• OMICS
• VEGFA
• cancer stem cells
• cancer therapy
• immunotherapy
• neuropilins
• semaphorins
• transcriptomics
• tumor biology

• Humans
• Neuropilin-1/metabolism
• Neuropilin-1/antagonists & inhibitors
• Neuropilin-1/genetics
• Neoplasms/metabolism
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neoplasms/therapy
• Molecular Targeted Therapy
• Animals

• CA78383 NIH HHS
• R01 CA150190 NCI NIH HHS
• R29 CA078383 NCI NIH HHS
• R01 HL140411 NHLBI NIH HHS
• R01 CA078383 NCI NIH HHS
• CA150190 NIH HHS

• Biomarker
• CTSK
• Gastric cancer
• Immune infiltration
• Tumor microenvironment

• Biomarker
• Hepatocellular carcinoma
• Neuropilins
• Systematic review

• Humans
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/pathology
• Neuropilins/genetics
• Neuropilins/metabolism
• Liver Neoplasms/diagnosis
• Liver Neoplasms/metabolism
• Signal Transduction
• Biomarkers
• Biomarkers, Tumor
• Tumor Microenvironment

• MCIN/AEI/10.13039/501100011033 Ministry of Science and Innovation
• Instituto de Salud Carlos III
• MCIN/AEI/10.13039/501100011033 Ministry of Education
• FPU17/01995 Fundación Científica Asociación Española Contra el Cáncer

• cancer
• clinical trials
• immunotherapy
• targeted therapy
• toll-like receptors

• Toll-Like Receptors

• National Natural Science Foundation of China
• Sichuan Province Science and Technology Support Program

• arteriovenous malformation
• blood flow velocity
• carotid artery
• disease progression
• peritoneal carcinomatosis
• pseudomyxoma peritonei
• superior mesenteric artery
• wall shear stress

Toll-like receptor 3 (TLR3) is an important member of the TLR family, which is an important group of pathogen-associated molecular patterns. TLR3 can recognize double-stranded RNA and induce activation of NF-κB and the production of type I interferons. In addition to its immune-associated role, TLR3 has also been detected in some tumors. However TLR3 can play protumor or antitumor roles in different tumors or cell lines. Here, we review the basic signaling associated with TLR3 and the pro- or antitumor roles of TLR3 in different types of tumors and discuss the possible reasons for the opposing roles of TLR3 in tumors.

• Toll-like receptor 3 - TLR-3
• dsRNA
• opposing role
• pathogen-associated molecular pattern
• tumors

• Celiac trunk
• Doppler ultrasound
• Ovarian peritoneal carcinomatosis
• Peritoneal carcinomatosis
• Superior mesenteric artery
• Tumor response

• Animals
• Antineoplastic Agents/therapeutic use
• Bevacizumab/therapeutic use
• Carboplatin/therapeutic use
• Celiac Artery/diagnostic imaging
• Female
• Mesenteric Artery, Superior/diagnostic imaging
• Mice
• Mice, Inbred C57BL
• Ovarian Neoplasms/blood supply
• Ovarian Neoplasms/drug therapy
• Peritoneal Neoplasms/blood supply
• Peritoneal Neoplasms/drug therapy
• Treatment Outcome
• Tumor Cells, Cultured
• Ultrasonography, Doppler

Neuropilin-1 is a co-receptor for semaphorins and vascular endothelial growth factor family members. Neuropilin-1 can be expressed on tumor cells, tumor-infiltrating myeloid and lymphoid cells and has been linked to a tumor-promoting environment. We investigated nanobodies (Nbs) targeting neuropilin-1 for their potential to hamper colorectal carcinoma development in mice. Our data suggest that targeting neuropilin-1 in cancer using neuropilin-1 blocking Nbs delays tumor growth and extends the survival through a shift in the anti-tumor macrophage/pro-tumor macrophage ratio and activation of colorectal cancer-specific CD8⁺ T cells. These findings provide a rationale for the further development of Nbs targeting human neuropilin-1 and bringing them from the bench to the bedside.

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-II^high/trophic MHC-II^low macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-II^high macrophages and a decrease in the expression of MHC-II^low macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8⁺ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity.

