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.

Quantitative Relaxometry Assessment of Brain Microstructural Abnormality of Preschool Children With Autism Spectrum Disorder With Synthetic Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to perform an assessment of brain microstructure in children with autism aged 2 to 5 years using relaxation times acquired by synthetic magnetic resonance imaging. MATERIALS AND METHODS: Thirty-four children with autism spectrum disorder (ASD) (ASD group) and 17 children with global developmental delay (GDD) (GDD group) were enrolled, and synthetic magnetic resonance imaging was performed to obtain T1 and T2 relaxation times. The differences in brain relaxation times between the 2 groups of children were compared, and the correlation between significantly changed T1/T2 and clinical neuropsychological scores in the ASD group was analyzed. RESULTS: Compared with the GDD group, shortened T1 relaxation times in the ASD group were distributed in the genu of corpus callosum (GCC) ( P = 0.003), splenium of corpus callosum ( P = 0.002), and right thalamus (TH) ( P = 0.014), whereas shortened T2 relaxation times in the ASD group were distributed in GCC ( P = 0.011), left parietal white matter ( P = 0.035), and bilateral TH (right, P = 0.014; left, P = 0.016). In the ASD group, the T2 of the left parietal white matter is positively correlated with gross motor (developmental quotient [DQ] 2) and personal-social behavior (DQ5), respectively ( r = 0.377, P = 0.028; r = 0.392, P = 0.022); the T2 of the GCC was positively correlated with DQ5 ( r = 0.404, P = 0.018); and the T2 of the left TH is positively correlated with DQ2 and DQ5, respectively ( r = 0.433, P = 0.009; r = 0.377, P = 0.028). All significantly changed relaxation values were not significantly correlated with Childhood Autism Rating Scale scores. CONCLUSIONS: The shortened relaxometry times in the brain of children with ASD may be associated with the increased myelin content and decreased water content in the brain of children with ASD in comparison with GDD, contributing the understanding of the pathophysiology of ASD. Therefore, the T1 and T2 relaxometry may be used as promising imaging markers for ASD diagnosis.

IGF2BP3 promotes the progression of colorectal cancer and mediates cetuximab resistance by stabilizing EGFR mRNA in an m6A-dependent manner.

Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an RNA-binding protein, is associated with tumorigenesis and progression. However, the exact molecular mechanisms of IGF2BP3 in colorectal cancer (CRC) oncogenesis, progression, and drug resistance remain unclear. This study found that IGF2BP3 was upregulated in CRC tissues. Clinically, the elevated IGF2BP3 level is predictive of a poor prognosis. Functionally, IGF2BP3 enhances CRC tumorigenesis and progression both in vitro and in vivo. Mechanistically, IGF2BP3 promotes epidermal growth factor receptor (EGFR) mRNA stability and translation and further activates the EGFR pathway by serving as a reader in an N6-methyladenosine (m6A)-dependent manner by cooperating with METTL14. Furthermore, IGF2BP3 increases the drug resistance of CRC cells to the EGFR-targeted antibody cetuximab. Taken together, our results demonstrated that IGF2BP3 was a functional and clinical oncogene of CRC. Targeting IGF2BP3 and m6A modification may therefore offer rational therapeutic targets for patients with CRC.

ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer.

Proficient mismatch repair or microsatellite stable (pMMR/MSS) colorectal cancers (CRCs) are vastly outnumbered by deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) tumors and lack a response to immune checkpoint inhibitors (ICIs). In this study, we reported two distinct expression patterns of ASCL2 in pMMR/MSS and dMMR/MSI-H CRCs. ASCL2 is overexpressed in pMMR/MSS CRCs and maintains a stemness phenotype, accompanied by a lower density of tumor-infiltrating lymphocytes (TILs) than those in dMMR/MSI CRCs. In addition, coadministration of anti-PD-L1 antibodies facilitated T cell infiltration and provoked strong antitumor immunity and tumor regression in the MC38/shASCL2 mouse CRC model. Furthermore, overexpression of ASCL2 was associated with increased TGFB levels, which stimulate local Cancer-associated fibroblasts (CAFs) activation, inducing an immune-excluded microenvironment. Consistently, mice with deletion of Ascl2 specifically in the intestine (Villin-Cre+, Ascl2 flox/flox, named Ascl2 CKO) revealed fewer activated CAFs and higher proportions of infiltrating CD8+ T cells; We further intercrossed Ascl2 CKO with ApcMin/+ model suggesting that Ascl2-deficient expression in intestinal represented an immune infiltrating environment associated with a good prognosis. Together, our findings indicated ASCL2 induces an immune excluded microenvironment by activating CAFs through transcriptionally activating TGFB, and targeting ASCL2 combined with ICIs could present a therapeutic opportunity for MSS CRCs.

