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1.
Hum Gene Ther ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216478

RESUMO

Virus targeted therapy for tumors can effectively prolong the survival rate of patients and has become a new trend for cancer biotherapy. Oncolytic adenovirus (OAd) can specifically replicate in tumor cells, allowing the therapeutic genes carried to be rapidly copied. As known, solid tumors are always hypoxic, and researchers often overlook a key point, the replication of oncolytic adenovirus depends not only on its own activity but also on the cellular hypoxic environment in which the virus replicates. Here we constructed an oncolytic adenovirus carrying Decorin, HRE-Ki67-Decorin, combining the Ki67 promoter up-streamed with hypoxia response element (HRE) sequences to drive adenoviral E1A. The oncolytic adenovirus HRE-Ki67-Decorin had better replication ability under hypoxic conditions, down-regulated cellular immunosuppressed growth factor TGF-ß. In addition, HRE-Ki67-Decorin was potent in suppressing tumor growth and participated in the assembly of tumor extracellular matrix (ECM) by expressing Decorin in subcutaneous renal cancer cells tumor models. Tumor sections from HRE-Ki67-Decorin-treated tissues had less collagen fibers and more spread of virus among tumor tissues. These results indicated that chimeric HRE-Ki67 promoter-regulated OAd carrying Decorin might be an effective anti-cancer treatment strategy.

2.
Ann Neurol ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196748

RESUMO

Observational studies showed alcohol drinking behaviors may be associated with the risk of ALS, whereas contradictory findings emerged and whether such association is causal is unclear. We here investigate the causal relationship between alcohol consumption and ALS. By leveraging instruments from large-scale genome-wide association studies, we performed a comprehensive Mendelian randomization analysis and found alcohol consumption was causally associated with ALS, leading to ~1.5 fold (95%CI 1.4 - 3.4) higher risk of ALS for each approximately 10g/d increase in alcohol intake. Our finding therefore suggests accumulative alcohol consumption may serve as a crucial risk factor in the pathogenesis of ALS. This article is protected by copyright. All rights reserved.

3.
Mol Cancer ; 19(1): 30, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32059672

RESUMO

Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)- and N6-methyladenosines (m6A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far.

4.
Cell Death Dis ; 11(1): 31, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949131

RESUMO

Transketolase (TKT), which is a metabolic enzyme in the nonoxidative phase of the pentose phosphate pathway (PPP), plays an important role in providing cancer cells with raw materials for macromolecular biosynthesis. The ectopic expression of TKT in hepatocellular carcinoma (HCC) was reported previously. However, the role of TKT in the initiation of liver cancer is still obscure. In our previous study, we found that TKT deficiency protects the liver from DNA damage by increasing levels of ribose 5-phosphate and nucleotides. What's more interesting is that we found TKT deficiency reduced bile acids and loss of TKT promoted the farnesoid receptor (FXR) expression. We further showed that TKT translocated into the nucleus of HCC cell lines through interacting with the signal transducer and activator of transcription 1 (STAT1), and then the complex inhibited FXR expression by promoting the binding of histone deacetylase 3 (HDAC3) to FXR promoter.

5.
Int J Biol Sci ; 16(2): 342-352, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929761

RESUMO

Prostate cancer (PCa) is the third leading malignancy engendering mortality among men globally. The present study aimed at determining the expression of hepatocellular carcinoma-related protein-1 (HCRP-1) in PCa, to explore its potential role in prostate tumorigenesis in vitro and in vivo. We evaluated HCRP-1 protein with immunohistochemistry (IHC) technology and found HCRP-1 expression was significantly low in PCa tissues (PCTs); In addition, the decreased HCRP-1 was significantly associated with TNM (tumor node metastasis) stage, advanced histology grade and gleason score. Transwell, tube formation, Western blot and co-immunoprecipitation (Co-IP) assays were utilized to determine the role of down-regulating HCRP-1 in PCa cell migration, invasion and angiogenesis. Meanwhile, we found HCRP-1 depletion induced Src and focal adhesion kinase (FAK) phosphorylation, which could be reversed by Src inhibitor PP2 or FAK inhibitor. Furthermore, down-regulated HCRP-1 evidently induced lung metastasis of PCa cells in xenograft mode. Taken together, our study indicates HCRP-1 plays an important role in PCa metastasis. HCRP-1 may serve as a potential therapeutic target for PCa.

