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Background and aims Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. Approach and results In this study, we demonstrated that PLAGL2 was up-regulated in HCC compared with that of adjacent nontumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF1/2A signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib. Conclusions This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.

The present study investigated the role of the Twist gene in epithelial-mesenchymal transition (EMT) and its effects on the invasion and metastasis of malignant tumors. In vitro, we transfected SW480, HCT116 and HT29 cells with recombinant plasmids, pTracer-CMV/BSD-Twist and pGenesil1.2-Twist-shRNA, to influence expression of Twist. The transfection efficacy of the plasmids in the cell lines was confirmed by flow cytometry. The relative mRNA and protein expression levels of Twist, E-cadherin and vimentin in the transfected cells were detected by RT-PCR and western blotting, respectively. In addition, migration and invasion were assessed by Transwell assays. In vivo, we established a xenogenic liver metastasis mouse model by intrasplenic injection with transfected SW480, HCT116 or HT29 human colon cancer cells and used hematoxylin and eosin (H&E) staining to demonstrate the effective establishment of the model. The relative mRNA levels of Twist and vimentin were detected by RT-PCR. In vitro, RT-PCR and western blotting showed higher relative mRNA and protein expression levels of Twist and vimentin in cell lines transfected with the recombinant, highly expressed Twist plasmid than in non-transfected cell lines (P0.05), along with inhibition of the migration and invasion abilities of the cell line (P

Although judicious use of tyrosine kinase inhibitors that target BCR-ABL constitutes an effective strategy for the control of chronic myeloid leukemia (CML), drug resistance is observed due to kinase domain mutations, among which a major one is BCR-ABLT315I. In this study, we identified SHC004-221A1 as a potent inhibitor of T315I and other BCR-ABL mutants. Biochemical assays demonstrated that SHC004-221A1 has an inhibitory effect on all selected BCR-ABL mutants. In vitro studies showed that SHC004-221A1 inhibited the proliferation of tumor cell lines carrying native and T315I mutant BCR-ABL. Signaling pathway analysis revealed that SHC004-221A1 inhibited the phosphorylation of STAT5 and CrkL, which contributed to the apoptosis of CML cells. In vivo studies indicated that SHC004-221A1 suppressed BCR-ALBT315I-driven tumor growth in mice. Taken together, the results of this study suggested that SHC004-221A1 may be a promising BCR-ABLT315I inhibitor for the treatment of CML.

APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma (HCC) and APOBEC3B (A3B) remains unknown. It has been confirmed that interleukin-6 (IL-6) has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3B in HepG2 cells. A3B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3B and IL-6, and thereby promoted the prolonged non-resolving inflammation. Collectively, these findings suggest that A3B is essential for oncogenesis of HCC, and is a potential target for preventive intervention.

Melittin is the main effective component of bee venom and has extensive biological functions; however, serious side effects have restricted its clinical application. Preclinical and clinical studies showed that the main adverse events were allergic reaction and pain at the administration site. To decrease the toxicity, we prepared melittin nano-liposomes by encapsulating melittin with poloxamer 188 and explored the inhibitory activities on liver cancer together with biological safety. Here, we showed that melittin nano-liposomes significantly inhibited the survival of hepatocellular carcinoma (HCC) cells in vitro and prominently suppressed the growth of subcutaneous and orthotopic HCC transplantation tumors in vivo. It was important that it induced less inflammation and allergy in mice compared with melittin. Overall, melittin nano-liposomes would have a better application in HCC therapy due to its significant anti-tumor activity and better biological safety. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0442-y) contains supplementary material, which is available to authorized users.

Colitis-associated cancer (CAC) has a close relationship with ulcerative colitis (UC). Therapeutic effect of Schisandrin B (SchB) on UC and CAC remains largely unknown. We investigated the preventative effect of SchB on the dextran sulphate sodium (DSS) model of UC and azoxymethane (AOM)/DSS model of CAC. Furthermore, focal adhesion kinase (FAK) activation and influence on commensal microbiota are important for UC treatment. Impact on FAK activation by SchB in UC development was evaluated in vivo and vitro. We also conducted 16S rRNA sequencing to detect regulation of gut microbiota by SchB. Enhanced protection of intestinal epithelial barrier by SchB through activating FAK contributed to protective effect on colon for the fact that protection of SchB can be reversed by inhibition of FAK phosphorylation. Furthermore, influence on gut microbiota by SchB also played a significant role in UC prevention. Our results revealed that SchB was potent to prevent UC by enhancing protection of intestinal epithelial barrier and influence on gut microbiota, which led to inhibition of CAC. SchB was potential to become a new treatment for UC and prevention of CAC.

ObjectiveAPOBEC3B (A3B), a cytidine deaminase acting as a contributor to the APOBEC mutation pattern in many kinds of tumours, is upregulated in patients with hepatocellular carcinoma (HCC). However, APOBEC mutation patterns are absent in HCC. The mechanism of how A3B affects HCC progression remains elusive.DesignA3B ­promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in HCC. A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. RNA­seq, flow cytometry and other techniques were conducted to analyse how A3B modulated the cytokine to enhance the recruitment of myeloid­-derived suppressor cells (MDSCs) and tumour­-associated macrophages (TAMs).ResultsA3B upregulation through non-classical nuclear factor-κB (NF-κB)signalling promotes HCC growth in immunocompetent mice, associated with an increase of MDSCs, TAMs and programmed cell death1 (PD1) exprssed CD8+ T cells. A CCR2 antagonist suppressed TAMs and MDSCs infiltration and delayed tumour growth in A3B and A3BE68Q/E255Q­ expressing mouse tumours. Mechanistically, A3B upregulation in HCC depresses global H3K27me3 abundance via interaction with polycomb repressor complex 2 (PRC2) and reduces an occupancy of H3K27me3 on promoters of the chemokine CCL2 to recruit massive TAMs and MDSCs.ConclusionOur observations uncover a deaminase-independent role of the A3B in modulating the HCC microenvironment and demonstrate a proof for the concept of targeting A3B in HCC immunotherapy.

Cholesterol plays an important role in maintaining normal physiological function of human body. However, excessive intake will induce a series of diseases including cancer. For melanoma, the relationship between hypercholesterolemia and its incidence remains unknown. The cholesterol metabolite 27-hydroxy cholesterol (27-HC) catalyzed by CYP27A1 has been reported to activate estrogen receptor (ER). As studies have indicated that melanoma expresses ER, we designed experiments to explore whether 27-HC could link hypercholesterolemia and melanoma. In this study, hepatocyte-specific CYP27A1-/- mice were generated by CRISPR/Cas9 technology. The results revealed that high-cholesterol diet induced metabolism disorder and promoted the melanoma growth through 27-HC. Further study found that 27-HC promoted the growth of melanoma cells by activating ERα and eliciting the AKT and MAPK signaling pathway. This study puts forward the important role of 27-HC in the development of melanoma for the first time, links hypercholesterolemia with melanoma progression. The research also provides the rationale for the use of tamoxifen in melanoma therapy. The levels of 27-HC in blood could act as a novel biomarker for tamoxifen treatment in melanoma patients.

Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CA1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3β activation, Wnt/β-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3β-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMs). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMs in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-β and TNF-α was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic.