Accumulation of evidence indicates that miRNAs have crucial roles in the regulation of EMT-associated properties, such as proliferation, migration and invasion. However, the underlying molecular ...mechanisms are not entirely illustrated. Here, we investigated the role of miR-296-5p in hepatocellular carcinoma (HCC) progression.
In vitro cell morphology, proliferation, migration and invasion were compared between HCC cell lines with up- or down-regulation of miR-296-5p. Immunofluorescence and Western blot immunofluorescence assays were used to detect the expression of EMT markers. Bioinformatics programs, luciferase reporter assay and rescue experiments were used to validate the downstream targets of miR-296-5p. Xenograft nude mouse models were established to observe tumor growth and metastasis. Immunohistochemical assays were conducted to study the relationships between miR-296-5p expression and Neuregulin-1 (NRG1)/EMT markers in human HCC samples and mice.
miR-296-5p was prominently downregulated in HCC tissues relative to adjacent normal liver tissues and associated with favorable prognosis. Overexpression of miR-296-5p inhibited EMT along with migration and invasion of HCC cells via suppressing NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling in vitro. More importantly, miR-296-5p disrupted intrahepatic and pulmonary metastasis in vivo. NRG1, as a direct target of miR-296-5p, mediates downstream biological responses. In HCC tissues from patients and mice, the levels of miR-296-5p and NRG1 also showed an inverse relationship.
miR-296-5p inhibited EMT-related metastasis of HCC through NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling.
Two isostructural Co(Cd)-antimony-oxo tartrate cluster-based compounds with a one-dimensional (1-D) belt-like structure, namely H
9.2
Co(H
2
O)
6
{
M
0.5
(H
2
O)
3.5
{
M
′(H
2
O)
4
Sb
V
O
6
Co
4.2
(H
...2
O)
5
Sb
III
6
(μ
3
-O)
2
(tta)
6
}}
2
·
n
H
2
O (
M
= Co,
M
′ = Co,
n
= 9 (
1
);
M
= Cd
0.39
/Co
0.61
,
M
′ = Cd
0.24
/Co
0.76
,
n
= 7 (
2
); H
4
tta = tartaric acid), have been synthesized by solvothermal methods. It is noteworthy that the relatively rare mixed-valence Sb(
iii
,
v
) exists in the structures. The anionic clusters in both compounds appear to be in a sandwich configuration; the top and bottom layers are based on {Sb
3
(μ
3
-O)(tta)
3
} brackets, and the intermediate layer is occupied by {Sb
V
O
6
Co
4.2
(H
2
O)
5
}. The title compounds have been characterized by single-crystal X-ray diffraction, powder X-ray diffraction, elemental analyses, thermogravimetric analyses, and UV-Vis spectroscopy. We chose compound
2
as a representative to test its proton conductivity, and the results show that the conductivity can reach 1.42 × 10
−3
S cm
−1
at 85 °C under 98% relative humidity.
Isostructural mixed-valence compounds H
9.2
Co(H
2
O)
6
{
M
0.5
(H
2
O)
3.5
{
M
'(H
2
O)
4
Sb
V
O
6
Co
4.2
(H
2
O)
5
Sb
III
6
(μ
3
-O)
2
(tta)
6
}}
2
·
n
H
2
O (
M
= Co,
M
' = Co,
n
= 9 (
1
);
M
= Cd
0.39
/Co
0.61
,
M
' = Cd
0.24
/Co
0.76
,
n
= 7 (
2
)) were synthesized. The proton conductivity of
2
is 1.42 × 10
−3
S·cm
−1
at 85 °C and 98% RH.
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•Mesoporous silica-based hybrid nanoparticles for targeted delivering 5-FU was fabricated.•The nanoparticles exhibited improved internalization into colon cancer cells and enhanced ...accumulation in tumor tissues.•The nanoparticles showed enhanced anticancer efficacy both in vitro and in vivo.
