Hepatocellular carcinoma (HCC) is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy. A new modality of epigenetic regulation has emerged ...involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs (ceRNAs) bind to the same microRNAs. However, the contribution of such mechanisms in HCC has not been well studied. Herein, potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages, identifying the mTORC2 component RICTOR as a potential HMGB1 ceRNA in HBV
early stage HCC. Indeed, elevated HMGB1 mRNA was found to promote the expression of RICTOR mRNA through competitively binding with the miR-200 family, especially miR-429. Functional assays employing overexpression or interference strategies demonstrated that the HMGB1 and RICTOR 3'untranslated regions (UTR) epigenetically promoted the malignant proliferation, self-renewal, and tumorigenesis in HCC cells. Intriguingly, interference against HMGB1 and RICTOR in HCC cells promoted a stronger anti-PD-L1 immunotherapy response, which appeared to associate with the production of PD-L1
exosomes. Mechanistically, the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms, activating a positive feedback loop involving mTORC2-AKT-C-MYC to upregulate glutamine synthetase (GS) expression, and inducing mTORC1 signaling to derepress SIRT4 on glutamate dehydrogenase (GDH). Meanwhile, this crosstalk network could impede the efficacy of immunotherapy through mTORC1-P70S6K dependent PD-L1 production and PD-L1
exosomes activity. In conclusion, our study highlights the non-coding regulatory role of HMGB1 with implications for RNA-based therapeutic targeting together with a prediction of anti-PD-L1 immunotherapy in HCC.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with unclear pathogenesis. Sphingomyelin phodiesterase acid-like 3A (SMPDL3A) affects cell differentiation and ...participates in immune regulation. However, its molecular biological function in HCC has not yet been elucidated.
Data from 180 HCC patients were analyzed the relationship between the expression of SMPDL3A in liver cancer tissues and the prognosis of liver cancer patients. Crispr-Cas9 dual vector lentivirus was used to knock out SMPDL3A in HCC cell lines. The effects of SMPDL3A on cell viability were determined by CCK8 assay, clone formation experiment, cell cycle assay, cell scratch, TUNEL experiment and flow cytometry. Xenograft tumor assays in BALB/c nude mice confirmed that SMPDL3A promoted tumor growth and
. Preliminary exploration of SMPDL3A interacting protein by mass spectrometry analysis and co-immunoprecipitation.
This study showed that the expression of SMPDL3A in HCC tissue differed from that in tumor-adjacent tissues. Moreover, the overall survival rate and tumor-free survival rate of patients with high-SMPDL3A expression were significantly lower than those with low-SMPDL3A expression. SMPDL3A expression was closely related to the level of protein induced by PIVKA-II, liver cirrhosis, tumor diameter, microvascular invasion, and Barcelona clinic liver cancer staging. Thus, SMPDL3A is an independent risk factor that affects the tumor-free survival rate and overall survival rate of HCC patients.
study using Crispr-Cas9 genome editing technology revealed the knockout effect of
on cell proliferation, apoptosis, and migration. Cell counting kit-8 assay and clone formation experiment showed that sgSMPDL3A inhibited tumor cell proliferation and migration. Flow cytometry and TUNEL assay showed that sgSMPDL3A promoted apoptosis in tumors. Moreover, sgSMPDL3A inhibited tumor growth during subcutaneous tumor formation in nude mice. Immunohistochemistry of Ki67 and PNCA also indicated that sgSMPDL3A inhibited subcutaneous tumor proliferation in tumor-bearing nude mice. Further experiments showed that SMPDL3A interacts with the enhancer of rudimentary homolog (ERH).
High-SMPDL3A expression was related to poor prognosis of patients with HCC. Knockout of
inhibited the proliferation and migration and accelerated the migration of HCC cells. SMPDL3A interacted with ERH to affect the tumorigenesis and progression of HCC.
Through a three-step study that relies on biomarker discovery, training, and validation, we identified a set of five exosomal microRNAs (miRNAs) that can be used to evaluate the risk of gallbladder ...carcinoma (GBC), including miR-552-3p, miR-581, miR-4433a-3p, miR-496, and miR-203b-3p. When validated in 102 GBC patients and 112 chronic cholecystitis patients from multiple medical centers, the AUC of this combinatorial biomarker was 0.905, with a sensitivity of 81.37% and a specificity of 86.61%. The performance of this biomarker is superior to that of the standard biomarkers CA199 and CEA and is suited for GBC early diagnosis. The multi-clinicopathological features and prognosis of GBC patients were significantly associated with this biomarker. After building a miRNA-target gene regulation network, cell functions and signaling pathways regulated by these five miRNAs were examined. This biomarker signature can be used in the development of a noninvasive tool for GBC diagnosis, screening and prognosis prediction.
