Horizontal gene transfer from chloroplast to mitochondria of seagrasses in the yellow-Bohai seas.

Seagrasses are ideal for studying plant adaptation to marine environments. In this study, the mitochondrial (mt) and chloroplast (cp) genomes of Ruppia sinensis were sequenced. The results showed an extensive gene loss in seagrasses, including a complete loss of cp-rpl19 genes in Zosteraceae, most cp-ndh genes in Hydrocharitaceae, and mt-rpl and mt-rps genes in all seagrasses, except for the mt-rpl16 gene in Phyllospadix iwatensis. Notably, most ribosomal protein genes were lost in the mt and cp genomes. The deleted cp genes were not transferred to the mt genomes through horizontal gene transfer. Additionally, a significant DNA transfer between seagrass organelles was found, with the mt genomes of Zostera containing numerous sequences from the cp genome. Rearrangement analyses revealed an unreported inversion of the cp genome in R. sinensis. Moreover, four positively selected genes (atp8, nad5, atp4, and ccmFn) and five variable regions (matR, atp4, atp8, rps7, and ccmFn) were identified.

Genome-scale signatures of adaptive gene expression changes in an invasive seaweed Gracilaria vermiculophylla.

Invasive species can successfully and rapidly colonize new niches and expand ranges via founder effects and enhanced tolerance towards environmental stresses. However, the underpinning molecular mechanisms (i.e., gene expression changes) facilitating rapid adaptation to harsh environments are still poorly understood. The red seaweed Gracilaria vermiculophylla, which is native to the northwest Pacific but invaded North American and European coastal habitats over the last 100 years, provides an excellent model to examine whether enhanced tolerance at the level of gene expression contributed to its invasion success. We collected G. vermiculophylla from its native range in Japan and from two non-native regions along the Delmarva Peninsula (Eastern United States) and in Germany. Thalli were reared in a common garden for 4 months at which time we performed comparative transcriptome (mRNA) and microRNA (miRNA) sequencing. MRNA-expression profiling identified 59 genes that were differently expressed between native and non-native thalli. Of these genes, most were involved in metabolic pathways, including photosynthesis, abiotic stress, and biosynthesis of products and hormones in all four non-native sites. MiRNA-based target-gene correlation analysis in native/non-native pairs revealed that some target genes are positively or negatively regulated via epigenetic mechanisms. Importantly, these genes are mostly associated with metabolism and defence capability (e.g., metal transporter Nramp5, senescence-associated protein, cell wall-associated hydrolase, ycf68 protein and cytochrome P450-like TBP). Thus, our gene expression results indicate that resource reallocation to metabolic processes is most likely a predominant mechanism contributing to the range-wide persistence and adaptation of G. vermiculophylla in the invaded range. This study, therefore, provides molecular insight into the speed and nature of invasion-mediated rapid adaption.

Intraspecific genetic variation matters when predicting seagrass distribution under climate change.

Seagrasses play a vital role in structuring coastal marine ecosystems, but their distributional range and genetic diversity have declined rapidly in recent decades. To improve conservation of seagrass species, it is important to predict how climate change may impact their ranges. Such predictions are typically made with correlative species distribution models (SDMs), which can estimate a species' potential distribution under present and future climatic scenarios given species' presence data and climatic predictor variables. However, these models are typically constructed with species-level data, and thus ignore intraspecific genetic variability, which can give rise to populations with adaptations to heterogeneous climatic conditions. Here, we explore the link between intraspecific adaptation and niche differentiation in Thalassia hemprichii, a seagrass broadly distributed in the tropical Indo-Pacific Ocean and a crucial provider of habitat for numerous marine species. By retrieving and re-analysing microsatellite data from previous studies, we delimited two distinct phylogeographical lineages within the nominal species and found an intermediate level of differentiation in their multidimensional environmental niches, suggesting the possibility for local adaptation. We then compared projections of the species' habitat suitability under climate change scenarios using species-level and lineage-level SDMs. In the Central Tropical Indo-Pacific region, models for both levels predicted considerable range contraction in the future, but the lineage-level models predicted more severe habitat loss. Importantly, the two modelling approaches predicted opposite patterns of habitat change in the Western Tropical Indo-Pacific region. Our results highlight the necessity of conserving distinct populations and genetic pools to avoid regional extinction due to climate change and have important implications for guiding future management of seagrasses.

