LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

Interpreting chemisorption strength with AutoML-based feature deletion experiments.

The chemisorption energy of reactants on a catalyst surface, [Formula: see text], is among the most informative characteristics of understanding and pinpointing the optimal catalyst. The intrinsic complexity of catalyst surfaces and chemisorption reactions presents significant difficulties in identifying the pivotal physical quantities determining [Formula: see text]. In response to this, the study proposes a methodology, the feature deletion experiment, based on Automatic Machine Learning (AutoML) for knowledge extraction from a high-throughput density functional theory (DFT) database. The study reveals that, for binary alloy surfaces, the local adsorption site geometric information is the primary physical quantity determining [Formula: see text], compared to the electronic and physiochemical properties of the catalyst alloys. By integrating the feature deletion experiment with instance-wise variable selection (INVASE), a neural network-based explainable AI (XAI) tool, we established the best-performing feature set containing 21 intrinsic, non-DFT computed properties, achieving an MAE of 0.23 eV across a periodic table-wide chemical space involving more than 1,600 types of alloys surfaces and 8,400 chemisorption reactions. This study demonstrates the stability, consistency, and potential of AutoML-based feature deletion experiment in developing concise, predictive, and theoretically meaningful models for complex chemical problems with minimal human intervention.

Matching actions to needs: shifting policy responses to the changing health needs of Chinese children and adolescents.

China is home to the second largest population of children and adolescents in the world. Yet demographic shifts mean that the government must manage the challenge of fewer children with the needs of an ageing population, while considering the delicate tension between economic growth and environmental sustainability. We mapped the health problems and risks of contemporary school-aged children and adolescents in China against current national health policies. We involved multidisciplinary experts, including young people, with the aim of identifying actionable strategies and specific recommendations to promote child and adolescent health and wellbeing. Notwithstanding major improvements in their health over the past few decades, contemporary Chinese children and adolescents face distinct social challenges, including high academic pressures and youth unemployment, and new health concerns including obesity, mental health issues, and sexually transmitted infections. Inequality by gender, geography, and ethnicity remains a feature of health risks and outcomes. We identified a mismatch between current health determinants, risks and outcomes, and government policies. To promote the health of children and adolescents in China, we recommend a set of strategies that target government-led initiatives across the health, education, and community sectors, which aim to build supportive and responsive families, safe communities, and engaging and respectful learning environments. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

APC mutations disrupt ß-catenin destruction complex condensates organized by Axin phase separation.

The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.

Recurrence risk assessment for stage III colorectal cancer based on five methylation biomarkers in plasma cell-free DNA.

For stage III colorectal cancer (CRC) patients with a high risk of recurrence, intensified adjuvant chemotherapy can improve overall survival. We aimed to develop a circulating tumor DNA (ctDNA) methylation marker model for predicting the relapse risk of stage III CRC patients. Differentially methylated markers identified between 53 normal mucosa samples and 165 CRC tissue samples, as well as between plasma samples from 75 stage I/II (early-stage) CRC patients and 55 stage IV (late-stage) CRC patients, were analyzed using Student's t-tests. The overlapping methylation markers shared by plasma and tissue samples were used to establish a methylation marker model to evaluate the tumor burden in the peripheral blood of CRC patients using the random forest method. This model was verified in the validation cohort (n = 44) and then applied to predict recurrence risk in 50 stage III CRC patients and monitor the clinical disease course in serial samples from four CRC patients. We built a five-marker-based ctDNA methylation model that had high sensitivity (84.21%) and specificity (84%) in identifying late-stage CRC in a validation cohort containing 24 stage I/II CRC patients and 20 stage IV CRC patients. The model achieved high sensitivity (87.5%) and specificity (94.12%) in predicting tumor relapse in an independent cohort of 50 stage III CRC patients and could be an independent recurrence risk factor for stage III patients [Hazard ratio (HR), 60.4; 95% confidence interval (CI): 7.68-397; p = 9.73e-5]. Analysis of serial blood samples of CRC showed that the model could monitor disease relapse earlier than imaging examination and serum carcinoembryonic antigen (CEA) and so may provide an opportunity for the early adjustment of therapeutic strategies. Moreover, the model could potentially monitor the clinical course and treatment response dynamically. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

GWAS of grain color and tannin content in Chinese sorghum based on whole-genome sequencing.

