Xingchun Gou

CD147/EMMPRIN: an effective therapeutic target for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by high resistance to conventional systemic therapies, rapid progression, easy metastasis and frequent recurrence. There is therefore an urgent requirement to develop novel systemic agents which specifically target hepatoma-associated antigen in the tumors of HCC patients. CD147, a transmembrane glycoprotein, is highly expressed by HCC cells and is strongly associated with HCC progression and prognosis. CD147 in HCC cells modulates HCC growth, promotes invasion and metastasis by stimulating adjacent fibroblasts and HCC cells to produce elevated levels of several extracellular matrix metalloproteinases (MMPs) in the HCC microenvironment. It is also involved in HCC angiogenesis and multidrug resistance (MDR). Clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies. Here, we give an overview of the literature regarding the molecular features and expression of CD147 in human HCC tissues. We specifically focus on the role of CD147 in HCC invasion and metastasis, as well as in angiogenesis and multidrug resistance. In addition, advances in therapeutic strategies targeting HCC CD147 are summarized.

Targeted drug delivery to ischemic stroke via chlorotoxin-anchored, lexiscan-loaded nanoparticles

Ischemic stroke is a leading cause of disability and death worldwide. Current drug treatment for stroke remains inadequate due to the existence of the blood-brain barrier. We proposed an innovative nanotechnology-based autocatalytic targeting approach, in which the blood-brain barrier modulator lexiscan is encapsulated in nanoparticles to enhance blood-brain barrier permeability and autocatalytically augment the brain stroke-targeting delivery efficiency of chlorotoxin-anchored nanoparticles. The nanoparticles efficiently and specifically accumulated in the brain ischemic microenvironment and the targeting efficiency autocatalytically increased with subsequent administrations. When Nogo-66 receptor antagonist peptide NEP1-40, a potential therapeutic agent for ischemic stroke, was loaded, nanoparticles significantly reduced infarct volumes and enhanced survival. Our findings suggest that the autocatalytic targeting approach is a promising strategy for drug delivery to the ischemic microenvironment inside the brain. Nanoparticles developed in this study may serve as a new approach for the clinical management of stroke.

EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF

EMMPRIN, a cell adhesion molecule highly expressed in a variety of tumors, is associated with poor prognosis in cancer patients. Mechanistically, EMMPRIN has been characterized to contribute to tumor development and progression by controlling the expression of MMPs and VEGF. In the present study, by using fluorescently labeled bone marrow-derived cells (BMDCs), we found that the down-regulation of EMMPRIN expression in cancer cells reduces tumor growth and metastasis, and is associated with the reduced recruitment of BMDCs. Further protein profiling studies suggest that EMMPRIN controls BMDC recruitment through regulating the secretion of soluble factors, notably, VEGF and SDF-1. We demonstrate that the expression and secretion of SDF-1 in tumor cells are regulated by EMMPRIN. This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF.

Berberine sensitizes rapamycin‑mediated human hepatoma cell death in vitro.

Rapamycin is clinically used as an immunosuppressant. Increasing evidence suggests that rapamycin has an important inhibitory role in the development and progression of different types of cancer and that it is a promising candidate for cancer chemotherapy. Berberine is an isoquinoline alkaloid isolated from medicinal plant species, which has been used in traditional Chinese medicine with no significant side effects. Recent research has demonstrated that berberine has anticancer activity against various types of cancer, mediated through the suppression of mammalian target of rapamycin (mTOR). The present study aimed to investigate the in vitro synergistic anticancer effect of combined treatment of rapamycin at various concentrations (0, 10, 50, 100 and 200 nM) and berberine (62.5 µM) in SMMC7721 and HepG2 hepatocellular carcinoma (HCC) cell lines, and the potential underlying molecular mechanism. The combined use of rapamycin and berberine was found to have a synergistic cytotoxic effect, with berberine observed to maintain the cyotoxic effect of rapamycin on HCC cells at a lower rapamycin concentration. Moreover, the cells treated with the combination of the two agents exhibited significantly decreased protein levels of phosphorylated (p)‑p70S6 kinase 1 (Thr389), the downstream effector of mTOR, compared with the cells treated with rapamycin or berberine alone. Furthermore, overexpression of cluster of differentiation (CD) 147, a transmembrance glycoprotein associated with the anticancer effects of berberine, was found to upregulate p‑mTOR expression and inhibit cell death in SMMC7721 cells co‑treated with rapamycin and berberine. In conclusion, the findings of the present study suggest that the combined use of rapamycin and berberine may improve HCC therapy through synergistically inhibiting the mTOR signaling pathway, which is at least in part, mediated through CD147.

Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy

Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD3+CD56+ natural killer T cells, which can be easily expanded in vitro from peripheral blood mononuclear cells. CIK cells work as pharmacological tools for cancer immunotherapy as they exhibit MHC-unrestricted, safe, and effective antitumor activity. Much effort has been made to improve CIK cells cytotoxicity and treatments of CIK cells combined with other antitumor therapies are applied. This review summarizes some strategies, including the combination of CIK with additional cytokines, dendritic cells, check point inhibitors, antibodies, chemotherapeutic agents, nanomedicines, and engineering CIK cells with a chimeric antigen receptor. Furthermore, we briefly sum up the clinical trials on CIK cells and compare the effect of clinical CIK therapy with other immunotherapies. Finally, further research is needed to clarify the pharmacological mechanism of CIK and provide evidence to formulate uniform culturing criteria for CIK expansion.

The PHLDB1 rs498872 (11q23.3) polymorphism and glioma risk: A meta-analysis.

The association between the rs498872 single nucleotide polymorphism (SNP) and glioma risk has been studied, but these studies have yielded conflicting results. In order to explore this association, we performed a meta‐analysis. A comprehensive literature search was performed using PubMed and EMBASE database, with the last search up to August 23, 2013. Six articles including 10 case‐control studies in English with 18 002 controls and 8434 cases were eligible for the meta‐analysis. Subgroup analyses were conducted by source of controls and ethnicity. The combined results showed that rs498872 polymorphism was significantly associated with glioma risks (TT vs CC: OR = 1.337, 95% CI = 1.222–1.462; TC vs CC: OR = 1.173, 95% CI = 1.081–1.272; dominant model: OR = 1.199, 95% CI = 1.101–1.306; recessive model: OR = 1.237, 95% CI = 1.135–1.347; additive model: OR = 1.156, 95% CI = 1.085–1.232). Moreover, there was increased cancer risk in all genetic models after stratification of the SNP data by the source of controls and ethnicity, and no evidence of publication bias was produced. Our meta‐analysis suggested that rs498872 polymorphism was associated with increased risk of glioma. However, additional studies exploring the combined effects of rs498872 polymorphisms in Asian population should be investigated.

CD147 is increased in HCC cells under starvation and reduces cell death through upregulating p-mTOR in vitro

Transarterial chemoembolization (TACE) is the standard of care for treatment of intermediate hepatocellular carcinoma (HCC), however, key molecules involved in HCC cell survival and tumor metastasis post-TACE remain unclear. CD147 is a member of the immunoglobulin superfamily that is overexpressed on the surface of HCC cells and is associated with malignant potential and poor prognosis in HCC patients. In this study, using an Earle’s Balanced Salt Solution medium culture model that mimics nutrient deprivation induced by TACE, we investigated the regulation of CD147 expression on HCC cells under starvation conditions and its functional effects on HCC cell death. During early stages of starvation, the expression of CD147 was considerably upregulated in SMMC7721, HepG2 and HCC9204 hepatoma cell lines at the protein levels. Downregulation of CD147 by specific small interfering RNA (siRNA) significantly promoted starvation-induced cell death. In addition, CD147 siRNA-transfected SMMC7721 cells demonstrated significantly increased levels of both apoptosis and autophagy as compared to cells transfected with control siRNA under starvation conditions, whereas no difference was observed between the two treatment groups under normal culture conditions. Furthermore, silencing of CD147 resulted in a remarkable downregulation of phosphorylated mammalian target of rapamycin (p-mTOR) in starved SMMC7721 cells. Finally, the combined treatment of starvation and anti-CD147 monoclonal antibody exhibited a synergistic HCC cell killing effect. Our study suggests that upregulation of CD147 under starvation may reduce hepatoma cell death by modulating both apoptosis and autophagy through mTOR signaling, and that CD147 may be a novel potential molecular target to improve the efficacy of TACE.

