Arginine methylation-dependent cGAS stability promotes non-small cell lung cancer cell proliferation.

Cyclic GMP-AMP synthase (cGAS), promotes non-small cell lung cancer (NSCLC) cell proliferation. However, the specific mechanisms of cGAS-mediated NSCLC cell proliferation are largely unknown. In this study, we found asymmetric dimethylation by protein arginine methyltransferase 1 (PRMT1) at R127 of cGAS. This facilitated the binding of deubiquitinase USP7 and contributed to deubiquitination and stabilization of cGAS. PRMT1-and USP7-dependent cGAS stability, which also played a pivotal role in accelerating NSCLC cell proliferation through activating AKT pathway. We validated that the expression of cGAS and PRMT1 were positive correlated in human non-small cell lung cancer samples. Our study demonstrates a unique mechanism for managing cGAS stability by arginine methylation and indicates that PRMT1-cGAS-USP7 axis is a potential therapeutic target for NSCLC.

O-GlcNAc has crosstalk with ADP-ribosylation via PARG.

O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk with phosphorylation and ubiquitination. However, it is unclear whether it interplays with other PTMs. Here we studied its relationship with ADP-ribosylation, which involves decorating target proteins with the ADP-ribose moiety. We discovered that the poly(ADP-ribosyl)ation "eraser", ADP-ribose glycohydrolase (PARG), is O-GlcNAcylated at Ser26, which is in close proximity to its nuclear localization signal. O-GlcNAcylation of PARG promotes nuclear localization and chromatin association. Upon DNA damage, O-GlcNAcylation augments the recruitment of PARG to DNA damage sites and interacting with proliferating cell nuclear antigen (PCNA). In hepatocellular carcinoma (HCC) cells, PARG O-GlcNAcylation enhances the poly(ADP-ribosyl)ation of DNA damage-binding protein 1 (DDB1) and attenuates its auto-ubiquitination, thereby stabilizing DDB1 and allowing it to degrade its downstream targets, such as c-Myc. We further demonstrated that PARG-S26A, the O-GlcNAc-deficient mutant, promoted HCC in mouse xenograft models. Our findings thus reveal that PARG O-GlcNAcylation inhibits HCC, and we propose that O-GlcNAc glycosylation may crosstalk with many other PTMs.

ANGPTL2+cancer-associated fibroblasts and SPP1+macrophages are metastasis accelerators of colorectal cancer.

Background: Liver metastasis (LM) is a leading cause of cancer-related deaths in CRC patients, whereas the associated mechanisms have not yet been fully elucidated. Therefore, it is urgently needed to deeply explore novel metastasis accelerators and therapeutic targets of LM-CRC. Methods: The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from the TCGA and GEO databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed in the Tumor Immune Single-cell Hub (TISCH) database. The infiltration levels of cancer-associated fibroblasts (CAFs) and macrophages in CRC tissues were estimated by multiple immune deconvolution algorithms. The prognostic values of genes were identified by the Kaplan-Meier curve with a log-rank test. GSEA analysis was carried out to annotate the significantly enriched gene sets. The biological functions of cells were experimentally verified. Results: In the present study, hundreds of differentially expressed genes (DEGs) were selected in LM-CRC compared to primary CRC, and these DEGs were significantly associated with the regulation of endopeptidase activity, blood coagulation, and metabolic processes. Then, SPP1, CAV1, ANGPTL2, and COLEC11 were identified as the characteristic DEGs of LM-CRC, and higher expression levels of SPP1 and ANGPTL2 were significantly associated with worse clinical outcomes of CRC patients. In addition, ANGPTL2 and SPP1 mainly distributed in the tumor microenvironment (TME) of CRC tissues. Subsequent scRNA-seq analysis demonstrated that ANGPTL2 and SPP1 were markedly enriched in the CAFs and macrophages of CRC tissues, respectively. Moreover, we identified the significantly enriched gene sets in LM-CRC, especially those in the SPP1+macrophages and ANGPTL2+CAFs, such as the HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION and the HALLMARK_COMPLEMENT. Finally, our in vitro experiments proved that ANGPTL2+CAFs and SPP1+macrophages promote the metastasis of CRC cells. Conclusion: Our study selected four characteristic genes of LM-CRC and identified ANGPTL2+CAFs and SPP1+macrophages subtypes as metastasis accelerators of CRC which provided a potential therapeutic target for LM-CRC.