Enantio-discrimination via light deflection effect.

We propose a theoretical method for enantio-discrimination based on the light deflection effect in four-level models of chiral molecules. This four-level model consists of a cyclic three-level subsystem coupled by three strong driving fields and an auxiliary level connected to the cyclic three-level subsystem by a weak probe field. It is shown that the induced refractive index for the weak probe field is chirality-dependent. Thus, it will lead to chirality-dependent light deflection when the intensities of two of the three strong driving fields are spatially inhomogeneous. As a result, the deflection angle of the weak probe light can be utilized to detect the chirality of pure enantiomers and enantiomeric excess of the chiral mixture. Therefore, our method may act as a tool for enantio-discrimination.

Exosomal miR-451a Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Targeting LPIN1.

BACKGROUND/AIMS: Emerging evidence suggests that exosomal microRNAs (miRNAs) mediate hepatoma progression through the post-translational regulation of their targets. However, characteristically-expressed miRNAs and their functions in the tumor and tumor-associated angiogenesis remain poorly understood. METHODS: miRNA sequencing (HiSeq 2500 SE50) was performed to identify miRNA species that are involved in the hepatocellular carcinoma (HCC) pathogenesis. We identified miR-451a downregulation according to its expression and TCGA analysis. miR-451a was found to be mainly involved in cell viability, apoptosis, cell cycle and migration both in HCC and endothelial cell lines. LPIN1 was predicted to be a target of this miRNA based on TargetScan, GSEA analysis, and the Uniprot database. We performed real time PCR and dual luciferase assays to confirm these results. RESULTS: We identified that miR-451a is significantly downregulated in serum-derived exosomes from HCC patients, as compared to expression in those from normal individuals. We further confirmed that overexpression of miR-451a functions in HCC and endothelia cells in vitro and in vivo. Exosomal miR-451a, as a tumor suppressor, was found to induce apoptosis both in HCC cell lines and human umbilical vein endothelial cells (HUVECs). In addition, miR-451a suppressed HUVEC migration, tube formation, and vascular permeability. Importantly, we demonstrated that LPIN1 is a critical target of miR-451a, and promotes apoptosis in both HCC and endothelial cells. CONCLUSION: Our study provides the novel finding that exosomal miR-451a targets LPIN1 to inhibit hepatocellular tumorigenesis by regulating tumor cell apoptosis and angiogenesis. These results have clinical implications regarding the deregulation of miRNAs in HCC.

PI signal transduction and ubiquitination respond to dehydration stress in the red seaweed Gloiopeltis furcata under successive tidal cycles.

BACKGROUND: Intermittent dehydration caused by tidal changes is one of the most important abiotic factors that intertidal seaweeds must cope with in order to retain normal growth and reproduction. However, the underlying molecular mechanisms for the adaptation of red seaweeds to repeated dehydration-rehydration cycles remain poorly understood. RESULTS: We chose the red seaweed Gloiopeltis furcata as a model and simulated natural tidal changes with two consecutive dehydration-rehydration cycles occurring over 24 h in order to gain insight into key molecular pathways and regulation of genes which are associated with dehydration tolerance. Transcription sequencing assembled 32,681 uni-genes (GC content = 55.32%), of which 12,813 were annotated. Weighted gene co-expression network analysis (WGCNA) divided all transcripts into 20 modules, with Coral2 identified as the key module anchoring dehydration-induced genes. Pathways enriched analysis indicated that the ubiquitin-mediated proteolysis pathway (UPP) and phosphatidylinositol (PI) signaling system were crucial for a successful response in G. furcata. Network-establishing and quantitative reverse transcription PCR (qRT-PCR) suggested that genes encoding ubiquitin-protein ligase E3 (E3-1), SUMO-activating enzyme sub-unit 2 (SAE2), calmodulin (CaM) and inositol-1,3,4-trisphosphate 5/6-kinase (ITPK) were the hub genes which responded positively to two successive dehydration treatments. Network-based interactions with hub genes indicated that transcription factor (e.g. TFIID), RNA modification (e.g. DEAH) and osmotic adjustment (e.g. MIP, ABC1, Bam1) were related to these two pathways. CONCLUSIONS: RNA sequencing-based evidence from G. furcata enriched the informational database for intertidal red seaweeds which face periodic dehydration stress during the low tide period. This provided insights into an increased understanding of how ubiquitin-mediated proteolysis and the phosphatidylinositol signaling system help seaweeds responding to dehydration-rehydration cycles.

