Peike Peng

Up-Regulation of RACK1 by TGF-β1 Promotes Hepatic Fibrosis in Mice

Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury, and activation of quiescent hepatic stellate cells (HSCs) into a myofibroblast-like phenotype is considered as the central event of liver fibrosis. RACK1, the receptor for activated C-kinase 1, is a classical scaffold protein implicated in numerous signaling pathways and cellular processes; however, the role of RACK1 in liver fibrosis is little defined. Herein, we report that RACK1 is up-regulated in activated HSCs in transforming growth factor beta 1 (TGF-β1)-dependent manner both in vitro and in vivo, and TGF-β1 stimulates the expression of RACK1 through NF-κB signaling. Moreover, RACK1 promotes TGF-β1 and platelet-derived growth factor (PDGF)-mediated activation of pro-fibrogenic pathways as well as the differentiation, proliferation and migration of HSCs. Depletion of RACK1 suppresses the progression of TAA-induced liver fibrosis in vivo. In addition, the expression of RACK1 in fibrogenic cells also positively correlates well with the stage of liver fibrosis in clinical cases. Our results suggest RACK1 as a downstream target gene of TGF-β1 involved in the modulation of liver fibrosis progression in vitro and in vivo, and propose a strategy to target RACK1 for liver fibrosis treatment.

Decreased expression of STING predicts poor prognosis in patients with gastric cancer

STING (stimulator of interferon genes) has recently been found to play an important role in host defenses against virus and intracellular bacteria via the regulation of type-I IFN signaling and innate immunity. Chronic infection with Helicobacter pylori is identified as the strongest risk factor for gastric cancer. Thus, we aim to explore the function of STING signaling in the development of gastric cancer. Immunohistochemistry was used to detect STING expression in 217 gastric cancer patients who underwent surgical resection. STING protein expression was remarkably decreased in tumor tissues compared to non-tumor tissues, and low STING staining intensity was positively correlated with tumor size, tumor invasion depth, lymph mode metastasis, TNM stage, and reduced patients’ survival. Multivariate analysis identified STING as an independent prognostic factor, which could improve the predictive accuracy for overall survival when incorporated into TNM staging system. In vitro studies revealed that knock-down of STING promoted colony formation, viability, migration and invasion of gastric cancer cells, and also led to a defect in cytosolic DNA sensing. Besides, chronic H. pylori infection up-regulated STING expression and activated STING signaling in mice. In conclusion, STING was proposed as a novel independent prognostic factor and potential immunotherapeutic target for gastric cancer.

Pyrroloquinoline-Quinone Suppresses Liver Fibrogenesis in Mice

Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injuries, and its progression toward cirrhosis is the major cause of liver-related morbidity and mortality worldwide. However, anti-fibrotic treatment remains an unconquered area for drug development. Accumulating evidence indicate that oxidative stress plays a critical role in liver fibrogenesis. In this study, we found that PQQ, a natural anti-oxidant present in a wide variety of human foods, exerted potent anti-fibrotic and ROS-scavenging activity in Balb/C mouse models of liver fibrosis. The antioxidant activity of PQQ was involved in the modulation of multiple steps during liver fibrogenesis, including chronic liver injury, hepatic inflammation, as well as activation of hepatic stellate cells and production of extracellular matrix. PQQ also suppressed the up-regulation of RACK1 in activated HSCs in vivo and in vitro. Our data suggest that PQQ suppresses oxidative stress and liver fibrogenesis in mice, and provide rationale for the clinical application of PQQ in the prevention and treatment of liver fibrosis.

Lectin-like oxidized low-density lipoprotein receptor-1 facilitates metastasis of gastric cancer through driving epithelial-mesenchymal transition and PI3K/Akt/GSK3β activation

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern recognition receptor that plays a critical role in vascular diseases and host immune response. Recently, our research discovered that LOX-1 could facilitate the uptake of dying cells and cross-presentation of cellular antigen via binding with heat shock proteins, which have a close relationship with gastric neoplasia. Therefore, we speculated that LOX-1 may serve as an oncogene in gastric cancer (GC) development and progression. In this study, through immunohistochemistry staining assay and cancer-related databases, we found that LOX-1 expression was up-regulated in GC tissues and correlated with a poor prognosis in GC patients. The expression of LOX-1 was an independent prognostic factor for OS in GC patients, and the incorporation of LOX-1 with TNM stage is more accurate for predicting prognosis. Additionally, in vitro study by transwell assay and western blot analysis confirmed that LOX-1 could promote the migration and invasion of GC cells by driving epithelial-mesenchymal transition and PI3K/Akt/GSK3β activation. Taken together, we first explored the expression profiles, clinical significance and biological function of LOX-1 in GC, and these data suggest that LOX-1 may represent a promising prognostic biomarker for GC and offer a novel molecular target for GC therapies.