Inhibition of EZH2 alleviates SAHA-induced senescence-associated secretion phenotype in small cell lung cancer cells.

Chemotherapy has been widely used in small cell lung cancer (SCLC) treatment in the past decades. However, SCLC is easy to recur after chemotherapy. The senescence of cancer cells during chemotherapy is one of the effective therapeutic strategies to inhibit the progression of cancer. Nevertheless, the senescence-associated secretion phenotype (SASP) promotes chronic inflammation of the cancer microenvironment and further accelerates the progression of tumors. Therefore, inducing the senescence of cancer cells and inhibiting the production of SASP factors during anticancer treatment have become effective therapeutic strategies to improve the anticancer effect of drugs. Here we reported that SCLC cells treated with an FDA-approved HDAC inhibitor SAHA underwent senescence and displayed remarkable SASP. In particular, SAHA promoted the formation of cytoplasmic chromatin fragments (CCFs) in SCLC cells. The increased CCFs in SAHA-treated SCLC cells were related to nuclear porin Tpr, which activated the cGAS-STING pathway, and promoted the secretion of SASP in cancer cells. Inhibition of EZH2 suppressed the increase of CCFs in SAHA-treated SCLC cells, weakened the production of SASP, and increased the antiproliferative effect of SAHA. Overall, our work affords new insight into the secretion of SASP in SCLC and establishes a foundation for constructing a new therapeutic strategy for SCLC patients.

Integrated analysis of single cell and bulk RNA sequencing identifies CTHRC1+ INHBA+ CAF as drivers of colorectal cancer progression.

Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and a critical factor in the progression of colorectal cancer (CRC). The aim of this study was to screen for CAFs specific genes that could serve as promising therapeutic targets for CRC patients. Our findings showed a significant increase in the proportion of fibroblasts in CRC tissues, and a high proportion of fibroblasts was associated with immune escape and poor prognosis in CRC. Collagen triple helix repeat containing 1 (CTHRC1) and inhibin subunit beta A (INHBA) were identified as key genes in the progression of CRC, primarily expressed in CAFs and significantly upregulated in CRC tissues. We defined CTHRC1 and INHBA as cancer-associated fibroblast-related genes (CAFRGs), which were associated with poor prognosis in CRC and macrophage polarization. CAFRGs promoted immune escape and metastasis in CRC and were good predictors of immune therapy response. Drug sensitivity analysis showed that the high expression group of CAFRGs was sensitive to 15 chemotherapy drugs, while the low expression group was sensitive to only 3. Clustering of fibroblasts in the tumor revealed that CTHRC1+ INHBA+ CAF was a poor prognostic factor in CRC and was associated with extracellular matrix remodeling and immune regulation. In conclusion, our study provides new theoretical basis for effective treatment strategies and therapeutic targets for CRC.

Slow-Coagulation Transscleral Cyclophotocoagulation Laser Treatment for Medically Uncontrolled Secondary Aphakic Adult Glaucoma.

PRCIS: Slow-coagulation CW-TSCPC is an efficacious, relatively safe, and non-incisional laser treatment option as an initial surgical glaucoma management choice, in secondary aphakic adult glaucoma that is medically uncontrolled. PURPOSE: This study evaluates the outcomes of slow-coagulation continuous wave transscleral cyclophotocoagulation (CW-TSCPC) laser for treating secondary aphakic adult glaucoma after complicated cataract surgery as a primary surgical intervention. MATERIALS AND METHODS: A retrospective chart review of adult aphakic eyes with medically uncontrolled glaucoma underwent slow-coagulation CW-TSCPC as a primary surgical glaucoma intervention was performed. Surgical success was the primary outcome measure. Success was defined as postoperative intraocular pressure (IOP) between 6 and 21 mm Hg with ≥20% reduction compared with baseline and no need for further glaucoma surgeries or development of vision-threatening complications. The secondary outcomes included changes in IOP, glaucoma medication numbers, visual acuity, and postoperative complications during the first year after laser treatment after laser treatment. RESULTS: This study included 41 eyes of 41 patients. The mean age of study participants was 66.7±13.1 years, with a mean follow-up duration of 19±3.5 months. At one year, the success rate was 63.4%. A statistically significant reduction of the IOP was observed, with the mean IOP decreasing from 29.6±5.8 mm Hg with a mean of 3.9±1.0 medications at baseline to a mean of 19.0±6.4 mm Hg with a mean of 2.5±1.2 medications at 12 months ( P <0.001). Four eyes received CW-TSCPC retreatment, and 2 eyes required incisional glaucoma surgeries. Reported postoperative complications included: visual acuity decline ≥2 lines in 7 eyes, iritis in 6 eyes, hyphema in 5 eyes, cystoid macular edema in 2 eyes, and transient hypotony in 1 eye. CONCLUSION: Slow-coagulation CW-TSCPC is an efficacious, relatively safe, and non-incisional laser treatment option as an initial surgical glaucoma management choice, in secondary aphakic adult glaucoma that is medically uncontrolled.

