Oleoylethanolamide ameliorates motor dysfunction through PPARα-mediates oligodendrocyte differentiation and white matter integrity after ischemic stroke.

BACKGROUND AND AIM: Our previous study has revealed that OEA promotes motor function recovery in the chronic stage of ischemic stroke. However, the neuroprotective mechanism of OEA on motor function recovery after stroke still is unexplored. Therefore, the aim of this study was to explore the effects of OEA treatment on angiogenesis, neurogenesis, and white matter repair in the peri-infarct region after cerebral ischemia. EXPERIMENTAL PROCEDURE: The adult male rats were subjected to 2 h of middle cerebral artery occlusion. The rats were treated with 10 and 30 mg/kg OEA or vehicle daily starting from day 2 after ischemia induction until they were sacrificed. KEY RESULTS AND CONCLUSIONS: The results revealed that OEA increased cortical angiogenesis, neural progenitor cells (NPCs) proliferation, migration, and differentiation. OEA treatment enhanced the survival of newborn neurons and oligodendrogenesis, which eventually repaired the cortical neuronal injury and improved motor function after ischemic stroke. Meanwhile, OEA treatment promoted the differentiation of oligodendrocyte progenitor cells (OPCs) and oligodendrogenesis by activating the PPARα signaling pathway. Our results showed that OEA restores motor function by facilitating cortical angiogenesis, neurogenesis, and white matter repair in rats after ischemic stroke. Therefore, we demonstrate that OEA facilitates functional recovery after ischemic stroke and propose the hypothesis that the long-term application of OEA mitigates the disability after stroke.

Cause of Death in Patients with Oropharyngeal Carcinoma by Human Papillomavirus Status: Comparative Data Analysis.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinomas (OPSCC) has increased in recent decades, and human papillomavirus (HPV) infection is the main cause of OPSCC. The data regarding causes of death (CODs) are vitally important in informing follow-up strategies and revising treatment strategies to deal with any possible preventable treatment-related COD. However, limited studies have assessed the competing COD by HPV status in patients with OPSCC. OBJECTIVE: We aimed to analyze the distribution of the competing COD according to HPV status in OPSCC. METHODS: We retrospectively included stage I-IVB patients with OPSCC from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. The association between HPV status and head and neck cancer-specific mortality (HNCSM), second primary cancer mortality (SPCM), and noncancer-caused mortality (NCCM) were analyzed. The chi-square test, Kaplan-Meier analysis, and Fine and Gray model were used for statistical analysis. RESULTS: We included 5852 patients in this study and 73.2% (n=4283) of them had HPV-related tumors. A total of 1537 (26.3%) patients died, including 789 (51.3%), 333 (21.7%), and 415 (27%) patients who died from head and neck cancer, second cancer, and noncancer causes, respectively. The 5-year HNCSM, SPCM, NCCM, and overall mortality were 14.7%, 6.5%, 7.7%, and 26.4%, respectively. Those with HPV-positive disease had a lower cumulative incidence of HNCSM (subdistribution hazard ratio [sHR] 0.362, 95% CI 0.315-0.417; P<.001), SPCM (sHR 0.400, 95% CI 0.321-0.496; P<.001), and NCCM (sHR 0.460, 95% CI 0.378-0.560; P<.001) than those with HPV-negative disease. The 5-year risk of HNCSM was 26.9% and 10.7% in those with HPV-negative and HPV-positive disease, respectively (P<.001). The 5-year risk of SPCM was 12.4% and 4.6% in those with HPV-negative and HPV-positive disease, respectively (P<.001). The 5-year risk of NCCM of death was 13.7% and 5.8% in those with HPV-negative and HPV-positive disease, respectively (P<.001). Using the Fine and Gray competing-risks model, our results show that those with HPV-negative tumors had a significantly higher risk of HNCSM (P<.001), SPCM (P<.001), and NCCM (P<.001) than those with HPV-negative tumors. CONCLUSIONS: HPV-positive OPSCC has a lower NCSM, SPCM, and NCCM as compared to those with HPV-negative OPSCC. HPV positivity is a favorable prognostic factor in the context of overcoming cancer as well as in terms of reducing the risk of other CODs in OPSCC. Our finding supports the need to tailor patient follow-up based on the HPV status of patients with OPSCC.

The Prognostic and Predictive Effects of Human Papillomavirus Status in Hypopharyngeal Carcinoma: Population-Based Study.

