The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound 1 retained high antiproliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared with free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacologic efficacy while improving its safety profile. Cancer Res; 77(24); 6963-74. Ó2017 AACR.

BackgroundHepatitis B virus (HBV) is one of the major risk factors of hepatocellular carcinoma (HCC). Increasing evidence indicates that microRNA (miRNA)–mRNA axis is involved in HCC. However, a comprehensive miRNA–mRNA regulatory network in HBV-related HCC is still absent. This study aims to identify potential miRNA–mRNA regulatory pathways contributing to pathogenesis of HBV-related HCC.MethodsMicroarray GSE69580 was downloaded from Gene Expression Omnibus (GEO) database. GEO2R and ‘R-limma’ were used to conduct differential expression analysis. The common miRNAs appeared in the two analytic sets were screened as potential differentially expressed miRNAs (DE-miRNAs). The prognostic roles of screened DE-miRNAs in HCC were further evaluated using Kaplan–Meier plotter database. Target genes of DE-miRNAs were predicted by miRNet. Then, protein–protein interaction (PPI) networks were established for these targets via the STRING database, after which hub genes in the networks were identified by Cytoscape. Functional annotation and pathway enrichment analyses for the target genes were performed through DAVID database. Three enriched pathways related to HBV-related HCC were selected for further analysis and potential target genes commonly appeared in all three pathways were screened. Cytoscape was employed to construct miRNA-hub gene network. The expression and correlation of potential miRNAs and targets were further detected in clinical HBV-related HCC samples by qRT-PCR.Results7 upregulated and 9 downregulated DE-miRNAs were accessed. 5 of 7 upregulated DE-miRNAs and 5 of 7 downregulated DE-miRNAs indicated significant prognostic roles in HCC. 2312 and 1175 target genes were predicted for the upregulated and downregulated DE-miRNAs, respectively. TP53 was identified as the hub gene in the PPI networks. Pathway enrichment analysis suggested that these predicted targets were linked to hepatitis B, pathways in cancer, microRNAs in cancer and viral carcinogenesis. Further analysis of these pathways screened 20 and 16 target genes for upregulated and downregulated DE-miRNAs, respectively. By detecting the expression of 36 target genes, six candidate target genes were identified. Finally, a potential miRNA–mRNA regulatory network was established based on the results of qRT-PCR and expression correlation analysis.ConclusionsIn the study, potential miRNA–mRNA regulatory pathways were identified, exploring the underlying pathogenesis and effective therapy strategy of HBV-related HCC.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1761-7) contains supplementary material, which is available to authorized users.

Chemoresistance often leads to the failure of breast cancer treatment. MicroRNAs (miRNAs) play an important role in the progression and chemoresistance of cancer. However, because of the complexity of the mechanisms of chemoresistance and the specificity of miRNA regulation in different cell types, the function of miR-20a in breast cancer chemoresistance is still unclear. Here, by using miRNA microarray and high-content screening techniques, we found that miR-20a/b were significantly downregulated in breast cancer tissues compared with normal breast tissues, and low miR-20a/b expression was correlated with poor survival in breast cancer patients. Ectopic overexpression of miR-20a sensitized breast cancer cells to a broad spectrum of chemotherapy drugs and suppress their proliferation both in vitro and in vivo. Further study demonstrated that miR-20a directly targeted the 3'untranslated region of MAPK1, and thus downregulated the expression of P-gp and c-Myc by inhibiting the MAPK/ERK signaling pathway, whereas c-Myc can bind to the promoter region of the miR-20a gene to promote the expression of miR-20a. Together, our study identified a novel miR-20a/MAPK1/c-Myc feedback loop that regulates breast cancer growth and chemoresistance. These findings suggest that miR-20a synergizing with anticancer drugs will be a promising treatment strategy, especially for chemoresistant patients.

