LITAF Enhances Radiosensitivity of Human Glioma Cells via the FoxO1 Pathway.

Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF), also called p53-induced gene 7 (PIG7), was identified as a transcription factor that activates transcription of proinflammatory cytokines in macrophages in response to lipopolysaccharide (LPS). Previous studies have identified LITAF as a potential tumor suppressor in several neoplasms, including prostate cancer, B-NHL, acute myeloid leukemia, and pancreatic cancer. However, the expression and function of LITAF in human glioma remain unexplained. The present study aimed to analyze the regulation of LITAF in gliomas. Data from The Cancer Genome Atlas (TCGA) database revealed that LITAF mRNA expression in glioma tissues was higher than that in normal brain tissues, and lower LITAF expression in gliomas showed a good prognosis in patients who received radiotherapy, by Kaplan-Meier analysis. In our collected specimens, however, LITAF showed low expression in glioma tissues compared to that in the normal brain tissue. Proliferation and apoptosis of glioma cells were not affected by knockdown or overexpression of LITAF in glioma U251, U373, and U87 cells, but LITAF was able to enhance the radiosensitivity of glioma cells. Furthermore, we found that LITAF enhanced radiosensitivity via FoxO1 and its specific downstream targets BIM, TRAIL, and FASLG. Taken together, our present results demonstrate that LITAF expression is decreased in glioma tissues and might enhance radiosensitivity of glioma cells via upregulation of the FoxO1 pathway.

Predicting potential therapeutic targets and small molecule drugs for early-stage lung adenocarcinoma.

Lung cancer is a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting the majority, and its main subtype being lung adenocarcinoma (LUAD). Despite substantial advances in LUAD diagnosis and treatment, early diagnostic biomarkers inadequately fulfill clinical requirements. Thus, we conducted bioinformatics analysis to identify potential biomarkers and corresponding therapeutic drugs for early-stage LUAD patients. Here we identified a total of 10 differentially expressed genes (DEGs) with survival significance through the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Subsequently, we identified a promising small molecule drug, Aminopurvalanol A, based on the 10 key genes using the L1000FWD application, which was validated by molecular docking followed by in vivo and in vitro experiments. The results highlighted TOP2A, CDH3, ASPM, CENPF, SLC2A1, and PRC1 as potential detection biomarkers for early LUAD. We confirmed the efficacy and safety of Aminopurvalanol A, providing valuable insights for the clinical management of LUAD.

Case Report: sintilimab-induced Stevens-Johnson Syndrome in a patient with advanced lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have been widely applicated in clinical therapy in recent years. Skin-related adverse reaction is one of the most common adverse events for ICIs. Stevens-Johnson syndrome (SJS) is one of the serious cutaneous reactions threatening the life. Here, we reported a case of 76-year-old male patient with poorly differentiated metastatic lung adenocarcinoma, after 9 weeks exposure of sintilimab (3 doses) combined with paclitaxel liposome after concurrent chemotherapy/radiotherapy, experienced Stevens-Johnson syndrome involving limbs, trunk, lip and the oral mucosa. Biopsy of the skin tissue showed infiltration of CD4 and CD8 positive T lymphocytes. We also found PD-L1 expression in the glands and the basal layer of the skin. This finding is distinct from the previously reported expression of PD-L1 on the surface of epidermal keratinocytes in patients with SJS due to immunotherapy.

Clinical characteristics of primary hepatic angiosarcoma outcomes: a SEER database analysis.

