Roles of USP9X in cellular functions and tumorigenesis (Review).

Ubiquitin-specific peptidase 9X (USP9X) is involved in certain human diseases, including malignancies, atherosclerosis and certain diseases of the nervous system. USP9X promotes the deubiquitination and stabilization of diverse substrates, thereby exerting a versatile range of effects on pathological and physiological processes. USP9X serves vital roles in the processes of cell survival, invasion and migration in various types of cancer. The present review aims to highlight the current knowledge of USP9X in terms of its structure and the possible mediatory mechanisms involved in certain types of cancer, providing a thorough introduction to its biological functions in carcinogenesis and further outlining its oncogenic or suppressive properties in a diverse range of cancer types. Finally, several perspectives regarding USP9X-targeted pharmacological therapeutics in cancer development are discussed.

Higher thymocyte selection-associated high mobility group box (TOX) expression predicts poor prognosis in patients with ovarian cancer.

BACKGROUND: Ovarian cancer is one of the most lethal gynecologic malignancies with a dismal prognosis that poses a serious threat to human health, highlighting the need for more knowledge about what is required for identifying some biomarkers for early diagnosis, prediction of prognosis and disease monitoring. TOX, a critical transcription factor related to the development of malignancies that contributing to lymphocytes not just T cells, had been proved prognostic value in some spectrum of cancers. Here, we aimed to study the prognostic role of TOX in ovarian cancer. RESULTS: We found that TOX was not only expressed in CD8 T cells but also tumor cells. TOX expression score was higher in ovarian cancer tissues and correlated with survival status. Survival analysis revealed that ovarian cancer patients with high TOX expression score generally shorter overall survival and disease-free survival times. Univariate and Multivariate Cox demonstrated that TOX expression score could be used as an independent prognostic factor for patients with ovarian cancer. CONCLUSION: TOX expression in ovarian cancer could be a promising tool for predict overall survival of ovarian cancer patients.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Aloin Against Gastric Cancer.

Purpose: This study was designed to evaluate the pharmacological mechanisms of Aloin against gastric cancer (GC) via network pharmacology analysis combined with experimental verification. Methods: Using network pharmacology methods, the potential targets of Aloin and targets related to GC were screened from public databases. The protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the core targets and pathways of Aloin against GC. The expressions of major targets predicted by network pharmacology in normal stomach tissues and GC tissues and their relationships with overall survival of GC were searched in GEPIA, HPA and DriverDBv3 database. The results of network pharmacology analysis were verified by in vitro experiments. Results: A total of 129 potential targets were retrieved by searching the intersection of Aloin and GC targets. PPI network analysis indicated that 10 targets, including AKT1 and CASP3, were hub genes. GO enrichment analysis involved 93 biological processes, 19 cellular components, and 37 molecular functions. KEGG enrichment analysis indicated that the anti-cancer effect of Aloin was mediated through multiple pathways, such as PI3K-AKT, FoxO and Ras signaling pathway. Among them, the PI3K-AKT signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of GC. The validation of key targets in GEPIA, HPA and DriverDBv3 database showed that the verification results for most core genes were consistent with this study. Then, the results of in vitro experiment indicated that Aloin could inhibit proliferation of NCI-N87 cells and induce cell apoptosis. The results also showed that Aloin could decrease the mRNA and protein expressions of PI3K and AKT, suggesting that Aloin can treat GC by inducing cell apoptosis and regulating the PI3K-AKT signaling pathway. Conclusion: This study identified the potential targets of Aloin against GC using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Aloin in treatment of GC.

Prognostic Value of Radiotherapy and Chemotherapy in Stage I-III Merkel Cell Carcinoma.