BACKGROUND: The role of the Human Papillomavirus (HPV) status in patients with hypopharyngeal squamous cell carcinoma (HSCC) remains controversial. OBJECTIVE: Our aim was to determine the prognostic and predictive effects of HPV status in patients with locally advanced HSCC (stage III-IVB) receiving primary radiotherapy. METHODS: Patients diagnosed with stage III-IVB HSCC between 2010 and 2016 were identified. HPV status, demographics, clinicopathological characteristics, treatment, and survival data were captured. Kaplan-Meier analysis, multivariable Cox regression analysis, and propensity score matching analysis were performed. RESULTS: We identified 531 patients in this study and 142 (26.7%) patients with HPV-positive diseases. No significant differences were observed between those with HPV-negative and HPV-positive diseases with regard to demographics, clinicopathological characteristics, and chemotherapy use. HPV-positive HSCC had better head and neck cancer-specific survival (HNCSS; P=.001) and overall survival (OS; P<.001) compared to those with HPV-negative tumors. Similar results were found using the multivariable Cox regression analysis. Sensitivity analyses showed that the receipt of chemotherapy was associated with significantly improving HNCSS (P<.001) and OS (P<.001) compared to not receiving chemotherapy in HPV-negative HSCC, whereas comparable HNCSS (P=.59) and OS (P=.12) were found between both treatment arms in HPV-positive HSCC. Similar results were found after propensity score matching. CONCLUSIONS: Approximately one-quarter of HSCC may be HPV-related, and HPV-positive HSCC is associated with improved survival outcomes. Furthermore, additional chemotherapy appears to be not related to a survival benefit in patients with HPV-positive tumors who received primary radiotherapy.

Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/ß-catenin-Lin28/let7-PDK1 cascade.

BACKGROUND: Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. METHODS: Gene expression pattern of NPC cells were used to test associations between Chibby and ß-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, ß-Catenin, and PDK1 by immunostaining. RESULTS: We observed that Chibby, a ß-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/ß-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/ß-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/ß-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/ß-Catenin signaling and PDK1. CONCLUSIONS: Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/ß-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment.

Anti-oncogenic activity of Chibby in the development of human nasopharyngeal carcinoma.

The Wnt/ß-catenin pathway serves important roles in cancer development. The expression and function of Chibby (Cby), as a direct antagonist of ß-catenin, in nasopharyngeal carcinoma (NPC) has not been fully investigated. The present study revealed that the mRNA and protein expression of Cby was significantly lower in NPC tissue than in the adjacent normal tissue. Low expression of Cby was significantly associated with the tumor and the clinical staging. Furthermore, Cby overexpression inhibited the proliferation of human NPC SUNE1 cells and induced cell cycle arrest. In addition, Cby overexpression also significantly enhanced the susceptibility of SUNE1 cells to apoptosis. These results indicated that Cby might serve as an anti-oncogenic gene in the development of NPC and could represent a potential therapeutic target for the human NPC therapy.

Aldose reductase interacts with AKT1 to augment hepatic AKT/mTOR signaling and promote hepatocarcinogenesis.

Marked up-regulation of aldose reductase (AR) is reportedly associated with the development of hepatocellular carcinoma (HCC). We investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues. We found that overexpressed AR interacted with the kinase domain of AKT1 to increase AKT/mTOR signaling. In both cultured liver cancer cells and liver tissues in DEN-induced transgenic HCC model mice, we observed that AR overexpression-induced AKT/mTOR signaling tended to enhance lactate formation and hepatic inflammation to enhance hepatocarcinogenesis. Conversely, AR knockdown suppressed lactate formation and inflammation. Using cultured liver cancer cells, we also demonstrated that AKT1 was essential for AR-induced dysregulation of AKT/mTOR signaling, metabolic reprogramming, antioxidant defense, and inflammatory responses. These findings suggest that aberrantly overexpressed/over-activated hepatic AR promotes HCC development at least in part by interacting with oncogenic AKT1 to augment AKT/mTOR signaling. Inhibition of AR and/or AKT1 might serve as an effective strategy for the prevention and therapy of liver cancer.

An oncogenic function of retinoic acid receptor-α in the development of laryngeal squamous cell carcinoma.

The aberrant expression of retinoic acid receptor-α (RARα) has been reported in various types of cancer. However, its association with the prognosis and development of laryngeal squamous cell carcinoma (LSCC) has not yet been determined. Therefore, the present study aimed to examine the expression and function of RARα in patients with LSCC. The expression of RARα in LSCC tissues was investigated using immunostaining. An MTT assay and flow cytometry analysis were also performed to investigate the function of RARα in the proliferation and cell cycle of LSCC cells. The expression of RARα was significantly elevated in LSCC tissues compared with adjacent noncancerous tissues (78.1 vs. 6.3%, P<0.05). The overexpression of RARα was associated with poorly differentiated features of LSCC (P<0.05). Furthermore, the downregulation of RARα inhibited the proliferation of LSCC cells, and arrested the cell cycle at the G1 phase via upregulation of cyclin dependent kinase inhibitor 1A, which may be associated with inhibition of the protein kinase B signaling pathway. Therefore, the overexpression of RARα may contribute to the development of LSCC through the regulation of the cell cycle. The results of the present study provide evidence that RARα serves an important function in LSCC development and may be a potential therapeutic target or prognostic predictor for LSCC.

