Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6

Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3′UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.     

Cordycepin prevents oxidative stress-induced inhibition of osteogenesis

Oxidative stress is known to be involved in impairment of osteogenesis and age-related osteoporosis. Cordycepin is one of the major bioactive components of Cordyceps militaris that has been shown to exert antioxidant and anti-inflammatory activities. However, there are few reports available regarding the effects of cordycepin on osteogenesis and the underlying mechanism. In this study, we investigated the potential osteoprotective effects of cordycepin and its mechanism systematically using both in vitro model as well as in vivo mouse models. We discovered that hydrogen peroxide (H₂O₂) induced inhibition of osteogenesis which was rescued by cordycepin treatment in human bone marrow mesenchymal stem cells (BM-MSCs). Cordycepin exerted its protective effects partially by increasing or decreasing expression of osteogenic and osteoclastogenesis marker genes. Treatment with cordycepin increased Wnt-related genes'' expression whereas supplementation of Wnt pathway inhibitor reversed its protective effects. In addition, administration of cordycepin promoted osteogenic differentiation of BM-MSCs by reducing oxidative stress in both ovariectomized and aged animal models. Taken together, these results support the protective effects of cordycepin on oxidative stress induced inhibition of osteogenesis by activation of Wnt pathway.     

Breastfeeding and the incidence of endometrial cancer: A meta-analysis

Several epidemiological studies have investigated the association between breastfeeding and endometrial cancer (EC). However, the results of the studies are controversial. Thus, we conduct this meta-analysis to explore the association between breastfeeding and EC and to evaluate the possible does-response relationship between duration of breastfeeding and EC. PubMed, Web of Science, Chinese National Knowledge Infrastructure, China biology medical literature database, Wan fang databases and Database of Chinese Scientific and Technical Periodicals were searched for eligible observational studies up to 11 July 2015. Random effects model was used to calculate the pooled relative risks (RRs) and restricted cubic spline model was adopted for the does-response analysis.Fifteen articles with 623570 participants were identified. The RRs of these studies suggested that breastfeeding was associated with the reduced risk of EC (high versus low/no: RR = 0.74; 95% confidence interval (CI), 0.58–0.95). In subgroup analyses, a significant association of breastfeeding with EC risk was found in Asia (RR = 0.57, 95% CI 0.37–0.87), and an inverse association of breastfeeding with EC risk was found in cohort studies (RR = 0.62, 95% CI 0.41–0.94). The results were also significant after adjusted for hormone use (RR = 0.63, 95% CI 0.41–0.97) and body mass index (RR=0.65, 95% CI 0.44–0.96). A linear relationship was found of breastfeeding with EC (p for nonlinearity = 0.93), and it indicated that EC risk decreased by 1.2% for one month increment of breastfeeding. This meta-analysis indicates that long term breastfeeding might be associated with decreased risk of EC.     

Dynamic cellular and molecular modulations of diabetes mediated head and neck carcinogenesis

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. While numerous potent dietary insults were considered as oncogenic players for HNSCC development, the impact of metabolic imbalance was less emphasized during HNSCC carcinogenesis. Previous preclinical and epidemiological investigations showed that DM could possibly be correlated with greater incidence and poorer prognosis in HNSCC patients; however, the outcomes from different groups are contradictive and underlying mechanisms remains elusive. In the present study, the changes of cellular malignancy in response to prolonged glucose incubation in HNSCC cells were examined. The results demonstrated that hyperglycemia enhanced HNSCC cell malignancy over time through suppression of cell differentiation, promotion of cell motility, increased resistance to cisplatin, and up-regulation of the nutrient-sensing Akt/AMPK-mTORC1 pathway. Further analysis showed that a more aggressive tongue neoplastic progression was found under DM conditions compared to non-DM state whereas DM pathology led to a higher percentage of cervical lymph node metastasis and poorer prognosis in HNSCC patients. Taken together, the present study confirms that hyperglycemia and DM could enhance HNSCC malignancy and the outcomes are of great benefit in providing better anti-cancer treatment strategy for DM patients with HNSCC.     

Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status,and it regulates cell proliferation by inhibiting Erk1/2 phosphorylation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Significantly downregulated histidine-rich glycoprotein (HRG) during the dynamic stages (WB, WB7, and WB11) of neoplastic transformation of WB F344 hepatic oval-like cells was screened out by iTRAQ labeling followed by 2DLC-ESI-MS/MS analysis. HRG expression was significantly lower in HCC tissues. HRG overexpression in Huh7 and MHCC-97H hepatoma cell lines led to decreased cell proliferation, colony-forming ability, and tumor growth, and increased cell apoptosis. HRG could inhibit cell proliferation via the FGF-Erk1/2 signaling pathway by reducing Erk1/2 phosphorylation. On the other hand, the functional expression of HRG was also dependent on the glycosylation status at its N-terminal, especially at the glycosylation site Asn 125. The glycosylation of HRG may play a key competitive role in the interaction between HRG and heparin sulfate for binding bFGF and activating the FGF receptor. These findings provide novel insights into the molecular mechanism of HRG in HCC.     

