Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in ...primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet.
A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis.
A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness.
Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
DNA high methylation is one of driving force for colorectal carcinoma (CRC) pathogenesis. Transcription factors (TFs) can determine cell fate and play fundamental roles in multistep process of ...tumorigenesis. Dysregulation of DNA methylation of TFs should be vital for the progression of CRC. Here, we demonstrated that TBX20, a T‐box TF family protein, was downregulated with hypermethylation of promoter in early‐stage CRC tissues and correlated with a poor prognosis for CRC patients. Moreover, we identified PDZRN3 as the E3 ubiquitin ligase of TBX20 protein, which mediated the ubiquitination and degradation of TBX20. Furthermore, we revealed that TBX20 suppressed cell proliferation and tumor growth through impairing non‐homologous DNA end joining (NHEJ)‐mediated double‐stranded break repair by binding the middle domain of both Ku70 and Ku80 and therefore inhibiting their recruitment on chromatin in CRC cells. Altogether, our results reveal the tumor‐suppressive role of TBX20 by inhibiting NHEJ‐mediated DNA repair in CRC cells, and provide a potential biomarker for predicting the prognosis of patients with early‐stage CRC and a therapeutic target for combination therapy.
Our study highlights the dysregulation of TBX20 in early‐stage CRC tissues and the mechanism suppressing NHEJ‐mediated DSBs repair by inhibiting the interaction of Ku70 and Ku80, which indicates the potential of TBX20 as an effective biomarker for predicting the prognosis of patients with early‐stage CRC.
Circular RNAs (circRNAs) regulate various biological activities and have been shown to play crucial roles in hepatocellular carcinoma (HCC) progression. However, only a few coding circRNAs have been ...identified in cancers, and their roles in HCC remain elusive. This study aimed to identify coding circRNAs and explore their function in HCC.
CircMAP3K4 was selected from the CIRCpedia database. We performed a series of experiments to determine the characteristics and coding capacity of circMAP3K4. We then used in vivo and in vitro assays to investigate the biological function and mechanism of circMAP3K4 and its protein product, circMAP3K4-455aa, in HCC.
We found circMAP3K4 to be an upregulated circRNA with coding potential in HCC. IGF2BP1 recognized the circMAP3K4 N6-methyladenosine modification and promoted its translation into circMAP3K4-455aa. Functionally, circMAP3K4-455aa prevented cisplatin-induced apoptosis in HCC cells by interacting with AIF, thus protecting AIF from cleavage and decreasing its nuclear distribution. Moreover, circMAP3K4-455aa was degraded through the ubiquitin-proteasome E3 ligase MIB1 pathway. Clinically, a high level of circMAP3K4 is an independent prognostic factor for adverse overall survival and adverse disease-free survival of HCC patients.
CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, circMAP3K4 encoded circMAP3K4-455aa, protected HCC cells from cisplatin exposure, and predicted worse prognosis of HCC patients. Targeting circMAP3K4-455aa may provide a new therapeutic strategy for HCC patients, especially for those with chemoresistance. CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, IGF2BP1 facilitates circMAP3K4 peptide translation, then the circMAP3K4 peptide inhibits AIF cleavage and nuclear distribution, preventing HCC cells from cell death under stress and promoting HCC progression.
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•Structural features of silver sulfide/thiolate and silver thiolate clusters.•Structural features of silver selenide/selenolate clusters.•Structural features of silver tellurolate and ...silver telluride/tellurolate clusters.•Structural features of silver dithiophosphate/diselenophosphate clusters.•Optical and electronic properties of high nuclearity silver(I) chalcogenolate clusters.
The high-nuclearity silver(I) clusters, a novel class of supramolecular assembly of silver(I) complexes, were usually prepared by incorporating silver ions with various ligands. Notably, a large number of argentophilic interactions exist in the high-nuclearity silver clusters. These interactions influence significantly a variety of structural and other physical characteristics. Thus, we will summarize the synthesis and structure of high-nuclearity silver(I) clusters with chalcogenide E2− (E=S, Se and Te), chalcogenolate RE− (E=S, Se and Te), dichalcogenophosphate (RO)2PE2− (E=S and Se), and dichalcogenophosphonate R(R’O)PS2− or RP(O)S22−. This results in deeper understanding of the relationship between synthesis conditions and the finally isolated products. The literature survey is up to December 2015 and the review represents the first article covering the span of various types of high-nuclearity Ag-E clusters and should contribute considerable value for future research.
The fruit of
L. (FLB) has been used as medicines and functional foods for more than 2000 years in East Asia. In this study, carotenoid, phenolic, flavonoid, and polysaccharide contents as well as the ...antioxidant activities of FLB from 13 different regions in China from a total of 78 samples were analyzed. The results showed that total carotenoid contents ranged from 12.93 to 25.35 mg β-carotene equivalents/g DW. Zeaxanthin dipalmitate was the predominant carotenoid (4.260-10.07 mg/g DW) in FLB. The total phenolic, total flavonoid, and total polysaccharide contents ranged from 6.899 to 8.253 mg gallic acid equivalents/g DW, 3.177 to 6.144 mg rutin equivalents/g DW, and 23.62 to 42.45 mg/g DW, respectively. Rutin content ranged from 0.1812 to 0.4391 mg/g DW, and ferulic acid content ranged from 0.0994 to 0.1726 mg/g DW. All of these FLB could be divided into two clusters with PCA analysis, and both individual carotenoids and total carotenoid contents could be used as markers for regional characterization. The phenolic components were the main substance for the antioxidant activity of FLB. Considering the functional component and antioxidant activities, FLB produced in Guyuan of Ningxia was the closest to Daodi herbs (Zhongwei of Ningxia), which is commercially available high quality FLB. The results of this study could provide guidance for comprehensive applications of FLB production in different regions.
