Osteoglycin (OGN) promotes tumorigenesis of pancreatic cancer cell via targeting ID4.

Pancreatic cancer (PC) is the seventh-leading cause of cancer-related mortality, and is associated with limited therapeutic options and poor prognosis. The extracellular matrix (ECM) represents the main component of the tumor microenvironment. Studies have found controversial roles of osteoglycin (OGN), a classical small leucine-rich proteoglycan found in the ECM in human malignancies; however, the significance of OGN in PC has not been determined. Here, the expression profiles of OGN in PC tissues and cell lines were evaluated by Gene Expression Profiling Interactive Analysis (GEPIA) database, immunohistochemistry, western blot, and quantitative PCR. OGN was found to be significantly upregulated in PC tissues and cell lines. Moreover, the expression of OGN was observed to be closely associated with TNM stage, stage III showed a higher OGN expression than that of stages I and II. Survival analysis showed that patients with PC showing high levels of OGN had low survival rates. The effects of OGN on cell proliferation and apoptosis were analyzed using MTT, CCK8, EdU and TUNEL assays. Wound-healing and invasion assays were conducted to test migratory and invasive abilities. Overexpression of OGN was demonstrated to promote proliferation, migration, and invasion, and inhibit apoptosis of PC cells. Further experiments revealed that inhibitor of DNA binding 4 (ID4) was upregulated by OGN. Silencing ID4 by small interfering RNA was shown to partially reverse the tumor-promoting effect of OGN. Collectively, our preliminary results indicate that the elevated expression of OGN may be associated with PC progression and may serve as a potential biomarker for the diagnosis and prognosis of PC. Targeting of OGN/ID4 axis may be a promising strategy in PC therapy.

Correction to: Identifying the active components of Baihe-Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests.

[This corrects the article DOI: 10.1186/s13020-019-0254-9.].

Identifying the active components of Baihe-Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests.

BACKGROUND: Modern pharmacological studies have demonstrated that Baihe-Zhimu decoction (BZD) has antidepressant effects. However, the complex composition and lack of clear evaluation standards for BZD make it less likely to be understood and accepted than evidence-based active natural compounds. METHODS: In this study, an effective method for the identification of antidepressant components was demonstrated and applied to BZD. The first step was to evaluate the efficacy of BZD by the forced swimming test (FST) and the tail suspension test (TST), followed by successive quantitative analyses of the absorbed constituents at different stages, such as before hepatic disposition, liver distribution, after hepatic disposition and brain distribution after the oral administration of BZD. Finally, the compounds detected in the brain were confirmed by activity testing. RESULTS: Our investigation observed that timosaponin BII and timosaponin BIII were accurately determined in the brain after oral administration of BZD, and they were further confirmed to reduce the immobility time in the FST and TST. As described above, timosaponin BII and timosaponin BIII were used to scientifically and reasonably explain the effective chemical basis of the effect of BZD on depression. CONCLUSIONS: This research affords an effective method to discover lead molecules for antidepressants from traditional Chinese medicine.

Induction of tolerogenic dendritic cells by activated TGF-ß/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells.

BACKGROUND: Dendritic cells (DCs) alter their role from being immunostimulatory to immunosuppressive at advanced stages of tumor progression, but the influence of cancer stem cells (CSCs) and their secreted factors on generation and phenotypic change of DCs is unknown. Retinoic acid-inducible gene I (RIG-I) plays a role in regulation of other cellular processes including leukemic stemness besides its antiviral function. METHODS: Short hairpin RNA-mediated gene silencing was employed to generate stable RIG-I-knocked-down human hepatocellular carcinoma (HCC) cell lines. Expression levels of genes and proteins in spheres of those HCC cells were determined by quantitative real-time PCR and Western bot, respectively. Levels of secreted cytokines were measured by ELISA. The surface molecule expression levels of DCs were analyzed using flow cytometry. The ability of DCs to induce proliferation of T cells was assessed by a mixed lymphocyte reaction (MLR) assay. RESULTS: RIG-I-knocked-down HCC cells showed upregulated expression of stem cell marker genes, enhanced secretion of factors suppressing in vitro generation of DCs into the conditioned medium (CM), and induction of a phenotype of tumor-infiltrating DCs (TIDCs) with low levels of DC markers in their tumors in nude mice. Those DCs and TIDCs showed reduced MLR, indicating RIG-I deficiency-induced immunotolerance. The RIG-I-deficient HCC cells secreted more TGF-ß1 than did reference cells. The tumors formed after injection of RIG-I-deficient HCC cells had higher TGF-ß1 contents than did tumors derived from control cells. DC generation and MLR suppressed by the CM of RIG-I-deficient HCC cells were restored by an anti-TGF-ß1 antibody. TGF-ß1-induced phosphorylation of Smad2 and Akt was enhanced in RIG-I-deficient HCC spheres, knockdown of AKT gene expression abolishing the augmentation of TGF-ß1-induced Smad2 phosphorylation. Akt and p-Akt were co-immunoprecipitated with Smad2 in cytoplasmic proteins of RIG-I-deficient spheres but not in those of control spheres, the amounts of co-immunoprecipitated Akt and p-Akt being increased by TGF-ß stimulation. CONCLUSIONS: Our results demonstrate that RIG-I deficiency in HCC cells induced their stemness, enhanced secretion and signaling of TGF-ß1, tolerogenic TIDCs and less generation of DCs, and the results suggest involvement of TGF-ß1 in those RIG-I deficiency-induced tolerogenic changes and involvement of CSCs in DC-mediated immunotolerance.