KEY MESSAGE: Seventy-three QTL related to grain color and tannin content were identified in Chinese sorghum accessions, and a new recessive allelic variant of TAN2 gene was discovered. Sorghum is mainly used for brewing distilled liquors in China. Since grain tannins play an important role in liquor brewing, accurately understanding the relationship between grain color and tannin content can provide basis for selection standards of tannin sorghum. We resequenced a panel of 242 Chinese sorghum accessions and performed population structure and genome-wide association study (GWAS) to identify quantitative trait locus (QTL) affecting pericarp color, testa pigment, and tannin content. Phylogenetic analysis, principal component analysis (PCA), and admixture model were used to infer population structure. Two distinct genetic sub-populations were identified according to their corresponding northern and southern geographic origin. To investigate the genetic basis of natural variation in sorghum grain color, GWAS with 2,760,264 SNPs was conducted in four environments using multiple models (Blink, FarmCPU, GLM, and MLM). Seventy-three QTL were identified to be associated for the color of exocarp, mesocarp, testa, and tannin content on all chromosomes except chromosome 5, of which 47 might be novel QTL. Some important QTL were found to colocalize with orthologous genes in the flavonoid biosynthetic pathway from other plants, including orthologous of Arabidopsis (Arabidopsis thaliana) TT2, TT7, TT12, TT16 and AT5G41220 (GST), as well as orthologous of rice (Oryza sativa) MYB61 and OsbHLH025. Our investigation of the variation in grain color and tannin content in Chinese sorghum germplasm may help guide future sorghum breeding for liquor brewing.

A-to-I RNA editing of BLCAP promotes cell proliferation by losing the inhibitory of Rb1 in colorectal cancer.

The bladder cancer-associated protein (BLCAP) gene is a tumor-suppressor gene as its encoded protein can inhibit cell proliferation by stimulating apoptosis in many malignant tumors. It is also a novel site of adenosine-to-inosine (A-to-I) RNA editing by ADAR (adenosine deaminase acting on RNA). In this study, we found by exome and transcriptome sequencing that there was an abnormal RNA editing event of the BLCAP gene in colorectal cancer (CRC) tissues compared to adjacent normal tissues. The editing of BLCAP transcripts promoted the degradation of BLCAP by ubiquitination, so BLCAP could not maintain its function as a tumor suppressor gene in CRC. Moreover, our further studies revealed that BLCAP could interact with Rb1 and inhibit its phosphorylation, while the loss of repressive effect due to reduced BLCAP protein levels caused by A-to-I RNA editing facilitates the transition from G1 to S phase of the cell cycle, leading to increased cell proliferation and reduced apoptosis. Thus, A-to-I RNA editing events tend to play an essential role in CRC carcinogenesis.

MIF/SCL3A2 depletion inhibits the proliferation and metastasis of colorectal cancer cells via the AKT/GSK-3ß pathway and cell iron death.

