Shanshan Shen

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.

Piperlongumine induces gastric cancer cell apoptosis and G2/M cell cycle arrest both in vitro and in vivo.

Recently, several studies have shown that piperlongumine (PL) can selectively kill cancer cells by targeting reactive oxygen species (ROS). However, the potential therapeutic effects and detailed mechanism of PL in gastric cancer are still not clear. In the current report, we found that PL significantly suppressed gastric cancer both in vitro and in vivo. PL obviously increased ROS generation in gastric cancer cells. Anti-oxidant glutathione (GSH) and N-acetyl-l-cysteine (NAC) can abrogate PL-induced gastric cancer cell death and proliferation inhibition. GADD45α was induced in PL-treated cancer cells and led to G2/M phase arrest, whereas genetic depletion of GADD45α by small interfering RNAs (siRNAs) could partly reverse PL-induced cell cycle arrest in gastric cancer cells. Interestingly, we also found that PL treatment decreased the expression of telomerase reverse transcriptase (TERT) gene, which plays an essential role in cancer initiation and progression. Our findings thus revealed a potential anti-tumor effect of PL on gastric cancer cells and may have therapeutic implications.

A Strategy to Delay the Development of Cisplatin Resistance by Maintaining a Certain Amount of Cisplatin-Sensitive Cells

Cisplatin (ddp), which is commonly employed in the treatment of many advanced cancers, often results in initial therapeutic success; however, rapid progression of ddp-resistant cells remains the main reason for treatment failure. Facd with such a problem, we investigated the fitness differences between ddp-sensitive and ddp-resistant cell lines. We found that the growth of ddp-resistant cells was significantly slower than that of sensitive cells due to elevated ROS levels, which suggested that the ddp resistance mechanisms may have negative impacts on the growth of resistant cells. Furthermore, we observed that, when mixed with ddp-sensitive cells, ddp-resistant cells failed to compete, and the growth of ddp-resistant cells could therefore be suppressed by treatment in vivo. We propose a mathematical model parameterized based on in vivo experiments to describe the allometric growth of tumors consisting of two competing subclones. According to our model, a quantitative strategy with a variant drug-dosing interval is proposed to control tumor growth. Taking advantage of intratumoral competition, our strategy with appropriate dosing intervals could remarkably delay the development of ddp resistance and prolong overall survival. Maintaining a certain number of ddp-sensitive cells rather than eradicating the tumor with continuous treatment is feasible for future tumor treatment.

Efficacy and safety of endoscopic submucosal dissection for elderly patients with superficial squamous esophageal neoplasms

Background Little is known about the outcomes of endoscopic submucosal dissection in elderly patients with superficial squamous esophageal neoplasms. Objective To assess the efficacy and safety of endoscopic submucosal dissection for superficial squamous esophageal neoplasms in elderly patients (≥65 years) compared with non-elderly patients. Methods All patients with superficial squamous esophageal neoplasms receiving endoscopic submucosal dissection were retrospectively analyzed. Among them, 130 were aged 65 or older (group A), and 201 were aged younger than 65 years (group B). Therapeutic efficacy, adverse events, and follow-up data were evaluated. Results Group A had a higher prevalence of concomitant diseases than group B (52.3% vs. 14.9%, respectively). R0 resection rate was 82.3% in group A and 84.6 % in group B (P = 0.717). The curative resection rate was 80.8% in group A and 83.6% in group B (P = 0.653). The rate of procedure-related non-cardiopulmonary adverse events was 20.8% in group A and 16.9% in group B (P = 0.377). The incidence of cardiopulmonary adverse events during or after the procedure was 6.2% in group A and 2.5% in group B (P = 0.094). No procedure-related mortality was reported in either group. Conclusion Endoscopic submucosal dissection is effective and safe for treating superficial squamous esophageal neoplasms in elderly patients.

The Effects of HSP27 on Gemcitabine-Resistant Pancreatic Cancer Cell Line Through Snail.

