PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1.

Background: Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis.

Deficient Rnf43 potentiates hyperactive Kras-mediated pancreatic preneoplasia initiation and malignant transformation.

Background: Largely due to incidental detection, asymptomatic pancreatic cystic lesions (PCLs) have become prevalent in recent years. Among them, intraductal papillary mucinous neoplasm (IPMN) infrequently advances to pancreatic ductal adenocarcinoma (PDAC). Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients.

αB-crystallin/HSPB2 is critical for hyperactive mTOR-induced cardiomyopathy.

Even though aberrant mechanistic target of rapamycin (mTOR) signaling is known to cause cardiomyopathy, its underlying mechanism remains poorly understood. Because augmentation of αB-crystallin and hspB2 was presented in the cortical tubers and lymphangioleiomyomatosis of tuberous sclerosis complex patients, we deciphered the role of αB-crystallin and its adjacent duplicate gene, hspB2, in hyperactive mTOR-induced cardiomyopathy. Cardiac Tsc1 deletion (T1-hKO) caused mouse mTOR activation and cardiomyopathy.

mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs.

Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression.

mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis.

Loss of either TSC1 or TSC2 causes tuberous sclerosis complex (TSC) via activation of mTOR signaling pathway. The two prominent features of TSC are skin lesions including hypomelanic macules and benign tumors in multiple organs, whose molecular alterations are largely unknown. We report here that X cystine/glutamate antiporter (xCT) was elevated in Tsc2 or Pten cells, Tsc1 knockout mouse tissues and TSC2-deficient human kidney tumor.

mTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice.

Background & Aims: Levels of the Golgi protein 73 (GP73) increase during development of hepatocellular carcinoma (HCC); GP73 is a serum marker for HCC. However, little is known about the mechanisms or effects of GP73 during hepatic carcinogenesis.

Methods: GP73 was overexpressed from a retroviral vector in HepG2 cells, which were analyzed in proliferation and migration assays.

PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade.

Mechanistic target of rapamycin (mTOR) integrates multiple extracellular and intracellular signals to regulate cell growth and survival. Hyperactivation of mTOR has been observed in various cancers. Regulation of mTOR activity is thus of importance in physiological processes and tumor development.

Value of Golgi protein 73 monoclonal antibody in diagnosis of hepatocellular carcinoma.

Objective: To explore the sensitivity and specificity of Golgi protein 73 (GP73) monoclonal antibody in the diagnosis of hepatocellular carcinoma (HCC).

Methods: Self-prepared GP73 monoclonal antibody was used as the primary antibody for detecting the serum GP73 levels in healthy controls(n=31)and HCC patients (n=59). The baseline level of the healthy controls was determined by semiquantitative analysis.

Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth.

Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism.

Lactate dehydrogenase B is critical for hyperactive mTOR-mediated tumorigenesis.

Mammalian target of rapamycin (mTOR) is a major downstream effector of the receptor tyrosine kinase (RTK)-phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homologue 1 (AKT) signaling pathway. Although this signaling network is frequently altered in cancer, the underlying mechanisms that cause tumorigenesis as a result of activated mTOR remain largely unknown. We report here that expression of lactate dehydrogenase B (LDHB), a critical enzymatic activator of glycolysis, was upregulated in an mTOR-dependent manner in TSC1(-/-), TSC2(-/-), PTEN(-/-), or activated AKT1-expressing mouse embryonic fibroblasts (MEF).

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade.

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation.

Glycosylation-induced depolarization facilitates subthreshold membrane oscillation in injured primary sensory neurons.

Subthreshold membrane potential oscillations (SMPO) in the injured dorsal root ganglion (DRG) neurons are involved in the generation of spontaneous activity, which can directly evoke neuropathic pain. Nerve injury usually triggers the synthesis of large quantities of membrane protein in nerve injured DRG neurons. Membrane proteins are glycosylated by addition of sugars, especially negatively charged sialic acid residues, which may depolarize the resting membrane potential (Vm), open voltage-gated channels in injured neurons, and cause spontaneous activity.

Sialic acid contributes to generation of ectopic spontaneous discharges in rats with neuropathic pain.

Ectopic spontaneous discharges (ESD) of teased myelinated fibers were recorded from the sciatic nerve proximal to the site of 'chronic constriction nerve injury' in the rat. Ca(2+), Mg(2+), Mn(2+), Ni(2+), La(3+) and some positively charged organic compounds (hexamethonium and poly-lysine) when applied topically to the injured site abolished or significantly reduced the rate of ESD. After enzymatic removal of sialic acid by neuraminidase (2 units/ml), the ESD was silenced in 11, reduced in four and unchanged in four of 19 fibers.