Electrochemically Reconstructed Vanadic Oxide-Doped Cobalt Pyrophosphate as an Electrocatalyst for the Oxygen Evolution Reaction.

More and more attention has been paid to the development of the efficient electrocatalysts for the oxygen evolution reaction (OER). Herein, a porous vanadic oxide-doped cobalt pyrophosphate electrocatalyst, namely V2O5-Co2P2O7, was exploited by using the electrochemical reconstruction method in the alkaline electrolyte and selecting a cobalt vanadium phosphate Co(H2O)4(VOPO4)2 as a precursor. The reconstructed vanadic oxide-doped cobalt pyrophosphate catalyst V2O5-Co2P2O7 exhibited efficient electrocatalytic activity for the OER in 1.0 M KOH, requiring a low overpotential of 199 mV at 10 mA cm-2, compared to the reported pyrophosphate electrocatalysts. The porous morphology and doping of vanadic oxide after electrochemical reconstruction were beneficial to enhance the electrocatalytic performance for the OER, through improving the surface area to bring in more accessibly active sites and regulating the electronic structures. The results provided a promising strategy to prepare the pyrophosphate electrocatalysts and improve the performance of the OER catalyst.

COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer.

RNA editing is among the most common RNA level modifications for generating amino acid changes. We identified a COPA A-to-I RNA editing event in CRC metastasis. Our results showed that the COPA A-to-I RNA editing rate was significantly increased in metastatic CRC tissues and was closely associated with aggressive tumors in the T and N stages. The COPA I164V protein damaged the Golgi-ER reverse transport function, induced ER stress, promoted the translocation of the transcription factors ATF6, XBP1 and ATF4 into the nucleus, and activated the expression of MALAT1, MET, ZEB1, and lead to CRC cell invasion and metastasis. Moreover, the COPA A-to-I RNA editing rate was positively correlated with the immune infiltration score. Collectively, the COPA I164V protein hijacked ER stress to promote the metastasis of CRC, and the COPA A-to-I RNA editing rate may be a potential predictor for patient response to immune checkpoint inhibitor (ICIs) treatment.

[Effects of electroacupuncture combined with passive stretch exercise on disused muscle atrophy and expression of skeletal troponin in mice].

OBJECTIVE: To observe the efficacy of electroacupuncture (EA) plus passive stretch exercise in the treatment of disused atrophy of gastrocnemius and soleus muscles in mice. METHODS: Fifty C57BL/6 mice were randomly and equally divided into 5 groups: blank control, model, passive stretch exercise (exercise), EA and EA+exercise groups. The muscular atrophy model was established by fixing the gastrocnemius and soleus muscles with plaster immobilization (by putting the right leg into a plastic vial and then twining the vial with medical plaster bandage from the ankle upwards to the thigh and groin to maintain the knee-joint flexion and ankle joint plantar flexion for 7 days). EA (2 Hz/100 Hz, 1 mA)was applied to bilateral "Zusanli"(ST36) for 10 min, once a day for 4 weeks. For mice with the passive exercise, the plastic vial was removed first, followed by pulling out the hindleg to seize the toes to stretch them until the right hindleg is fully extended, then, pushed the leg towards the body. The procedures were repeated once again and again for 10 min. The exercise was conducted once daily, for 4 weeks. The cross-sectional area of fast and slow muscle fibers of the soleus and gastrocnemius was measured under electronic microscope after ATPase histochemical stain and the expression of slow skeletal muscle troponin (TNNI1) and fast skeletal muscle troponin (TNNI2) in the soleus and gastrocnemius was detected by Western blot. RESULTS: Compared with the blank control group, the cross-sectional areas of the fast and slow muscle fibers of the soleus and gastrocnemius muscles were significantly decreased in the model group (P<0.05, P<0.01). Following the interventions, the cross-sectional areas of the fast and slow muscle fibers of soleus muscle in the EA+exercise group, and those of the fast and slow muscle fibers of the gastrocnemius muscle in the EA and EA+exercise groups, and the expression levels of TNNI1 and TNNI2 proteins in the gastrocnemius muscle of the EA+exercise group were significantly increased in comparison with the model group (P<0.05, P<0.01). CONCLUSION: EA combined with passive stretch exercise can promote the recovery of the soleus and gastrocnemius muscles in disused muscle atrophy mice, which may be related to its effect in up-regulating the expression of TNNI1 and TNNI2 proteins.

Application of capsular bag relaxation for capsular contraction syndrome.

