hOGG1: A novel mediator in nitrosamine-induced esophageal tumorigenesis.

BACKGROUND: The effect of human 8-Oxoguanine DNA Glycosylase (hOGG1) on exogenous chemicals in esophageal squamous cell carcinoma (ESCC) remain unclear. The study plans to determine hOGG1 expression levels in ESCC and possible interactions with known environmental risk factors in ESCC. MATERIAL AND METHODS: We analyzed levels of exposure to urinary nitrosamines in volunteers from high and low prevalence areas by GC-MS. And we performed the interaction between hOGG1 gene and nitrosamine disinfection by-products by analyzing hOGG1 gene expression in esophageal tissues. RESULTS: In ESCC, nitrosamine levels were significantly increased and hOGG1 mRNA expression levels were significantly decreased. There was a statistically significant interaction between reduced hOGG1 mRNA levels and non-tap drinking water sources in ESCC. The apparent indirect association between ESCC and NMEA indicated that 33.4% of the association between ESCC and NMEA was mediated by hOGG1. CONCLUSION: In populations which exposed to high levels of environmental pollutants NDMA, low expression of hOGG1 may promote the high incidence of esophageal cancer in Huai'an. hOGG1 may be a novel mediator in nitrosamine-induced esophageal tumorigenesis.

Colorectal adenocarcinoma patients with M1a diseases gain more clinical benefits from palliative primary tumor resection than those with M1b diseases: A propensity score matching analysis.

BACKGROUND: Surgical resection is regarded as the only potentially curative treatment option for patients with metastatic colorectal cancer (CRC). The National Comprehensive Cancer Network clinical practice guidelines do not recommend palliative surgery unless there is a risk of severe symptoms. However, accumulating evidence has shown that palliative surgery is associated with more favorable outcomes for patients with metastatic CRC. AIM: To investigate the separate role of palliative primary tumor resection for patients with stage IVA (M1a diseases) and stage IVB (M1b diseases) colorectal adenocarcinoma (CRA). METHODS: CRA patients diagnosed from 2010 to 2015 with definite M1a and M1b categories according to the 8th edition of American Joint Committee on Cancer staging system were selected from the Surveillance Epidemiology and End Results (SEER) database. To minimize potential selection bias, the data were adjusted by propensity score matching (PSM). Baseline characteristics, including gender, year of diagnosis, age, marital status, primary site, surgical information, race, grade, chemotherapy, and radiotherapy, were recorded and analyzed. Univariate and multivariate analyses were performed to explore the separate role of palliative surgery for patients with M1a and M1b diseases. RESULTS: A total of 19680 patients with metastatic CRA were collected from the SEER database, including 10399 cases of M1a diseases and 9281 cases of M1b diseases. Common independent prognostic factors for both M1a and M1b patients included year of diagnosis, age, race, marital status, primary site, grade, surgery, and chemotherapy. After PSM adjustment, 3732 and 3568 matched patients in the M1a and M1b groups were included, respectively. Patients receiving palliative primary tumor resection had longer survival time than those without surgery (P < 0.001). For patients with M1a diseases, palliative resection could increase the median survival time by 9 mo; for patients with M1b diseases, palliative resection could prolong the median survival time by 7 mo. For M1a diseases, patients with lung metastasis had more clinical benefit from palliative resection than those with liver metastasis (15 mo for lung metastasis vs 8 mo for liver metastasis, P < 0.001). CONCLUSION: CRA patients with M1a diseases gain more clinical benefits from palliative primary tumor resection than those with M1b diseases. Those patients with M1a (lung metastasis) have superior long-term outcomes after palliative primary tumor resection.

PGK1 inhibitor CBR-470-1 protects neuronal cells from MPP+.

The neurotoxin MPP+ (1-methyl-4-phenylpyridinium ion) disrupts mitochondrial function leading to oxidative stress and neuronal death. Here we examine whether activation of the Keap1-Nrf2 cascade can protect SH-SY5Y neuroblastoma cells from MPP+-induced cytotoxicity. Treatment of SH-SY5Y cells with CBR-470-1, an inhibitor of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1), leads to methylglyoxal modification of Keap1, Keap1-Nrf2 disassociation, and increased expression of Nrf2 responsive genes. Pretreatment with CBR-470-1 potently attenuated MPP+-induced oxidative injury and SH-SY5Y cell apoptosis. CBR-470-1 neuroprotection is dependent upon Nrf2, as Nrf2 shRNA or CRISPR/Cas9-mediated Nrf2 knockout, abolished CBR-470-1-induced SH-SY5Y cytoprotection against MPP+. Consistent with these findings, PGK1 depletion or knockout mimicked CBR-470-1-induced actions and rendered SH-SY5Y cells resistant to MPP+-induced cytotoxicity. Furthermore, activation of the Nrf2 cascade by CRISPR/Cas9-induced Keap1 knockout protected SH-SY5Y cells from MPP+. In Keap1 or PGK1 knockout SH-SY5Y cells,CBR-470-1 failed to offer further cytoprotection against MPP+. Collectively PGK1 inhibition by CBR-470-1 protects SH-SY5Y cells from MPP+ via activation of the Keap1-Nrf2 cascade.

Pigment Epithelium-Derived Factor Promotes the Growth and Migration of Human Esophageal Squamous Cell Carcinoma.