This study investigated the mechanisms of migration inhibitory factor (MIF) and solute carrier family 3 member 2 (SLC3A2) in colorectal cancer progression. The levels of MIF and SLC3A2 expression in cells were measured by RT-qPCR. SW480 and SW620 cells were transfected with sh-MIF and sh-SLC3A2, respectively. MIF, SLC3A2, GPX4, E-cadherin and N-cadherin expression were detected by immunofluorescence (IF). CCK8 and Transwell assays were performed to detect cell proliferation and migration. Co-immunoprecipitation (CoIP) was used to measure the binding activity of MIF and SLC3A2. Finally, a nude mouse tumorigenicity assay was used to confirm the functions of MIF and SLC3A2 in colorectal cancer. Results showed that the levels of MIF and SLC3A2 expression were up-regulated in colorectal cancer cells. Inhibition of MIF or SLC3A2 expression prevented cell proliferation, migration, epithelial-mesenchymal transition (EMT) and invasion. In addition, knockdown of MIF and SLC3A2 promoted iron death in SW480 and SW620 cells. CoIP results showed that MIF and SLC3A2 directly interact with each other. Knockdown of both MIF and SLC3A2 inhibited tumour growth and metastasis via the AKT/GSK-3ß pathway in vivo. The Akt/GSK-3ß pathway was found to participate in regulating MIF and SLC3A2 both in vivo and in vitro. MIF and SLC3A2 might be potential biomarkers for monitoring the treatment of colorectal cancer.

Genome-wide identification, phylogenetic analysis, and expression profiles of trihelix transcription factor family genes in quinoa (Chenopodium quinoa Willd.) under abiotic stress conditions.

BACKGROUND: The trihelix family of transcription factors plays essential roles in the growth, development, and abiotic stress response of plants. Although several studies have been performed on the trihelix gene family in several dicots and monocots, this gene family is yet to be studied in Chenopodium quinoa (quinoa). RESULTS: In this study, 47 C. quinoa trihelix (CqTH) genes were in the quinoa genome. Phylogenetic analysis of the CqTH and trihelix genes from Arabidopsis thaliana and Beta vulgaris revealed that the genes were clustered into five subfamilies: SIP1, GTγ, GT1, GT2, and SH4. Additionally, synteny analysis revealed that the CqTH genes were located on 17 chromosomes, with the exception of chromosomes 8 and 11, and 23 pairs of segmental duplication genes were detected. Furthermore, expression patterns of 10 CqTH genes in different plant tissues and at different developmental stages under abiotic stress and phytohormone treatment were examined. Among the 10 genes, CqTH02, CqTH25, CqTH18, CqTH19, CqTH25, CqTH31, and CqTH36, were highly expressed in unripe achenes 21 d after flowering and in mature achenes compared with other plant tissues. Notably, the 10 CqTH genes were upregulated in UV-treated leaves, whereas CqTH36 was consistently upregulated in the leaves under all abiotic stress conditions. CONCLUSIONS: The findings of this study suggest that gene duplication could be a major driver of trihelix gene evolution in quinoa. These findings could serve as a basis for future studies on the roles of CqTH transcription factors and present potential genetic markers for breeding stress-resistant and high-yielding quinoa varieties.

Genome-wide identification and expression profile analysis of trihelix transcription factor family genes in response to abiotic stress in sorghum [Sorghum bicolor (L.) Moench].

BACKGROUND: Transcription factors, including trihelix transcription factors, play vital roles in various growth and developmental processes and in abiotic stress responses in plants. The trihelix gene has been systematically studied in some dicots and monocots, including Arabidopsis, tomato, chrysanthemum, soybean, wheat, corn, rice, and buckwheat. However, there are no related studies on sorghum. RESULTS: In this study, a total of 40 sorghum trihelix (SbTH) genes were identified based on the sorghum genome, among which 34 were located in the nucleus, 5 in the chloroplast, 1 (SbTH38) in the cytoplasm, and 1 (SbTH23) in the extracellular membrane. Phylogenetic analysis of the SbTH genes and Arabidopsis and rice trihelix genes indicated that the genes were clustered into seven subfamilies: SIP1, GTγ, GT1, GT2, SH4, GTSb8, and orphan genes. The SbTH genes were located in nine chromosomes and none on chromosome 10. One pair of tandem duplication gene and seven pairs of segmental duplication genes were identified in the SbTH gene family. By qPCR, the expression of 14 SbTH members in different plant tissues and in plants exposed to six abiotic stresses at the seedling stage were quantified. Except for the leaves in which the genes were upregulated after only 2 h exposure to high temperature, the 12 SbTH genes were significantly upregulated in the stems of sorghum seedlings after 24 h under the other abiotic stress conditions. Among the selected genes, SbTH10/37/39 were significantly upregulated, whereas SbTH32 was significantly downregulated under different stress conditions. CONCLUSIONS: In this study, we identified 40 trihelix genes in sorghum and found that gene duplication was the main force driving trihelix gene evolution in sorghum. The findings of our study serve as a basis for further investigation of the functions of SbTH genes and providing candidate genes for stress-resistant sorghum breeding programmes and increasing sorghum yield.