BACKGROUND: Primary hepatic angiosarcoma (PHA) is a rare malignant tumor. We explored the demographic features and prognostic factors of PHA. METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database to extract patients diagnosed with PHA from 1975 to 2016. We used the Kaplan-Meier method and Cox proportional hazards regression to evaluate the risk factors for overall survival (OS) and disease-specific survival (DSS). The nomograms were constructed and validated using the concordance index (C-index) and calibration plots. RESULTS: In total, 366 patients were included in this study. The disease onset was hidden, and most patients already had advanced disease when diagnosed. The prognosis of PHA was very poor, and the overall 6-month, 1-year and 2-year survival rates were 20.3%, 12.8% and 9.3%, respectively. Sex, age and surgery were all predictors of both OS and DSS in multivariate analysis. Women had better survival rates than men, and patients aged <60 years benefited from surgery in the multivariate models. The nomograms presented good accuracy, with C-index values of 0.679 and 0.665 for the OS and DSS prognostic models, respectively. The calibration plots showed good agreement between the nomogram predictions and actual observations. CONCLUSIONS: PHA has a poor prognosis. Regular physical examinations are essential for the elderly. Patients aged <60 years could benefit from surgery. We constructed accurate nomograms to predict survival that can greatly benefit clinicians.

CENPA is one of the potential key genes associated with the proliferation and prognosis of ovarian cancer based on integrated bioinformatics analysis and regulated by MYBL2.

BACKGROUND: Ovarian cancer (OV) is a highly lethal disease, and the fifth leading cause of all cancer-related deaths in women. The study aimed to identify potential key genes associated with the proliferation and prognosis of OV. METHODS: Differentially expressed genes (DEGs) between ovarian cancer and normal tissues were screened by the robust rank aggregation (RRA) method. The expression of CENPA and MYBL2 were examined in SKOV3 and A2780 ovarian cancer cell lines and tumor tissues by qRT-PCR and western blot. Small RNA interference assays, plasmid overexpression assays and EdU assays were used to validate the proliferative effect of the MYBL2-CENPA axis in ovarian cancer cell lines. The ChIP assay was used to verify the direct regulation of MYBL2 on CENPA. RESULTS: 133 up-regulated genes and 158 down-regulated genes were identified, and the up-regulated genes mainly enrichment in cell cycle. The three up-regulated gene with DNA separation (CENPA, CENPF and CEP55) might be tightly correlated with proliferation and prognosis of OV. Knockdown CENPA expression inhibited the proliferation of A2780 and SKOV3 cells After the knockout of MYBL2, the expression of CENPA significantly decreased. MYBL2 directly binds to the promoter region of CENPA. CONCLUSIONS: The MYBL2-CENPA pathway plays an important role in the proliferation of ovarian cancer cells, suggesting that this pathway may be a potential target for the treatment of ovarian cancer.

Stereotactic Body Radiotherapy Is Effective in Modifying the Tumor Genome and Tumor Immune Microenvironment in Non-Small Cell Lung Cancer or Lung Metastatic Carcinoma.

Background and Purpose: To directly reveal the change in genome mutation, RNA transcript of tumor cells, and tumor microenvironment (TME) after stereotactic body radiotherapy (SBRT) in paired human lung tumor specimens. Materials and Methods: Paired tumor samples were collected from 10 patients with non-small cell lung cancer (NSCLC) or lung metastatic carcinoma within a week before and after SBRT. DNA and RNA of tumor tissues was extracted from the paired samples. Whole-exome and RNA sequencing assays were performed by next-generation sequencing. Gene mutation, genomic expression, T-cell receptor (TCR) repertoire, and profiling of tumor-infiltrating immune cells were analyzed through bioinformatics analysis in paired tumor samples. CD8+ T-cell infiltration and PD-L1 expressions were detected by immunostaining in tumor tissues. Results: The diversity of TCR repertoire and PD-L1 expression increased significantly in the TME, and the most enriched term of the gene ontology analysis was the immune response gene after receiving SBRT. SBRT induced neo-mutation of genes in tumor cells but did not increase tumor mutation burden in tumor tissues. TME displayed complex immune cell changes and infiltration and expression of immune-regulating factors such as C-X-C motif chemokine (CXCL) 10, CXCL16, interferons (IFNs), and IFN receptors. CD8+ T-cells in tumor tissues did not improve significantly after SBRT while the infiltrating TH1 and TH2 cells decreased remarkably. Conclusion: SBRT improved the TCR repertoire diversity and PD-L1 expression in the TME and induced neo-mutation of genes in tumor cells but did not increase CD8+ T-cell infiltration and IFN expression in the tumor tissue within a week.

