ERAP2 as a potential biomarker for predicting gemcitabine response in patients with pancreatic cancer.

OBJECTIVE: Pancreatic cancer is one of the most malignant tumors, with rapid metastasis, high mortality rate, and difficult early screening. Currently, gemcitabine is a first-line drug for pancreatic cancer patients, but its clinical effect is limited due to drug resistance. It is particularly important to further identify biomarkers associated with gemcitabine resistance to improve the sensitivity of gemcitabine treatment. METHODS: Drug sensitivity data and the corresponding transcript data derived from the Genomics of Drug Sensitivity in Cancer (GDSC) database for correlation analysis was adopted to obtain genes related to gemcitabine sensitivity. Moreover, the survival model of pancreatic cancer patients treated with gemcitabine in The Cancer Genome Atlas (TCGA) database was utilized to obtain key genes. Multiple in vitro assays were performed to verify the function of the key biomarker. RESULTS: Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) was identified as a biomarker promoting gemcitabine resistance, and its high expression resulted in a worse prognosis. Besides, gemcitabine significantly increased the mRNA and protein levels of ERAP2 in pancreatic cancer cells. Additionally, ERAP2 knockdown suppressed tumorigenesis and potentiated gemcitabine-induced growth, migration and invasion inhibition in human pancreatic cancer cells. CONCLUSIONS: ERAP2 may be a novel key biomarker for gemcitabine sensitivity and diagnosis, thus providing an effective therapeutic strategy for pancreatic cancer treatment.

Diabetic kidney disease-predisposing proinflammatory and profibrotic genes identified by weighted gene co-expression network analysis (WGCNA).

Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes. Despite enormous efforts, the underlying underpinnings of DKD remain incompletely appreciated. We sought to perform novel and informative bioinformatic analysis to explore the molecular mechanism of DKD. The gene expression profiles of GSE142025, GSE30528, and GSE30529 datasets were downloaded from the Gene Expression Omnibus database. After the GSE142025 data set was preprocessed, a gene co-expression network was constructed by weighted gene co-expression network analysis (WGCNA), and hub genes were selected in the key modules. Meanwhile, differentially expressed genes (DEGs) upregulated commonly were identified between the GSE30528 and GSE30529 datasets. Then, pathway and process enrichment analysis were performed for hub genes and commonly upregulated DEGs. Next, candidate targets were identified by comparing hub genes to commonly upregulated DEGs. Finally, reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was carried out to validate the expression of candidate targets, and protein-protein interaction (PPI) network was constructed. A total of 17 modules were clustered by WGCNA, and the most significant turquoise module was selected. Based upon MM > 0.7 and GM > 0.7, 313 hub genes were screened out in turquoise module. Functional analysis of these 313 genes demonstrated their enrichment in pathways involved in leukocyte differentiation, cell morphogenesis, lymphocyte activation, vascular development, collagen synthesis, chemotaxis, and chemokine signaling. A total of 115 commonly upregulated DEGs were identified between the GSE30528 and GSE30529 datasets. Intriguingly, a total of six proinflammatory and profibrotic candidate targets were selected and validated in DKD mice in vivo, including CCR2, MOXD1, COL6A3, COL1A2, PYCARD, and C7. Based on WGCNA and DEG analysis of DKD datasets, six DKD-predisposing candidate targets were uncovered. The data suggest that inflammation and fibrosis are key mechanisms of DKD, and future studies may determine the causal link between the six proinflammatory and profibrotic genes and DKD.

Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential.

Mesenchymal stem cells (MSCs) were known to have excellent properties in cell therapy. However, the risk of immune rejection associated with cell transplant therapy hampers its use. Extracellular vesicles secreted by MSCs derived from different sources that contain therapeutic molecules such as RNA and proteins, which is a novel strategy for cell-free therapy. Recently, researches show EVs from MSCs (MSC-EVs) of different sources have special functions and effects on different diseases. Here, we collected these researches and compared them to each other. In addition, their potential and possible application in clinical treatment are described.

Effect of CXCL12/CXCR4 on migration of decidua-derived mesenchymal stem cells from pregnancies with preeclampsia.

PROBLEM: Systemic immuno-inflammatory response caused by maternal immune imbalance is central to the pathogenesis of preeclampsia (PE). We hypothesized that changes in the number of decidual mesenchymal stem cells (dMSCs) may be associated with maternal immune imbalance. We aimed to evaluate the expression of CXCL12/CXCR4 axis in patients with PE and its influence on the migration behavior of dMSCs, to further clarify the pathogenesis of PE. METHOD OF STUDY: Fourteen women with PE and 11 controls were included. DMSCs were extracted from decidual tissue by type II collagenase digestion and adherence. ELISA and immunohistochemistry analysis were used to measure serum and tissue levels of CXCL12. Q-PCR and Western blotting were used to detect CXCR4 expression on dMSCs, whereas transwell assay was used to measure the migration ability of dMSCs. RESULTS: Decidual mesenchymal stem cells from women with PE showed higher expressions of CXCR4 and HIF-1α than the dMSCs of controls did. Tissues from women with PE showed the highest CXCL12 levels in the decidua, followed by the placenta and umbilical cord, whereas tissues from controls showed the highest CXCL2 levels in the umbilical cord, followed by the placenta and decidua. dMSCs from women with PE showed possibly higher migration ability than that of dMSCs from controls, under the induction of CXCL12, whereas dMSCs showed a decreasing trend in hypoxic than in normoxic environment. CONCLUSION: Decidual mesenchymal stem cells from women with PE can migrate to the decidua layer with the concentration gradient of CXCL12, which may play a role in the occurrence and development of PE.

Glycyrrhetinic acid-modified TPGS polymeric micelles for hepatocellular carcinoma-targeted therapy.

In this study, glycyrrhetinic acid (GA)-modified D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymeric micelles (TGA PMs) were developed for the delivery of etoposide (ETO) to hepatoma cells. GA was incorporated as a ligand because of its high affinity to the hepatocytes, while TPGS functioned as a P-gp inhibitor to reverse multidrug resistance. ETO-loaded TGA PMs (ETO-TGA PMs) displayed a mean particle size of 133.6±1.2nm with a low poly-dispersity index (0.224±0.013) and negative zeta potential (-16.30mV). The drug loading and entrapment efficiency of ETO-TGA PMs were 10.4% and 79.8%, respectively. ETO-TGA PMs also exhibited faster drug release behavior at pH 5.8 and relatively stable drug release at pH 7.4. Confocal laser scanning microscope (CLSM) observations and in vivo imaging studies revealed that TGA PMs displayed higher cellular uptake and selective accumulation at the tumor site, indicating good tumor targetability. Furthermore, ETO-TGA PMs displayed significant cytotoxicity towards HepG2 cells and higher anti-tumor efficacy (75.96%), compared to the control group. This could be due to TGA-mediated targeted drug delivery to the hepatocytes as well as P-gp inhibition. These findings suggest that TGA PMs have the potential to be used as a targeted drug delivery system for hepatic cancer therapy.