CMTM6 expression in M2 macrophages is a potential predictor of PD-1/PD-L1 inhibitor response in colorectal cancer.

BACKGROUND: CMTM6 is a novel key regulator of PD-L1. High expression of both CMTM6 and PD-L1 may predict the benefit of PD-1 axis blockade in lung cancer. We aimed to investigate the expression pattern of CMTM6 between mismatch repair-defective (dMMR) and mismatch repair-proficient (pMMR) colorectal cancer (CRC) tissues and assess its correlation with the response to PD-1/PD-L1 pathway blockade. METHODS: Immunohistochemistry (IHC) was used to analyze CMTM6 and PD-L1 expression and immune cell density in dMMR/pMMR CRC. Quantitative multiplex immunofluorescence (IF) was performed to detect CMTM6, PD-L1, CD4, CD8, CD68 and CD163 expression in CRC patients treated with PD-1/PD-L1 inhibitors. RESULT: IHC analysis showed that CMTM6 and PD-L1 were both expressed in tumor cells (TCs) and invasion front immune cells (ICs). CMTM6 and PD-L1 expression and CD4+, CD8+, CD68+ or CD163+ cell density were significantly higher in dMMR CRC patients than in pMMR CRC patients. CMTM6 expression was positively correlated with PD-L1 expression and CD163+ M2 macrophage density in dMMR CRC. IF analysis showed that the coexpression rate of CMTM6/PD-L1 and the expression rate of CMTM6 in CD8+ T cells and CD163+ M2 macrophages were significantly increased in the group that exhibited clinical benefit. CMTM6 expression in M2 macrophages was identified as the best biomarker for predicting the responsiveness to PD-1/PD-L1 inhibitors. CONCLUSIONS: CMTM6 expression in M2 macrophages may predict the PD-1/PD-L1 inhibitor response rate in CRC patients more accurately than dMMR/microsatellite instability-high (MSI-H) status. It can also identify pMMR CRC patients who could benefit from PD-1/PD-L1 inhibitors.

A newly identified small molecular compound acts as a protein kinase inhibitor to suppress metastasis of colorectal cancer.

BACKGROUND: Targeted therapy has demonstrated high efficacy in the treatment of advanced cancer, and protein kinase inhibitors are a major focus of that therapy; therefore, our study aimed to identify a new protein kinase inhibitor that could be used in the treatment of advanced cancers. METHODS: We analyzed the expression profile of colorectal cancer (CRC), combined the driver gene and drug target databases, and identified protein kinase kalirin RhoGEF kinase (kalirin/KALRN) which is related to CRC metastasis. Based on the structure of kalirin, we screened for the small molecular compound ZINC65387069. We first compared the kinase inhibitory activities and molecular properties of ZINC65387069 and tyrosine kinase inhibitors (TKIs). We then determined the effects of ZINC65387069 on the phosphorylation of protein kinase B-Raf. Finally, we determined the effects of ZINC65387069 on migration and apoptosis of HCT116 cells as well as RKO cells. The cell cytoskeleton was also determined. RESULTS: Compared with traditional TKIs, ZINC65387069 had stronger kinase inhibitory activity, a simpler structure, higher water solubility, a smaller polar surface area, and lower molecular weight and volume. In CRC cells, ZINC65387069 could significantly inhibit the phosphorylation of B-Raf as well as inhibit cell migration, destroy the cell cytoskeleton, and promote cell apoptosis. CONCLUSION: ZINC65387069 is a newly identified protein kinase inhibitor that deserves additional research as a lead compound for drug development to help create targeted therapy against CRC.

