Identification of shared immune infiltration characteristic molecules in dermatomyositis and nasopharyngeal carcinoma using bioinformatics: Traits in dermatomyositis and nasopharyngeal cancer.

BACKGROUND: Dermatomyositis (DM) is a kind of dermatologically associated autoimmune disease that is notably associated with an increased risk of concurrent malignancies, although the underlying mechanisms remain to be fully elucidated. The purpose of this investigation was to examine the immunological parallels between DM and nasopharyngeal carcinoma (NPC), with the aim of identifying pivotal biomarkers that could facilitate a deeper understanding and enhance the predictive capabilities of NPC in DM patients. METHOD: Data for DM and NPC were sourced from the Gene Expression Omnibus (GEO) database. Immune infiltration was analyzed using the "cibersort" R package, differentially expressed genes (DEGs) were identified with the "limma" package, and functional pathways were investigated through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Characteristic genes were determined by Utilizing Protein-Protein Interaction (PPI) and Least Absolute Shrinkage and Selection Operator (LASSO), and their features were validated using the GSE53819 dataset. RESULTS: In comparison to normal samples, significant infiltration of macrophage M1 was observed in both DM and NPC. The analysis revealed 77 DEGs in DM and 1051 DEGs in NPC, with 22 genes found to be co-DEGs. Following PPI and LASSO analysis, six distinctive genes were retained. Notably, CCL8, IFIH1, CXCL10, and CXCL11 exhibited optimal diagnostic efficacy for NPC and displayed significant correlation with macrophage M1 infiltration within the carcinoma. CONCLUSION: Four characteristic genes, CCL8, IFIH1, CXCL10, and CXCL11 are risk factors for both DM and NPC. They exhibit a robust correlation with the incidence of NPC and offer a commendable diagnostic efficacy. Furthermore, they may serve as prospective predictive biomarkers for the emergence of NPC in DM.

Targeting TPX2 suppresses proliferation and promotes apoptosis via repression of the PI3k/AKT/P21 signaling pathway and activation of p53 pathway in breast cancer.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein required for mitosis and spindle assembly. Previous studies showed that TPX2 is overexpressed in various human cancers and promotes cancer progression. In this study, the differentially expressed genes including TPX2 were screened in GEO database for gene expression microarray of breast cancer. The TPX2 expression level was significantly increased in breast cancer cells and the breast malignant tissues compared with those controls. In vitro experiment further confirmed that knockdown of TPX2 by small hairpin RNA inhibited breast cancer cell proliferatio, migration, and induced cell apoptosis. TPX2 silencing decreased the expression of PI3K and extent of AKT phosphorylation, as well as increased expression of p53 and p21. Taken together, our findings indicate that TPX2 silencing negatively regulates the PI3K/AKT and activates p53 signaling pathway by which breast cancer cells proliferation were inhibited whereas cellulars apoptosis were accelerated, suggesting that TPX2 may be a potential target for anticancer therapy in breast cancer.

MYSM1 induces apoptosis and sensitizes TNBC cells to cisplatin via RSK3-phospho-BAD pathway.

Breast cancer is one of the leading causes of mortality among women. Triple-negative breast cancer (TNBC) is responsible for a large percentage of all breast cancer deaths in women. This study demonstrated the function of Myb-like, SWIRM, and MPN domains 1 (MYSM1), an H2A deubiquitinase (DUB), in TNBC. MYSM1 expression was drastically decreased in breast cancer, especially in TNBC, suggesting a potential anticancer effect. Overexpressing and suppressing MYSM1 expression in TNBC cell lines led to significant biological changes in cell proliferation. Furthermore, MYSM1 overexpression increased cisplatin-induced apoptosis, which might be attributed to RSK3 inactivation and the subsequently decreased phosphorylation of Bcl-2 antagonist of cell death (BAD) (Ser 112). The findings suggest that MYSM1 is a potential target for regulating cell apoptosis and suppressing resistance to cisplatin in TNBC.

VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway.

Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel-Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.

Clinical Significance of Glucose to Lymphocyte Ratio (GLR) as a Prognostic Marker for Patients With Pancreatic Cancer.

Glucose metabolism and systemic inflammation have been associated with cancer aggressiveness and patient prognosis in various malignancies. This study aimed to evaluate the prognostic significance of pretreatment GLR(glucose to lymphocyte ratio) and systemic immune inflammation in patients with pancreatic cancer. We studied 360 patients with pathologically diagnosed pancreatic adenocarcinoma that was clinically unresectable. Baseline clinicopathological characteristics and laboratory investigations including fasting blood glucose, platelet count, lymphocyte count, neutrophil count, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA199), and follow-up data were collected for further analysis. The patients were randomly divided into a training cohort (n = 238) and a validation cohort (n = 122). Univariate and multivariate Cox proportional hazard regression analyses were performed to identify the prognostic value of GLR, systemic immune-inflammation markers, and tumor biomarkers. A nomogram model was developed based on the identified prognostic factors, and we used the C-index to evaluate the accuracy of the Cox regression model prediction. Multivariate analysis revealed that GLR [hazard ratio (HR): 2.597; 95% confidence interval (CI): 1.728-3.904)] and CA199 (HR: 2.484; 95% CI: 1.295-4.765) are independent predictors of poor overall survival in the training cohort and were incorporated into the nomogram for OS as independent factors. Moreover, the C-index analyses demonstrated that the C-indexes in the training cohort and the validation cohort were 0.674 and 0.671, respectively. The nomogram model predicts overall survival relatively accurately. We found that the baseline GLR is an independent prognostic factor for patients with pancreatic cancer, and the proposed nomogram can be used as an effective tool for predicting the outcomes of prognosis of patients with pancreatic cancer.