6.
J Immunother ; 43(1): 16-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31574023

RESUMO

Treatment with chimeric antigen receptor-modified T cell (CAR-T) has demonstrated promising therapeutic efficacy in hematologic malignancies. However, the therapeutic efficacy is still very limited for solid tumors. An immunosuppressive microenvironment is one of the main reasons for the limited efficacy. Some chemotherapeutic agents exhibit immune microenvironment modulation. Therefore, combination with chemotherapeutic agents may be one of the promising strategies to enhance the therapeutic efficacy of CAR-T against solid tumors. Sunitinib modulates the antitumor immune response by improving T-cell infiltration and function while reducing immunosuppressive factors. The authors constructed a second-generation CAR targeting human renal cell carcinoma (RCC)-specific antigen carbonic anhydrase IX (CAIX) with the costimulatory domain of 4-1BB. The results of cytokine releasing and cell killing assays showed that the CAIX-CAR-T cells have specific effector functions against CAIX renal cancer cells in vitro. Combination therapy with CAIX-CAR-T and sunitinib showed synergistic efficacy against a mouse lung metastasis model of human RCC. CAIX-CAR-T cells in the mice of the combination therapy group showed stronger proliferation and tumor infiltration than that in the mice of the CAIX-CAR-T monotherapy group. The possible mechanisms of the synergistic efficacy are: (1) sunitinib caused upregulation of CAIX in tumor cells; (2) sunitinib decreased frequency of myeloid-derived suppressor cells in the tumor microenvironment. Our study supplied an innovative immunotherapeutic approach whereby combining CAIX-CAR-T with sunitinib induces a potent antitumor response in an experimental model of metastatic RCC. The combination strategy should be considered as a potential approach to augment adoptive CAR-T cell immunotherapy.

7.
BMC Med ; 17(1): 225, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31796040

RESUMO

BACKGROUND: Associations between type 2 diabetes (T2D) and amyotrophic lateral sclerosis (ALS) were discovered in observational studies in both European and East Asian populations. However, whether such associations are causal remains largely unknown. METHODS: We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of T2D with the risk of ALS in both European and East Asian populations. Our analysis was implemented using summary statistics obtained from large-scale genome-wide association studies with ~660,000 individuals for T2D and ~81,000 individuals for ALS in the European population, and ~191,000 individuals for T2D and ~4100 individuals for ALS in the East Asian population. The causal relationship between T2D and ALS in both populations was estimated using the inverse-variance-weighted methods and was further validated through extensive complementary and sensitivity analyses. RESULTS: Using multiple instruments that were strongly associated with T2D, a negative association between T2D and ALS was identified in the European population with the odds ratio (OR) estimated to be 0.93 (95% CI 0.88-0.99, p = 0.023), while a positive association between T2D and ALS was observed in the East Asian population with OR = 1.28 (95% CI 0.99-1.62, p = 0.058). These results were robust against instrument selection, various modeling misspecifications, and estimation biases, with the Egger regression and MR-PRESSO ruling out the possibility of horizontal pleiotropic effects of instruments. However, no causal association was found between T2D-related exposures (including glycemic traits) and ALS in the European population. CONCLUSION: Our results provide new evidence supporting the causal neuroprotective role of T2D on ALS in the European population and provide empirically suggestive evidence of increasing risk of T2D on ALS in the East Asian population. Our results have an important implication on ALS pathology, paving ways for developing therapeutic strategies across multiple populations.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31786240

RESUMO

Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events, including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased fibrinogen degradation product (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged activated partial thromboplastin time (16/100, 16%), and prolonged prothrombin time (10/100, 10%). Coagulation disorders occurred mainly during day 6 to day 20 after CAR-T cell infusion. The changes in coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia, more lines of prior therapies, lower baseline platelet count, and especially cytokine release syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to nonrelapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce nonrelapse mortality for patients with DIC and severe CRS.