Novel methods to improve the anticancer performance of 5-fluorouracil (5-FU) is quite necessary for clinical medicines. In the present work, we fabricated a novel type of mesoporous silica nanoparticles (MSNs)-based inorganic/organic hybrid nanoparticles covalently attached with poly(oligo(ethylene glycol) monomethyl ether methacrylate) (POEGMA) for improved stabilization and targeting peptide (RGD) for targeted delivery with the aim of improving the anticancer performance of 5-FU. Atom transfer radical polymerization (ATRP) initiator functionalized MSN (MSN-Br) was synthesized at first, which was followed by surface-initiated ATRP of water soluble OEGMA and carboxyl-containing monomer (2-succinyloxyethyl methacrylate, SEMA). Functionalization of RGD onto the hydrophilic P(OEGMA-co-SEMA) chains afforded the final hybrid nanoparticle, MSN-P(OEGMA-co-RGD). 5-FU can be effectively loaded into the meso-pores of MSN-P(OEGMA-co-RGD) (5-FU@MSN-RGD) with drug content ∼7.5wt%. And the dynamic diameter (Dh) and zeta potential (ζ) of 5-FU@MSN-RGD were determined to be 199.3±5.4nm and −8.7±0.5mV, respectively. It was demonstrated that MSN-P(OEGMA-co-RGD) exhibited improved internalization into colon cancer cells and enhanced accumulation in tumor tissues. In addition, compared with free 5-FU, 5-FU@MSN-RGD showed enhanced anticancer efficacy both in vitro and in vivo, implying promising clinical applications.
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The development of small molecule anticancer drugs, with low water solubility and high toxicity, into polymeric prodrugs has developed into a promising strategy in clinical ...application. In this study, we synthesized a novel G3-C12-mediated esterase-sensitive tumor-targeting polymeric prodrug of camptothecin (CPT), P(OEGMA-co-CPT-co-G3-C12), and explored its anticancer activity against androgen-independent prostate cancer in vitro and in vivo. Compared to free CPT, the multifunctional polymeric prodrug demonstrated improved water solubility and stability, higher intracellular uptake, and enhanced cytotoxicity in DU145 cells in vitro. Furthermore, it displayed an improved accumulation in the tumor and an enhanced anticancer activity in vivo. Hence, P(OEGMA-co-CPT-co-G3-C12) could be a promising drug in the treatment of androgen-independent prostate cancer.
Background: Fucoidan is a fucose-enriched, sulfated polysaccharide found in brown algae; in recent years, this polysaccharide has been found to exert several biological effects, including antitumor ...effects, such as antiproliferation, activating apoptosis, and anti-angiogenesis of cancer cells. However, the antimetastatic effect of fucoidan and the related targeting receptors remain unknown. In the present study, we examined the inhibition of invadopodia formation and underlying mechanism of fucoidan on human liver cancer cells. Methods: We used 98% purified fucoidan from Sargassum species to treat the hepatocellular carcinoma (HCC) cells SMMC-7721, Huh7 and HCCLM3 in vitro and the HCCLM3 cell line in vivo. The HCC cells were cultured with various concentrations of Fucoidan-Sargassum (0-30 mg/mL). Migration, invasion and wound healing assays were performed to determine the antimetastatic effect of fucoidan on the HCC cells. Western blot analysis and immunofluorescence staining were conducted to determine the expression levels of invadopodia formation-regulating proteins and the targeting membrane receptor proteins. Results: Fucoidan-Sargassum inhibited the migration and invasion of HCC SMMC-7721, Huh7 and HCCLM3 cells in a dose-dependent manner. In the HCCLM3 cells, Fucoidan-Sargassum also decreased the expression levels of invadopodia-related proteins including Src, Cortactin, N-WASP, ARP3, CDC42, MMP2, MT1-MMP, and the targeting receptors integrin αV and β3 in a dose-dependent manner. Fucoidan-Sargassum also increased the levels of endoplasmic reticulum-related proteins, including GRP78, IRE1, SPARC, and the type IV collagen receptor proteins integrin α1 and β1. In vivo, Fucoidan-Sargassum reduced the size of liver tumors and decreased the number of lung metastatic foci in nude mice with hepatocellular carcinoma xenografts. Conclusion: These findings indicate that Fucoidan-Sargassum has an antimetastatic effect on SMMC-7721, Huh7 and HCCLM3 liver cancer cells, and the underlying mechanism involves targeting ITGαVβ3 and mediating the ITGαVβ3/SRC/E2F1 signaling pathway. These results suggest that Fucoidan-Sargassum may be a promising therapeutic antimetastatic compound in the development of a metastasis-preventive drug for treating liver cancer.
BACKGROUND Colorectal cancer is one of the leading causes of death in China, and the development of effective drugs is urgently needed. Here, we report on Paeoniflorin (PF), a product isolated from ...the roots of the peony plant, as a possible candidate because of its anti-tumor effects on epithelial-to-mesenchymal transition (EMT) of PF in human colorectal cancer (CRC). MATERIAL AND METHODS Cell proliferation, wound healing, and Transwell assays were used to analyze the effects of PF on in vitro cell migration and invasion of HCT116 and SW480, 2 colorectal cancer cell lines. The tumor xenograft model was used to verify the anti-metastasis effects of PF in vivo. The RNA and protein levels of epithelia-cadherin (E-cadherin), Vimentin, and histone deacetylase2 (HDAC2) were measured by qPCR and Western blot analysis to explore the mechanism involved. RESULTS Our results showed that PF inhibited colorectal cancer cell migration and invasion and suppressed the metastatic potential of the cancer cells in vivo. Moreover, PF significantly decreased the expression of HDAC2 and Vimentin, while increasing the expression of E-cadherin. CONCLUSIONS These results suggest that PF inhibits colorectal cancer cell migration and invasion ability and reverses the EMT process, through inhibiting the expression of HDAC2, and then affects the expression level of E-cadherin and Vimentin at the cell level. Our results were also verified in the tumor xenograft model. This indicates that PF may be a candidate for colorectal cancer treatment.
