Shu Zhang

Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-β/β-catenin signaling and epithelial–mesenchymal transition

The effect of proton pump inhibitor (PPI) on cancer risk has received much attention recently. In this study, we investigated the mechanism underlying multidrug resistance and the effect of a PPI pantoprazole using an adriamycin-resistant gastric cancer cell model (SGC7901/ADR). Compared with the parental cell line, SGC7901/ADR cells showed reduced proliferation rate, but higher resistance to adriamycin under both anchorage-dependent and -independent conditions. Notably, SGC7901/ADR cells underwent epithelial to mesenchymal transition (EMT) and showed increased migrating and invading capabilities. At molecular level, SGC7901/ADR cells showed strong activation of Wnt/β-catenin signaling pathway compared with parental sensitive cells. Interestingly, we found that a PPI pantoprazole can effectively reverse the aggressiveness and EMT marker expression of SGC7901/ADR cells. Furthermore, pantoprazole treatment resulted in a profound reduction of both total and phosphorylated forms of Akt and GSK-3β, which in turn suppressed the adriamycin-induced Wnt/β-catenin signaling in SGC7901/ADR cells. Taken together, we demonstrate that the aggressive phenotype of adriamycin-resistant SGC7901/ADR cells is mediated by induction of EMT and activation of the canonical Wnt/β-catenin signaling pathway. And for the first time, we show that it is possible to suppress the invasiveness of SGC7901/ADR cells by pantoprazole which targets the EMT and Akt/GSK-3β/β-catenin signaling.

Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives.

Gene therapy has promised to be a highly effective antitumor treatment by introducing a tumor suppressor gene or the abrogation of an oncogene. Among the potential therapeutic transgenes, the tumor suppressor gene p53 serves as an attractive target. Restoration of wild-type p53 function in tumors can be achieved by introduction of an intact complementary deoxyribonucleic acid copy of the p53 gene using a suitable viral vector, in most cases an adenoviral vector (Adp53). Preclinical in vitro and in vivo studies have shown that Adp53 triggers a dramatic tumor regression response in various cancers. These viruses are engineered to lack certain early proteins and are thus replication defective, including Gendicine, SCH-58500, and Advexin. Several types of tumor-specific p53-expressing conditionally replicating adenovirus vectors (known as replication-competent CRAdp53 vectors) have been developed, such as ONYX 015, AdDelta24-p53, SG600-p53, OBP-702, and H101. Various clinical trials have been conducted to investigate the safety and efficiency of these adenoviral vectors. In this review we will talk about the biological mechanisms, clinical utility, and therapeutic potentials of the replication-deficient Adp53-based and replication-competent CRAdp53-based gene therapy.

The diagnostic value of EUS in pancreatic cystic neoplasms compared with CT and MRI

Background and Objectives: Pancreatic cystic neoplasms (PCNs) are being increasingly identified. Recent reports have described the utility of endoscopic ultrasound (EUS) in the characterization of PCNs. This study presents the diagnostic value of EUS in PCNs. Materials and Methods: A total of 108 patients (78 women and 30 men; average age, 50 years) who were confirmed pathologically to have PCNs were analyzed retrospectively. We analyzed the clinical characteristics of 108 patients and compared the diagnostic performance of computed tomography (CT), magnetic resonance imaging (MRI), and EUS with or without fine-needle aspiration (FNA). Results: EUS with or without FNA significantly increased the accuracy for diagnosing PCNs compared with CT (P = 0.002) and MRI (P = 0.006). According to the tumor size, the further analysis of these impacts was provided. EUS was superior to CT in the characterization of PCNs in small (< 3 cm) lesions (P = 0.003), similarly superior to MRI in large (>3 cm) lesions (P = 0.030). Furthermore, EUS is valuable for precisely characterizing internal structures, for example, septa (P = 0.004, compared with CT; P = 0.033, compared with MRI) and mural nodules (P = 0.028, compared with CT). Conclusions: In our study, EUS with or without FNA is the ideal tool for providing detailed imaging of PCNs and performed better than MRI and CT.

Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo

Cucurbitacin-I (Cu-I, also known as Elatericin B or JSI-124) is developed to inhibit constitutive and abnormal activation of STAT3 in many cancers, demonstrating a potent anticancer activity by targeting disruption of STAT3 function. Here, we for the first time systematically studied the underlying molecular mechanisms of Cu-I-induced gastric cancer cell death both in vitro and in vivo. In our study, we show that Cu-I markedly inhibits gastric cancer cell growth by inducing G2/M phase cell cycle arrest and apoptosis at low nanomolar concentrations via a STAT3-independent mechanism. Notably, Cu-I significantly decreases intracellular GSH/GSSG ratio by inhibiting NRF2 pathway to break cellular redox homeostasis, and subsequently induces the expression of GADD45α in a p53-independent manner, and activates JNK/p38 MAPK signaling. Interestingly, Cu-I-induced GADD45α and JNK/p38 MAPK signaling form a positive feedback loop and can be reciprocally regulated by each other. Therefore, the present study provides new insights into the mechanisms of antitumor effects of Cu-I, supporting Cu-I as an attractive therapeutic drug in gastric cancer by modulating the redox balance.

Downregulation of FOXP3 inhibits invasion and immune escape in cholangiocarcinoma

FOXP3 is known as a master control of regulatory T cells with recently studies indicating its expression in several tumor cells. In order to study the precise role of FOXP3 in cholangiocarcinoma, FOXP3 was knocked down in cholangiocarcinoma cell lines. Down regulation of FOXP3 inhibits tumor cell invasion by reducing the quantity of MMP-9 and MMP-2. With FOXP3 knocking down, IL-10 and TGF-β1 secreted by cancer cells diminishes and the cell survival of T cells is significant up-regulation. These results suggest that FOXP3 plays an important role in tumor malignant phenotype, especially the invasion and immune escape.

Elevated PRC1 in gastric carcinoma exerts oncogenic function and is targeted by piperlongumine in a p53-dependent manner

Gastric carcinoma is one of the most common malignancies worldwide and the second most frequent cause of cancer‐related death in China. Protein regulator of cytokinesis 1 (PRC1) is involved in cytokinesis and plays key roles in microtubule organization in eukaryotes. This study was aimed to analyse the expression and to investigate the functional role of PRC1 in gastric tumorigenesis. The expression of PRC1 was evaluated by qRT‐PCR, Western blot and immunohistochemistry. The biological function of PRC1 was determined by CCK‐8 proliferation assays, monolayer colony formation, xenografted nude mice and cell invasion assays by shRNA‐mediated knockdown in AGS and HGC27 cells. The regulation of PRC1 expression by piperlongumine was also investigated using dual‐luciferase reporter assay and ChIP‐qPCR analysis. PRC1 was up‐regulated in primary gastric cancers. Overexpression of PRC1 in gastric cancers was associated with poor disease‐specific survival and overall survival. PRC1 knockdown in AGS and HGC27 cell lines suppressed proliferation, reduced monolayer colony formation, inhibited cell invasion and migration ability and induced cell‐cycle arrest and apoptosis. Inhibition of PRC1 also suppressed tumour growth in vivo. We finally confirmed that PRC1 is a novel downstream target of piperlongumine in gastric cancer. Our findings supported the oncogenic role of PRC1 in gastric carcinogenesis. PRC1 might serve as a prognostic biomarker and potential therapeutic target for gastric carcinoma.

Co-ordinated overexpression of SIRT1 and STAT3 is associated with poor survival outcome in gastric cancer patients.

In many gastric cancer patients, the disease is diagnosed in an advanced stage and therefore the mortality levels are high. Because there is a need to identify novel early diagnostic and prognostic biomarkers, we tested whether SIRT1 and STAT3 are good candidates. Towards this, we used patient tissues representing different stages of gastric cancer including gastric pre-cancerous lesions, early gastric cancer, and advanced gastric cancer, and probed SIRT1, STAT3 and phosphorylated STAT3 (pSTAT3) levels using immunohistochemistry. Our results revealed upregulated expression of SIRT1 in all stages of gastric cancer compared with noncancerous gastric mucosa, suggesting that high SIRT1 levels are likely involved in establishing gastric neoplasticity. However, STAT3 and pSTAT3 levels remained low until the gastric mucosa reached the tumor stage. Moreover, co-ordinated high expression of SIRT1 and STAT3 predicted poor overall survival for advanced gastric cancer patients. In addition, through analysis of gastric cancer patients from the TCGA dataset, we identified SIRT2 as an independent prognostic factor in gastric cancer patients. We postulate that SIRT1 and STAT3 are potential early diagnostic and prognostic markers of gastric cancer. Our study also shows that SIRT1 acts a gatekeeper during gastric tumorigenesis.