BackgroundHepatocellular carcinoma (HCC) is one of the most lethal cancer, mainly attributing to its high tendency to metastasis. Vascular invasion provides a direct path for solid tumor metastasis. Mounting evidence has demonstrated that microRNAs (miRNAs) are related to human cancer onset and progression including invasion and metastasis.MethodsIn search of invasion-metastasis-associated miRNAs in HCC, microarray dataset GSE67140 was downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DE-miRNAs) were obtained by R software package and the potential target genes were predicted by miRTarBase. The database for annotation, visualization and integrated discovery (DAVID) was introduced to perform functional annotation and pathway enrichment analysis for these potential targets of DE-miRNAs. Protein–protein interaction (PPI) network was established by STRING database and visualized by Cytoscape software. The effects of the miR-494-3p and miR-126-3p on migration and invasion of HCC cell lines were evaluated by conducting wound healing assay and transwell assay.ResultsA total of 138 DE-miRNAs were screened out, including 57 upregulated miRNAs and 81 downregulated miRNAs in human HCC tumors with vascular invasion compared with human HCC tumors without vascular invasion. 762 target genes of the top three upregulated and downregulated miRNAs were predicted, and they were involved in HCC-related pathways, such as pathway in cancer, focal adhesion and MAPK signaling pathway. In the PPI network, the top 10 hub nodes with higher degrees were identified as hub genes, such as TP53 and MYC. Through constructing the miRNA-hub gene network, we found that most of hub genes could be potentially modulated by miR-494-3p and miR-126-3p. Of note, miR-494-3p and miR-126-3p was markedly upregulated and downregulated in HCC cell lines and tissues, respectively. In addition, overexpression of miR-494-3p could significantly promote HCC migration and invasion whereas overexpression of miR-126-3p exerted an opposite effect.ConclusionsTargeting miR-494-3p and miR-126-3p may provide effective and promising approaches to suppress invasion and metastasis of HCC.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1639-8) contains supplementary material, which is available to authorized users.

Pancreatic cancer is one of the most aggressive cancers worldwide with a high mortality rate. Prognosis remains poor even in this era of advanced medicine mainly due to early metastasis and invasion. The present study aimed to explore and validate predictors of distant metastasis and prognosis in pancreatic cancer. In our preliminary experiment, we established a novel metastatic pancreatic cancer cell line BxPC-M8 from parent BxPC-3 cells. Via whole genome sequencing, RT-qPCR, western blotting, migration and invasion assays, we initially found that BxPC-M8 shared similar biological characteristics to BxPC-3, but only differed in enhanced metastatic and invasive capabilities with a significant increase in collagen type VI α1 chain (COL6A1) expression. Knockdown of COL6A1 via small interfering RNA led to a significant decrease in migration and invasion of BxPC-M8 cells, suggesting suppressed epithelial-mesenchymal transition. Furthermore, a significant increase in COL6A1 expression was observed in cancerous tissue compared with paracancerous tissue (40.7 vs 3.7, P=0.001). Additionally, its expression was observed to be significantly associated with distant metastasis and vascular invasion at the time of surgery. Multivariate analysis revealed that COL6A1 expression (hazard ratio 1.90, 95% confidence interval 1.04-3.47, P=0.037) is an independent predictor of overall survival (OS). The median OS observed for COL6A1 + and COL6A1patients was found to be 8±4 and 14±7 months (P= 0.021), respectively. Of note, we identified that COL6A1 expression in tissue samples was associated with significantly reduced OS (P= 0.001), demonstrating that COL6A1 may serve an important role in the metastatic process and could be considered as a predictor of poor outcomes in patients with pancreatic cancer. In addition, our findings suggest that COL6A1 could be an indicator of distant metastasis and a valid prognostic predictor in such patients; however, further investigation is required.

Both dose-dense and dose-escalation chemotherapy are administered in clinic. By approximately imitating the schedules of dose-dense and dose-escalation administration with paclitaxel, two novel multidrug resistant (MDR) cell lines Bads-200 and Bats-72 were successfully developed from drug-sensitive breast cancer cell line BCap37, respectively. Different from Bads-200, Bats-72 exhibited stable MDR and significantly enhanced migratory and invasive properties, indicating that they represented two different MDR phenotypes. Our results showed that distinct phenotypes of MDR could be induced by altered administration strategies with a same drug. Administrating paclitaxel in conventional dose-escalation schedule might induce recrudescent tumor cells with stable MDR and increased metastatic capacity.