The present study analyzed the surgical method and clinical effects of capsular bag relaxation surgery (CBRS) for the treatment of capsular contraction syndrome (CCS), which usually occurs post-phacoemulsification. The retrospective case study comprised of a total of 25 patients (25 eyes) who developed CCS after phacoemulsification and subsequently underwent CBRS. Among these patients, 15 patients (15 eyes) received actinoid relaxing incisions and 10 patients (10 eyes) underwent a second continuous curvilinear capsulorhexis. Postoperative naked-eye visual acuity was determined and compared with preoperative naked-eye visual acuity. Size changes of the transparent zone of the anterior capsule opening were observed under a slit lamp, as well as the anterior and posterior capsular membrane conditions and position of the intraocular lens (IOL). In addition, the presence of any subjective symptom, including glare or monocular diplopia, was investigated. A final 6-month postoperative follow-up was conducted for each patient. Visual acuity of all operated eyes improved to various extents. Notably, glare and monocular diplopia were no longer evident and patients could observe things clearly. Visual differences pre- and post-surgery were statistically significant (u=5.143, P<0.01). In addition, capsular bag shrinkage and relaxation were revealed under a slit lamp, the area of the transparent zone of the anterior capsule opening was expanded and the IOL remained centered. To conclude, CBRS is an effective treatment method for patients with CCS who are not suitable to receive laser treatment.

Upregulation of OSBPL3 by HIF1A promotes colorectal cancer progression through activation of RAS signaling pathway.

Oxysterol-binding protein like protein 3 (OSBPL3) has been shown involving in the development of several human cancers. However, the relationship between OSBPL3 and colorectal cancer (CRC), particularly the role of OSBPL3 in the proliferation, invasion and metastasis of CRC remains unclear. In this study, we investigated the role of OSBPL3 in CRC and found that its expression was significantly higher in CRC tissues than that in normal tissues. In addition, high expression of OSBPL3 was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. Further experiments showed that over-expression of OSBPL3 promoted the proliferation, invasion and metastasis of CRC in vitro and in vivo models. Moreover, we revealed that OSBPL3 promoted CRC progression through activation of RAS signaling pathway. Furthermore, we demonstrated that hypoxia induced factor 1 (HIF-1A) can regulate the expression of OSBPL3 via binding to the hypoxia response element (HRE) in the promoter of OSBPL3. In summary, Upregulation of OSBPL3 by HIF1A promotes colorectal cancer progression through activation of RAS signaling pathway. This novel mechanism provides a comprehensive understanding of both OSBPL3 and the RAS signaling pathway in the progression of CRC and indicates that the HIF1A-OSBPL3-RAS axis is a potential target for early therapeutic intervention in CRC progression.

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.

Expression and function of long non-coding RNA LINC01420 in thyroid cancer.

The Human Genome Project revealed that >90% of the human genome was found to transcribe non-coding RNAs, including micro RNAs and long non-coding RNAs (lncRNAs). lncRNAs have been identified to play a crucial role in cancer progression. Thyroid cancer (TC) is a common type of endocrine cancer; however, the functional roles of lncRNAs in TC have yet to be fully elucidated. The present study investigated whether LINC01420 was upregulated in TC tissues, compared with normal thyroid tissues, and the results suggested that LINC01420 may play a regulatory role in TC. Bioinformatics analysis demonstrated that LINC01420 was associated with translation, rRNA processing, mRNA splicing, regulation of transcription, DNA repair and double-strand break repair. Furthermore, the exact role of LINC01420 in TC was explored by performing a loss-of-function assay, which revealed that the knockdown of LINC01420 inhibited TC cell proliferation and cell cycle progression. The findings of the present study provide a novel insight into the molecular mechanisms underlying TC development. Moreover, they suggest that LINC01420 may serve as a potential therapeutic target for the treatment of TC, and that increased LINC01420 expression levels show potential as a prognostic marker for the disease.

Long non-coding RNA small nucleolar RNA host gene 7 is upregulated and promotes cell proliferation in thyroid cancer.

Thyroid cancer (THCA) is one of the most common types of endocrine cancer worldwide. However, the mechanisms underlying THCA progression have not been fully elucidated. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are dysregulated in human diseases, and are involved in regulating various biological processes. Furthermore, several reports have indicated that lncRNAs serve important roles in THCA. In the present study, a dataset from The Cancer Genome Atlas was used to analyze the expression levels and the clinical information of small nucleolar RNA host gene 7 (SNHG7) in THCA. Starbase was used to construct the competing endogenous RNA network. The Molecule Annotation System was used to analyze the data from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Furthermore, cell proliferation and cell cycle assays were used to detect the functions of SNHG7 in THCA. The present study revealed for the first time, to the best of our knowledge, that SNHG7 is markedly upregulated in THCA samples following analysis of The Cancer Genome Atlas datasets. SNHG7 expression was higher in advanced stage compared with early stage THCA samples. In addition, high expression levels of SNHG7 were associated with shorter survival times in THCA patients compared with low expression levels. Bioinformatics analysis revealed that SNHG7 was associated with the processes of 'protein translation', 'viral life cycle', 'RNA processing', 'mRNA splicing', 'histone ubiquitination', 'endoplasmic reticulum-to-Golgi vesicle-mediated transport', 'sister chromatid cohesion', 'DNA damage checkpoint regulation', 'translation' and 'the spliceosome'. Additionally, knockdown of SNHG7 significantly inhibited thyroid cancer cell proliferation and cell cycle progression in vitro. Taken together, the results obtained in the present study suggested that SNHG7 may serve as a novel therapeutic and prognostic target for THCA.