[PyRERT: Python Research Environment for Radiation Therapy].

OBJECTIVE: The Python research environment for radiation therapy (PyRERT) is a set of business software for hospital physicists to conduct radiation therapy research. METHODS: Choose the open source Enthought Tool Suite（ETS） as the core external dependency library of PyRERT. PyRERT is divided into base layer, content layer and interaction layer, and each layer is composed of different functional modules. RESULTS: PyRERT V1.0 provide a good development environment for scientific research programming in DICOM RT file processing, batch processing of water tank scan data, digital phantom creation, 3D medical image volume visualization, virtual radiotherapy equipment driver, and film scan image analysis. CONCLUSIONS: PyRERT enables the results of the research group to be iteratively inherited in the form of software. It's reusable basic classes and functional modules greatly improve the efficiency of scientific research task programming.

Giant Cell Tumor of Lumbar Vertebrae on MR and 18F- FDG PET/CT: A Case Report and Literature Review.

Teaching Point: Giant cell tumor of bone may show a moderate to high FDG uptake, and attention should be paid to differentiate from malignant tumors.

The role and regulatory mechanism of FSCN1 in breast tumorigenesis and progression.

FSCN1, an actin-bundling protein, is highly expressed in almost all metastatic tumors and is associated with the poor prognosis. In breast cancer FSCN1 is highly expressed in basal-like and triple negative subgroups. There is significant progress in understanding the role of fascin in breast cancer. Studies on FSCN1 in recent years have revealed that FSCN1 not only promotes tumor migration, invasion, metastic colonization, cancer cell self-renewal and drug resistance, but also regulates glucose and lipid metabolism and mitochondrial remodeling in tumor cells. In this review, we focus on the structure and regulatory mechanism of FSCN1 in breast tumorigenesis and metastasis, and discuss the clinical value of FSCN1 with the aim to provide a direction for further research in this field.

Circular RNA circ0104103 inhibits colorectal cancer progression through interactions with HuR and miR-373-5p.

Emerging evidence has suggested that circular RNAs (circRNAs) have vital functions during the initiation and progression of various diseases. However, circRNA potential mechanisms in colorectal cancer (CRC) are largely unknown. Here, we sought to investigate the role and underlying regulatory mechanism of circ0104103 in CRC. circ0104103 was validated by quantitative RT-PCR (qRT-PCR) and Sanger sequencing. Gain- and loss-of-function assays in cell lines and mouse xenograft models were utilized to investigate the effects of circ0104103 in CRC. RNA pull-down assays, RNA immunoprecipitation assays, bioinformatics analyses, RNA FISH, and luciferase reporter assays were used to elucidate the potential mechanism of circ0104103 in CRC. We identified circ0104103, which is strongly downregulated in CRC tissues and cell lines. Functional studies revealed that circ0104103 inhibited CRC cell growth, migration, and invasion both in vitro and in vivo. Mechanistically, circ0104103 binds to HuR, a functional RNA-binding protein commonly expressed in CRC. HuR binds to the 3'UTR of LACTB mRNA to facilitate stabilization and increase its expression. Moreover, circ0104103 was verified as a competing endogenous RNA (ceRNA) via negative regulation of miR-373-5p to increase LACTB expression, resulting in inhibiting the occurrence and progression of CRC. Taken together, our study revealed that circ0104103 acts as a tumor suppressor and may be a novel biomarker and therapeutic target in CRC.

Reclassifying TNM stage I/II colorectal cancer into two subgroups with different overall survival, tumor microenvironment, and response to immune checkpoint blockade treatment.