• cancer
• immune checkpoint
• immunotherapy
• nanobody
• neuropilin-1
• plexin
• semaphorin
• single-domain antibody fragment
• tumor-associated macrophage

• apoptosis
• double-stranded RNA
• endothelial cell
• pulmonary hypertension
• toll-like receptor 3

• Animals
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary/genetics
• Hypertension, Pulmonary/metabolism
• Lung/metabolism
• Mice
• Rats
• Signal Transduction
• Toll-Like Receptor 3/genetics
• Toll-Like Receptor 3/metabolism

• PG/11/46/28979 British Heart Foundation
• P01 HL103455 NHLBI NIH HHS
• R24 HL123767 NHLBI NIH HHS
• FS/13/48/30453 British Heart Foundation
• P30 CA016059 NCI NIH HHS
• R21 HL123044 NHLBI NIH HHS
• FS/18/13/33281 British Heart Foundation
• R03 HL114816 NHLBI NIH HHS
• PG/18/1/33430 British Heart Foundation
• R01 HL139881 NHLBI NIH HHS
• PG/19/41/34426 British Heart Foundation

Neuropilin-1 (NRP-1) is involved in a range of physiological and pathological processes, including neuronal cell guidance, cardiovascular development, immunity, angiogenesis and the pathogenesis of cancer. Targeting of NRP-1 is considered to be a potential cancer therapy and a number of approaches have been investigated, including the use of small interfering RNA, peptides, soluble NRP antagonists and monoclonal antibodies. The present study used a novel anti-neuropilin-1 monoclonal antibody (anti-NRP-1 mAb) to investigate its potential anti-tumor effects on human gastric cancer cells in vitro and in vivo, as well as its underlying mechanisms of action. Using an MTT assay, it was observed that anti-NRP-1 mAb (<150 µg/ml) had no effects on the viability of gastric cancer cell line BGC-823, while a Boyden chamber assay indicated that treatment with anti-NRP-1 mAb suppressed the migration and invasion of BGC-823 cells. Western blot analysis also demonstrated that phosphorylation of Akt was reduced in BGC-823 cells treated with anti-NRP-1 mAb. Furthermore, anti-NRP-1 mAb suppressed the growth of gastric cancer xenograft tumors and downregulated the expression of vascular endothelial growth factor proteins within tumors in nude mice. These data indicate the potential effects of anti-NRP-1 mAb on malignant tumors and suggest that inhibition of NRP-1 function with anti-NRP-1 mAb may be a novel therapeutic approach in the treatment of cancer.

• antibody
• gastric cancer
• invasion
• migration
• neuropilin-1
• vascular endothelial growth factor

The Toll-like receptor 3 (TLR3) agonists as polyriboinosinic–polyribocytidylic acid (poly (I:C)) have been implicated as potential immunotherapy adjuvant for cancer whereas the exact roles of TLR3 agonists in hepatocellular carcinoma (HCC) treatment have not been clearly evaluated. In consistent with previous reports, we found that poly (I:C) triggering of TLR3 inhibited cell proliferation and induced apoptosis in HCC cells. However, poly (I:C), when used at lower concentration that cannot remarkably inhibit proliferation and induce apoptosis in HCC cells, enhanced the migration and invasion in vitro and the metastasis in vivo. More importantly, we found that bufalin, a prominent component of toad venom, could suppress poly (I:C)-inspired migration, invasion and metastasis of HCC cells despite that bufalin could not potentiate poly (I:C)-induced inhibition of proliferation and induction of apoptosis. In MHCC97 H cells, bufalin impaired poly (I:C)-induced activation of Tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway and NF-κB pathway. Inhibitor for TBK1 but not NF-κB suppressed poly (I:C)-inspired migration and invasion, which was further supported by using TBK1 deficient (Tbk1^–/–) cells. In another model using poly (I:C) transfection, bufalin could also suppress the migration and invasion of HCC cells, which was not observed in Tbk1^–/– MHCC97 H cells. Our data suggest that bufalin can suppress the metastasis of HCC cells in poly (I:C) therapy by impairing TBK1 activation, indicating that bufalin may be used in combination with poly (I:C) therapy in HCC treatment for the sake of reversing poly (I:C)-triggered metastasis of HCC cells.

