Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.     

The GNAQ T96S Mutation Affects Cell Signaling and Enhances the Oncogenic Properties of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using The Cancer Genome Atlas (TCGA) data analysis. We found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was present in 12 out of 373 HCC patients (3.2%). To examine the effect of the GNAQ T96S mutation on HCC, we transfected the SK-Hep-1 cell line with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the wild-type GNAQ expression vector enhanced anchorage-independent growth, migration, and the MAPK pathways in the SK-Hep-1 cells compared to control vector transfection. Moreover, cell proliferation, anchorage-independent growth, migration, and the MAPK pathways were further enhanced in the SK-Hep-1 cells transfected with the GNAQ T96S expression vector compared to the wild-type GNAQ-transfected cells. In silico structural analysis shows that the substitution of the GNAQ amino acid threonine 96 with a serine may destabilize the interaction between the regulator of G protein signaling (RGS) protein and GNAQ. This may reduce the inhibitory effect of RGS on GNAQ signaling, enhancing the GNAQ signaling pathway. Single nucleotide polymorphism (SNP) genotyping analysis for Korean HCC patients shows that the GNAQ T96S mutation was found in only one of the 456 patients (0.22%). Our data suggest that the GNAQ T96S hotspot mutation may play an oncogenic role in HCC by potentiating the GNAQ signal transduction pathway.     

Oncogenic MicroRNAs Characterization in Clear Cell Renal Cell Carcinoma

A key challenge for the improvement of clear cell renal cell carcinoma (ccRCC) management could derive from a deeper characterization of the biology of these neoplasms that could greatly improve the diagnosis, prognosis and treatment choice. The aim of this study was to identify specific miRNAs that are deregulated in tumor vs. normal kidney tissues and that could impact on the biology of ccRCC. To this end we selected four miRNAs (miR-21-5p, miR-210-3p, miR-185-5p and miR-221-3p) and their expression has been evaluated in a retrospective cohort of formalin-fixed paraffin-embedded (FFPE) tissues from 20 ccRCC patients who underwent surgical nephrectomy resection. miR-21-5p and miR-210-3p resulted the most significantly up-regulated miRNAs in this patient cohort, highlighting these onco-miRNAs as possible relevant players involved in ccRCC tumorigenesis. Thus, this study reports the identification of specific oncogenic miRNAs that are altered in ccRCC tissues and suggests that they might be useful biomarkers in ccRCC management.     

The Role of HMGB1 Signaling Pathway in the Development and Progression of Hepatocellular Carcinoma: A Review

The story of high mobility group protein B1 (HMGB1) in cancer is complicated and the function of HMGB1 in different cancers is uncertain. This review aims to retrieve literature regarding HMGB1 from English electronic resources, analyze and summarize the role of the HMGB1 signaling pathway in hepatocellular carcinoma (HCC), and provide useful information for carcinogenesis and progression of HCC. Results showed that HMGB1 could induce cell proliferation, differentiation, cell death, angiogenesis, metastasis, inflammation, and enhance immunofunction in in vitro and in vivo HCC models. HMGB1 and its downstream receptors RAGE, TLRs and TREM-1 may be potential anticancer targets. In conclusion, HMGB1 plays an important role in oncogenesis and represents a novel therapeutic target, which deserves further study.     

Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I–II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%–0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC.     

High SPARC Expression Starting from Dysplasia,Associated with Breast Carcinoma,Is Predictive for Bone Metastasis without Enhancement of Plasma Levels

In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ET_AR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ET_AR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ET_AR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer.     