Early variations in lymphocytes and T lymphocyte subsets are associated with radiation pneumonitis in lung cancer patients and experimental mice received thoracic irradiation.

There were no ideal markers to predict the development of radiation pneumonitis (RP). We want to investigate the value of variations of lymphocytes and T lymphocyte subsets in predicting RP after radiotherapy (RT) of lung cancer based on previous clinical findings. A total of 182 lung cancer patients who received RT were retrospectively analyzed. Circulating lymphocytes and T lymphocyte subsets were measured before, during, and after RT. Patients were evaluated from the start of RT to 6 months post-RT. A mice model with acute radiation-induced lung injury was established and circulating lymphocytes were measured weekly until 8 weeks after irradiation. Univariate and multivariate analyses were adopted to identify risk factors of RP. Lymphocyte levels significantly decreased (P < .001) in patients before RP symptoms developed that also was able to be seen in the mice model and the values recovered during remission of symptoms. The decrease in lymphocyte count reflected the severity of RP. Meanwhile, CD4+  T lymphocyte count was significantly lower during the occurrence of symptoms in patients with RP than in those without RP (P < .001), and it improved along with RP recovery. Levels of lymphocytes and CD4+  T lymphocyte subsets proved as independent predictors of RP. Here we showed that lower peripheral blood levels of lymphocytes and CD4+  T lymphocyte were associated with an increased risk of RP, which was validated by this mice model, and thus are associated with differences in radiation-induced lung toxicity among individuals and help identify those who are susceptible to developing RP after RT.

ERRα Regulates OTUB1 Expression to Promote Colorectal Cancer Cell Migration.

Ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) is overexpressed in many cancers and plays an important role in tumor progression and metastasis. However, the molecular mechanisms underlying OTUB1 overexpression are not clear. In this study, we found that estrogen-related receptor alpha (ERRα, also called NR3B1) binds to OTUB1 promoter and regulates its expression in colorectal cancer. Furthermore, ERRα promoted the migration of CRC cells by inducing vimentin expression via OTUB1. Our data show that OTUB1 is a novel target of ERRα and indicate that ERRα-OTUB1 signaling may play a significant role in CRC metastasis.

Intracellular Activation of Complement C3 Leads to PD-L1 Antibody Treatment Resistance by Modulating Tumor-Associated Macrophages.

Complement aids in the construction of an immunosuppressive tumor microenvironment. Tumor cell-derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell-derived C3 in suppressing antitumor immunity. Tumor cell-derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity. Deletion of C3 in tumor cells that had high C3 expression enhanced efficacy of anti-PD-L1 treatment. Collectively, our results suggest tumor cell-derived C3 may be a useful target for cancer immunotherapy and that targeting C3 in tumor cells may enhance antitumor immunity.

Overexpression of centrosomal protein 55 regulates the proliferation of glioma cell and mediates proliferation promoted by EGFRvIII in glioblastoma U251 cells.

The epidermal growth factor receptor (EGFR) is often amplified in glioma, with the most common extracellular domain mutation being EGFR variant III (EGFRvIII). Abnormal EGFRvIII signaling has been shown to be important in driving tumor progression. Centrosomal protein 55 (CEP55), a member of the centrosomal relative proteins family, participates cytokinesis in the cell cycle. It exists in a few normal tissues and various tumor cells. The expression and function of CEP55 in human glioma cells need to investigate. In this study, the expression of CEP55 was detected in 40 cases of glioma tissues and 10 cases of non-tumor brain tissue. The proliferation of glioblastoma U251 cells was analyzed after transfection with EGFRvIII and CEP55 siRNA. We found that the expression of CEP55 was increased significantly in the glioma tissues than in normal brain tissue. The proliferation of U251 cells increased remarkably after transfection with EGFRvIII. Knockdown of CEP55 inhibited proliferation of U251 cells and was able to eliminate the effect of promoting proliferation induced by EGFRvIII in U251 cells. CEP55 played a key role in the proliferation of glioma cells and mediated EGFRvIII-stimulated proliferation in glioma cells. CEP55 might be a novel molecular therapeutic target in patients with gliomas expressing EGFRvIII.