As a unique type of ecosystem, tropical coastal sandy vegetation lies in the transition zone extending from coastal beaches to further inland and provides important ecosystem services such as ...windproofing, tourism, and agriculture. However, the energy and matter fluxes of these tropical coastal ecosystems have been rarely studied. We reported one-year eddy flux observations in a tropical sandy coastal ecosystem and specifically focused on the carbon and water exchanges between the atmosphere and the ecosystem. The studied ecosystem was a carbon sink (approximately –560 gC m−2 yr−1) and approximately 1000 mm of water evaporated from the ecosystem into the atmosphere during the study year. The highest levels of vegetation photosynthesis occurred in April, shortly before the wet season. This can be attributed to an endogenous self-adjustment of the ecosystem to improve the water- and carbon-use efficiency during the wet season. This study is expected to not only fill the data gap with respect to the gas exchange between tropical sandy coastal plains and the atmosphere but also provide knowledge about the function and ecological service of these specific ecosystems.
A square-planar bis(σ-acetylide) Pt( ii ) complex containing dual-recognition sites was designed, synthesized and used as a colorimetric/luminescent sensor for detecting the vapor of benzene ...compounds.
Objective:To investigate the potential role of human cytomegalovirus lower matrix phosphoprotein 65(HCMV-pp65) in murine systemic lupus erythematosus(SLE).Methods:The prokaryotic plasmid pET-28b-pp65 ...was constructed to express the HCMVpp65 protein.BXSB mice and C57BL/6 mice were inoculated with pp65 eukarvotic plasmid pcDNA3.0-pp65 intramuscularly 5 times at 2-week intervals,and then the blood of the mice was subsequently collected via the retro-orbital vein.Indirect ELISAs were used to evaluate the concentration of anti-pp65 immunoglobulin G,anti-double-stranded DNA and antinuclear antibodies.lnterleukin-1β and tumor necrosis factor-α were also determined by competitive ELISA.At the same time,3 major SLE-related circulating microRNAs were examined by quantitative RT-PCR.Results:The early production of autoantibodies was observed in pp65-immunized male BXSB as well as C57BL/6 mice.Overexpression of interleukin-1β and tumor necrosis factor-a were detected in pp65-immunized male BXSB mice.Quantitative RT-PCR analyses showed that three SLE related microRNAs(microRNA-126,microRNA-125 a,and microRKA-146a) were dovvnrcgulatcd in peripheral blood mononuclear cells of pp65-immunizcd mice.Conclusions:Our findings indicate that HCMV-pp65 immunization strongly triggers the development and progression of" SLE-like disease in both BXSB and C57BL/6 mice,which indicates that the immune responses induced by HCMV-pp65 may be involved in the development of SLE.
We report on the fabrication of a multifunctional polymeric prodrug covalently linked with an anticancer drug (bufalin, BUF) and tumor-targeting peptide (RGD) and investigate its anticancer ...performance against colon cancer in mice. The polymerizable monomer, 3-((2-(methacryloyloxy)ethyl) thio)propanoic acid (BSMA), was synthesized first. Atom radical transfer polymerization (ATRP) of BSMA and oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) afforded random copolymers, P(OEGMA- co -BSMA). The polymeric prodrug of BUF, P(OEGMA- co -BUF), was obtained by an esterification reaction between the carboxyl groups of P(OEGMA- co -BSMA) and the hydroxyl group of BUF. Finally, a tumor-targeting polymeric prodrug, P(OEGMA- co -BUF- co -RGD), was obtained via an aminolysis reaction of P(OEGMA- co -BUF) in the presence of RGD and the final drug content was determined to be ∼32.9 wt%. In aqueous media, P(OEGMA- co -BUF- co -RGD) self-assembles into micelles and the hydrodynamic diameter ( D h ) of the micelles was determined to be ∼33.0 (±2.5) nm by dynamic laser light scattering (LLS). It was demonstrated that the tumor-targeting polymeric prodrug showed improved anticancer performance both in vitro and in vivo in comparison with that of free BUF.
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