PURPOSE: Merkel cell carcinoma (MCC) is a highly malignant cancer associated with dismal survival outcomes. Surgery is the cornerstone for the management of MCC, but the benefit of radiotherapy (RT) and chemotherapy (CT) is still controversial. We aimed to investigate the prognostic value of RT and CT in the management of stage I-III MCC patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Patients with a histopathological diagnosis of MCC between 2010 and 2016 were included. The primary endpoint of this study was overall survival (OS). The prognostic significance for OS was analyzed by Cox proportional hazard regression model. RESULTS: A total of 1,691 patients were identified in the SEER database. Over half of the patients had received RT (56.7%), and 9.8% of the patients were documented to have received CT. The median OS for the entire cohort was 66.0 months, and the 5-year OS rate was 53.8%. In the multivariate analysis, receiving RT was associated with significantly improved OS (P < 0.001), while receiving CT significantly negatively impacted OS (P = 0.010). In stage III patients who underwent treatment based on surgical resection, RT was still demonstrated to be a positive factor (P = 0.002), while CT had no significant association with OS in the univariate analysis (P = 0.295). CONCLUSIONS: The current data in the SEER database are consistent with earlier studies supporting the benefit of adjuvant RT for stage I-III MCC patients, but caution should be taken regarding the routine use of CT. For stage III MCC patients, the value of adjuvant CT needs to be confirmed in future studies.

Continuous intravenous infusion of recombinant human endostatin using infusion pump plus chemotherapy in non-small cell lung cancer.

BACKGROUND: Lung cancer is one of the deadliest cancers in the world with the highest incidence and mortality rate among all cancers. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of primary lung cancer. However, efficacy and safety of the current regimens for NSCLC is unsatisfactory. Therefore, there has been an increasing urgency for development of potential therapeutic therapies for NSCLC. AIM: To investigate the therapeutic outcomes and safety of continuous intravenous infusion of recombinant human endostatin (Rh-endostain) using an infusion pump in retreated advanced NSCLC. METHODS: Patients with retreated advanced NSCLC who were admitted to Zhejiang Provincial People's Hospital from October 2017 to April 2019 were recruited. These patients received continuous intravenous infusion of Rh-endostain using an infusion pump. Objective response rate (ORR), clinical benefit rate (CBR), median progression-free survival (mPFS), and incidences of adverse events (AEs) were analyzed after treatment. RESULTS: A total of 45 patients with retreated advanced NSCLC were included, and all of them were evaluated. In these patients, ORR was 22.2%, CBR was 84.4%, and mPFS was 5.3 mo. The following AEs were observed, decreased hemoglobin (34 cases, 75.6%), nausea/vomiting (32 cases, 71.1%), elevated transaminase (24 cases, 53.3%), leukopenia (16 cases, 35.6%), thrombocytopenia (14 cases, 31.1%), and constipation (1 case, 3.4%). None of the patients had leukopenia, nausea /vomiting, and constipation of grade III and above. CONCLUSION: The patients showed improved adherence to 5-d continuous intravenous infusion of Rh-endostain using an infusion pump. Favorable efficacy and safety of this treatment regimen were achieved in retreated advanced NSCLC.

Effect of long-term saline mulched drip irrigation on soil-groundwater environment in arid Northwest China.

Water shortage and soil salinization are the two main factors that are limiting the sustainability of agriculture in arid and semi-arid areas. The mulched drip irrigation (MDI) with brackish groundwater is widely used in the arid areas of Northwest China. In this study, field experiments were carried out to study the effect of long-term MDI with brackish groundwater on the soil and groundwater environment. It was found that the groundwater level decreased in the Peacock river watershed steadily from 2008 to 2019, resulted from escalating groundwater exploitation due to the expanding agricultural irrigation area and increasing irrigation water demand. The decline of groundwater level reduced the evaporation of phreatic surface (ETg) and groundwater recharge from MDI (Rg). The ETg and Rg would be very small, where ETg tended to be zero and Rg would decrease to a constant value, while the water table depth was larger than 3 m. In addition, MDI had little effect on the soil moisture content (SMC) during the MDI period while the groundwater level was shallow (less than 1.9 m), and it increased SMC gradually as the cycle of irrigations increased while the groundwater level was deep (greater than 4.2 m). MDI reduced the concentration of soluble salt ions (Na+, K+ and Cl-) and increased the concentration of Ca2+ and SO42- in the soil. The accumulation of Ca2+ and SO42- in bare soil was more serious than that in the mulched land. The SMC, soil ions concentrations, soil salinity and the total dissolved solids of groundwater decreased significantly with the decrease of the groundwater level, and the salinization degree of the soil and groundwater tended to be weak in the field experimental site. However, groundwater level dropped too much caused by increasing agricultural irrigation would be harmful to the sustainable ecological environment.

A novel Diels-Alder adduct of mulberry leaves exerts anticancer effect through autophagy-mediated cell death.