Background: The traditional TNM staging system is often insufficient to differentiate the survival discrepancies of colorectal cancer (CRC) patients at TNM stage I/II. Our study aimed to reclassify stage I/II CRC patients into several subgroups with different prognoses and explore their suitable therapeutic methods. Methods: Single-cell RNA (scRNA) sequencing data, bulk RNA sequencing data, and clinicopathological information of CRC patients were enrolled from the TCGA and GEO databases. The tumor microenvironment of CRC tissues was accessed by the ESTIMATE algorithm. The prognostic genes were identified by Cox regression analysis. GO and KEGG analyses were conducted in the DAVID database. GSEA analysis was performed for annotation of the correlated gene sets. Results: We successfully reclassified stage I/II CRC patients into two subgroups and discovered that patients in cluster-2 underwent worse overall survival than those in cluster-1. GSEA analysis showed that immune-associated gene sets were positively enriched in cluster-2. Besides, the differentially expressed genes (DEGs) between cluster-1 and cluster-2 patients also participated in immune-related biological processes and signaling pathways. Moreover, we found that more immune cells infiltrated the microenvironment of cluster-2 patients compared to that of cluster-1 patients, such as Tregs and tumor-associated macrophages. ScRNA sequencing analysis uncovered that most of the enriched immune-associated signaling in cluster-2 patients was mainly attributed to these upregulated immune cells whose infiltration levels were also high in CRC tissues rather than in normal tissues. In addition, we demonstrated that the expression of immune checkpoint genes was significantly higher in cluster-2 patients compared to cluster-1 patients. ScRNA sequencing analysis revealed that the infiltrated CD8+T cells in CRC were naïve T cells and can be activated into effector T cells after immune checkpoint blockade (ICB) treatment. Conclusion: TNM stage I/II CRC patients can be divided into two subgroups, which have different overall survival rates, tumor microenvironment, and response to ICB therapy.

Hematogenous Macrophages Contribute to Fibrotic Scar Formation After Optic Nerve Crush.

Although glial scar formation has been extensively studied after optic nerve injury, the existence and characteristics of traumatic optic nerve fibrotic scar formation have not been previously characterized. Recent evidence suggests infiltrating macrophages are involved in pathological processes after optic nerve crush (ONC), but their role in fibrotic scar formation is unknown. Using wild-type and transgenic mouse models with optic nerve crush injury, we show that macrophages infiltrate and associate with fibroblasts in the traumatic optic nerve lesion fibrotic scar. We dissected the role of hematogenous and resident macrophages, labeled with Dil liposomes intravenously administered, and observed that hematogenous macrophages (Dil+ cells) specifically accumulate in the center of traumatic fibrotic scar while Iba-1+ cells reside predominantly at the margins of optic nerve fibrotic scar. Depletion of hematogenous macrophages results in reduced fibroblast density and decreased extracellular matrix deposition within the fibrotic scar area following ONC. However, retinal ganglion cell degeneration and function loss after optic nerve crush remain unaffected after hematogenous macrophage depletion. We present new and previously not characterized evidence that hematogenous macrophages are selectively recruited into the fibrotic core of the optic nerve crush site and critical for this fibrotic scar formation.

Chromosome 1q21 gain is an adverse prognostic factor for newly diagnosed multiple myeloma patients treated with bortezomib-based regimens.

Chromosome 1q21 aberration is one of the most common cytogenetic abnormalities in multiple myeloma, and is considered an important prognostic factor. The present study analyzed the clinical relevance and prognostic impact of 1q21 gain in 194 patients with newly diagnosed multiple myeloma treated with bortezomib-based regimens. 1q21 gain was detected in 45.9% (89/194) of patients, and those with 1q21 gain had a worse prognosis. Strikingly, our results showed that excluding the effects of other coinciding genetic anomalies, patients carrying at least four copies of 1q21 had worse survival outcome. Moreover, del(13q) strongly correlates with 1q21 gain, and the coexistence of del(13q) and 1q21 gain plays an important role in reducing PFS and OS times. Therefore, 1q21 gain should be considered a high-risk feature in multiple myeloma patients treated with a bortezomib-based regimen.

LncRNA SNHG16 promotes colorectal cancer proliferation by regulating ABCB1 expression through sponging miR-214-3p.