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•A five exosomal miRNAs-set is identified to diagnose GBC through a three-step study•The efficacy of this noninvasive biomarker is superior to that of conventional ones•This biomarker is correlated with multiple GBC clinical features and the prognosis•The functions and signal pathways that this biomarker may affect were estimated
Health sciences; Cancer systems biology; Cancer
Ubiquitin-related modifier 1 (URM1) is a member of the ubiquitin-like regulator family, which acts as a post-translational protein modifier in the oxidative emergency response mechanism. Previous ...studies have shown that URM1 may be involved in the process of apoptosis and may play a role in JNK signaling pathway. In this study, we aimed to investigate the role and possible mechanism of URM1 in HCC progression.
Expression of URM1 was determined in 90 pairs of matched liver cancer and adjacent non-cancerous tissues by immunohistochemistry. The impacts of URM1 on HCC cell proliferation, apoptosis, migration and invasion capacities were verified by CCK-8, colony formation, TUNEL staining, wound healing assay and transwell, respectively. Then, the effect of URM1 on subcutaneous tumor formation in vitro was explored by nude mouse xenograft model of liver cancer. Finally, the expression of apoptosis-related proteins was analyzed in URM1 knockdown samples by Western blotting.
In this study, compared with paired adjacent non-cancerous tissues, the expression of URM1 was higher in liver cancer tissues (P <0.01). Kaplan-Meier survival analysis showed that high URM1 expression was significantly associated with poor prognosis (P <0.05). Moreover, URM1 knockdown inhibited liver cancer cell proliferation and migration. Furthermore, URM1 knockdown promoted apoptosis of liver cancer cells. At the same time, URM1 knockdown inhibited tumor growth in nude mouse xenograft model of liver cancer. In addition, URM1 knockdown downregulated the expression of the apoptosis-related factors JNK1/2 and TP53 and upregulated the phosphorylation of JNK1/2 and P53.
In summary, our results suggested that URM1 expression is increased in liver cancer tissues, and URM1 knockdown inhibits the proliferation and migration of liver cancer cells and accelerates apoptosis. High URM1 expression is associated with poor prognosis in patients with HCC.
Gallbladder carcinoma (GBC) remains a highly lethal disease worldwide. MiR-552 family members promote the malignant progression of a variety of digestive system tumors, but the role of miR-552-3p in ...GBC has not been elucidated. miR-552-3p was predicted to target the 3'-untranslated region (3'UTR) of the mRNA for the tumor suppressor gene "repulsive guidance molecule BMP co-receptor a" (
). The aim of the present study was to clarify the roles and mechanisms of miR-552-3p targeting
in the malignant progression of GBC.
: expression of miR-552-3p was detected by real-time quantitative PCR (qRT-PCR) in tumor and non-tumor adjacent tissues (NATs). Lentivirus-miR-552-3p was employed to knockdown this miRNA in GBC cell lines. Stem cell-related transcription factors and markers were assessed by qRT-PCR. Cell Counting Kit-8 (CCK-8), sphere formation and transwell assays were used to determine the malignant phenotypes of GBC cells. Targeting the 3'UTR of
by miR-552-3p was verified by integrated analysis including bioinformatics prediction, luciferase assays, measures of changes of gene expression and rescue experiments.
: mouse models of subcutaneous tumors and lung metastases were established to observe the effect of miR-552-3p on tumorigenesis and organ metastasis, respectively.
MiR-552-3p was abnormally highly expressed in GBC tissues and cancer stem cells. Interference with miR-552-3p in SGC-996 and GBC-SD cells significantly inhibited GBC stem cell expansion. Reciprocally, miR-552-3p promoted GBC cell proliferation, migration and invasion both
and
; hence, interference with this miRNA impeded the malignant progression of GBC. Furthermore, the important tumor suppressor gene
was identified as a target of miR-552-3p. The effects of miR-552-3p on cell proliferation and metastasis were abrogated or enhanced by gain or loss of
function, respectively. Mechanistically, miR-552-3p promoted GBC progression by reactivating the Akt/β-catenin pathway and epithelial-mesenchymal transformation (EMT). Clinically, miR-552-3p correlated with multi-malignant characteristics of GBC and acted as a prognostic marker for GBC outcome.
MiR-552-3p promotes the malignant progression of GBC by inhibiting the mRNA of the tumor suppressor gene
, resulting in reactivation of the Akt/β-catenin signaling pathway.
Optical metasurfaces have shown unprecedented capabilities in the local manipulation of the light's phase, intensity, and polarization profiles, and represent a new viable technology for applications ...such as high‐density optical storage, holography and display. Here, a novel metasurface platform is demonstrated for simultaneously encoding color and intensity information into the wavelength‐dependent polarization profile of a light beam. Unlike typical metasurface devices in which images are encoded by phase or amplitude modulation, the color image here is multiplexed into several sets of polarization profiles, each corresponding to a distinct color, which further allows polarization modulation‐induced additive color mixing. This unique approach features the combination of wavelength selectivity and arbitrary polarization control down to a single subwavelength pixel level. The encoding approach for polarization and color may open a new avenue for novel, effective color display elements with fine control over both brightness and contrast, and may have significant impact for high‐density data storage, information security, and anticounterfeiting.