MicroRNA-99b-3p promotes angiotensin II-induced cardiac fibrosis in mice by targeting GSK-3ß.

Cardiac fibrosis is a typical pathological change in various cardiovascular diseases. Although it has been recognized as a crucial risk factor responsible for heart failure, there is still a lack of effective treatment. Recent evidence shows that microRNAs (miRNAs) play an important role in the development of cardiac fibrosis and represent novel therapeutic targets. In this study we tried to identify the cardiac fibrosis-associated miRNA and elucidate its regulatory mechanisms in mice. Cardiac fibrosis was induced by infusion of angiotensin II (Ang II, 2 mg·kg-1·d-1) for 2 weeks via osmotic pumps. We showed that Ang II infusion induced cardiac disfunction and fibrosis accompanied by markedly increased expression level of miR-99b-3p in heart tissues. Upregulation of miR-99b-3p and fibrotic responses were also observed in cultured rat cardiac fibroblasts (CFs) treated with Ang II (100 nM) in vitro. Transfection with miR-99b-3p mimic resulted in the overproduction of fibronectin, collagen I, vimentin and α-SMA, and facilitated the proliferation and migration of CFs. On the contrary, transfection with specific miR-99b-3p inhibitor attenuated Ang II-induced fibrotic responses. Similarly, intravenous injection of specific miR-99b-3p antagomir could prevent Ang II-infused mice from cardiac dysfunction and fibrosis. We identified glycogen synthase kinase-3 beta (GSK-3ß) as a direct target of miR-99b-3p. In CFs, miR-99b-3p mimic significantly reduced the expression of GSK-3ß, leading to activation of its downstream profibrotic effector Smad3, whereas miR-99b-3p inhibitor caused anti-fibrotic effects. GSK-3ß knockdown ameliorated the anti-fibrotic role of miR-99b-3p inhibitor. These results suggest that miR-99b-3p contributes to Ang II-induced cardiac fibrosis at least partially through GSK-3ß. The modulation of miR-99b-3p may provide a new approach for tackling fibrosis-related cardiomyopathy.

MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction.

Reduction of expression and activity of sirtuin 3 (SIRT3) contributes to the pathogenesis of cardiomyopathy via inducing mitochondrial injury and energy metabolism disorder. However, development of effective ways and agents to modulate SIRT3 remains a big challenge. In this study we explored the upstream suppressor of SIRT3 in angiotensin II (Ang II)-induced cardiac hypertrophy in mice. We first found that SIRT3 deficiency exacerbated Ang II-induced cardiac hypertrophy, and resulted in the development of spontaneous heart failure. Since miRNAs play crucial roles in the pathogenesis of cardiac hypertrophy, we performed miRNA sequencing on myocardium tissues from Ang II-infused Sirt3-/- and wild type mice, and identified microRNA-214 (miR-214) was significantly up-regulated in Ang II-infused mice. Similar results were also obtained in Ang II-treated neonatal mouse cardiomyocytes (NMCMs). Using dual-luciferase reporter assay we demonstrated that SIRT3 was a direct target of miR-214. Overexpression of miR-214 in vitro and in vivo decreased the expression of SIRT3, which resulted in extensive mitochondrial damages, thereby facilitating the onset of hypertrophy. In contrast, knockdown of miR-214 counteracted Ang II-induced detrimental effects via restoring SIRT3, and ameliorated mitochondrial morphology and respiratory activity. Collectively, these results demonstrate that miR-214 participates in Ang II-induced cardiac hypertrophy by directly suppressing SIRT3, and subsequently leading to mitochondrial malfunction, suggesting the potential of miR-214 as a promising intervention target for antihypertrophic therapy.

The elite exclusion: stratified access and production during the Chinese higher education expansion.

