression of miR-148b was able to inhibit tumorigenicity in nude mice. Further studies revealed that AMPKα1 might be the direct target gene of miR-148b, and overexpressed AMPKα1 inversely correlated with miR-148b in pancreatic cancer. Silencing of AMPKα1 with RNA interference inhibited the growth of pancreatic cancer cells in vitro and in vivo and also induced apoptosis, cell-cycle arrest, and inhibited invasion of cancer cells, which is consistent with the effects of miR-148b overexpression. In conclusion, miR-148b can inhibit cell proliferation, invasion, and enhance chemosensitivity of pancreatic cancer by targeting AMPKα1. Our present results implicate the potential effects of miR-148b on prognosis and treatment of pancreatic cancer.