• Bufalin
• HCC
• TBK1
• TLR3
• metastasis
• poly (I:C)

• SV40
• cancer
• mouse model
• transgenic

• RNAi
• adenovirus vector
• short hairpin RNA
• type I interferon

• Anti-angiogenic drugs
• Duplex Doppler ultrasound imaging
• Hepatocellular carcinoma
• Murine model

• Angiogenesis Inhibitors/administration & dosage
• Animals
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/physiopathology
• Drug Evaluation, Preclinical
• Liver Circulation/drug effects
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/drug therapy
• Liver Neoplasms/physiopathology
• Male
• Mice
• Mice, Transgenic
• Neovascularization, Pathologic/complications
• Neovascularization, Pathologic/diagnostic imaging
• Neovascularization, Pathologic/drug therapy
• Reproducibility of Results
• Sensitivity and Specificity
• Treatment Outcome
• Ultrasonography/methods

Hepatocarcinoma (HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago. Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis. An effective innate immunity response relies on the toll-like receptors (TLR) found in several different liver cells which, through different ligands and many signaling pathways can elicit, not only a pro-inflammatory but also an oncogenic or anti-oncogenic response. Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets. We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015. TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNA-damages and to cell survival. However, pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis. TLR3 has a well-known protective role influencing crucial processes like angiogenesis, cell growth or proliferation. TLR4 works as an interesting epithelial-mesenchymal transition’s inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed. TLR9’s influence on carcinogenesis is also controversial and despite a potential anti-cancer capacity, a pro-tumorigenic role is more likely. Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported. As therapeutic targets, TLRs are already in use and have a great potential. In conclusion, TLRs have been shown to be an interesting influence on the HCC’s microenvironment, with TLR3 clearly determining an anti-tumour influence. TLR4 and TLR9 are considered to have a positive relationship with tumour development even though, in each of them anti-tumorigenic signals have been described. TLR2 presents a more ambiguous role, possibly depending on the stage of the inflammation-HCC axis.

• Hepatocarcinoma
• Carcinogenesis
• Toll-like receptor
• Innate immunity
• Chronic inflammation

• Angiogenesis
• [pIC(PEI)]
• apoptosis
• leiomyoma
• mouse model

• Endometriosis
• angiogenesis
• apoptosis
• mouse model
• pIC(PEI)

• Angiogenesis Inhibitors/pharmacology
• Animals
• Apoptosis/drug effects
• Cell Proliferation/drug effects
• Disease Models, Animal
• Endometriosis/drug therapy
• Endometriosis/genetics
• Endometriosis/metabolism
• Endometriosis/pathology
• Endometrium/drug effects
• Endometrium/metabolism
• Endometrium/pathology
• Endometrium/transplantation
• Endothelial Growth Factors/pharmacology
• Estrogen Replacement Therapy
• Female
• Genes, Reporter
• Heterografts
• Humans
• Luminescent Proteins/biosynthesis
• Luminescent Proteins/genetics
• Mice, Nude
• Neovascularization, Pathologic
• Ovariectomy
• Peptides, Cyclic/pharmacology
• Poly I-C/pharmacology
• Polyethyleneimine/analogs & derivatives
• Polyethyleneimine/pharmacology
• Time Factors
• Red Fluorescent Protein

• Angiogenesis
• Liver fibrosis
• Neuropilin-1
• Neuropilin-2
• Neuropilins
• Transforming growth factor β1
• Vascular endothelial growth factor

• Animals
• Humans
• Liver/metabolism
• Liver/pathology
• Liver/physiopathology
• Liver Cirrhosis/diagnosis
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/physiopathology
• Liver Neoplasms/blood supply
• Liver Neoplasms/diagnosis
• Liver Neoplasms/metabolism
• Liver Neoplasms/physiopathology
• Liver Regeneration
• Neovascularization, Pathologic
• Neuropilins/metabolism
• Signal Transduction

Neuropilin-1 (NRP-1) is a transmembrane glycoprotein that acts as a co-receptor for various members of the vascular endothelial growth factor (VEGF) family. Its ability to bind or modulate the activity of a number of other extracellular ligands, such as class 3 semaphorins, TGF-β, HGF, FGF, and PDGF, has suggested the involvement of NRP-1 in a variety of physiological and pathological processes. Actually, this co-receptor has been implicated in axon guidance, angiogenesis, and immune responses. NRP-1 is also expressed in a variety of cancers (prostate, lung, pancreatic, or colon carcinoma, melanoma, astrocytoma, glioblastoma, and neuroblastoma), suggesting a critical role in tumor progression. Moreover, a growing amount of evidence indicates that NRP-1 might display important functions independently of other VEGF receptors. In particular, in the absence of VEGFR-1/2, NRP-1 promotes melanoma invasiveness, through the activation of selected integrins, by stimulating VEGF-A and metalloproteinases secretion and modulating specific signal transduction pathways. This review is focused on the role of NRP-1 in melanoma aggressiveness and on the evidence supporting its use as target of therapies for metastatic melanoma.