Oncoprotein HBXIP induces PKM2 via transcription factor E2F1 to promote cell proliferation in ER-positive breast cancer.

We have reported that hepatitis B X-interacting protein (HBXIP, also termed LAMTOR5) can act as an oncogenic transcriptional co-activator to modulate gene expression, promoting breast cancer development. Pyruvate kinase muscle isozyme M2 (PKM2), encoded by PKM gene, has emerged as a key oncoprotein in breast cancer. Yet, the regulatory mechanism of PKM2 is still unexplored. Here, we report that HBXIP can upregulate PKM2 to accelerate proliferation of estrogen receptor positive (ER+) breast cancer. Immunohistochemistry analysis using breast cancer tissue microarray uncovered a positive association between the expression of HBXIP and PKM2. We also discovered that PKM2 expression was positively related with HBXIP expression in clinical breast cancer patients by real-time PCR assay. Interestingly, in ER+ breast cancer cells, HBXIP was capable of upregulating PKM2 expression at mRNA and protein levels in a dose-dependent manner, as well as increasing the activity of PKM promoter. Mechanistically, HBXIP could stimulate PKM promoter through binding to the -779/-579 promoter region involving co-activation of E2F transcription factor 1 (E2F1). In function, cell viability, EdU, colony formation, and xenograft tumor growth assays showed that HBXIP contributed to accelerating cell proliferation through PKM2 in ER+ breast cancer. Collectively, we conclude that HBXIP induces PKM2 through transcription factor E2F1 to facilitate ER+ breast cancer cell proliferation. We provide new evidence for the mechanism of transcription regulation of PKM2 in promotion of breast cancer progression.

Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis.

T-cell acute lymphoblastic leukaemia (T-ALL) is a hematological malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. ZEB1, a member of zinc finger-homeodomain family transcription factor, exhibits crucial function in promoting T-cell differentiation and potentially acts as a tumor suppressor in T-ALL. However, the molecular mechanism by which ZEB1 regulates T-ALL leukaemogenesis remains obscure. Here, we showed that oncogenic LIM only 2 (LMO2) could recruit Sap18 and HDAC1 to assemble an epigenetic regulatory complex, thus inducing histone deacetylation in ZEB1 promoter and chromatin remodeling to achieve transcriptional repression. Furthermore, downregulation of ZEB1 by LMO2 complex results in an increased leukaemia stem cell (LSC) phenotype as well as unsensitivity in response to methotrexate (MTX) chemotherapy in T-ALL cells. Importantly, we demonstrated that Trichostatin A (TSA, a HDAC inhibitor) addition significantly attenuates MTX unsensitivity caused by dysfunction of LMO2/ZEB1 signaling. In conclusion, these findings have identified a molecular mechanism underlying LMO2/ZEB1-mediated leukaemogenesis, paving a way for treating T-ALL with a new strategy of epigenetic inhibitors.

Magnetic ring anastomosis of suprahepatic vena cava: novel technique for liver transplantation in rat.

To improve the technique of suprahepatic vena cava (SHVC) reconstruction in rat OLT, novel magnetic rings were designed and manufactured to facilitate reconstruction of SHVC and shorten the anhepatic time. One-hundred and twenty adult male Wistar rats were randomly divided into two groups: rings group (n = 30), using magnetic rings for SHVC reconstruction; suture group (n = 30), 7/0 prolene suture was used for SHVC running anastomosis as control. Cuff techniques were used for portal vein and infrahepatic vena cava reconstruction as Kamada and Calne described. The bile duct was reconnected with a stent. The hepatic re-arterialization was omitted. In the rings group, the SHVC reconstruction took 0.91 ± 0.24 (mean ± SD) min; the anhepatic phase and the recipient operation time were 5.63 ± 0.65 min and 36.02 ± 8.02 min, respectively. In suture group, the anastomotic time of SHVC was 10.40 ± 2.11 min; the anhepatic phase and the recipient operation time were 17.76 ± 2.51 and 49.38 ± 12.06 min, respectively, and there was statistically significant difference between the two groups. The ALT levels reached peak at 24 h post-OLT (186.2 ± 32.5 IU/l) and restored to normal level at 96 h gradually. In the rings group, 29 of 30 rats survived at day 7 and 28 of 30 rats survived at day 30. In contrast, only 25 of 30 recipients in suture group remained alive at day 7 and 22 of 30 remained alive at day 30 (P < 0.05). Better anastomotic healing was founded in rings group by pathology and scanning electron microscope. The magnetic rings technique provides a novel, simple method for SHVC reconstruction of OLT in rat. It significantly shortens anhepatic phase, while the success rate of the operation is satisfactory.