Targeting Ku86 enhances X-ray-induced radiotherapy sensitivity in serous ovarian cancer cells.

Drug resistance and recurrence are significant contributors to the poor prognosis of serous ovarian cancer (SOC). Radiotherapy is primarily used for the treatment of cancer recurrence; however, it is rarely applied in cases of SOC. Ku86, also known as XRCC5(X-ray repair cross complementing 5), has rarely been reported in the radiotherapy of SOC. Therefore, this study aimed to investigate the role of Ku86 in the development of SOC and in radiotherapy sensitivity induced by X-ray. In vitro experiments and database analysis showed significantly elevated expression of Ku86 in SOC. Further, after down-regulating Ku86 using RNAi technology, cell proliferation was inhibited. Further, the cell cycle was blocked in the G2 phase, and G2/G1 was increased since X-ray irradiation led to an increase in γ-H2AX. Down-regulation of Ku86 in the case of X-ray irradiation will promote the above biological effects, with more γ-H2AX and higher G2/G1. Here, we further deduce that Ku86 promotes the X-ray induced effect is most likely to activate the ATR pathway to block the cell cycle while inhibiting the NHEJ pathway to inhibit DNA damage response(DDR). Together these findings suggest that the down-regulation of Ku86 can improve X-ray-induced radiotherapy by affecting ATR and NHEJ pathways, and provide a new strategy for the treatment of ovarian cancer.

Identification of the key genes associated with chemotherapy sensitivity in ovarian cancer patients.

BACKGROUND: Ovarian cancer (OC) is the deadliest gynecological cancer. The absence of biomarkers in early detection and chemotherapy resistance is a principal cause of treatment failure in OC. METHODS: In this study, next generation sequencing (NGS) was used to sequence the mRNA of 44 OC patients including 14 chemotherapy insensitive and 18 sensitive patients. Differentially expressed genes (DEGs) from OC patients (compared with healthy controls) and chemotherapy sensitive patients (compared with chemotherapy insensitive patients) were identified by edgeR v3.12.0 in R v3.2.2, which were enriched using Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG). The common DEGs in cancer occurring and chemotherapy sensitivity were further screened. Among them, genes participating in chemotherapy sensitivity associated pathways were regarded as chemotherapy sensitivity-related key genes. Quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) were used to verify the expression of the key genes. RESULTS: We found 1588 DEGs between OC patients and healthy controls (HCs), which were mainly enriched in cell cycle pathway. Meanwhile, 249 DEGs were identified between chemotherapy sensitive and insensitive OC patients, which were mainly enriched in MAPK signaling pathway, ERBB signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. Thirty-five DEGs were shared in chemotherapy sensitivity group and cancer occurring group. Among them, there are five genes (JUND, JUNB, MUC5B, NRG1, and NR4A1) participating in the above four chemotherapy sensitivity-related pathways. It is remarkable that JUND is in the upstream of MUC5B in IL-17 signaling pathway and their expressions were verified by qPCR and IHC. CONCLUSIONS: The expression levels of the key genes related to chemotherapy sensitivity might be used as biomarkers to predict the treatment outcome and as a target to improve prognosis.

Elevated serum HER-2 predicts poor prognosis in breast cancer and is correlated to ADAM10 expression.

Human epidermal growth factor receptor-2 (HER-2) overexpression in breast tumor tissues is associated with a poor prognosis but may benefit from treatment with trastuzumab. The extracellular domain (ECD) of HER-2 can be measured in serum and which has been a new inspection item in clinical laboratory of several hospitals. However, whether serum HER-2 ECD can be a marker of HER-2 status in tumor tissues still confused clinicians. This study is a retrospective observation to explore the correlation between serum HER-2 ECD shedding and tissue HER-2 status in breast cancer patients. Meanwhile, we will further uncover the potential clinical significance of serum HER-2 ECD detection. A total of 545 unselected breast cancer patients from Fudan University Shanghai Cancer Center were enrolled in this study. At primary diagnosis without any treatment, serum HER-2 ECD was measured on ADVIA Centaur assay; meanwhile, tissue HER-2 from core needle biopsy was tested through immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). We showed that serum HER-2 ECD concentration was related to tissue HER-2 status. Nevertheless, 36.9% of patients with tissue HER-2 overexpression had low levels of HER-2 ECD shedding (<15 ng/mL) in serum. Here, we demonstrated that HER-2 ECD shedding was also associated with protein expression and alpha-secretase activity of a disintegrin and metalloproteinase 10 (ADAM10) using tumor tissues and cell lines. Progression-free survival (PFS) data from breast cancer patients in TNM phase II and III with tissue HER-2 IHC 3+ were analyzed using Kaplan-Meier plotter. The patients with serum HER-2 ECD above 15 ng/mL had lower progression-free survival than those with serum HER-2 ECD <15 ng/mL. Thus, serum HER-2 ECD could be a biomarker to identify the subgroup of poorer outcome among HER-2 overexpression breast cancer patients. Inhibition of ADAM10 activity may have potential therapeutic benefit for this most aggressive tumor subgroup.