UBN2 promotes tumor progression via the Ras/MAPK pathway and predicts poor prognosis in colorectal cancer.

BACKGROUND: Ubinuclein-2 (UBN2) is a nuclear protein that interacts with many transcription factors. The molecular role and mechanism of UBN2 in the development and progression of cancers, including colorectal cancer (CRC), is not well understood. The current study explored the role of UBN2 in the development and progression CRC. METHODS: Oncomine network and The Cancer Genome Atlas (TCGA) database were downloaded and Gene Set Enrichment Analysis (GSEA) was performed to compare the UBN2's expression between normal and tumor tissues, as well as the potential correlation of UBN2 expression with signaling pathways. Immunohistochemistry (IHC), qRT-PCR and Western blotting were performed to determine the expression of UBN2 in CRC tissues or cell lines. In vitro proliferation and invasion assays, and orthotopic mouse metastatic model were used to analyze the effect of UBN2 on the development and progression of CRC. RESULTS: The analysis of UBN2 expression using Oncomine network showed that UBN2 was upregulated in CRC tissues compared to matched adjacent normal intestinal epithelial tissues. IHC, qRT-PCR and Western blotting confirmed that UBN2 expression is higher in CRC tissues compared with matched adjacent normal intestinal epithelial tissues. In addition, analyses of TCGA data revealed that high UBN2 expression was associated with advanced stages of lymph node metastasis, distant metastasis, and short survival time in CRC patients. IHC showed that high UBN2 expression is correlated with advanced stages of CRC. Moreover, UBN2 is highly expressed in the liver metastatic lesions. Furthermore, knockdown of UBN2 inhibited the growth, invasiveness and metastasis of CRC cells via regulation of the Ras/MAPK signaling pathway. CONCLUSION: The current study demonstrates that UBN2 promotes tumor progression in CRC. UBN2 may be used as a promising biomarker for predicting the prognosis of CRC patients.

Hypermethylation of DMTN promotes the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through Rac1 signaling activation.

BACKGROUND: Colorectal cancer (CRC) is one of the most common digestive malignant tumors, and DMTN is a transcriptionally differentially expressed gene that was identified using CRC mRNA sequencing data from The Cancer Genome Atlas (TCGA). Our preliminary work suggested that the expression of DMTN was downregulated in CRC, and the Rac1 signaling pathway was significantly enriched in CRC tissues with low DMTN expression. However, the specific functions and underlying molecular mechanisms of DMTN in the progression of CRC and the upstream factors regulating the downregulation of the gene remain unclear. METHODS: DMTN expression was analyzed in CRC tissues, and the relationship between DMTN expression and the clinicopathological parameters was analyzed. In vitro and in vivo experimental models were used to detect the effects of DMTN dysregulation on invasion and metastasis of CRC cells. GSEA assay was performed to explore the mechanism of DMTN in invasion and metastasis of CRC. Westernblot, Co-IP and GST-Pull-Down assay were used to detect the interaction between DMTN and ARHGEF2, as well as the activation of the RAC1 signaling. Bisulfite genomic sequence (BSP) assay was used to test the degree of methylation of DMTN gene promoter in CRC tissues. RESULTS: We found that the expression of DMTN was significantly decreased in CRC tissues, and the downregulation of DMTN was associated with advanced progression and poor survival and was regarded as an independent predictive factor of CRC patient prognosis. The overexpression of DMTN inhibited, while the knockdown of DMTN promoted, invasion and metastasis in CRC cells. Moreover, hypermethylation and the deletion of DMTN relieved binding to the ARHGEF2 protein, activated the Rac1 signaling pathway, regulated actin cytoskeletal rearrangements, and promoted the invasion and metastasis of CRC cells. CONCLUSION: Our study demonstrated that the downregulation of DMTN promoted the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through RAC1 signaling activation, potentially providing a new therapeutic target to enable cancer precision medicine for CRC patients.