Activatable Protein Nanoparticles for Targeted Delivery of Therapeutic Peptides

Clinical translation of therapeutic peptides, particularly those that require penetration of the cell membrane or are cytolytic, is a major challenge. A novel approach based on a complementary mechanism, which has been widely used for guided synthesis of DNA or RNA nanoparticles, for de novo design of activatable protein nanoparticles (APNPs) for targeted delivery of therapeutic peptides is described. APNPs are formed through self-assembly of three independent polypeptides based on pairwise coiled-coil dimerization. They are capable of long circulation in the blood and can be engineered to target diseases. Peptides to be delivered are incorporated into APNPs and released into the disease microenvironment by locally enriched proteases. It is demonstrated that APNPs mediate efficient delivery of NR2B9c, a neuroprotective peptide that functions after cell penetration, and melittin, a cytolytic peptide that perturbs the lipid bilayer, for effective treatment of stroke and cancer, respectively. Due to their robust properties, simple design, and economic costs, APNPs have great potential to serve as a versatile platform for controlled delivery of therapeutic peptides.

Disrupted in schizophrenia 1 (DISC1) inhibits glioblastoma development by regulating mitochondria dynamics

Glioblastoma(GBM) is one of the most common and aggressive malignant primary tumors of the central nervous system and mitochondria have been proposed to participate in GBM tumorigenesis. Previous studies have identified a potential role of Disrupted in Schizophrenia 1 (DISC1), a multi-compartmentalized protein, in mitochondria. But whether DISC1 could regulate GBM tumorigenesis via mitochondria is still unknown. We determined the expression level of DISC1 by both bioinformatics analysis and tissue analysis, and found that DISC1 was highly expressed in GBM. Knocking down of DISC1 by shRNA in GBM cells significantly inhibited cell proliferation both in vitro and in vivo. In addition, down-regulation of DISC1 decreased cell migration and invasion of GBM and self renewal capacity of glioblastoma stem-like cells. Furthermore, multiple independent rings or spheres could be observed in mitochondria in GBM depleted of DISC1, while normal filamentous morphology was observed in control cells, demonstrating that DISC1 affected the mitochondrial dynamic. Dynamin-related protein 1 (Drp1) was reported to contribute to mitochondrial dynamic regulation and influence glioma cells proliferation and invasion by RHOA/ ROCK1 pathway. Our data showed a significant decrease of Drp1 both in mRNA and protein level in GBM lack of DISC1, indicating that DISC1 maybe affect the mitochondrial dynamic by regulating Drp1. Taken together, our findings reveal that DISC1 affects glioblastoma cell development via mitochondria dynamics partly by down regulation of Drp1.

MicroRNA targeting microtubule cross-linked protein (MACF1) would suppress the invasion and metastasis of malignant tumor

Cancer is one of the most serious diseases that endanger human health in the world today, and the incidence and mortality of cancer increases year by year. Invasion and metastasis is the most prominent feature of malignant tumors, but also becomes the primary factor of threatening patients health. Tumor cell invasion and metastasis which closely related to the dynamic changes of the cytoskeleton is an important factor influencing the survival of patients. Therefore, inhibition of tumor cell invasion and metastasis is a key strategy for the treatment of cancer. MACF1 is a microtubule microfilament cross-linking factor that plays an important role in cell polarization, cell migration, and maintenance of tissue integrity. A lot of studies have shown that microRNAs play an important role in tumorigenesis, invasion and metastasis. Therefore, we propose the following scientific assumptions: MACF1, an important molecule in adjusting the invasion and metastasis of tumor cells, regulates microfilaments, microtubules participating in cytoskeleton dynamics to promote malignant tumor cell migration and invasion; MicroRNA targeting MACF1 can decrease the expression of MACF1 and thus disrupt the dynamic balance of microtubule or microfilaments as an effective way to inhibit the invasion and metastasis of tumor cells. So we can use it as a new target for clinical early diagnosis and treatment of malignant tumor invasion and metastasis.