• T regulatory cells
• angiogenesis
• cell-penetrating peptides
• melanoma
• metastasis
• neuropilin-1
• peptidomimetics

Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa.

• IRF-3
• apoptosis
• poly I:C
• prostate cancer
• toll-like receptor

Death receptor 3 (DR3) belongs to the tumor necrosis factor (TNF) receptor superfamily, primarily found in lymphoid tissues. Reports have determined that DR3 may also be distributed in numerous types of tumors. Therefore, it is thought that DR3 may have an important role in the process of tumorigenesis. The aim of the present study was to observe the effect of silencing DR3 expression on hepatocarcinoma cell growth, apoptosis and invasion in order to elucidate the role of DR3 in tumor development. The hepatocarcinoma cell lines (HepG2, Huh7, SMMC7721 and Bel-7402) and normal human liver cells (HL-7702) were transfected with three stealth RNA interference (RNAi) sequences that target the DR3 gene. Reverse transcription quantitative polymerase chain reaction was used to detect the expression levels of DR3 in hepatocarcinoma cell lines and normal liver HL-7702 cells. MTT assay and flow cytometry (FCM) were used to determine the rates of cell proliferation and apoptosis, respectively. Following silencing of the DR3 gene, western blot analysis was used to determine the protein expression of P53, Fas, Caspase8, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Caspase3. DR3 messenger RNA (mRNA) expression in hepatocarcinoma cell lines was significantly increased compared with that in the normal liver cell line. Three targeted DR3 gene small interfering RNAs significantly inhibited DR3 gene expression in Bel-7402 cells at the nucleic acid level. AF02670.1_stealth_883 and cocktail demonstrated the most efficient inhibition of DR3 gene expression at 48 and 72 h following transfection, with mRNA inhibition rates of 89.46 and 92.75%, and 90.53 and 94.25% (P<0.01), respectively. Cell viability was significantly reduced by AF02670.1_stealth_883 and RNAi cocktail at 24, 48 and 72 h following transfection. The inhibition rates of cell proliferation were 50.76 and 61.76% (P<0.05) at 72 h following transfection. FCM revealed that AF02670.1_stealth_883 and RNAi cocktail also induced apoptosis in Bel-7402 cells at 72 h following transfection. Reduction of NF-κB and P53 levels was observed (P<0.05) in Bel-7402 cells following DR3 silencing, whereas levels of Fas, Caspase3 and Caspase8 were markedly elevated (P<0.05). DR3 expression levels in hepatocellular carcinoma cells were significantly higher than those in normal cells. DR3 silencing effectively inhibited proliferation and invasion of hepatocellular carcinoma cells in vitro. However, silencing of the DR3 gene affect levels of apoptosis antigen-3 ligand in cells, therefore indicating that it may be involved with other pathways that regulate apoptosis in HCCs. In conclusion, the results of the present study indicated that DR3 may be a promising therapeutic target molecule for further study of hepatocellular carcinoma gene therapy.

Advances in molecular biology have significantly increased the understanding of the biology of different diseases. However, these discoveries have not yet been fully translated into improved treatments for patients with diseases such as cancers. One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. In this brief review, we will discuss the advantages and disadvantages of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases in the mouse and the preclinical studies that have already been undertaken. We will also discuss how recent improvements in imaging technologies may increase the information derived from using these GEMs during early assessments of potential therapeutic pathways. Furthermore, it is interesting to note that one of the values of using a mouse model is the very rapid turnover rate of the animal, going through the process of birth to death in a very short timeframe relative to that of larger mammalian species.