Clinicopathological characteristics, treatment, and survival outcomes of cystadenocarcinoma of the salivary gland: a population-based study.

BACKGROUND: The aim of this study was to investigate the clinicopathological characteristics, treatment, and survival of cystadenocarcinoma of the salivary gland. PATIENTS AND METHODS: Cases in the Surveillance, Epidemiology, and End Results database from 1991 to 2012 were identified. Factors significantly associated with survival were identified using Kaplan-Meier survival analysis and Cox proportional hazard regression. RESULTS: A total of 65 patients were identified; of these patients, 64 received surgical treatment, 25 underwent lymphadenectomy, and four (16.0%) patients had nodal metastasis and only one (2.1%) patient had poorly differentiated disease. The most common tumor location was the parotid gland (87.7%). The median follow-up was 55 months. None of the patients died of salivary gland malignant-tumor-related disease. The 5- and 10-year cause-specific survival rates were 97.0% and 81.4%, respectively. The 5- and 10-year overall survival rates were 84.6% and 60.7%, respectively. Surgical procedures, lymphadenectomy, and adjuvant radiotherapy did not affect survival. CONCLUSION: Salivary gland cystadenocarcinoma is extremely rare but has an excellent prognosis, and surgery is the mainstay of treatment.

ß-escin reverses multidrug resistance through inhibition of the GSK3ß/ß-catenin pathway in cholangiocarcinoma.

AIM: To develop a safe and effective agent for cholangiocarcinoma (CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of ß-escin in combination with chemotherapy on CCA cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of ß-escin and common chemotherapeutics on the proliferation of human CCA cells (QBC939, Sk-ChA-1, and MZ-ChA-1). Immunocytochemistry was used to detect the expression of P-glycoprotein (P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/ß-catenin pathway. The protein levels of P-gp, pS9-GSK3ß, pT216-GSK3ß, GSK3ß, ß-catenin, and p-ß-catenin were further confirmed by western blotting. RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil (5-FU) cells to 5-FU, vincristine sulfate (VCR), or mitomycin C was significantly enhanced by ß-escin compared with either agent alone (P<0.05). In addition, the combination of ß-escin (20 µmol/L) with 5-FU and VCR was synergic with a combination index<1. Further investigation found that the mRNA and protein expression of P-gp was down-regulated by ß-escin. Moreover, ß-escin induced GSK3ß phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of ß-catenin. Interestingly, activation of the GSK3ß/ß-catenin pathway induced by Wnt3a resulted in up-regulation of P-gp, which was effectively abolished by ß-escin, indicating that ß-escin down-regulated P-gp expression in a GSK3ß-dependent manner. CONCLUSION: ß-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3ß/ß-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.

Downregulated Chibby in laryngeal squamous cell carcinoma with increased expression in laryngeal carcinoma Hep-2 cells.

Chibby (Cby) inhibits Wnt/ß-catenin-mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of ß-catenin) to bind to ß-catenin. This suggests that Cby could be a tumor suppressor protein. In the present study, we examined Cby expression in laryngeal squamous cell carcinoma (LSCC) and its function and mechanism in laryngeal carcinoma cell lines. Cby expression levels were investigated by immunohistochemistry in a panel of 36 LSCC patient cases. The expression of ß-catenin, c-myc and cyclin D1 in Hep-2 were determined through RT-PCR and western blot analysis. Activity of Wnt/ß-catenin signaling pathway after overexpression of Cby was measured by TCF/LEF luciferase reporter gene assay. Proliferation, clone forming ability, cell cycle distribution and cell apoptosis of Hep-2 cells were detected by MTT assay, plate colony forming assay, flow cytometry and TUNEL assay, respectively. This study showed that expression of Cby protein was strongly downregulated in LSCC tumor tissues in comparison to normal laryngeal mucosa samples. No significant correlation was found between the expression of Cby in tumor tissue and gender, age, clinical stage and tumor differentiation of laryngeal cancer patients. When Cby was overexpressed in Hep-2 cells, the expression of cyclin D1 was reduced and ß-catenin activity was inhibited. Proliferation and plate colony forming assays revealed a significant inhibitory effect of Cby on growth and colony formation ability of Hep-2 cells after Cby overexpression in comparison to control and mock-infected cells. In addition, we also found that upregulated expression of Cby resulted in accumulation of numbers of cells in G0/G1 phase with concomitant decrease in S phase by cell cycle assay. TUNEL staining demonstrated that, compared with the control group, the rate of apoptosis in the plv-cs2.0-Cby group was significantly increased. Taken together, downregulation of Cby was observed in LSCC, but with no significant correlation to the clinicopathological features of LSCC patients. Overexpression of Cby effectively suppressed laryngeal carcinoma cell growth and promoted its apoptosis. A better understanding of the mechanisms of Cby gene activation in LSCC could provide potential novel therapeutic targets for human laryngeal carcinoma.