SPARC stabilizes ApoE to induce cholesterol-dependent invasion and sorafenib resistance in hepatocellular carcinoma.

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastasis. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC.

Beneficial effects of protocatechuic acid on diabetic retinopathy in streptozocin-induced diabetic rats.

AIM: To determine the effects of protocatechuic acid (PCA) on streptozocin-induced diabetic retinopathy (DR) in rats. METHODS: Wistar rats were given a 50 mg/kg intraperitoneal injection of streptozocin to induce diabetes. Animals were assigned randomly one of four groups (8 rats per group): control, diabetic, diabetic plus PCA (25 mg/kg·d), and diabetic plus PCA (50 mg/kg·d). After inducing diabetes, treatments were started one week later and continued for eight weeks. After the experiment, the rats were sacrificed, and their retinas were taken for biochemical and molecular analysis. RESULTS: PCA administration diminished the blood glucose and glycated haemoglobin levels relative to the diabetic group. In diabetic rats, PCA lowered elevated levels of advanced glycosylated end products (AGEs) and receptor for AGEs (RAGE). In the retina of diabetic rats, PCA effectively decreased inflammatory cytokine, nuclear factor-κB, tumour necrosis factor-α, interleukin-1ß, and vascular endothelial growth factor, and increased antioxidant markers glutathione, superoxide dismutase, and catalase. CONCLUSION: The protective benefits of PCA against DR may be attributable to its suppression of the AGEs and RAGE and its antioxidant and anti-inflammatory properties.

MSP58 knockdown inhibits the proliferation of esophageal squamous cell carcinoma in vitro and in vivo.

Esophageal carcinoma (EC) is one of the most aggressive cancers with a poor prognosis. Understanding the molecular mechanisms underlying esophageal cancer progression is a high priority for improved EC diagnosis and prognosis. Recently, MSP58 was shown to behave as an oncogene in colorectal carcinomas and gliomas. However, little is known about its function in esophageal carcinomas. We therefore examined the effects of MSP58 knockdown on the growth of esophageal squamous cell carcinoma (ESCC) cells in vitro and in vivo in order to gain a better understanding of its potential as a tumor therapeutic target. We employed lentiviral-mediated small hairpin RNA (shRNA) to knock down the expression of MSP58 in the ESCC cell lines Eca-109 and EC9706 and demonstrated inhibition of ESCC cell proliferation and colony formation in vitro. Furthermore, flow cytometry and western blot analyses revealed that MSP58 depletion induced cell cycle arrest by regulating the expression of P21, CDK4 and cyclin D1. Notably, the downregulation of MSP58 significantly inhibited the growth of ESCC xenografts in nude mice. Our results suggest that MSP58 may play an important role in ESCC progression.

Prevention of pancreatic leakage after pancreaticoduodenectomy by modified Child pancreaticojejunostomy.

BACKGROUND: Pancreatic leakage after pancreaticoduodenectomy is associated with a morbidity and mortality. Different techniques have been used to make a safe anastomosis to the left pancreatic remnant. METHODS: We performed "modified Child pancreaticojejunostomy" for 31 patients, by which end-to-end pancreaticojejunal anastomosis was made with a two-layer polypropylene continuous running suture. RESULTS: In the patients who underwent pancreaticojejunostomy, the average operative time was 14.2 minutes. There was no pancreaticoenterostomy leakage in all patients, and no deaths occurred. CONCLUSIONS: In pancreaticojejunostomy, pancreatic anastomosis is time-saving and free from complications. Thus it is an improvement of pancreaticojejunostomy.

[Induction of apoptosis of HepG2 cells by NDRG2].

AIM: To explore the induction of HepG2 cells by NDRG2 gene. METHODS: Human NDRG2 gene was obtained by RT-PCR. Sequence analysis proved that sequence of NDRG2 gene was correct. Then the gene was inserted into the eukaryotic expression vector pIRES2-EGFP and transfected into NDRG2 gene-negative HepG2 cells. The changes of cell morphology and structure were observed under light, fluorescence and transmission electron microscope, respectively. The variation of cell cycle was detected by flow cytometry. RESULTS: The NDRG2 gene had been obtained and its expression vector was constructed successfully. The NDRG2 gene-transfected HepG2 cells were shown a bad condition, structure damage, and a great number of died cells. The expression of target gene in cytoplasm of HepG2 cells was seen under fluorescence microscope. Flow cytometry analysis showed G1 phase arrest and apoptosis peak appeared.The typical manifestation of cell apoptosis could be observed under transmission electron microscope. CONCLUSION: NDRG2 gene can arrest HepG2 cell proliferation and induce their apoptosis.