9.
Am J Cancer Res ; 9(11): 2379-2396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815041

RESUMO

The adoptive transfer of chimeric antigen receptor-modified T (CAR-T) cells is a novel cancer treatment that has led to encouraging breakthroughs in the treatment of haematological malignancies. The efficacy of infused CAR-T cells is associated with a high CAR-positive expression rate, a strong proliferative response and the persistence of CAR-T cells in vivo. Manufacturing CAR-T cells is a process usually associated with the decreased CAR-positive expression rate and terminal differentiation of the infused CAR-T cells, which causes decreased proliferation and persistence of CAR-T cells in vivo. Therefore, the preparation of a high CAR-positive expression rate and few differentiated CAR-T cells is particularly important for clinical cancer treatment. In this study, we transduced and expanded CAR-T cells targeting the epithelial cell adhesion molecule (EpCAM) in the presence of an Akt inhibitor (MK2206) during the initial stage of CAR-T cell preparation. We show that the Akt inhibitor did not suppress the proliferation or effector function of the EpCAM-CAR-T cells but increased the CAR-positive expression rate and decreased the number of terminally differentiated EpCAM-CAR-T cells. Furthermore, EpCAM-CAR-T cells prepared using this protocol appeared to have enhanced antitumor activity in vivo. Taken together, these findings suggest that Akt inhibition during the initial stage of CAR-T cell preparation could improve the performance of CAR-T cells.

10.
Cancer Manag Res ; 11: 9749-9759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819613

RESUMO

Purpose: DNA methylation plays major regulatory roles in gene transcription. Our previous studies confirmed that Ki-67 promoter is hypomethylated and Sp1 is a transcriptional activator of Ki-67 gene in cancer cells. However, whether Sp1-mediated transcriptional activation of Ki-67 is related to its methylation has not been studied yet. Materials and methods: In this study, we confirmed that methylated CpG binding protein 2 (MBD2) binding to methylated DNA hindered the binding of Sp1 to Ki-67 promoter and then repressed Ki-67 transcription through chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR). Co-immunoprecipitation (Co-IP), ChIP, methylation-specific PCR (MS-PCR) and Western blot were utilized to analyze the effects of Sp1 binding to Ki-67 promoter on its methylation status. Results: Less DNA methyltransferase 1 (DNMT1) bound to the Ki-67 promoter in MKN45 cells than in HK-2 cells. Histone acetyltransferase p300 that was recruited by Sp1 to Ki-67 promoter could attenuate the methylation level of Ki-67 promoter. Furthermore, higher expression of Sp1 and Ki-67 was related to the overall survival (OS), first progression (FP) and post-progression survival (PPS) in gastric cancer by scrutinizing bioinformatics datasets. Conclusion: Taken together, our findings suggested that hypomethylation of Ki-67 promoter enhanced the binding of Sp1, which in turn maintained hypomethylation of promoter, leading to increase Ki-67 expression in cancer cells. Sp1 and Ki-67 could act promising prognostic biomarkers for clinical diagnosis and treatment of cancer.

11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1682-1690, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607332

RESUMO

OBJECTIVE: To knockout ADRB2 gene rapidly and efficiently in human primary T cells by using CRISPR/Cas9 technology and multiple sgRNAs strategy. METHODS: Six paired-sgRNAs, which were designed to target the 5' constitutive coding exons of ADRB2 gene, were cloned into pGL3-U6-sgRNA-PGK-Puro vector separately. The expre-ssion vectors containing the single sgRNAs were constructed and transiently co-transfected into HEK-293T cell line with Cas9 expression vector. The sgRNA-mediated cleavage efficiency was tested by T7EN I digestion assay. Concatenating four highly efficient paired sgRNAs were cloned into pGL3-U6-sgRNA-ccdB-EF1α-Puro expression vector. The reco-mbinant plasmid allows the cells to express 4 sgRNAs, which target different sites on the ADRB2 genomic locus. The cleavage efficiency and mutation model were tested by T7EN I digest assay and T-A cloning technique. Multiple sgRNAs plasmid and Cas9 plasmid was transiently transferred into human primary T cells by electroporation. Flow cytometry (FCM) was used to detect the knockout efficiency of ß2 adrenergic receptor (ß2-AR). RESULTS: The results of T7EN I digestion and TA cloning sequencing showed that the multiple sgRNAs strategy could obtain more abundant mutation types and higher gene editing efficiency than single sgRNA. In addition to the deletion and insertion of bases, large fragment DNA deletions and inversions could be observed. All of the random 10 TA clones for detection were genetically modified, thus the mutation efficiency was as high as 100%. FCM assay showed that 43.09% of the cells in the control T cells were ß2-AR positive, but the proportion of ß2-AR positive cells in the multiple sgRNAs electrotransformed T cells decreased to 25.61%. CONCLUSION: A method, which is simple and operable, for knocking out ß2-AR in human primary T cells has been established preliminarily. The results are helpful for the further study of the role of ß2-AR in human T cells.