Centromere protein U expression promotes non-small-cell lung cancer cell proliferation through FOXM1 and predicts poor survival.

PURPOSE: Centromere protein U (CENPU) abnormally exhibits high expression in various types of human tumor tissues and participates in tumor progression; however, its expression pattern and biological function in lung cancer have not yet been elucidated. In the present study, we explored the clinical significance and biological function of CENPU in lung cancer. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) data analyses, quantitative real-time PCR (RT-PCR), and Western blotting were performed to quantify CENPU and FOXM1 expression in non-small-cell lung cancer (NSCLC) samples. Survival data were obtained from Kaplan-Meier plotter or PROGgene V2 prognostic database. The function of CENPU in lung cancer cell proliferation was determined using 5-ethynyl-2'-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and cell cycle assays, and the underlying mechanism was determined through bioinformatic analyses and validated by in vitro siRNA or plasmid transfection experiments. RESULTS: CENPU was abnormally overexpressed in NSCLC samples compared with matched paired normal tissues. Higher expression of CENPU predicted worse overall survival (OS) and relapse-free survival (RFS) in NSCLC patients. Knockdown of CENPU expression by siRNA significantly inhibited proliferation and delayed cell cycle progression of lung cancer cells. To figure out the mechanism, bioinformatic analyses were performed and the results showed that the transcription factor, FOXM1, positively correlated with CENPU. Further in vitro experiments indicated that FOXM1 was the possible downstream transcription factor of CENPU as the knockdown of CENPU led to lower expression of FOXM1 and the overexpression of FOXM1 significantly reversed the inhibition of proliferation caused by CENPU knockdown. Furthermore, FOXM1 was highly expressed in NSCLC. The knockdown of FOXM1 also attenuated proliferation and induced G1 arrest in lung cancer cells. CONCLUSION: CENPU was highly expressed in NSCLC tissues, wherein it promoted lung cancer cell proliferation via the transcription factor, FOXM1, which could be a potential target for therapeutic strategies.

Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter.

BACKGROUND: Gliomas are the most common primary tumors in central nervous system. The prognosis of the patients with glioma is poor regardless of the development of therapeutic strategies. Its aggressive behavior mainly depends on the potent ability of proliferation. The transcription factor EGR1 (early growth response 1) is a member of a zinc finger transcription factor family which plays an essential role in cell growth and proliferation. METHODS: EGR1 expression levels in 39 glioma tissues and 10 normal brain tissues were tested by RT-qPCR and Western-blotting. The effects of EGR1 on U251 cells, U251 stem-like cells (GSCs), and U87 cells proliferation were assessed using in vitro and in vivo cell proliferation assays. The specific binding between EGR1 and CCND1 promoter was confirmed by CHIP assay. EGF was used to improve EGR1 expression in this assay. RESULTS: EGR1 expression levels in human gliomas are decreased compared with normal brain tissues, however, the patients with low EGR1 expression level showed significantly enhanced patient survival in all glioma patients. EGR1 silencing inhibited proliferation and induced G1 phase arrest in glioma cells. EGR1 contributed to proliferation by directly raising CCND1. Meanwhile, EGR1 overexpression induced by EGF was able to promote the proliferation of glioma cells. CONCLUSIONS: Our results show that stable knockdown EGR1 would inhibit glioma proliferation. The results suggest EGR1 showing lower expression in cancer tissues compared with normal tissues maybe still play an important role in tumor proliferation.