Qiyu Zhang

Decreased Expression of LKB1 Correlates with Poor Prognosis in Hepatocellular Carcinoma Patients Undergoing Hepatectomy

AIMnTo study any correlation of LKB1 expression with prognosis in hepatocellular carcinoma (HCC) cases.nnnMETHODSnA total of 70 HCC patients and 20 primary intrahepatic stone patients in the first affiliated hospital of Wenzhou Medical College were enrolled in this study. LKB1 expression was detected by immunohistochemistry. Patients were followed-up and prognostic factors were evaluated.nnnRESULTnLKB1 expression was decreased in the HCC samples. Loss of LKB1 expression in HCC was significantly related to histologic grade (P=0.010), vascular invasion (P=0.025) and TMN stage (P=0.011). Patients showing negative LKB1 expression had a significantly shorter disease-free and overall survival than those with positive expression (P = 0.001, P=0.000, respectively). Multivariate Cox regression analysis indicated that LKB1 expression level was an independent factor of survival (P = 0.033).nnnCONCLUSIONnHCC patients with decreased expression LKB1 have a poor prognosis. The loss of LKB1 expression is correlated with a lower survival rate.

Correlation between tuberous sclerosis complex 2 and glycogen synthase kinase 3 beta levels, and outcomes of patients with hepatocellular carcinoma treated by hepatectomy.

Tuberous sclerosis complex 2 (TSC2), a tumor suppressor, may play an essential role in the regulation of cell growth and cell survival under energy stress conditions. In addition, TSC2 may act in concert with Wnt and energy signals by additional phosphorylation of glycogen synthase kinase 3β (GSK3β) to regulate cell growth. The expression levels and function of TSC2 and GSK3β in hepatocellular carcinoma (HCC) remain unclear.

Effect of NK4 Transduction in Bone Marrow-Derived Mesenchymal Stem Cells on Biological Characteristics of Pancreatic Cancer Cells

Pancreatic cancer usually has a poor prognosis, and no gene therapy has yet been developed that is effective to treat it. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting pancreatic cancer. First, we successfully extracted MSCs from SD rats. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF) which comprising the N-terminal and the subsequent four kringle domains of HGF, by an adenoviral vector. Then, we confirmed that rat MSCs preferentially migrate to pancreatic cancer cells. Last, MSCs expressing NK4 (NK4-MSCs) strongly inhibited proliferation and migration of the pancreatic cancer cell line SW1990 after co-culture. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting pancreatic cancer.

Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway

The antidiabetic drug metformin has been shown to possess antitumor functions in many types of cancers. Although studies have revealed its beneficial effects on the prognosis of hepatocellular carcinoma (HCC), the detailed molecular mechanism underlying this event remains largely unknown. In this work, we showed that miR-23a was significantly induced upon metformin treatment; inhibition of miR-23a abrogated the proapoptotic effect of metformin in HepG2 cells. We next established forkhead box protein A1 (FOXA1) as the functional target of miR-23a, and silencing FOXA1 mimicked the effect of metformin. Moreover, the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of p53 were increased upon metformin treatment, and the inhibition of p53 abrogated the induction of miR-23a by metformin, suggesting that AMPK/p53 signaling axis is responsible for the induction of miR-23a by metformin. In summary, we unraveled a novel AMPK/p53/miR-23a/FOXA1 axis in the regulation of apoptosis in HCC, and the application of metformin could, therefore, be effective in the treatment of HCC.

The rat pancreatic body tail as a source of a novel extracellular matrix scaffold for endocrine pancreas bioengineering

BackgroundRegenerative medicine and tissue engineering are promising approaches for organ transplantation. Extracellular matrix (ECM) based scaffolds obtained through the decellularization of natural organs have become the preferred platform for organ bioengineering. In the field of pancreas bioengineering, acellular scaffolds from different animals approximate the biochemical, spatial and vascular relationships of the native extracellular matrix and have been proven to be a good platform for recellularization and in vitro culture. However, artificial endocrine pancreases based on these whole pancreatic scaffolds have a critical flaw, specifically their difficult in vivo transplantation, and connecting their vessels to the recipient is a major limitation in the development of pancreatic tissue engineering. In this study, we focus on preparing a novel acellular extracellular matrix scaffold derived from the rat pancreatic body tail (pan-body-tail ECM scaffold).ResultsSeveral analyses confirmed that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. DNA quantification demonstrated an obvious reduction of DNA compared with that of the natural organ (from 931.9u2009±u2009267.8 to 11.7u2009±u20093.6xa0ng/mg, Pxa0<u20090.001); the retention of the sGAG in the decellularized pancreas (0.878u2009±u20090.37) showed no significant difference from the natural pancreas (0.819u2009±u20090.1) (Pxa0>u20090.05). After transplanted with the recellularized pancreas, fasting glucose levels declined to 9.08u2009±u20092.4xa0mmol/l within 2xa0h of the operation, and 8xa0h later, they had decreased to 4.7u2009±u20091.8xa0mmol/l (Pxa0<u20090.05).ConclusionsThe current study describes a novel pancreatic ECM scaffold prepared from the rat pancreatic body tail via perfusion through the left gastric artery. We further showed the pioneering possibility of in vivo circulation-connected transplantation of a recellularized pancreas based on this novel scaffold. By providing such a promising pancreatic ECM scaffold, the present study might represent a key improvement and have a positive impact on endocrine pancreas bioengineering.