Assuntos
Sistemas CRISPR-Cas , Receptores Adrenérgicos beta 2/genética , Edição de Genes , Técnicas de Inativação de Genes , Humanos , RNA Guia , Linfócitos T
12.
Med Oncol ; 36(12): 96, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659495

RESUMO

Oncolytic adenovirus is an emerging alternative to current therapeutics. The adenoviral E1A, the first protein expressed upon oncolytic adenoviral infection, has been identified as an antitumor agent, but the mechanisms of its tumor inhibition ability are unclear enough. Decorin is ubiquitous in the extracellular matrix (ECM), which regulates multiple functions through interaction with ECM. Here, we intended to explore the effects of adenoviral E1A on the tumor extracellular matrix during gene therapy. We demonstrated that reduced decorin expression was found in patients with lung cancer. The adenoviral E1A or a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa, 120-127aa deletion) could increase the expression of decorin and down-regulate VEGF, two members of tumor ECM, involved in both vasculogenesis and angiogenesis. E1A/mE1A-mediated suppressing the migration and invasion ability of tumor cells was depended on decorin. E1A interacted with decorin directly and induced the proteasomal degradation of VEGF. In addition, E1A or mE1A can inhibit tumor growth in a subcutaneous lung cancer xenograft model. It suggested that decorin might be a crucial mediator among ECM components for adenoviral E1A-mediated antitumor activities. These studies on adenovirus E1A provide a new mechanism for the emerging therapies of tumor gene therapy.

13.
Front Immunol ; 10: 1988, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552016

RESUMO

Foxp3 expressing regulatory T (Treg) cells, as the central negative regulator of adaptive immune system, are essential to suppress immune response and maintain immune homeostasis. However, the function of Treg cells is frequently compromised in autoimmunity and hyper-activated in infections and tumor microenvironments. Thus, manipulating Treg cells becomes a promising therapeutic strategy for treating various diseases. Here we reported that inhibition of Cdk8/Cdk19 activity by small molecule inhibitors CCT251921 or Senexin A greatly promoted the differentiation of Treg cells and the expression of Treg signature genes, such as Foxp3, CTLA4, PD-1, and GITR. Mechanistically, we found that the augmented Treg cell differentiation was due to sensitized TGF-ß signaling by Cdk8/Cdk19 inhibition, which was associated with attenuation of IFN-γ-Stat1 signaling and enhancement of phosphorylated Smad2/3. Importantly, treatment with Cdk8/Cdk19 inhibitor CCT251921 significantly increased Treg population and ameliorated autoimmune symptoms in an experimental autoimmune encephalomyelitis (EAE) model. Taken together, our study reveals a novel role of Cdk8/Cdk19 in Treg cell differentiation and provides a potential target for Treg cell based therapeutics.

