Background Tumor targeting small molecular inhibitors are the most popular treatments for many malignant diseases, including cancer. However, the lower clinical response and drug resistance still limit their clinical efficacies. HGFK1, the first kringle domain of hepatocyte growth factor, has been defined as a potent anti-angiogenic factor. Here, we aimed to develop and identify novel nanoparticles—PH1/pHGFK1 as potential therapeutic agents for the treatment of renal cell carcinoma (RCC). Methods We produced a novel cationic polymer—PH1 and investigated the anti-tumor activity of PH1/pHGFK1 nanoparticle alone and its combination therapy with sorafenib in RCC cell line xenografted mice model. Then, we figured out its molecular mechanisms in human RCC cell lines in vitro. Results We firstly demonstrated that intravenous injection of PH1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice, as well as synergistically enhanced anti-tumor activities of sorafenib. Furthermore, we elucidated that recombinant HGFK1 improved sorafenib-induced cell apoptosis and arrested cell cycle. In addition, HGFK1 could also decrease sorafenib-induced autophagy and stemness via blockading NF-κB signaling pathway in RCC both in vitro and in vivo. Conclusions HGFK1 could inhibit tumor growth, synergistically enhance anti-tumor activities of sorafenib and reverse its drug resistance evolution in RCC. Our results provide rational basis for clinical application of sorafenib and HGFK1 combination therapy in RCC patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1348-z) contains supplementary material, which is available to authorized users.
Dendritic cell-cytokine-induced killer (DC-CIK) cell therapy has been experimentally implemented for enhancing anti-tumoral immunity in patients with hepatocellular carcinoma (HCC) undergoing postoperative transcatheter arterial chemoembolization (POTACE). We performed a retrospective study to evaluate the clinical efficacies of DC-CIK cell therapy and its correlations with several immune factors of the primary tumors. The overall survival time of HCC patients with HBV infection in the study group (POTACE plus DC-CIK cell therapy) was significantly longer than that of the control group (POTACE alone). The expression level of PD-L1 but not the tumor-infiltrated CD8 and CD4 T cells in the tumor tissues showed significant negative correlations with relapse-free survival (RFS) and overall survival (OS), which was also an independent prognostic factor for the five-years' suvival of patients with HCC receiving POTACE treatment. Furthermore, our study validated that PD-L1 expression was significantly inversely correlated with the survival time of HCC patients receiving POTACE plus DC-CIK cell therapy treatment. More importantly, DC-CIK cell therapy provided the best clinical benefits to HCC patients with the low PD-L1 expression receiving POTACE, which indicate that PD-L1 expression level can serve as a pivotal predictor for the therapeutic efficacy of DC-CIK cell therapy for HCC patients receiving POTACE treatment.
Background Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers. Methods We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity. Results FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion. Conclusions Our findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.
In this study, a homologous gene named plzfa was identified and characterized in medaka Oryzias latipes. Oryzias latipes plzfa was detected in all the tissues including brain, gill, muscle, liver, intestine, kidney, spleen, testis and ovary using reverse transcriptase (RT)-PCR. plzfa was detected in the oocytes of the ovary and in the spermatogonia and somitic cells of the testis by in situ hybridization. plzfa had a maternal origin with continuous and dynamic expression during embryonic development. plzfa was observed in the brain, neural rod and sensor organs including the eyes, ears and nose during embryogenesis. plzfa was also detected in the neural crest, somite, pectoral fin, intestine and skin. These results indicate that plzfa is a pleiotropic gene that may play major roles in various tissues.
We present here the three-dimensional (3D) visualization fused with ultrasound and to evaluate its clinical application effect preliminarily. One hundred and eighteen patients with renal calculi in our hospital from September 2017 to December 2019 were prospectively randomized into two groups. The experimental group was treated with percutaneous renal puncture guided by the 3D visualization fused with ultrasound. The control group was treated with percutaneous renal puncture guided by B-ultrasonography (B-US). The puncture time in the experimental versus control group was 4.36 ± 1.28 min versus 10.72 ± 2.94 min (P = 0.000), operation time was 65.85 ± 10.63 min versus 81.34 ± 12.52 min (P = 0.000), and the loss of hemoglobin was 8.55 ± 3.76 g/L min versus 13.33 ± 5.81 g/L(P = 0.000), and the success rate of establishing the channel at one time was 98.41% versus 81.82% (P = 0.002), and the coincidence rate between the channel and the longitudinal axis of the target renal calyx was 88.89% versus 60.00% (P = 0.000). The 3D visualization fused with ultrasound could guide precise puncture to target calyces, reduce operation time, bleeding, and difficulty of puncture.
Background: Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers.Methods: We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion.Conclusions: Our findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.
Protein arginine methylation is important for gene regulation and biological processes. Methylosome protein 50 (Mep50) is identified as a partner of protein arginine methyltransferase 5 (Prmt5), a major enzyme capable of symmetric dimethylation, in mammals and Xenopus. The isolation and characterization of medaka mep50 were reported in this paper. Medaka Mep50 is a homolog of human MEP50 with six WD40 domains. Medaka mep50 was ubiquitously expressed in the adult tissues and had maternal origin with continuous and dynamical expression during embryonic development detected by RT-PCR and in situ hybridization. A strong interaction of medaka Mep50 and Prmt5 was shown by yeast two hybridization. The expression pattern of mep50 is similar to that of prmt5 in medaka. The results suggested that medaka Mep50 could be a partner of Prmt5 and might play major roles in a variety of tissues in medaka.
Background: Prmt5 plays major role in regulation of gene expression, RNA processing, cell growth and differentiation, signal transduction, germ cell development, etc in mammals. Prmt5 is also related to cancer. Knowing the proteins interacting with Prmt5 is important to understand Prmt5’s function in cells. Although there have been reports on proteins binding with Prmt5 in mammals, the partner proteins of Prmt5 in fish are still unclear. Objectives: The objective was to obtain proteins that bind with Prmt5 in medaka, a model fish. Methods: Yeast two hybridization was adopted to achieve the objective. Medaka Prmt5 was used as a bait to fish the prey, binding proteins in a cDNA library of medaka. Co-immunoprecipitation and in silicon analysis were performed to study the interaction of medaka Mep50 and Prmt5. Results: Eight proteins were identified to bind with Prmt5 from 69 preliminary positive colonies. The binding proteins are methylosome protein 50 (Mep50), apolipoprotein A-I-like (Apo-AI), PR domain containing protein 1a with zinc fingers (Prdm1a), Prdm1b, T-cell immunoglobulin mucin family member 3 (Tim-3), phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (Paics), NADH dehydrogenase subunit 4 (ND4) and sciellin (Scl). Co-immunoprecipitation confirmed the interaction of medaka Prmt5 and Mep50. Predicted structures of medaka Prtm5 and Mep50 are similar to that of human PRMT5 and MEP50. Conclusion: Medaka Mep50, Prdm1a, Prdm1b, Apo-AI, Tim-3, Paics, ND4, and Scl bind with Prmt5.
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