Low levels of ITLN1 have been correlated with obesity-related colorectal carcinogenesis, however, the specific functions and underlying mechanisms remain unclear. Thus, we sought to explore the ...inhibitory role of ITLN1 in the tumor-permissive microenvironment that exists during the first occurrence and subsequent development of colorectal carcinoma (CRC). Results indicated that ITLN1 was frequently lost in CRC tissues and ITLN1 to be an independent prognostic predictor of CRC. Orthotopic and subcutaneous tumor xenograft approaches were then used to further confirm the protective role of ITLN1 during tumor progression. Increased ITLN1 expression in CRC cells significantly inhibited local pre-existing vessels sprouting, EPC recruitment and the infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) into tumor tissues without affecting the behavior of CRC cells in vitro. Comparatively, ITLN1-derived MDSCs had a lower suppressive effect on T cell proliferation, NOS2 expression, and ROS production. In addition, ITLN1 overexpression markedly suppressed bone marrow (BM)-derived hematopoietic progenitor cells (HPC) differentiation into MDSCs as well as NOS2 activity on MDSCs. Using H-2b+YFP + chimerism through bone marrow transplantation, increased ITLN1 in HCT116 significantly reduced the BM-derived EPCs and MDSCs in vivo mobilization. Mechanistically, results indicated ITLN1 inhibited tumor-derived IL-17D and CXCL2 (MIP2) through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-ĸB/CXCL2 signaling cascades dependent on PI3K/AKT/GSK3ß. This effect was reversed by the PI3K selective inhibitor LY294002. Collectively, ITLN1 synergistically suppressed IL-17D and CXCL2-mediated tumor vascularization, bone marrow derived EPC recruitment, as well as MDSCs generation and trafficking. Thus, ITLN1 potentially serves as a critical prognostic and therapeutic target for CRC.
Histidine-tryptophan-ketoglutarate (HTK) and del Nido (DN) cardioplegia are intracellular-type and extracellular-type solution respectively, both can provide a long period of myocardial protection ...with single-dose infusion, but studies comparing the two are rare for adult cardiac surgery. This study aims to evaluate whether DN is suitable for cardioplegia in complex and high-risk valve surgery with long-term cardiac ischemia when compared with HTK.
The perioperative records of adult patients infused with DN/HTK as a cardioplegic solution who underwent complex valve surgery with an expected myocardial ischaemic duration longer than 90 min between Oct 2018 and Oct 2019 were analysed retrospectively.
Of the 160 patients who received DN/HTK and underwent complex valve surgery, we propensity matched 73 pairs. Both groups achieved satisfactory cardiac arrest effects, and no significant difference was found in their cTnI and CK-MB levels within 12 to 72 h postoperatively. The DN group had a higher rate of return to spontaneous rhythm (0.88 v 0.52, P < 0.001), a lower frequency of postoperative severe arrythmias (12% v 26%, P = 0.036), a higher postoperative stroke volume (65 v 59 ml, P = 0.011) and a higher cardiac output (6.0 v 4.9 L/min, P = 0.007) as evaluated by echocardiography, fewer transfusions and shorter ICU stays (both P < 0.05). The two groups had similar inotrope usage and similar incidences of low cardiac output, morbidities and mortality. Subgroup analysis showed that when the aortic clamping time was greater than 120 min, the advantages of DN were weakened.
DN can be safely applied to complex valve surgery, and it has a similar myocardial protection effect as HTK. Further prospective studies are required to verify these retrospective findings. Trial registration retrospectively registered.
Four silver thiolate clusters, H3O(Ag3S3)(BF4)@Ag27(tBuS)18(hfac)6H2O⋅H2O (1; hfac = hexafluoroacetylacetone), (Ag3S3)(CF3CO2)@Ag30(tBuS)16(CF3CO2)9(CH3CN)4⋅CF3CO2⋅4 CH3CN (2), ...(Ag3S3)(MoO4)@Ag30(tBuS)16(CF3CO2)9(CH3CN)4⋅2 CH3CN (3), and (Ag3S3)(CrO4)@Ag30(tBuS)16(CF3CO2)9(CH3CN)4⋅4 CH3CN (4), were isolated. They have similar nestlike structures assembled by an Ag3S33− template together with one of the BF4−, CF3CO2−, MoO42−, or CrO42− anions. Interestingly, the solid‐state emissions of 2–4 are dependent on the templating anions and are tunable from green to orange and then to red by changing the template from CF3CO2− to MoO42− and to CrO42−, and this may be correlated to the charge transfer between these templates to metal atoms. This work helps to understand the templating role of heteroanions and the relationship between structure and properties.
Nested templates: Nestlike silver thiolate clusters (Ag3S3)(BF4)@Ag27 (1), (Ag3S3)(CF3CO2)@Ag30 (2), (Ag3S3)(MoO4)@Ag30 (3), and (Ag3S3)(CrO4)@Ag30 (4) were obtained by heteroanion‐templated synthesis and structurally characterized. The solid‐state emissions of 2–4 are dependent on the templating anions and are tunable from green to orange and then to red by changing the template from CF3CO2− to MoO42− and to CrO42−.
Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. ...Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.
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