Evaluation of the green economic value added index in the game of enterprise capital providers.

This study explores the performance evaluation of steel enterprises, emphasizing the importance of green environmental performance. Based on the review of the current situation of green investment research, economic added value evaluation system, and game analysis of enterprise capital providers, this study discusses the comprehensive evaluation of games among enterprise capital providers from the perspective of green economic added value. It constructs a game model of capital providers from the perspective of green investment. This model is based on the probability of creditors making green bond investments and shareholders pledging equity, deriving game results, and using economic added value returns to measure enterprise performance. The main data in this study are from the CSMAR database, a corporate governance project, and the relevant environmental protection data from Nangang's annual report. The results show that the green economic added value return rate is higher than the traditional economic added value return rate, indicating that environmental investments do not reduce the operational performance of enterprises. The game of capital providers leans towards equity investment and does not enhance enterprise performance at the expense of the environment. The green economic added value index only reflects past operational performance, based on which enterprises can design reasonable performance evaluation mechanisms, encouraging capital providers to favor environmental investments. This study has important theoretical and practical significance, guiding enterprises' strategic choices during green transformation.

The wavelength dependence of oxygen-evolving complex inactivation in Zosteramarina.

Zostera marina, a critical keystone marine angiosperm species in coastal seagrass meadows, possesses a photosensitive oxygen evolving complex (OEC). In harsh environments, the photoinactivation of the Z. marina OEC may lead to population declines. However, the factors underlying this photosensitivity remain unclear. Therefore, this study was undertaken to elucidate the elements contributing to Z. marina OEC photosensitivity. Our results demonstrated a gradual decrease in photosystem II performance towards shorter wavelengths, especially blue light and ultraviolet radiation. This phenomenon was characterized by a reduction in Fv/Fm and the rate of O2 evolution, as well as increased fluorescence at 0.3 ms on the OJIP curve. Furthermore, exposure to shorter light wavelengths and longer exposure durations significantly reduced the relative abundance of the OEC peripheral proteins, indicating OEC inactivation. Analyses of light-screening substances revealed that carotenoids, which increased most notably under 420 nm light, might primarily serve as thermal dissipators instead of efficient light filters. In contrast, anthocyanins reacted least to short-wavelength light, in terms of changes to both their content and the expression of genes related to their biosynthesis. Additionally, the levels of aromatically acylated anthocyanins remained consistent across blue-, white-, and red-light treatments. These findings suggest that OEC photoinactivation in Z. marina may be linked to inadequate protection against short-wavelength light, a consequence of insufficient synthesis and aromatic acylation modification of anthocyanins.

Series of Intravoxel Incoherent Motion and T2* Magnetic Resonance Imaging Mapping in Detection of Liver Perfusion Changes and Regeneration Among Partial Hepatectomy in Sprague-Dawley Rats.

RATIONALE AND OBJECTIVES: To evaluate liver perfusion changes and their effect on liver regeneration (LR) after partial hepatectomy (PH) using intravoxel incoherent motion (IVIM) and T2* mapping in a rat model. METHODS: One hundred and two rats underwent 30%, 50%, or 70% PH. Within each group (n = 34), rats in MR imaging subgroup (n = 10) underwent liver IVIM and T2* mapping before and within 2 h, 1, 2, 3, 5, 7, 14, and 21 days post-PH to measure D*, perfusion fraction (PF), and T2* values. Three rats from histologic subgroup (n = 24) sacrificed at each time point for hepatocyte Ki-67 indices and diameters measurement. RESULTS: Liver D* and PF values decreased immediately post-PH, then returned to original level as LR progressed in all groups. PF values in 70% PH group were significantly lower than in the other two groups (p < .05). D* and PF values correlated significantly with hepatocyte Ki-67 indices (r = -0.588 to -0.915; p < .05) and hepatocyte diameter (r = -0.555 to -0.792; p < .05). Liver T2* values decreased immediately within 2 h post-PH, then increased to a high level and followed with returning to original level gradually. The duration of the high T2* levels was consistent with Ki-67 indices. CONCLUSIONS: Liver perfusion decreased immediately followed with increasing gradually after PH. IVIM and T2* mapping are promising methods for monitoring changes of liver perfusion. IVIM-derived D* value is the best indicator in reflecting the process of LR noninvasively.