A novel metasurface platform is proposed and experimentally demonstrated to simultaneously encode color and intensity information into the wavelength‐dependent polarization profile of a light beam. This unique approach features the combination of wavelength selectivity and arbitrary polarization control down to a single subwavelength pixel level. A linear polarizer is required for the acquisition of the image's color and brightness profiles.
As wind power resources are abundant, China’s wind power industry has entered a period of rapid growth since 2005, and constantly facing new challenges at the same time. In this paper, the general ...situation of China’s wind power resource and wind power industry development are introduced. On this basis, future development potential and target of wind power industry are analyzed combining with the recent introduction of the policy and the “Twelfth Five-Year Plan”. The main obstacles prevailing in the development such as grid integration, price mechanism, industry standard system, and supporting policies are discussed. In addition, strategy advice for promoting the further development of China’s wind power is proposed. In general, the development prospect of China’s wind power industry will be even brighter.
Dielectric metasurfaces are capable of completely manipulating the phase, amplitude, and polarization of light with high spatial resolutions. The emerging design based on high-index and low-loss ...dielectrics has led to the realization of novel metasurfaces with high transmissions, but these devices usually operate at the limited bandwidth, and are sensitive to the incident polarization. Here, we report the realization of the polarization-independent and high-efficiency silicon metasurfaces spanning the visible wavelengths about 200 nm. The fabricated computer-generated meta-holograms exhibit a 90% diffraction efficiency, which are verified by gradient metasurfaces with measured efficiencies up to 93% at 670 nm, and exceeding 75% at the wavelengths from 600 to 800 nm for the two orthogonally polarized incidences. These dielectric metasurfaces effectively decouple the phase modulation from the polarization states and frequencies for visible light, which hold great potential for novel flat optical devices operating over a broad spectrum.
Summary
In rice (Oryza sativa L.), later flowering inferior spikelets (IS), which are located on proximal secondary branches, fill slowly and produce smaller and lighter grains than earlier flowering ...superior spikelets (SS). Many genes have been reported to be involved in poor grain filling of IS, however the underlying molecular mechanisms remain unclear. The present study determined that GF14f, a member of the 14‐3‐3 protein family, showed temporal and spatial differences in expression patterns between SS and IS. Using GF14f–RNAi plants, we observed that a reduction in GF14f expression in the endosperm resulted in a significant increase in both grain length and weight, which in turn improved grain yield. Furthermore, pull‐down assays indicated that GF14f interacts with enzymes that are involved in sucrose breakdown, starch synthesis, tricarboxylic acid (TCA) cycle and glycolysis. At the same time, an increase in the activity of sucrose synthase (SuSase), adenosine diphosphate‐glucose pyrophosphorylase (AGPase), and starch synthase (StSase) was observed in the GF14f–RNAi grains. Comprehensive analysis of the proteome and metabolite profiling revealed that the abundance of proteins related to the TCA cycle, and glycolysis increased in the GF14f–RNAi grains together with several carbohydrate intermediates. These results suggested that GF14f negatively affected grain development and filling, and the observed higher abundance of the GF14f protein in IS compared with SS may be responsible for poor IS grain filling. The study provides insights into the molecular mechanisms underlying poor grain filling of IS and suggests that GF14f could serve as a potential tool for improving rice grain filling.
Significance Statement
The 14‐3‐3 protein GF14f negatively affects grain filling of inferior spikelets and therefore may be useful in improving rice grain filling.
Metal–organic framework (MOF) glasses can be used as references to investigate the atomic structure–activity correlation of bimetallic electrocatalysts, considering their stable framework structure ...as well as well-defined active sites. In this work, a bimetallic MOF glass, a cobalt-based zeolitic imidazole framework with guest nickel ions (ZIF-62(Co)–Ni), is fabricated to study its bimetallic functions in oxygen and hydrogen evolution, using a simple dipping–melting–quenching approach based on the ZIF-62(Co) glassy behavior. We elucidate the specific roles of the host cobalt and guest nickel sites in these two electrocatalytic processes through in situ Raman analysis and density functional theory calculations. When generating oxygen, nickel sites facilitate the process by utilizing the hydroxyl spillover from the cobalt sites. However, when producing hydrogen, nickel sites dominate. This distinct bimetallic functionality enables the superior electrocatalytic performance of ZIF-62(Co)–Ni. The cell voltage for overall water splitting is as low as 1.74 V at a current density of 100 mA cm −2 and remains stable for over 200 h, outperforming most state-of-the-art bifunctional non-precious electrocatalysts.
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