• Cancer
• genetically modified animals
• human diseases
• rodents
• transgenic

• neuropilin 1
• t regulatory cells
• plasmacytoid dendritic cells
• cancer
• therapeutic target

• Animals
• Dendritic Cells/immunology
• Humans
• Lymphocyte Activation
• Neoplasms/immunology
• Neoplasms/therapy
• Neuropilin-1/antagonists & inhibitors
• Neuropilin-1/physiology
• Proto-Oncogene Proteins c-met/physiology
• Semaphorin-3A/physiology
• Semaphorins/physiology
• T-Lymphocytes, Regulatory/immunology
• Transforming Growth Factor beta/physiology
• Vascular Endothelial Growth Factor A/physiology

Recent studies have demonstrated that synthetic dsRNAs may produce therapeutic effects in a target-independent manner through stimulation of the toll-like receptor-3 (TLR3)/interferon pathway; as a result, angiogenesis and proliferation of tumor cells are inhibited. Thus, this pathway may become a potential target of dsRNA in tumor suppression. In this study, we evaluated the role of synthetic dsRNA as a TLR3 synergist and by combining with sorafenib in anti-hepatocellular carcinoma (HCC) in vitro and in vivo.

Four dsRNAs were designed and synthesized. One of them that was capable of activating TLR3 most effectively in human HCC cell line (HepG2.2.15) was selected as a TLR3 synergist (called BM-06). Subsequently, the expression of proteins relating to TLR3 signaling pathway, such as NF-κB, caspase 8 survivin, bcl-2 and PCNA affected by BM-06, sorafenib alone or in combination, was compared. The migration, proliferation and apoptosis of HepG2.2.15 cells were evaluated in presence of BM-06, sorafenib alone or in combination of both. The similar treatments were also applied in an SD rat primary HCC model.

qRT-PCR data showed that the expression of TLR3 and NF-κB in HepG2.2.15 cells was enhanced. BM-06 was selected as a TLR3 synergist capable of activating the TLR3/interferon pathway most effective among 4 synthetic dsRNAs. The migration and proliferation were significantly inhibited in treated HepG2.2.15 cells with BM-06 or Sorafenib alone as compared with PBS-sham control (P < 0.01). However, the role of combination BM-06 with Sorafenib was the most prominent. Tumor cell apoptotic rate was increased by BM-06 or combination when compared to PBS or poly(I:C) (P < 0.05). Similarly, in orthotopic HCC SD rats, the effect of the combination was superior to either agent alone on the inhibition of tumor growth and induction of HCC cell apoptosis (P < 0.05).

dsRNA alone was capable of inhibiting the proliferation of HepG2.2.15 cells and tumor growth of orthotopic HCC SD rats, but the effect of combination of dsRNA with sorafenib was more prominent. These findings implicate the potential role of combined use of a dsRNA, a TLR3 synergist, and sorafenib in inhibition of HCC.

• TLR
• chemotherapy
• innate immunity
• radiotherapy
• single nucleotide polymorphism

Aim: To construct short hairpin RNAs (shRNAs) and miR30-based shRNAs against heparanase (HPSE) to compare their safety and their effects on HPSE down-modulation in vitro and in vivo to develop a more ideal therapeutic RNA interference (RNAi) vector targeting HPSE.

Methods: First, we constructed shRNAs and miR30-based shRNAs against HPSE (HPSE-shRNAs and HPSE-miRNAs) and packed them into lentiviral vectors. Next, we observed the effects of the shRNAs on knockdown for HPSE expression, adhesion, migration and invasion abilities in human malignant melanoma A375 cells in vitro. Furthermore, we compared the effects of the shRNAs on melanoma growth, metastasis and safety in xenograft models.

Results: Our data showed that these artificial miRNAs targeting HPSE could be effective RNAi agents mediated by Pol II promoters in vitro and in vivo, although these miRNAs were not more potent than the HPSE-shRNAs. It was noted that obvious lung injuries, rarely revealed previously, as well as hepatotoxicity could be caused by lentivirus-mediated shRNAs (LV shRNAs) rather than lentivirus-mediated miRNAs (LV miRNAs) in vivo. Furthermore, enhanced expression of pro-inflammatory cytokines IL-6 and TGF-β1 and endogenous mmu-miR-21a-5p were detected in lung tissues of shRNAs groups, whereas the expression of mmu-let-7a-5p, mmu-let-7b-5p and mmu-let-7c-5p were down-regulated.