Intrinsic Photosensitivity of the Vulnerable Seagrass Phyllospadix iwatensis: Photosystem II Oxygen-Evolving Complex Is Prone to Photoinactivation.

Phyllospadix iwatensis, a foundation species of the angiosperm-dominated marine blue carbon ecosystems, has been recognized to be a vulnerable seagrass. Its degradation has previously been reported to be associated with environmental changes and human activities, while there has been a limited number of studies on its inherent characteristics. In this study, both the physiological and molecular biological data indicated that the oxygen-evolving complex (OEC) of P. iwatensis is prone to photoinactivation, which exhibits the light-dependent trait. When exposed to laboratory light intensities similar to typical midday conditions, <10% of the OEC was photoinactivated, and the remaining active OEC was sufficient to maintain normal photosynthetic activity. Moreover, the photoinactivated OEC could fully recover within the same day. However, under harsh light conditions, e.g., light intensities that simulate cloudless sunny neap tide days and continual sunny days, the OEC suffered irreversible photoinactivation, which subsequently resulted in damage to the photosystem II reaction centers and a reduction in the rate of O2 evolution. Furthermore, in situ measurements on a cloudless sunny neap tide day revealed both poor resilience and irreversible photoinactivation of the OEC. Based on these findings, we postulated that the OEC dysfunction induced by ambient harsh light conditions could be an important inherent reason for the degradation of P. iwatensis.

Antitumor effects of new glycoconjugated PtII agents dual-targeting GLUT1 and Pgp proteins.

A novel and highly efficient dual-targeting PtII system was designed to improve the drug delivery capacity and selectivity in cancer treatment. The dual-targeting monofunctional PtII complexes (1-8) having glycosylated pendants as tridentated ligand were achieved by introducing glycosylation modification in the thioaminocarbazone compounds with potential lysosomal targeting ability. The structures and stability of 1-8 were further established by various techniques. Molecular docking studies showed that 2 was efficiently docked into glucose transporters protein 1 (GLUT1) and P-glycoprotein (Pgp) proteins with the optimal CDocker-interaction-energy of -64.84 and -48.85 kcal mol-1. Complex 2 with higher protein binding capacity demonstrated significant and broad-spectrum antitumor efficacy in vitro, even exhibiting a half maximal inhibitory concentration (IC50) value (∼10 µM) than cisplatin (∼17 µM) against human lung adenocarcinoma cells (A549). The inhibitor experiment revealed GLUT-mediated uptake of 2, and the subcellular localization experiment in A549 also proved that 2 could be localized in the lysosome, thereby causing cell apoptosis. Moreover, cellular thermal shift assay (CETSA) confirmed the binding of 2 with the target proteins of GLUT1 and Pgp. The above results indicated that 2 represents a potential anticancer candidate with dual-targeting functions.

Assessment of Fibrotic Liver Regeneration After Partial Hepatectomy With Intravoxel Incoherent Motion Diffusion-Weighted Imaging: An Experimental Study in a Rat Model With Carbon Tetrachloride Induced Liver Injury.

PURPOSE: To determine whether intravoxel incoherent motion (IVIM) parameters correlate with liver regeneration and function recovery after partial hepatectomy (PH) in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Sixty-two adult Sprague-Dawley rats were divided into the control group and the fibrosis group with CCl4 injection for 8 weeks. At the end of the 8th week, all rats received left lateral lobe liver resection. Within each group, IVIM imaging (n = 10/group) and histologic and biochemical analyses (n = 3/group/time point) were performed pre- and post-PH (on days 1, 2, 3, 5, 7, 14, and 21). Differences in liver IVIM parameters and correlation between IVIM parameters and Ki-67 indices, hepatocyte diameter, alanine transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) values were analyzed. RESULTS: Post-PH, liver true diffusion coefficient (D) values decreased and pseudodiffusion coefficient (D*) and perfusion fraction (PF) values increased, then recovered to pre-PH levels gradually in both fibrosis and control rats. PF in fibrosis group were significantly higher than in controls from 3 to 21 days (P < 0.05). In fibrosis rats, both Ki-67 indices and hepatocyte diameters increased, and a strong correlation was found between PF and Ki-67 indices (r = -0.756; P = 0.03), D* and PF values and ALT, AST, and TBil values (r = -0.762 to -0.905; P < 0.05). In control rats, only hepatocyte diameters increased, and all IVIM parameters correlated well with hepatocyte diameters, ALT, AST and TBil values (r = 0.810 to -1.000; P < 0.05). CONCLUSION: The regeneration pattern in fibrotic liver tissue was different compared with control livers. IVIM parameters can monitor liver regeneration and functional recovery non-invasively after PH.

A Low-Cost and Scalable Carbon Coated SiO-Based Anode Material for Lithium-Ion Batteries.

Silicon monoxide (SiO) is considered as one of the most promising alternative anode materials thanks to its high theoretical capacity, satisfying operating voltage and low cost. However, huge volume change, poor electrical conductivity, and poor cycle performance of SiO dramatically hindered its commercial application. In this work, we report an affordable and simple way for manufacturing carbon-coated SiO-C composites with good electrochemical performance on kilogram scales. Industrial grade SiO was modified by carbon coating using cheap and environment friendly polyvinyl pyrrolidone (PVP) as carbon source. High-resolution transmission electron microscopy (HRTEM) and Raman spectra results show that there is an amorphous carbon coating layer with a thickness of about 40 nm on the surface of SiO. The synthesized SiO-C-650 composite shows great electrochemical performance with a high capacity of 1491 mAh.g-1 at 0.1 C rate and outstanding capacity retention of 67.2 % after 100 cycles. The material also displays an excellent performance with a capacity of 1100 mAh.g-1 at 0.5 C rate. Electrochemical impedance spectroscopy (EIS) results also prove that the carbon coating layer can effectively improve the conductivity of the composite and thus enhance the cycling stability of SiO electrode.

Photoinactivation of the oxygen-evolving complex regulates the photosynthetic strategy of the seagrass Zostera marina.

Zostera marina, a widespread seagrass, evolved from a freshwater ancestor of terrestrial monocots and successfully transitioned into a completely submerged seagrass. We found that its oxygen-evolving complex (OEC) was partially inactivated in response to light exposure, as evidenced by both the increment of the relative variable fluorescence at the K-step and the downregulation of the OEC genes and proteins. This photosynthetic regulation was further addressed at both proteome and physiology levels by an in vivo study. The unchanged content of the ΔpH sensor PsbS protein and the non-photochemical quenching induction dynamics, described by a single exponential function, verified the absence of the fast qE component. Contents and activities of chlororespiration, Mehler reaction, malic acid synthesis, and photorespiration key enzymes were not upregulated, suggesting that alternative electron flows remained unactivated. Furthermore, neither significant production of singlet oxygen nor increment of total antioxidative capacity indicated that reactive oxygen species were not produced during light exposure. In summary, these low electron consumptions may allow Z. marina to efficiently use the limited electrons caused by partial OEC photoinactivation to maintain a normal carbon assimilation level.

Exosomal MiR-1290 Promotes Angiogenesis of Hepatocellular Carcinoma via Targeting SMEK1.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, relies on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its proangiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1.

Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). However, it is largely unknown how signals from the tumor microenvironment (TME) contribute to aberrant Zeb1 expression. Here, we show that Zeb1 depletion suppresses stemness, colonization and the phenotypic plasticity of breast cancer. Moreover, we demonstrate that, with direct cell-cell contact, TME-derived endothelial cells provide the Notch ligand Jagged1 (Jag1) to neighboring breast CSCs, leading to Notch1-dependent upregulation of Zeb1. In turn, ectopic Zeb1 in tumor cells increases VEGFA production and reciprocally induces endothelial Jag1 in a paracrine manner. Depletion of Zeb1 disrupts this positive feedback loop in the tumor perivascular niche, which eventually lessens tumor initiation and progression in vivo and in vitro. In this work, we highlight that targeting the angiocrine Jag1-Notch1-Zeb1-VEGFA loop decreases breast cancer aggressiveness and thus enhances the efficacy of antiangiogenic therapy.

CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism.

Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of p-RB, p-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.