Guangsangon E (GSE) is a novel Diels-Alder adduct isolated from leaves of Morus alba L, a traditional Chinese medicine widely applied in respiratory diseases. It is reported that GSE has cytotoxic effect on cancer cells. In our research, we investigated its anticancer effect on respiratory cancer and revealed that GSE induces autophagy and apoptosis in lung and nasopharyngeal cancer cells. We first observed that GSE inhibits cell proliferation and induces apoptosis in A549 and CNE1 cells. Meanwhile, the upregulation of autophagosome marker LC3 and increased formation of GFP-LC3 puncta demonstrates the induction of autophagy in GSE-treated cells. Moreover, GSE increases the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes. Next, we investigated that endoplasmic reticulum (ER) stress is involved in autophagy induction by GSE. GSE activates the ER stress through reactive oxygen species (ROS) accumulation, which can be blocked by ROS scavenger NAC. Finally, inhibition of autophagy attenuates GSE-caused cell death, termed as "autophagy-mediated cell death." Taken together, we revealed the molecular mechanism of GSE against respiratory cancer, which demonstrates great potential of GSE in the treatment of representative cancer.

Increased ABCC2 expression predicts cisplatin resistance in non-small cell lung cancer.

Long-term use of platinum-based drugs can cause non-small cell lung cancer (NSCLC) to develop extremely strong drug resistance. Increasing the drug dosage does not have better treatment effects and could lead to serious complications. High levels of drug resistance are considered to be characteristic of human tumours and are usually mediated by genes related to multidrug resistance. Multidrug resistance-associated protein 2 (ABCC2), an ATP-binding cassette multidrug resistance transporter, was found to be overexpressed in various human cancers. In this study, we found that ABCC2 was also upregulated in cisplatin (DDP)-resistant A549 cells (A549/DDP). Functional studies demonstrated that ABCC2 knockdown reversed DDP resistance and promoted G1 phase arrest in A549/DDP cells, and PARP and caspase-3 were activated in A549/DDP cells following ABCC2 knockdown. In vivo, ABCC2 knockdown enhanced the cytotoxicity of DDP to subcutaneous A549 tumours. Together, these results suggest that ABCC2 may be a potential therapeutic strategy for overcoming DDP resistance in NSCLC patients. SIGNIFICANCE OF THE STUDY: In this study, we investigated the role of ABCC2 in cisplatin resistance of NSCLC cells. Our data show that ABCC2 expression was associated with resistance to cisplatin and that knockdown ABCC2 could reverse cisplatin resistance in NSCLC cells. Taken together, our study suggests that reducing the expression of ABCC2 could become an important strategy for enhancing the sensitivity of NSCLC cells to cisplatin.

PRDX2 Promotes the Proliferation and Metastasis of Non-Small Cell Lung Cancer In Vitro and In Vivo.

PURPOSE: Previous studies have reported that the levels of PRDX2 were correlated with tumorigenicity, recurrence, and prognosis of patients with different cancers. We investigated the association between PRDX2 levels and the prognosis of lung cancer patients. We also measured PRDX2 expression of non-small cell lung cancer (NSCLC) cells and examined its roles in the proliferation and migration in vitro and in vivo. METHODS: We used the Kaplan-Meier plotter to analyze the survival of different levels of PRDX2 in lung cancer patients. The expression of PRDX2 in normal bronchial epithelial cell line and NSCLC cell lines was measured by qRT-PCR and western blot assays. Biological functions of NSCLC cells were detected by CCK8 and Transwell assays. We constructed tumor growth model using subcutaneously injection of nude mice and metastasis model by tail vein injection in vivo. The protein levels of proliferation related markers were measured by immunohistochemistry assay. Immunofluorescence method was used to detected EMT-related proteins. RESULTS: The high levels of PRDX2 were associated with bad prognosis in lung cancer patients, especially in patients with adenocarcinoma. The expression of PRDX2 in NSCLC cell lines was higher than normal bronchial epithelial cells. Knockdown of PRDX2 inhibited the proliferation, migration, and invasion in A549 cells, while overexpression of PRDX2 promoted the malignancy in NCI-H1299 cells in vitro. Silencing PRDX2 restrained tumor growth and repressed lung metastasis by EMT in vivo. CONCLUSION: Our data indicates that PRDX2 functions as a protumor regulator and is involved in tumorigenesis and tumor progression of lung cancer.