Conclusion: These findings suggest that artificial miRNAs display an improved safety profile of lowered lung injury or hepatotoxicity relative to shRNAs in vivo. The mechanism of lung injuries caused by shRNAs may be correlated with changes of endogenous miRNAs in the lung. Our data here increase the flexibility of a miRNA-based RNAi system for functional genomic and gene therapy applications.

• RNA interference
• heparanase
• metastasis
• microRNA(miRNA)
• safety

• Dendritic cells
• IFN-β
• TLR3
• Tumor immunity
• dsRNA

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Case-Control Studies
• DNA/genetics
• Female
• Follow-Up Studies
• Genetic Predisposition to Disease
• Genotype
• Hepatitis B/genetics
• Hepatitis B/pathology
• Hepatitis B/virology
• Hepatitis B virus/pathogenicity
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Male
• Middle Aged
• Neoplasm Staging
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide/genetics
• Prognosis
• Risk Factors
• Survival Rate
• Toll-Like Receptor 3/genetics

Recent successes in clinical trials have provided important proof of concept that small interfering RNAs (siRNAs) indeed constitute a new promising class of therapeutics. Although great efforts are still needed to ensure efficient means of delivery in vivo, the siRNA molecule itself has been successfully engineered by chemical modification to meet initial challenges regarding specificity, stability, and immunogenicity. To date, a great wealth of siRNA architectures and types of chemical modification are available for promoting safe siRNA-mediated gene silencing in vivo and, consequently, the choice of design and modification types can be challenging to individual experimenters. Here we review the literature and devise how to improve siRNA performance by structural design and specific chemical modification to ensure potent and specific gene silencing without unwarranted side-effects and hereby complement the ongoing efforts to improve cell targeting and delivery by other carrier molecules.

• LNA
• OMe
• RNAi
• chemical modification
• immunogenicity
• off-target effect
• siRNA
• siRNA therapeutic

• Adaptor Proteins, Vesicular Transport/immunology
• Adaptor Proteins, Vesicular Transport/metabolism
• Animals
• Cell Adhesion/immunology
• Cell Movement/immunology
• Cell Proliferation
• HEK293 Cells
• Humans
• Immunoblotting
• Immunoprecipitation
• Membrane Microdomains/immunology
• Membrane Microdomains/metabolism
• Mice
• RNA, Double-Stranded/immunology
• RNA, Viral/immunology
• Signal Transduction/immunology
• Toll-Like Receptor 3/immunology
• Toll-Like Receptor 3/metabolism
• Virus Diseases/immunology

• P01 CA062220 NCI NIH HHS
• R01 CA068782 NCI NIH HHS
• CA068782 NCI NIH HHS
• CA062220 NCI NIH HHS

• Animals
• Antineoplastic Agents/therapeutic use
• Drug Discovery
• Humans
• Immunity, Innate
• Immunotherapy, Active/methods
• Ligands
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/immunology
• Toll-Like Receptors/agonists
• Tumor Escape
• Tumor Microenvironment

Recent investigations highlighted strong similarities between neural crest migration during embryogenesis and metastatic processes. Indeed, some families of axon guidance molecules were also reported to participate in cancer invasion: plexins/semaphorins/neuropilins, ephrins/Eph receptors, netrin/DCC/UNC5. Neuropilins (NRPs) are transmembrane non tyrosine-kinase glycoproteins first identified as receptors for class-3 semaphorins. They are particularly involved in neural crest migration and axonal growth during development of the nervous system. Since many types of tumor and endothelial cells express NRP receptors, various soluble molecules were also found to interact with these receptors to modulate cancer progression. Among them, angiogenic factors belonging to the Vascular Endothelial Growth Factor (VEGF) family seem to be responsible for NRP-related angiogenesis. Because NRPs expression is often upregulated in cancer tissues and correlated with poor prognosis, NRPs expression might be considered as a prognostic factor. While NRP1 was intensively studied for many years and identified as an attractive angiogenesis target for cancer therapy, the NRP2 signaling pathway has just recently been studied. Although NRP genes share 44% homology, differences in their expression patterns, ligands specificities and signaling pathways were observed. Indeed, NRP2 may regulate tumor progression by several concurrent mechanisms, not only angiogenesis but lymphangiogenesis, epithelial-mesenchymal transition and metastasis. In view of their multiples functions in cancer promotion, NRPs fulfill all the criteria of a therapeutic target for innovative anti-tumor therapies. This review focuses on NRP-specific roles in tumor progression.