Cumulative data suggest that some chemotherapeutic agents may be less effective in estrogen receptor alpha positive (ER+) breast tumors than ER negative (ER-) tumors, which has raised a clinically relevant question as to how to reverse this ER-mediated chemoresistance in ER+ breast tumors. This study is to investigate the possible influence of estrogen receptor alpha (ERalpha) on the therapeutic effects of vinblastine and vinorelbine on breast cancer cells and explore whether combination of anti-estrogen agent fulvestrant (ICI 182, 780) may enhance the sensitivity of ERalpha+ cells to these chemotherapeutic agents. Through comparing ER+ with ER- human breast tumor cells or through stable transfection of an ERalpha expression vector into ER negative human breast cancer BCap37 cells, a series of assays were applied to determine the sensitivity of ER+ and ER- breast tumor cells to vinblastine and vinorelbine in the presence or absence of 17-beta-estradiol and/or fulvestrant. 17-beta-Estradiol showed no effect on the sensitivity of ER- MDA-MB-468 and BCap37 cells to the treatment of vincristine or vinblastine, but it significantly reduced the sensitivity of ER+ T47D cells and BCap37 cells expressing ERalpha to the two drugs mentioned. Further analyses show that ERalpha has little effect on vinca alkaloids-induced mitotic arrest, but dramatically affects their ability to induce tumor cell apoptosis. Moreover, through a series of assays, we also demonstrated that the combination of fulvestrant, a selective ER down-regulator, could reverse the resistance of ER+ breast tumor cells to vinca alkaloids and even produce synergistic effects. The findings obtained from this study have provided important evidence that expression and subsequent activation of ERalpha are associated with resistance of breast cancer cells to vinca alkaloids. This study also suggested that the combination of anti-estrogen agents, such as fulvestrant, might be a novel strategy to reverse ER-mediated chemoresistance or sensitize ER+ breast tumors to vinca alkaloids and possibly other chemotherapeutic agents.

SummaryBackground. Condyloma acuminatum (CA) is a disease that appears as proliferative lesions of the genital epithelium caused by human papillomavirus (HPV) infection. The balance between type 1 and type 2 T-cell subsets in patients with CA is thought to modulate antiviral immunity. CD4+CD25+ regulatory T cells (Tregs) inhibit proliferation and cytokine production by both T-helper (Th)1 and Th2 cells and reversibly suppress CTL-mediated immunity. A better understanding of the mechanisms of T-cell regulation in CA might help in developing more effective therapeutic strategies. Objective. To evaluate the balance of Th1 ⁄ Th2 and Tc1 ⁄ Tc2 and to assess their correlation with changes in number of Tregs in CA. Methods. The percentage of Th1, Th2, Tc1, Tc2 and Tregs were detected by flow cytometry after intracellular staining for cytokines (interferon-c and interleukin-4) and Foxp3 of T lymphocytes in the peripheral blood of 30 patients and 20 healthy volunteers. Results. Patients with CA showed a decreased proportion of Th1 and Tc1 cells and a decreased ratio of Th1 ⁄ Th2 and Tc1 ⁄ Tc2. In particular, strikingly decreased ratios of Th1 ⁄ Th2 were found in 15 patients with relapsed CA (P < 0.01). The mean ± SD number of Foxp3+CD4+CD25+ Tregs increased significantly in patients with CA (3.37 ± 1.03%) and patients with relapsed CA (4.68 ± 1.17%) compared with healthy controls (1.18 ± 0.53%) (P < 0.001). Conclusion. Tregs appear to downregulate cytokine expression in both Tc1 and Th1 subsets of effector T cells, which may be responsible for antivirus responses.