Mounting evidence indicates that long non-coding RNAs (lncRNAs) have critical roles in colorectal cancer (CRC) progression, providing many potential diagnostic biomarkers, prognostic biomarkers, and treatment targets. Here, we sought to investigate the role and underlying regulatory mechanism of lncRNA small nucleolar RNA host gene 16 ( SNHG16) in CRC. The expressions of SNHG16 in CRC were identified by RNA-sequencing and quantitative reverse transcription PCR. The functions of SNHG16 were explored by a series of in vitro and in vivo assays (colony formation assay, flow cytometry assay, and xenograft model). Bioinformatics analysis, RNA fluorescence in situ hybridization and luciferase reporter assay were used to investigate the regulatory mechanism of effects of SNHG16. SNHG16 was found to be significantly elevated in human CRC tissues and cell lines. Functional studies suggested that SNHG16 promoted CRC cell growth both in vitro and in vivo. Mechanistically, we identified that SNHG16 is expressed predominantly in the cytoplasm. SNHG16 could interact with miR-214-3p and up-regulated its target ABCB1. This study indicated that SNHG16 plays an oncogenic role in CRC, suggesting it could be a novel biomarker and therapeutic target in CRC.

Hepatic epithelioid angiomyolipoma mimicking hepatocellular carcinoma on MR and 18F-FDG PET/CT imaging: A case report and literature review.

Hepatic epithelioid angiomyolipoma (HEAML) is a rare hepatic mesenchymal tumor with malignant potential. Unlike hepatic angiomyolipoma, HEAML is devoid of adipocytes. Thus, it is easy to be misdiagnosed as other tumors of liver, especially hepatocellular carcinoma (HCC) on preoperative imaging examinations. Herein, we present a case of HEAML mimicking HCC on magnetic resonance (MR) and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in a 50-year-old female. After the primary diagnosis of HCC, the patient underwent a laparoscopic resection. The histopathology and immunohistochemical staining helped to reach the final diagnosis of HEAML. The important sign of central vessel can be seen on MRI in this case. The average apparent diffusion coefficient (ADC) value of the HEAML is 0.86±0.13x10-3mm2/s, which is lower than that of 0.97±0.02?10-3mm2/s of the normal liver. Previous literature on 18F-FDG PET/CT imaging of HEAML is limited to only 2 cases. The 18F-FDG PET/CT images of HEAML with high 18F-FDG accumulation with a maximum standardized uptake value (SUVmax) of 8.88 and extensive necrosis are presented, indicating its malignant potential. This case aims to improve the ability of differential diagnosis from HCC on multimodal imaging, and provides values for further 18F-FDG PET/CT related studies.

Retraction Notice to: YTHDF1 Facilitates the Progression of Hepatocellular Carcinoma by Promoting FZD5 mRNA Translation in an m6A-Dependent Manner.

[This retracts the article DOI: 10.1016/j.omtn.2020.09.036.].

Upregulated LINC01088 facilitates malignant phenotypes and immune escape of colorectal cancer by regulating microRNAs/G3BP1/PD-L1 axis.

PURPOSE: Long intergenic non-coding RNA LINC01088 is a newly discovered long non-coding RNA (lncRNA). Its biological function in colorectal cancer (CRC) remains unknown. METHODS: Here, 36 paired CRC and para-cancerous tissues were collected. In vitro, fluorescence in situ hybridization (FISH) assay, qPCR, western blotting analysis and cellular functional experiments, RNA immunoprecipitation (RIP) assay and dual-luciferase reporter system analysis were performed. In vivo, xenograft tumor mouse models were generated. Besides, patient-derived intestinal organoid (PDO) was generated ex vivo. RESULTS: We found that LINC01088 was significantly upregulated in colorectal cancer tissues and CRC cell lines compared to adjacent normal tissues and colonic epithelial cells. High LINC01088 levels were correlated with adverse outcomes in patients with CRC. LINC01088 was mainly located in the cytoplasm. LINC01088 knockdown suppressed the proliferation, migration, invasion, and immune escape of colorectal cancer cells. Mechanistically, LINC01088 bound directly to miR-548b-5p and miR-548c-5p that were significantly upregulated Ras GTPase-activating protein-binding proteins 1 (G3BP1) and programmed death ligand 1 (PD-L1) expression, altering CRC cell phenotypes. In mouse xenograft models, LINC01088 knockdown restrained CRC tumor growth and lung metastasis. Furthermore, G3BP1 overexpression reversed LINC01088-knockdown-mediated inhibitory effects on tumor growth. Notably, LINC01088 knockdown downregulated PD-L1 expression, while G3BP1 overexpression restored PD-L1 expression in xenograft tumors. Besides, LINC01088 knockdown repressed CRC organoid growth ex vivo. CONCLUSION: Overall, these findings suggested that LINC01088 directly targeted miR-548b-5p and miR-548c-5p, promoting G3BP1 and PD-L1 expression, which facilitated colorectal cancer progression and immune escape.