Pigment epithelium-derived factor (PEDF) is an oncogene found in various types of cancers. However, how PEDF affects the development of human esophageal squamous cell carcinoma (ESCC) is unknown. This study investigates the role of PEDF in ESCC cell proliferation, migration, and cell cycle both in vitro and in vivo. The PEDF expression was examined in patient tumor samples and ESCC cell lines. Short hairpin RNA technology was used to inhibit the PEDF expression in ESCC EC9706 and KYSE150 cells. In vitro cell proliferation and migration assays were performed. The effects of PEDF on tumor growth and progression were examined in vivo in murine subcutaneous xenograft tumor models. It was found that PEDF was overexpressed in esophageal cancer cells and patient tumor tissues compared to normal control samples. PEDF enhanced cell cycle progression and inhibited cell apoptosis. Knock down of PEDF inhibited esophageal cell proliferation and migration in vitro. Moreover, Inhibition of PEDF significantly reduced tumor growth and tumor size in vivo. These results indicate that PEDF induce tumorigenesis in ESCC and can be a potential therapeutic target for cancer treatment.

Targeting cyclophilin-D by compound 19 protects neuronal cells from oxygen glucose deprivation/re-oxygenation.

Oxygen and glucose deprivation (OGD) with re-oxygenation (OGDR) is applied to neuronal cells to mimic ischemia-reperfusion injuries. Activation of cyclophilin D (Cyp-D)-dependent programmed necrosis pathway mediates OGDR-induced neuronal cell damages. Here, we tested the potential effect of Compound 19 (C19), a novel Cyp-D inhibitor, in this process. In both established neuronal cell lines (Neuro-2a and NB41A3 cells) and the primary murine CA1 hippocampal neurons, pretreatment with C19 largely attenuated OGDR-induced cell viability reduction and cell death. Significantly, C19 was ineffective in Cyp-D-silenced Neuro-2a cells. OGDR induced mitochondria-dependent programmed necrosis in neuronal cells. OGDR induced p53 translocation to mitochondria and association with Cyp-D, causing mitochondrial depolarization, cytochrome C release and reactive oxygen species production. Such effects were largely attenuated with pre-treatment of C19. Importantly, C19 was significantly more efficient than other known Cyp-D inhibitors in protecting neuronal cells from OGDR. These results suggest that targeting Cyp-D by C19 protects neuronal cells from OGDR.

Involvement of HMGB1 mediated signalling pathway in diabetic retinopathy: evidence from type 2 diabetic rats and ARPE-19 cells under diabetic condition.

AIMS: Inflammation is considered to play a critical role in the pathogenesis of diabetic retinopathy, and high mobility group box protein 1 (HMGB1) could promote inflammation as an alarmin. We investigated the expression of HMGB1 signalling pathway components in type 2 diabetic rat retinas and in high glucose cultured ARPE-19 cells. METHODS: Retinal expression of HMGB1 and its receptors in type 2 diabetic rats were detected by western blot and immunohistochemistry. ARPE-19 cells were cultured with low glucose, high glucose (with or without anti-HMGB1 antibody) or mannitol (control) for different lengths of time (12, 24, 48, 72 h). Then expression of HMGB1 and its receptors was measured by immunocytochemistry, ELISA or western blot. Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity and tumour necrosis factor α (TNFα)/vascular endothelial growth factor (VEGF) production in retinas as well as in ARPE-19 cells were detected by ELISA. Furthermore, blood-retinal barrier permeability and ARPE-19 cell viability were measured by Evans-Blue and Cell Counting Kit-8 assay, respectively. RESULTS: HMGB1 signalling pathway components including receptors for HMGB1 as well as NF-κB and TNFα/VEGF were significantly upregulated in type 2 diabetic retinas and in high glucose treated ARPE-19 cells, compared to their respective counterparts. HMGB1 blockage significantly alleviated NF-κB activity and VEGF secretion in ARPE-19 cells cultured with high glucose. In addition, blood-retinal barrier permeability of the diabetic retinas increased, while cell viability of high glucose treated ARPE-19 cells decreased. CONCLUSIONS: Expression of HMGB1 signalling pathway components were increased in diabetic rat retinas and in ARPE-19 cells exposed to high glucose.

[Comparison of the short-term outcomes of patients with esophageal cancer after subtotal esophagectomy via thoracoscopy in left lateral position and in prone position].

OBJECTIVE: To compare the short-term outcomes in patients with esophageal cancer after subtotal esophagectomy via thoracoscopy in prone position and in left lateral position. METHODS: Between September 2008 and September 2010, thoraco-laparoscopic esophagectomy (TLE) with thoracoscopic mobilization of the esophagus and mediastinal esophagectomy was performed in 41 patients in prone position (group A) and other 41 patients (group B) performed by the same surgeon in left lateral position. RESULTS: Preoperatively, the endoscopic location of the tumor was in the upper third in 5 cases (2 vs. 3), the middle third in 21 cases (12 vs. 9), and the lower third in 56 cases (27 vs. 29). The median operative time was 230 (range 170-310) min in group A and 280 (range 190-380) min in group B (P=0.04). The median intraoperative blood loss was 275 (range 100-320) ml in group A and 360 (range 120-670) ml in group B (P=0.09). The median number of lymph nodes dissected was 8.4 (range 4-23) in group A and 6.9 (range 6-21) in group B (P=0.03). The postoperative complications totaled 6 (14.6%) in group A and 8 (17.1%) in group B (P=0.44). After a median follow-up period of 15.7 (range 2-28) months for group A and 16.3 (range 3-31) months for group B, 19 patients in group A died and 21 patients in group B. CONCLUSIONS: For esophageal cancer under T3N1M0, surgical outcomes are similar between prone thoracoscopic esophageal mobilization and left lateral position. Prone position may be associated with better lymph node dissection.