High expression of GFAT1 predicts poor prognosis in patients with pancreatic cancer

Pancreatic cancer is one of the most lethal of all types of cancer, with the 5-year survival rate ranging only at 6–7%. The aberrant glucose metabolism is one of the hallmarks of cancer cells, and as a branch of glucose metabolism, hexosamine biosynthesis pathway (HBP) has been reported to play a critical role in the insulin resistance and progression of cancer. Glutamine:fructose-6-phosphate amidotransferase (GFAT1) is the rate-limiting enzyme of the HBP; nevertheless, the prognostic value of GFAT1 in pancreatic cancer remains elusive. In this study, we found that the expression of GFAT1 was increased in pancreatic cancer samples compared to peri-tumor tissues. High expression of GFAT1 was positively associated with lymph node metastasis, pTNM stage and shorter overall survival (OS) in pancreatic cancer patients. GFAT1 was identified as an independent prognosticator for OS, and combining GFAT1 expression with pTNM stage generated a predictive nomogram, which showed better prognostic efficiency for OS in patients with pancreatic cancer. In summary, high GFAT1 expression is identified as an independent predictor of adverse clinical outcome in our small number of pancreatic cancer patients, and the practical prognostic nomogram model may help clinicians in decision making and the design of clinical studies.

Decreased expression of Calpain-9 predicts unfavorable prognosis in patients with gastric cancer

Calpain-8 and calpain-9 belong to the family of calcium-dependent cysteine proteases, which are highly expressed in the stomach. However, the roles of calpain-8 and calpain-9 in gastric tumorigenesis remain little understood. Herein, we demonstrated that calpain-9 was generally decreased in gastric cancer cell lines and primary tumor tissues, while calpain-8 expression was not significantly altered. Calpain-9, but not calpain-8, induced cell cycle arrest in the G1 phase and cellular apoptosis in vitro, and it attenuated the growth of subcutaneous tumor xenografts in vivo. Low expression of calpain-9 was positively associated with male sex, late T stage, lymph node metastasis, and advanced TNM stage. Further analysis identified calpain-9 as an independent prognostic factor for poor prognosis, and combining calpain-9 with TNM stage generated a better predictive model for patient outcomes. In conclusion, calpain-9 is a tumor suppressor that can be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer.

RACK1-mediated translation control promotes liver fibrogenesis

Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1α1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1-stimulated collagen 1α1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap-dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis.

High expression of GFAT1 predicts unfavorable prognosis in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. As a branch of glucose metabolism, hexosamine biosynthesis pathway (HBP) has been reported to play a critical role in the insulin resistance and progression of cancer. Glutamine:fructose-6-phosphate amidotransferase (GFAT) is the rate-limiting enzyme of the HBP; nevertheless, the prognostic value of GFAT1 in HCC remains elusive. In this study, we found that high expression of GFAT1 was significantly associated with serum alpha-fetoprotein (AFP), serum alanine aminotransferase (ALT), tumor size, tumor encapsulation, T stage and TNM stage. High GFAT1 expression was identified as an independent prognostic factor which predicted poor overall survival (OS) and recurrence-free survival (RFS) in HCC patients. Incorporation of GFAT1 expression could improve the prognostic accuracy of traditional TNM stage system. Integration of GFAT1 expression with other independent prognosticators generated a predictive nomogram, which showed better prognostic efficiency for OS and RFS in HCC patients. In vitro studies also revealed that GFAT1 promoted the proliferation, cell cycle progression, migration and invasion of HCC cells. In conclusion, GFAT1 is a potential prognostic biomarker for overall survival and recurrence-free survival of HCC patients after surgery.

High Hepsin expression predicts poor prognosis in Gastric Cancer

Hepsin, a membrane-associated serine protease, is frequently upregulated in epithelial cancers and involved in cancer progression. Our study aims to describe the expression pattern and evaluate the clinical implication of hepsin in gastric cancer patients. The mRNA expression of hepsin was analyzed in 50 gastric cancer and matched non-tumor tissues, which was downregulated in 78% (39/50) of gastric cancer. By searching and analyzing four independent datasets from Oncomine, we obtained the similar results. Furthermore, we evaluated the hepsin expression by IHC in tissue microarray (TMA) containing 220 Gastric Cancer specimens. More importantly, Kaplan-Meier survival and Cox regression analyses were taken to access the prognosis of gastric cancer and predicted that hepsin protein expression was one of the significant and independent prognostic factors for overall survival of Gastric Cancer.

PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα, but not PKCβI or βII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment.