The miRNA miR-106b-5p has been previously reported to be increased in hepatocellular carcinoma (HCC) tissues compared to cirrhotic tissues. The purpose of this study was to detect its expression in ...HCC cell lines with distinct metastatic potentials and to explore the molecular mechanisms underlying HCC stemness and migration.
miR-106b-5p expression was studied in HCC tissues and cell lines. In vitro cancer stem cell (CSC)-like properties, cell migration and invasion were compared between HCC cell lines with upregulation or downregulation of miR-106b-5p. In vivo tail vein injection models were established to evaluate the role of miR-106b-5p in lung metastasis. Bioinformatics programs, luciferase reporter assay and rescue experiments were used to validate the downstream targets of miR-106b-5p. The relationship between the expression of the targeted gene and clinicopathological parameters was also analyzed.
miR-106b-5p expression was higher in HCC tissues and cell lines than that in non-tumor tissues and hepatocyte Chang liver, respectively. Upregulation of miR-106b-5p exhibited a promoting role in CSC properties, cell migration and activation of phosphatidylinositol-3 kinase (PI3K)/Akt signaling in vitro, as well as in lung metastasis in vivo. However, downregulation of miR-106b-5p exhibited the opposite effect. Furthermore, PTEN was verified as a direct target of miR-106b-5p. Upon clinicopathological analysis, lower level of PTEN was significantly associated with more aggressive characteristics. Patients with high PTEN expression had longer overall survival and disease-free survival.
miR-106b-5p promotes HCC stemness maintenance and metastasis by targeting PTEN via PI3K/Akt pathway. Inhibition of miR-106b-5p might be effective therapeutic strategies to treat advanced HCC.
WRKYs are important regulators in plant development and stress responses. However, knowledge of this superfamily in soybean is limited. In this study, we characterized the drought- and salt-induced ...gene
based on RNA-Seq and qRT-PCR.
, which is 714 bp in length, encoded 237 amino acids and grouped into WRKY II. The promoter region of
included ABER4, MYB, MYC, GT-1, W-box and DPBF
-elements, which possibly participate in abscisic acid (ABA), drought and salt stress responses.
was minimally expressed in different tissues under normal conditions but highly expressed under drought and salt treatments. As a nucleus protein,
was responsive to drought, salt, ABA and salicylic acid (SA) stresses. Using a transgenic hairy root assay, we further characterized the roles of
in abiotic stress tolerance. Compared with control (Williams 82), overexpression of
enhanced drought and salt tolerance, increased proline (Pro) content and decreased malondialdehyde (MDA) content under drought and salt treatment in transgenic soybean seedlings. These results may provide a basis to understand the functions of
in abiotic stress responses in soybean.
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.
Melatonin (N-acetyl-5-methoxytryptamine) is involved in many developmental processes and responses to various abiotic stresses in plants. Most of the studies on melatonin focus on its functions and ...physiological responses in plants, while its regulation mechanism remains unknown. Caffeic acid 3-O-methyltransferase (COMT) functions at a key step of the biosynthesis process of melatonin. In this study, a COMT-like gene,
(Traes_1AL_D9035D5E0.1) was identified in common wheat (
L.). Transient transformation in wheat protoplasts determined that TaCOMT is localized in cytoplasm.
in wheat was induced by drought stress, gibberellin (GA)3 and 3-Indoleacetic acid (IAA), but not by ABA. In
transgenic
, melatonin contents were higher than that in wild type (WT) plants. Under D-Mannitol treatment, the fresh weight of the transgenic
was significantly higher than WT, and transgenic lines had a stronger root system compared to WT. Drought tolerance assays in pots showed that the survival rate of
-overexpression lines was significantly higher than that of WT lines. this phenotype was similar to that the WT lines treated with melatonin under drought condition. In addition, the
transgenic lines had higher proline content and lower malondialdehyde (MDA) content compared to WT lines after drought treatment. These results indicated that overexpression of the wheat
gene enhances drought tolerance and increases the content of melatonin in transgenic
. It could be one of the potential genes for agricultural applications.
Abstract
Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three ...cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%–24.3%) and 95% (95% CI: 85.4%–100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.
Metastasis is a landmark event for rapid postsurgical relapse and death of HCC patients. Although distinct genomic and transcriptomic profiling of HCC metastasis had been reported previously, the ...causal relationships of somatic mutants, mRNA levels and metastatic potentials were difficult to be established in clinic. Therefore, 11 human HCC cell lines and 7 monoclonal derivatives with definite metastatic potentials and tropisms were subjected to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). TP53, MYO5A, ROS1 and ARID2 were the prominent mutants of metastatic drivers in HCC cells. During HCC clonal evaluation, TP53, MYO5A and ROS1 mutations occurred in the early stage, EXT2 and NIN in the late stage. NF1 mutant was unique in lung tropistic cell lines, RNF126 mutant in lymphatic tropistic ones. PER1, LMO2, GAS7, NR4A3 expression levels were positively associated with relapse-free survival (RFS) of HCC patients. The integrative analysis revealed 58 genes exhibited both somatic mutation and dysregulated mRNA levels in high metastatic cells. Altogether, metastatic drivers could accumulate gradually at different stages during HCC progression, some drivers might modulate HCC metastatic potentials and the others regulate metastatic tropisms.
•TP53, MYO5A, ROS1 and ARID2 were the prominent metastatic drivers in HCC cells.•During HCC clonal evaluation, TP53, MYO5A and ROS1 mutations occurred in the early stage, EXT2 and NIN in the late stage. NF1 mutant was unique in lung tropistic cell lines, RNF126 mutant in lymphatic tropistic ones.•PER1, LMO2, GAS7, NR4A3 expression levels were positively associated with relapse-free survival (RFS) analyzed with HCC patients.
Prediction of drug-drug interactions (DDIs) can reveal potential adverse pharmacological reactions between drugs in co-medication. Various methods have been proposed to address this issue. Most of ...them focus on the traditional link prediction between drugs, however, they ignore the cold-start scenario, which requires the prediction between known drugs having approved DDIs and new drugs having no DDI. Moreover, they're restricted to infer whether DDIs occur, but are not able to deduce diverse DDI types, which are important in clinics.
In this paper, we propose a cold start prediction model for both single-type and multiple-type drug-drug interactions, referred to as CSMDDI. CSMDDI predict not only whether two drugs trigger pharmacological reactions but also what reaction types they induce in the cold start scenario. We implement several embedding methods in CSMDDI, including SVD, GAE, TransE, RESCAL and compare it with the state-of-the-art multi-type DDI prediction method DeepDDI and DDIMDL to verify the performance. The comparison shows that CSMDDI achieves a good performance of DDI prediction in the case of both the occurrence prediction and the multi-type reaction prediction in cold start scenario.
Our approach is able to predict not only conventional binary DDIs but also what reaction types they induce in the cold start scenario. More importantly, it learns a mapping function who can bridge the drugs attributes to their network embeddings to predict DDIs. The main contribution of CSMDDI contains the development of a generalized framework to predict the single-type and multi-type of DDIs in the cold start scenario, as well as the implementations of several embedding models for both single-type and multi-type of DDIs. The dataset and source code can be accessed at https://github.com/itsosy/csmddi .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Six lactone derivatives, including four α‐pyrones derivatives (1–4), two α‐furanone derivatives (5 and 6), were isolated from the Dendrobium pendulum. Structural elucidation of these undescribed ...lactone derivatives were accomplished on the basis of detailed nuclear magnetic resonance analysis, and the absolute configurations of compounds 1–4 were confirmed by electronic circular dichroism (ECD) techniques. The cytotoxic effects of isolated compounds on human breast cancer cell MDA‐MB‐231 were evaluated by the MTT assay.
Six lactone derivatives were isolated from the Dendrobium pendulum. Structural elucidation of these undescribed lactone derivatives were accomplished on the basis of detailed nuclear magnetic resonance analysis, and the absolute configurations of compounds 1–4 were confirmed by ECD techniques
Epithelial–mesenchymal transition (EMT), a pivotal event during cancer progression such as relapse and metastasis, is positively correlated with the stemness potency of tumor cells. Our previous ...study showed that miR-296-5p attenuated EMT program of hepatocellular carcinoma cells (HCC) through NRG1/ERBB2/ERBB3 signaling. In the present study, we uncovered that miR-296-5p was able to inhibit the stemness potency of HCC by decreasing the number and size of tumorspheres, downregulating the expression of CSC biomarkers and hampering the ability of tumorigenesis in NOD/SCID mice. Brahma-related gene-1 (Brg1), as the target protein of miR-296-5p detected by bioinformatics methods, activates a series of downstream cascades through directly binding to Sall4 promoter and enhancing Sall4 transcription. Importantly, the higher expressions of Brg1 and Sall4 in tumor tissues of HCC patients suggest poorer prognoses after surgical extraction. In conclusion, miR-296-5p exerts an inhibitory effect on stemness potency of HCC cells via Brg1/Sall4 axis.
Display omitted
•miR-296-5p suppressed CSC-like properties of HCC in vitro and in vivo.•miR-296-5p downregulated Sall4 by Brg1 in HCC.•Brg1 is a direct target of miR-296-5p.•Brg1 and Sall4 were high expressed in HCC patients and negatively associated with HCC prognoses.
LIM proteins have been found to play important roles in many life activities, including the regulation of gene expression, construction of the cytoskeleton, signal transduction and metabolic ...regulation. Because of their important roles in many aspects of plant development,
genes have been studied in many plant species. However, the
gene family has not yet been characterized in foxtail millet. In this study, we analyzed the whole genome of foxtail millet and identified 10
genes. All
gene promoters contain MYB and MYC
-acting elements that are related to drought stress. Based on the presence of multiple abiotic stress-related
-elements in the promoter of
, we chose this gene for further study. We analyzed
expression under abiotic stress and hormone treatments using qRT-PCR. We found that
was induced by various abiotic stresses and hormones. Under drought conditions, transgenic rice of
-overexpression had a higher survival rate, higher relative water content and less cell damage than wild type (WT) rice. These results indicate that overexpression of the foxtail millet
gene enhances drought tolerance in transgenic rice, and the
gene can potentially be used for molecular breeding of crops with increased resistance to abiotic stress.
PDF