Downregulation of leucine-rich repeats and immunoglobulin-like domains 1 by microRNA-20a modulates gastric cancer multidrug resistance

Multidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine‐rich repeats and immunoglobulin‐like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemosensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that upregulation of LRIG1 enhanced chemosensitivity in GC cells. Interestingly, miR‐20a, which was overexpressed in GC MDR cell lines and tissues, was identified to regulate LRIG1 expression by directly targeting its 3′ untranslated region. We also found that inhibition of miR‐20a suppressed GC MDR, and upregulation showed opposite effects. Moreover, we demonstrated that the miR‐20a/LRIG1 axis regulated GC cell MDR through epidermal growth factor receptor (EGFR)‐mediated PI3K/AKT and MAPK/ERK signaling pathways. Finally, LRIG1 expression in human GC tissues is inversely correlated with miR‐20a and EGFR. Taken together, the newly identified miR‐20a/LRIG1/EGFR link provides insight into the MDR process of GC, and targeting this axis represents a novel potential therapeutic strategy to block GC chemoresistance.

Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway†

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and represents a highly malignant tumor with a poor prognosis. Therapeutic modalities for HCC are limited and generally ineffective. UBE2Q1 is a putative E2 ubiquitin conjugating enzyme, and has been shown to be overexpressed in various types of cancers including HCC. How UBE2Q1 contributes to hepatocarcinogenesis remains unknown. Here, we show that UBE2Q1 is up‐regulated in HCC cell lines and in a subset of human HCC tissues. Up‐regulation of UBE2Q1 in primary HCC tumors was significantly correlated with shorter overall survival and disease‐free survival. Mechanistically, we showed that the frequent up‐regulation of UBE2Q1 in HCCs was attributed to the recurrent UBE2Q1 gene copy gain at chromosome 1q21. Functionally, we showed that knockdown of UBE2Q1 reduced HCC cell proliferation, promoted apoptosis via induction of GADD45α, and suppressed orthotopic tumorigenicity both in vitro and in vivo. Inactivation of UBE2Q1 also impeded HCC cell migration and invasion in vitro through regulating EMT process, and suppressed HCC metastasis in vivo. Interestingly, our data revealed a role of UBE2Q1 in the regulation of β‐catenin‐EGFR‐PI3K‐Akt‐mTOR signaling pathway. Our findings indicate that UBE2Q1 is a candidate oncogene involved in HCC development and progression and therefore a potential therapeutic target in applicable HCC patients.

Tumor rupture of gastric gastrointestinal stromal tumors during endoscopic resection: a risk factor for peritoneal metastasis?

Background and study aims  Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Up to the present time, complete surgical excision has been the standard treatment for primary GISTs greater than 2 cm. It is well known that tumor rupture during surgery is an independent risk factor for peritoneal metastasis; however, it is not known whether the risk of peritoneal metastasis increases in cases where the tumor is ruptured during endoscopic resection. Patients and methods  A total of 195 patients treated for GIST between January 2014 and December 2016 in our hospital were enrolled in this study. They were divided into two groups according to whether the tumor was ruptured during endoscopic resection. The rate of peritoneal metastasis in patients in the two groups who also suffered perforation was investigated from the follow-up results. Results  Approximately 55.4 % of all patients were female and the average age of the study group was 59.0 ± 10.3 years. Of the 195 patients, the tumors in 27 were ruptured and the remaining 168 patients underwent en bloc resection. There was no statistically significant difference in gender or age between the two groups. The median tumor size (maximum diameter) in all patients was 1.5 cm (0.3 – 5.0 cm): 2.5 cm (0.8 – 5.0 cm) and 1.4 cm (0.3 – 4.0 cm) in the tumor rupture group and en bloc resection group, respectively ( P  < 0.001). Most of the tumors were located in the gastric fundus. At a median follow-up of 18.7 ± 10.2 months, neither tumor recurrence (liver metastasis, peritoneal metastasis, local recurrence) nor mortality related to GISTs were detected. Conclusions  Tumor rupture during endoscopic resection of gastric GISTs may not be a risk factor for peritoneal metastasis.