Objectives To evaluate the regulation mechanism of heat shock protein 27 (HSP27) on gemcitabine (GEM) resistance of pancreatic cancer cell. Methods The expression vectors pEGFP-C1-HSP27 and the vectors of MicroRNA targeting Snail were introduced into GEM-sensitive pancreatic cancer SW1990 cells, and the vectors of small hairpin RNA targeting HSP27 were transfected into SW1990 and GEM-resistant SW1990/GEM cells. The expressions of HSP27, p-HSP27 (Ser82), Snail, ERCC1, and E-cadherin were evaluated by Western blotting. The sensitivity of transfected cells to GEM was detected by CCK-8 assay and Annexin V-FITC apoptosis assay. Results As compared to SW1990, SW1990/GEM showed significantly increased expressions of HSP27, p-HSP27, Snail and ERCC1 with decreased expression of E-cadherin. By increasing HSP27 expression, we found increase of Snail and ERCC1 with reduction of E-cadherin expressions, while reduction of HSP27 expression caused reduction of Snail and ERCC1 but increase of E-cadherin expressions. Downregulation of Snail resulted in the reduction of ERCC1 expression and increase of E-cadherin. Furthermore, downregulation of HSP27 or snail caused increased GEM sensitivity of pancreatic cancer cells, and upregulation of HSP27 showed the opposite results. Conclusions There is an inverse correlation between HSP27 expression and GEM sensitivity of SW1990 cells, which might be realized by regulating E-cadherin and ERCC1 expressions through Snail.

Over-the-scope clip to close a gastrocutaneous fistula after esophagectomy

Over-the-scope clip (OTSC) system is becoming a new reliable technique which is available for the endoscopic closure of fistulas, bleeding, perforations and so on. We describe the case of a patient with a non-healing gastrocutaneous fistula after esophagectomy for esophageal squamous cell carcinoma which was successfully closed using an OTSC system. This is the first report of the use of OTSC to treat a non-healing gastrocutaneous fistula successfully after esophagectomy. We believe our experience will give such patients an ideal way to cure the fistula without suffering too much and also explore new application of OTSC.

SIRT2 Promotes the Migration and Invasion of Gastric Cancer through RAS/ERK/JNK/MMP-9 Pathway by Increasing PEPCK1-Related Metabolism

Metastasis is the most important feature of gastric cancer (GC) and the most widely recognized reason for GC-related deaths. Unfortunately, the underlying mechanism behind this metastasis remains unknown. Mounting evidence suggests the dynamic regulatory role of sirtuin2 (SIRT2), a histone deacetylase (HDAC), in cell migration and invasion. The present study aims to evaluate the biological function of SIRT2 in GC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in GC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 overexpression marginally promoted proliferation in GC cell lines, SIRT2 knockdown or treatment with SirReal2 decreased the migration and invasion of GC cells. We demonstrated both in vitro and in vivo that SirReal2 could inhibit the deacetylation activity of SIRT2 and its downstream target PEPCK1, which is related to mitochondrial metabolism and RAS/ERK/JNK/MMP-9 pathway. Taken together, these results demonstrate for the first time that SirReal2 selectively targets SIRT2 and decreases migration as well as invasion in human GC cells. SirReal2 therefore shows promise as a new drug candidate for GC therapy.

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.

Risk factors for gastric intraepithelial neoplasia in Chinese adults: a case–control study

Background Gastric carcinoma (GC) is the third most frequent malignancy and the second most common cancer-related cause of death cause worldwide. Gastric intraepithelial neoplasia (GIN) is a well-documented precancerous lesion of GC. In this case–control study, we comprehensively explored the clinical and pathological characteristics of GIN, with the aim to identify its potential risk factors. Patients and methods A total of 630 consecutive patients who underwent endoscopic submucosal dissection or mucosal resection for GIN were initially included. The detailed characteristics of all eligible patients and well-matched healthy controls were recorded and analyzed. Both univariate and multivariate logistic regression analyses were performed and presented with odds ratio (OR) and 95% confidential interval (CI), with additional subgroup analyses based on lesion location. Results A total of 485 GIN-eligible patients were selected, among which 156 had proximal GIN. After follow-up, 434 patients with GIN and 310 age- and gender-matched healthy controls were included in the comparative analyses. Family cancer history (FCH); alcohol abuse; tobacco abuse; intake of high sodium, preserved food, spicy food, and less fruit; Helicobacter pylori (Hp) infection; and atrophic gastritis with intestinal metaplasia were more frequent in GIN patients. Thus, FCH (OR =3.485, 95% CI: 2.031–5.981), high sodium intake (OR =2.830, 95% CI: 1.645–4.868), less fruit intake (OR =4.082, 95% CI: 2.515–6.625), Hp infection (OR =2.307, 95% CI: 1.417–3.755), and atrophic gastritis with intestinal metaplasia (OR =15.070, 95% CI: 8.999–25.237) were independent risk factors for GIN. Further subgroup analyses demonstrated that the specific independent risk factor for proximal GIN was age (OR =2.001, 95% CI: 1.003–3.994), whereas that for distal GIN was intake of high sodium (OR =3.467, 95% CI: 1.896–6.338). Conclusion This study reported a comprehensive overview of the clinical and pathological characteristics of GIN. FCH, high sodium intake, less fruit intake, Hp infection, and atrophic gastritis were identified as the independent risk factors for GIN.