Monitoring the development of hepatocellular carcinoma in woodchucks using 31P-MRS

The woodchuck is one of the only lab animal models of chronic viral hepatitis infection and the development of hepatocellular carcinoma. Using this model, changes in tissue energetics in the liver due to the development of hepatocellular carcinoma can be monitored by repeated magnetic resonance imaging and localized phosphorus spectroscopy. Age- and sex-matched control (n=5) and chronically infected (n=5) adult woodchucks were imaged four times in a six-month period in a 7-T horizontal-bore magnet. Using a custom-built doubly tunable quadrature volume coil, sagittal and axial FLASH images (128×128, slice thickness = 5 mm, TR/TE=1000/4.1, 8 averages) were acquired to locate the largest portion of the liver with the least amount of signal contamination from surrounding abdominal muscle. Two-dimensional 31P chemical-shift imaging (2D-CSI) was acquired (16×16 data matrix, 24×24×2 cm³, 1024 data points, 16 averages) for all animals. The extent of liver injury was determined using serum gamma glutamyltransferase (GGT). The livers of infected woodchucks showed a significant increase (p=0.01) in phosphomonoesters (PME):β-adenosine triphosphate (NTP). Chronically infected woodchucks had higher levels of serum GGT compared to uninfected woodchucks (p=0.002). An increase in the PME:β-NTP ratio indicates cellular proliferation within the malignant tumor.     

Investigation of multidrug resistance in cultured human renal cell carcinoma cells by 31P-NMR spectroscopy and treatment survival assays

KTCTL-26 and KTCTL-2 are renal cell carcinoma (RCC) lines with high and lowexpression of P-170 glycoprotein, respectively. Inherent differences between the two cell lines in terms of phosphate metabolites and growth characteristics in culture were examined for possible association with multidrug resistance (MDR). Differences in response to drug treatment were investigated for 40 h incubations with various doses of vinblastine (VBL) alone or as cotreatments with various concentrations of the calcium antagonist diltiazem (DIL) and/or interferon–α (IFN-α). Treatment effects were quantitated using the MTT survival assay and ³¹P magnetic resonance spectroscopy (MRS) to determine phosphate metabolite profiles in intact cells. KTCTL-2 and KTCTL-26 cells exhibited significant inherent differences in phosphocholine, glycerophosphocholine, glycerophosphoethanolamine, and phosphocreatine levels. KTCTL-26 cells were more sensitive than KTCTL-2 to 0.011μM VBL alone (87% vs. 102% survival) or to 0.011μM BL + 10μM DIL (55% vs. 80% survival). The latter treatment resulted in a significant decrease in the ratio of phosphocholine to glycerophosphocholine in KTCTL-26 cells but no significant changes in phosphate metabolites in KTCTL-2 cells. Metabolomic ³¹P MRS detects different metabolite profiles for RCC cell lines with different MDR phenotypes and may be useful for noninvasive characterization of tumors in a clinical setting.This revised version was published online in August 2005 with a corrected sequence of authors.     

HSP70基因在人胃癌、宫颈癌中高表达和癌变关系的研究

采用人的HSP70基因探针P17与人的胃癌、宫颈癌的癌组织中提取的RNA进行northern杂交，结果均出现了比正常组织较强的杂交信号。表明HSP70基因在癌变组织中呈现高表达，与组织的癌变程度表现出了很强的相关性，为进一步了解细胞的癌变机理和对癌症的预防及基因治疗提供了可靠的实验依据。     

纳米羟基磷灰石对肝癌细胞端粒酶基因表达的影响

研究羟基磷灰石（HAP）纳米粒子对Bel-7402人肝癌细胞端粒酶基因表达的影响。采用均相沉淀法制备出稳定单分散的HAP纳米粒子,应用透射电镜、电位粒度仪对其进行表征。HAP纳米粒子作用Bel-7402肝癌细胞4 h后,采用原位杂交技术检测Bel-7402肝癌细胞的端粒酶基因表达。结果表明HAP纳米粒子作用组的Bel-7402肝癌细胞的端粒酶阳性细胞比例为61.38%,而对照组的端粒酶阳性细胞比例为87.89%,2组有显著性差异（P〈0.01）。HAP纳米粒子可使Bel-7402肝癌细胞的端粒酶基因表达下调。