Genetically engineered recombinant adenovirus expressing interleukin‑2 for hepatocellular carcinoma therapy

Regulatory and effector T cells possess immunological cytotoxicity for tumor cells in the tumor microenvironment during tumor progression and are the primary suppressors inhuman cancer therapy. Interleukin‑2 (IL‑2) is an anticancer cytokine, which triggers human innate and adaptive immunity by stimulating T cell propagation and lymphocyte infiltration into tumor sites. IL‑2 has been used successfully for cancer therapy. Recombinant adenovirus expressing IL‑2 (rAd‑IL‑2) injection is a gene therapy agent that may improve prognosis of hepatocellular carcinoma (HCC) patients. In the present study, the ability of IL‑2 to stimulate an immune response and the ability of recombinant adenovirus to inhibit tumor cell growth in HCC was investigated in a HCC tumor model. It was demonstrated that the regulatory and effector cell‑mediated tumor suppression by antitumor cluster of differentiation (CD)4+ and CD8+ Txa0cells stimulated by rAd‑IL‑2 is tumor‑specific. Furthermore, rAd‑IL‑2 significantly stimulated tumor‑specific cytotoxic T lymphocyte responses, increased interferon‑γ release and enhanced antitumor immunity by inducing CD4+ and CD8+ T cell recruitment into the tumor, and additionally induced memory to protect tumor‑bearing mice against tumor challenge. Treatment with rAd‑IL‑2 led to tumor regression and long‑term survival of mice in the 120‑day treatment period. Tumor challenge experiments demonstrated that rAd‑IL‑2 induced memory, protecting against reinfection. In conclusion, rAd‑IL‑2 may promote tumor‑associated effector and regulatory T cell expansion and may be a potential therapeutic agent for clinical immunotherapy application in the treatment of cancer.

[Corrigendum] Nuclear factor‑κB signaling negatively regulates high glucose‑induced vascular endothelial cell damage downstream of the extracellular signal‑regulated kinase/c‑Jun N‑terminal kinase pathway

[This corrects the article DOI: 10.3892/etm.2017.4999.].

Nuclear factor‑κB signaling negatively regulates high glucose‑induced vascular endothelial cell damage downstream of the extracellular signal‑regulated kinase/c‑Jun N‑terminal kinase pathway Corrigendum in /10.3892/etm.2017.5422

Diabetes mellitus (DM)-induced high blood sugar severely damages vascular endothelial cells (VECs), which are in direct contact with the blood. Diabetic complications cause difficulties in skin wound healing and VECs are important for this process. Previous studies demonstrated that high blood sugar delayed the repair of wounded VECs, but the underlying mechanism has remained elusive. To explore the effects of diabetic conditions on VEC damage, cells were incubated in a medium with high glucose and then subjected to RNA-sequencing based transcriptome analysis. The results revealed that numerous biological processes were altered by HG stress, including extracellular matrix-receptor interaction, NOD-like receptor signaling and the nuclear factor (NF)-κB pathway. HG treatment increased the levels of phosphorylated inhibitor of NF-κB (IκB-α), the key NF-κB signaling regulator as well as the transcripts of plasminogen activator inhibitor-1 and interleukin-8, two inflammatory response markers. Treatment with extracellular signal-regulated kinase (ERK)- and c-Jun N-terminal kinase (JNK)-specific inhibitors U0126 and sp600125, respectively, led to the activation of IκB-α; however, the inhibitor of IκBα phosphorylation Bay11-7082 did not affect ERK and JNK activity, suggesting that ERK/JNK signaling occurs upstream of NF-κB in VECs. The present study provided useful information regarding the effects of diabetes on VECs, which may provide approaches for therapies of diabetes-associated complications in the future.

Inhibition of trauma-associated inflammatory liver damage by blocking NF-κB activity.

BACKGROUND/AIMSnNF-κB protein family members act as transcription facts and play a key role in regulating the immune response to infection and inflammatory signals. We proposed to determine the role of NF-κB in the development of trauma-associated liver damage and inflammation.nnnMETHODOLOGYnNF-κB DNA-binding activity was inhibited using double-stranded oligodeoxynucleotides (ODN). A total of 288 Wistar rats were randomly divided into four groups: control (C), traumatic inflammation (T), traumatic inflammation plus NF-κB decoy (ODN) and traumatic inflammation plus mutant NF-κB decoy ODN (mODN).nnnRESULTSnOur data shows that inhibition of NF-κB activation significantly reduces liver tissue damage as evidenced by serum ALT levels and histological changes using both light microscopy and transmission electron microscopy. Furthermore, EMSA results showed that NF-κB activation was reduced in Group ODN rats compared to Group T and Group mODN rats. Expression of TNF-a and IL-6 protein in Group ODN rats were also reduced compared to Group T and Group mODN rats. We demonstrated that NF-κB plays an important role in trauma-associated inflammation and liver tissue damage.nnnCONCLUSIONSnSuppressing NF-κB activation effectively reduces the release of the pro-inflammatory cytokines TNF-a and IL-6 following liver trauma.

Discovery of a novel human lactate dehydrogenase A (LDHA) inhibitor as an anti-proliferation agent against MIA PaCa-2 pancreatic cancer cells

LDHA has recently emerged as an attractive target for cancer therapy. Herein, we present the discovery of a potent LDHA inhibitor 12, which has good inhibitory activity to LDHA (IC50 = 1.50 μM). Moreover, the inhibitor 12 strongly inhibits the proliferation of MIA PaCa-2 pancreatic cancer cells (EC50 = 3.16 μM), suggesting it could serve as a promising candidate for further investigation.