14.
Mol Cancer ; 18(1): 138, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526370

RESUMO

Cancer has become a major health issue worldwide, contributing to a high mortality rate. Tumor metastasis is attributed to the death of most patients. Epithelial-to-mesenchymal transition (EMT) plays a vital role in inducing metastasis. During EMT, epithelial cells lose their characteristics, such as cell-to-cell adhesion and cell polarity, and cells gain motility, migratory potential, and invasive properties to become mesenchymal stem cells. Circular RNAs (circRNAs) are closely associated with tumor metastasis and patient prognosis, as revealed by increasing lines of evidence. CircRNA is a type of single-stranded RNA that forms a covalently closed continuous loop. CircRNAs are insensitive to ribonucleases and are widespread in body fluids. This work is the first review on EMT-related circRNAs. In this review, we briefly discuss the characteristics and functions of circRNAs. The correlation of circRNAs with EMT has been reported, and we discuss the ways circRNAs can regulate EMT progression through EMT transcription factors, EMT-related signaling pathways, and other mechanisms. This work summarizes current studies on EMT-related circRNAs in various cancers and provides a theoretical basis for the use of EMT-related circRNAs in targeted management and therapy.

15.
Am J Cancer Res ; 9(7): 1382-1395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392076

RESUMO

Based on previous reports, the efficacy of lenvatinib against cancer is mainly attributed to its antiangiogenic activity and its ability to suppress tumor proliferation, which are mediated by targeting receptor tyrosine kinases (RTKs). However, the effects of lenvatinib on tumor immune modulation have rarely been explored. Here, we show that lenvatinib effectively inhibited murine melanoma and renal cancer, and this inhibition was associated with enhanced tumor infiltration by natural killer (NK) cells. Critically, lenvatinib-induced tumor growth inhibition was attenuated by antibody-mediated NK cell depletion or the blockade of NK cell chemotaxis with an anti-CXCR3 blocking antibody. In addition, the expression of natural cytotoxicity receptors (NCRs) by tumor-infiltrating NK cells and the expression of cytotoxic cytokines in the tumor tissue were also augmented by lenvatinib. These data thus suggest that lenvatinib may be used not only as a direct cytotoxic drug against tumor angiogenesis and proliferation but also as a potent adjunct for enhancing the efficacy of immune-based cancer therapies by enhancing the tumor infiltration and activation of NK cells.

16.
Lancet Haematol ; 6(10): e521-e529, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31378662

RESUMO

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has been shown to have activity in patients with relapsed or refractory multiple myeloma. Reports have suggested that a small subgroup of less differentiated myeloma clones express CD19 and anti-CD19 CAR T-cell therapy has shown activity in some of these patients. We aimed to assess the activity and safety of a combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma. METHODS: We did a single-centre, single-arm, phase 2 trial at the Affiliated Hospital of Xuzhou Medical University in China. Patients were eligible if they were aged 18-69 years, had histologically confirmed multiple myeloma, a Karnofsky Performance Score of 50 points or more, and met the International Myeloma Working Group diagnostic criteria for relapsed or refractory disease. Fludarabine (three daily doses of 30mg/m2) and cyclophosphamide (one daily dose of 750 mg/m2) were used to deplete lymphocytes before infusion of humanised anti-CD19 CAR T cells (1 × 106 cells per kg) and murine anti-BCMA CAR T cells (1 × 106 cells per kg). The primary outcome was the proportion of patients who achieved an overall response. Responses were assessed according to the International Myeloma Working Group criteria. This study is registered with the Chinese Clinical Trial Registration Center, number ChiCTR-OIC-17011272. FINDINGS: From May 1, 2017, to Jan 20, 2019, 22 patients were enrolled and 21 received an infusion of CAR T cells and were evaluable for safety and activity analyses. At a median follow-up of 179 days (IQR 72-295), 20 (95%) of 21 patients had an overall response, including nine (43%) stringent complete responses, three (14%) complete responses, five (24%) very good partial responses, and three (14%) partial responses. The most common adverse events included cytokine release syndrome (19 [90%] of 21), including 18 patients (86%) with grade 1-2 cytokine release syndrome. The most common serious adverse events were haematological toxicities, which occurred in 20 (95%) of 21 patients. Common grade 3 or higher adverse events included neutropenia (18 [86%]), anaemia (13 [62%]), and thrombocytopenia (13 [62%]). One patient died due to cerebral hemorrhage, which was considered related to sustained thrombocytopenia. No deaths were judged to be treatment-related. INTERPRETATION: Our results confirm that combined infusion of humanised anti-CD19 and anti-BCMA CAR T cells is feasible in patients with relapsed or refractory multiple myeloma, and the preliminary activity observed warrants further investigation in randomised trials. This dual CAR-T cell combinations might be a promising treatment option for relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China, Natural Science Foundation, Key Research and Development Plan of Jiangsu.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD19/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Ciclofosfamida/farmacologia , Feminino , Doenças Hematológicas/etiologia , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva , Índice de Gravidade de Doença , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/farmacologia , Adulto Jovem
17.
J Exp Clin Cancer Res ; 38(1): 362, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426831

RESUMO

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.


Assuntos
Autofagia , Carcinoma de Células Renais/patologia , Sinergismo Farmacológico , Fator de Crescimento de Hepatócito/administração & dosagem , Nanopartículas/administração & dosagem , Células-Tronco Neoplásicas/patologia , Sorafenibe/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Ácido Fólico/química , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Kringles , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Polietilenoglicóis/química , Polietilenoimina/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Ciclodextrinas/química
18.
J Exp Clin Cancer Res ; 38(1): 301, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291975

RESUMO

BACKGROUND: Colorectal cancer (CRC) remains the fourth most common cause of cancer-related mortality worldwide. We aimed to identify key molecules and signalling pathways mediating CRC growth and metastasis. Polypyrimidine tract-binding protein 3 (PTBP3) is a member of PTB family. A prooncogenic role for PTBP3 has also been discovered in several kinds of tumors. However, the expression and biological functions of the PTBP3 are still unknown in CRC. METHODS: We analysed the expression levels of PTBP3 using tissue microarray containing 568 CRC tissues and corresponding non-tumor adjacent tissues. The correlations between the PTBP3 expression level and clinicopathological features were evaluated using the chi-square test. The functional characterization for the role and molecular mechanism of PTBP3 in CRC was investigated through a series of in vitro and in vivo experiments. RESULTS: We showed that PTBP3 expression was increased in human CRC, and high PTBP3 expression was correlated with poor five-year overall survival and disease-free survival. Moreover, PTBP3 promoted tumor cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. PTBP3 enhanced HIF-1α protein expression by directly binding to the 5'UTR HIF-1α mRNA and activated translation of HIF-1α. Furthermore, HIF-1α was responsible for PTBP3-induced cell migration and invasion. CONCLUSIONS: PTBP3 appears to be a novel oncogene of CRC through binding to the IRES region of HIF-1α mRNA, which regulates HIF-1α translation. PTBP3 can serve as a promising predictive biomarker for recurrence and prognosis in patients with CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Biossíntese de Proteínas , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Prognóstico , Proteína 1 de Ligação a Y-Box/metabolismo
20.
Nanoscale ; 11(29): 13714-13719, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31314031

RESUMO

The selective formation of nanomedicines around cancer cells is very important for cancer therapy because it increases the inhibitory capacity and decreases the systemic toxicity. However, successful examples are rare. Taking advantage of the overexpression of both the enzyme alkaline phosphatase (ALP) and the cell membrane receptor (CCK2R), we demonstrated in this study the selective formation of supramolecular nanofibers and hydrogels in the pericellular space of two cancer cell lines (HeLa and HepG2 cells). Both cell lines showed high expression levels of extracellular ALP and membrane-bound CCK2R. ALP efficiently converted Comp. 1 to a self-assembling molecule (Comp. 2). Comp. 2 interacted with CCK2R, thereby facilitating the self-assembly and formation of hydrogels around the cancer cells. The selective pericellular hydrogelations efficiently inhibited cancer cells. Pericellular hydrogelation around cancer cells is a promising strategy to control the formation of nanomedicines spatiotemporally in cellular microenvironments for cancer therapy and diagnostics.


Assuntos
Fosfatase Alcalina/metabolismo , Hidrogéis/química , Receptor de Colecistocinina B/metabolismo , Fosfatase Alcalina/química , Fosfatase Alcalina/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Microscopia Confocal , Peptídeos/química , Peptídeos/farmacologia , Receptor de Colecistocinina B/química , Receptor de Colecistocinina B/genética
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