This paper presents new evidence on how enrollment expansion affects higher education access and production with a focus on social inequality and institutional stratification. From 1999 to 2012, the world's largest higher education expansion happened in China that annual college enrollment dramatically increased from 1,083,600 to 6,888,300. We evaluate this exogenous, unprecedented policy using nationally representative student-level survey data and newly available confidential institution-level data. Enrollment expansion, which reduced per-student resources, negatively impacted college quality as measured by value-added on graduates' employment and earnings. The inequality in access between high- and low-SES students and the stratified production between college institutional tiers persisted during expansion.

TUSC3 induces drug resistance and cellular stemness via Hedgehog signaling pathway in colorectal cancer.

Tumor suppressor candidate 3 (TUSC3) is a coding gene responsible for N-glycosylation of many critical proteins. TUSC3 gene plays an oncogenic role in colorectal cancer (CRC), however, the role of TUSC3 in drug resistance of CRC is still unclear. The aim of this study is to investigate the biological function and molecular mechanism of TUSC3 in CRC drug resistance. The expression of TUSC3 in CRC is positively correlated to tumor stage in 90 paired clinical samples, and negatively associated with overall survival and disease-free survival of CRC patients. In vitro, TUSC3 promotes the formation of stemness and induces the drug resistance to 5-fluorouracil and cis-dichlorodiammineplatinum(II) in CRC cells. The tissue microarray assay and bioinformatic analysis indicate that TUSC3 may promote the expression of CD133 and ABCC1 via Hedgehog signaling pathway. Treatment of Hedgehog signaling pathway agonist or inhibitor in TUSC3-silenced or TUSC3-overexpressed cells reverse the effects of TUSC3 in cellular stemness phenotype and drug resistance. Meanwhile, coimmunoprecipitation and immunofluorescence assays indicate a tight relationship between TUSC3 and SMO protein. Our data suggest that TUSC3 promotes the formation of cellular stemness and induces drug resistance via Hedgehog signaling pathway in CRC.

Hsa_circ_001680 affects the proliferation and migration of CRC and mediates its chemoresistance by regulating BMI1 through miR-340.

BACKGROUND: Accumulating evidence indicates that circular RNAs (circRNAs) act as microRNA (miRNA) sponges to directly inhibit specific miRNAs and alter their ability to regulate gene expression at the post-transcriptional level; this mechanism is believed to occur in various cancers. However, the expression level, precise function and mechanism of circ_001680 in colorectal carcinoma (CRC) are largely unknown. METHODS: qRT-PCR was used to detect the expression of circ_001680 and miR-340 in human CRC tissues and their matched normal tissues. Bioinformatics analyses and dual-fluorescence reporter assays were used to evaluate whether circ_001680 could bind to miR-340. Circ_001680 overexpression and knockdown cell lines were constructed to investigate the proliferation and migration abilities in vivo and in vitro through function-based experiments, including CCK8, plate clone formation, transwell, and wounding healing assays. The relationships among circ_001680, miR-340 and BMI1 were investigated by bioinformatics analyses, dual-fluorescence reporter system, FISH, RIP and RNA pull down assays. Sphere forming assays and flow cytometry analyses were used to assess the effect of circ_001680 on the stemness characteristics of CRC cells. RESULTS: Circ_001680 was more highly expressed in of CRC tissue than in matched adjacent normal tissues from the same patients. Circ_001680 was observed to enhance the proliferation and migration capacity of CRC cells. Furthermore, dual-fluorescence reporter assays confirmed that circ_001680 affects the expression of BMI1 by targeting miR-340. More importantly, we also found that circ_001680 could promote the cancer stem cell (CSC) population in CRC and induce irinotecan therapeutic resistance by regulating the miR-340 target gene BMI1. CONCLUSIONS: Our results demonstrated that circ_001680 is a part of a novel strategy to induce chemotherapy resistance in CRC through BMI1 upregulation. Moreover, circ_001680 may be a promising diagnostic and prognostic marker to determine the success of irinotecan-based chemotherapy.