GB virus type C E2 protein inhibits human immunodeficiency virus type 1 Gag assembly by downregulating human ADP-ribosylation factor 1

GB virus type C (GBV-C) glycoprotein E2 protein disrupts HIV-1 assembly and release by inhibiting Gag plasma membrane targeting, however the mechanism by which the GBV-C E2 inhibits Gag trafficking remains unclear. In the present study, we identified ADP-ribosylation factor 1 (ARF1) contributed to the inhibitory effect of GBV-C E2 on HIV-1 Gag membrane targeting. Expression of GBV-C E2 decreased ARF1 expression in a proteasomal degradation-dependent manner. The restoration of ARF1 expression rescued the HIV-1 Gag processing and membrane targeting defect imposed by GBV-C E2. In addition, GBV-C E2 expression also altered Golgi morphology and suppressed protein traffic through the secretory pathway, which are all consistent with a phenotype of disrupting the function of ARF1 protein. Thus, our results indicate that GBV-C E2 inhibits HIV-1 assembly and release by decreasing ARF1, and may provide insights regarding GBV-C E2''s potential for a new therapeutic approach for treating HIV-1.     

Upregulated β1-6 branch N-glycan marks early gliomagenesis but exhibited biphasic expression in the progression of astrocytic glioma

Glioma is the world’s commonest primary brain malignancy with much of its biology relating to translational and post-translational events still unknown. In this study, we investigated the clinicopathological significance of N-linked β1-6-GlcNAc branches and GnT-V enzyme in the development and progression of astrocytic glioma. Expression of GnT-V and its GlcNAc-β1-6 oligosaccharides by-product together with Con-A binding sugars were assessed immunohistochemically on tissue microarrays of 16 normal brain and 159 tissue samples of astrocytomas of variable grades and histology. Although tissues of both grade I astrocytomas and normal brain showed considerably higher GnT-V expression, GlcNAc-β1-6 expression was significantly high only in tissues of grade I astrocytomas (p < 0.001), which is attributable to elevated levels of the precursor Con-A binding sugar moieties (p < 0.001). The activity of GnT-V enzyme was found to be dependent on the degree of glioma pathogenesis, as the GlcNAc-β1-6 branched expression diminished with every progressive grade of glioma, reaching minimum in glioblastoma (p < 0.001). Having biphasic activity in gliomagenesis, the role of GnT-V in glioma was deciphered by generating different ectopic GnT-V expressions in U-87 cells, which showed the highest GnT-V expression among selected glioma cell lines. Transient GnT-V rescue was achieved in knockdown clones by transfection with GnT-V expression vector. Suppression of GnT-V in U-87 cells slowed cell proliferation with G0/G1 cell cycle phase arrest. Reduced tumorigenicity, invasiveness and cell-ECM interactions were also associated with suppressed in vitro GnT-V activity suggesting GnT-V may act as an oncoprotein. We report for the first time that GnT-V products are involved in early gliomagenesis but their reduced expression, correlating with low Con-A binding sugars level found in high tumor grades predicts the loss of total N-glycosylation in glioma development and may be of potential diagnostic and/or prognostic value in astrocytoma.     

SP1-mediated microRNA-520d-5p suppresses tumor growth and metastasis in colorectal cancer by targeting CTHRC1

Recent evidence suggests that miR-520 family has an important role in regulating tumorigenesis and development of various types of solid cancers. However, as one of the most common cancers in the world, there is little known about the underlying regulatory mechanisms of miR-520 in colorectal cancer (CRC). In the present study, we investigated the expression of microRNA-520d-5p (miR-520d-5p) in CRC specimens and then explored its potential role and mechanism in CRC progression. We found that miR-520d-5p was markedly down-regulated in CRC clinical specimens compared with adjacent normal tissues by real-time PCR. Dual-luciferase assays confirmed that miR-520d-5p directly targeting CTHRC1 and SP1 transactivate miR-520d-5p by binding to its upstream promoter region. The biological functional experiments showed that ectopic re-expression of miR-520d-5p suppressed CRC cell proliferation, migration and invasion, whereas the inhibition of miR-520d-5p displayed an inverse effect in vitro and in vivo. Western blot shown that miR-520d-5p abrogated the epithelial-mesenchymal transition by inactivating the phosphorylation of Erk1/2. In conclusion, our findings indicate that miR-520d-5p is significantly down-expressed and involved in CRC progression and metastasis by targeting CTHRC1 and regulated by SP1, which provide new support for miR-520d-5p maybe as a novel anti-onco molecular target for the treatment of CRC in the future.