Engagement of Robo1 by Slit2 induces formation of a trimeric complex consisting of Src-Robo1-E-cadherin for E-cadherin phosphorylation and epithelial-mesenchymal transition.

Loss of E-cadherin elicits epithelial-mesenchymal transition (EMT). While both the Src family of membrane-associated non-receptor tyrosine kinases (SFKs) and Slit2 binding to Roundabout 1 (Robo1) have been shown to induce E-cadherin repression and EMT, whether these two signaling pathways are mechanistically coupled remains unknown in epithelial cells. Here we found that Slit2 and Robo1 overexpression activated Src kinases for tyrosine phosphorylation, degradation of E-cadherin and induction of EMT. Specific blockade of Slit2 binding to Robo1 inactivated Src, prevented E-cadherin phosphorylation and EMT induction. Biochemically, the cytoplasmic CC3 motif of Robo1 (CC3) bound directly to the SH2 and 3 domains of c-Src and the cytoplasmic domains of E-cadherin. Slit2 induced Robo1 association with endogenous c-Src and E-cadherin, whereas ectopic expression of CC3 dissociated this protein complex in colorectal epithelial cells. These results indicate that Slit2 not only induces Robo1 binding to Src, but also recruits Src to E-cadherin for tyrosine phosphorylation of E-cadherin, leading to E-cadherin degradation and EMT induction in colorectal epithelial cells.

Sorghum qTGW1a encodes a G-protein subunit and acts as a negative regulator of grain size.

Grain size is a major determinant of grain yield in sorghum and other cereals. Over 100 quantitative trait loci (QTLs) of grain size have been identified in sorghum. However, no gene underlying any grain size QTL has been cloned. Here, we describe the fine mapping and cloning of one grain size QTL. From an F8 recombinant inbred line population derived from a cross between inbred lines 654 and LTR108, we identified 44 grain size QTLs. One QTL, qTGW1a, was detected consistently on the long arm of chromosome 1 in the span of 4 years. Using the extreme recombinants from an F2:3 fine-mapping population, qTGW1a was delimited within a ~33 kb region containing three predicted genes. One of them, SORBI_3001G341700, predicted to encode a G-protein γ subunit and homologous to GS3 in rice, is likely to be the causative gene for qTGW1a. qTGW1a appears to act as a negative regulator of grain size in sorghum. The functional allele of the putatively causative gene of qTGW1a from inbred line 654 decreased grain size, plant height, and grain yield in transgenic rice. Identification of the gene underlying qTGW1a advances our understanding of the regulatory mechanisms of grain size in sorghum and provides a target to manipulate grain size through genome editing.

Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the development of malignant tumors. However, the potential role and molecular mechanism of Siah1 in the development and progression of CRC is still unclear. METHODS: To explore the role and molecular mechanism of Siah1 in the development and progression of CRC, we examined the expression of Siah1 in CRC tissue samples and analyzed its association with progression and prognosis in CRC. In addition, overexpression and knockdown of Siah1 was used to investigate its activity in CRC cells. We also use bioinformatics to analyze and verify the significant roles of Siah1 in critical signaling pathways of CRC. RESULTS: We found that the expression of Siah1 was significantly downregulated in CRC tissues, and low expression of Siah1 was associated with aggressive TNM staging and poor survival of CRC patients. Moreover, we revealed that overexpression of Siah1 in CRC cells markedly inhibited CRC cell proliferation and invasion in vitro and in vivo, while knockdown of Siah1 enhanced CRC cell proliferation and invasion. Furthermore, we found that Siah1 prohibited cell proliferation and invasion in CRC partially through promoting AKT (the serine-threonine protein kinase) and YAP (yes associated protein) ubiquitylation and proteasome degradation to regulate the activity of MAPK(mitogen-activated protein kinase 1), PI3K-AKT (phosphatidylinositol 3-kinase-the serine-threonine protein kinase) and Hippo signaling pathways. CONCLUSIONS: These findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.