IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis due to the lack of therapeutic targets. Although immunotherapy brings survival benefits to patients diagnosed with TNBC, it remains limited and treatment resistance is widespread. Here we demonstrate that IFI35 is highly expressed in tumor tissues and can be induced by Interferon-γ in a time-dependent and concentration-dependent manner in breast cancer cells. In xenograft models, we reveal that IFI35 dramatically increases myeloid-derived suppressor cells infiltration in tumors, along with depletion and anergy of CD8+T cells. IFI35 ablation leads to prolonged survival of the mice. Mechanistically, RNA-sequencing reveals that IFI35 promotes CCL2 secretion, resulting in the remodeling of TNBC immune microenvironment. Ablation of IFI35 promotes the infiltration of effector CD8+T cells, and thereby sensitizes TNBC to anti-PD-1 immunotherapy. Our data suggest that IFI35 limits antitumor immunity and may be expected to become a new immunotherapy target in TNBC.

Single-cell RNA sequencing reveals cellular and molecular reprograming landscape of gliomas and lung cancer brain metastases.

BACKGROUND: Brain malignancies encompass gliomas and brain metastases originating from extracranial tumours including lung cancer. Approximately 50% of patients with lung adenocarcinoma (LUAD) will eventually develop brain metastases. However, the specific characteristics of gliomas and lung-to-brain metastases (LC) are largely unknown. METHODS: We applied single-cell RNA sequencing to profile immune and nonimmune cells in 4 glioma and 10 LC samples. RESULTS: Our analysis revealed that tumour microenvironment (TME) cells are present in heterogeneous subpopulations. LC reprogramed cells into immune suppressed state, including microglia, macrophages, endothelial cells, and CD8+ T cells, with unique cell proportions and gene signatures. Particularly, we identified that a subset of macrophages was associated with poor prognosis. ROS (reactive oxygen species)-producing neutrophils was found to participant in angiogenesis. Furthermore, endothelial cells participated in active communication with fibroblasts. Metastatic epithelial cells exhibited high heterogeneity in chromosomal instability (CIN) and cell population. CONCLUSIONS: Our findings provide a comprehensive understanding of the heterogenicity of the tumor microenvironment and tumour cells and it will be crucial for successful immunotherapy development for brain metastasis of lung cancer.

Mapping the Tumor Microenvironment in TNBC and Deep Exploration for M1 Macrophages-Associated Prognostic Genes.

Triple negative breast cancer (TNBC) remains the worst molecular subtype due to high heterogeneity and lack of effective therapeutic targets. Here we investigated the tumor and immune microenvironment heterogeneity of TNBC using scRNA-seq and bulk RNA-seq data from public databases and our cohort. Macrophage subpopulations accounted for a high proportion of tumor immune microenvironment (TIME), and M1 macrophages were associated with better clinical outcomes. Furthermore, three maker genes including IFI35, PSMB9, and SAMD9L showed a close connection with M1 macrophages. Specifically, IFI35 was positively associated with macrophage activation, chemotaxis, and migration. Also, patients with high IFI35 expression had a better prognosis. In vitro studies subsequently demonstrated that IFI35 was upregulated during the M1 subtype differentiation of macrophages. In summary, our data suggested that IFI35 maybe a promising novel target that helps to reshape macrophage polarization towards the M1 subtype for anti-tumor effects.

HTR1A Inhibits the Progression of Triple-Negative Breast Cancer via TGF-ß Canonical and Noncanonical Pathways.

Triple-negative breast cancer is the most aggressive subtype of breast cancer and the incidence of depression in breast cancer patients is high, which leading to worse survival and increased risk of recurrence. The effect of antidepressants on breast cancer patients remains contradictory, which might be due to variations in antidepression targets. Therefore, there is significant value to explore the antitumor potential of antidepressants and discover new therapeutic targets for breast patients. The authors screen antidepressant-related oncogenes or suppressors by using siRNAs. After combining functional experiments with online database analysis, 5-hydroxytryptamine receptor 1A (HTR1A is selected with antitumor potential in breast cancer cells in vivo and in vitro. RNA-seq analysis and coimmunoprecipitation assays indicate that HTR1A interacts with TRIM21 and PSMD7 to inhibit the degradation of TßRII through the ubiquitin-proteasome pathway, thereby inhibiting the transforming growth factor-ß (TGF-ß) canonical and noncanonical pathway. In addition, HTR1A is an independent predictive factor for breast cancer patients. The combined treatment of HTR1A agonists with demethylation drugs may significantly improve patient survival. It is of great significance to clarify the function and mechanism of the depression-related gene HTR1A in breast cancer, which might provide a new approach for triple-negative breast cancer patients.

Identification of a Three-RNA Binding Proteins (RBPs) Signature Predicting Prognosis for Breast Cancer.

BACKGROUND: To date, breast cancer remains the primary cause of tumor-related death among women, even though some leap-type developments of oncology have been done to slash the mortality. Considering the tumor heterogeneity and individual variation, the more reliable biomarkers are required to be identified for supporting the development of precision medicine in breast cancer. METHODS: Based on the TCGA-BRCA and METABRIC databases, the differently expressed RNA binding proteins (RBPs) between tumor and normal tissues were investigated. In this study, we focused on the communal differently expressed RBPs in four subtypes of breast cancer. Lasso-penalized Cox analysis, Stepwise-multivariate Cox analysis and Kaplan-Meier survival curve were performed to identify the hub RBP-coding genes in predicting prognosis of breast cancer, and a prognostic model was established. The efficiency of this model was further validated in other independent GSE20685, GSE4922 and FUSCC-TNBC cohorts by calculating the risk score and performing survival analysis, ROC and nomogram. Moreover, pathologic functions of the candidate RBPs in breast cancer were explored using some routine experiments in vitro, and the potential compounds targeting these RBPs were predicted by reviewing the Comparative Toxicogenomics Database. RESULTS: Here, we identified 62 RBPs which were differently expressed between the tumor and normal tissues. Thereinto, three RBPs (MRPL12, MRPL13 and POP1) acted as independent risk factors, and their expression pattern also correlated with poor prognosis of patients. A prognostic model, built with these 3-RBPs, possessed statistical significance to predict the survival probability of patients with breast cancer. Furthermore, experimental validations showed that down-regulating the expression of endogenous MRPL12, MRPL13 or POP1 could dramatically suppress the cellular viability and migration of breast cancer cells in vitro. Besides, some compounds (such as the Acetaminophen, Urethane and Tunicamycin) were predicted for curing breast cancer via targeting MRPL12, MRPL13 and POP1 simultaneously. CONCLUSION: This study identified and established a 3-RBPs-based signature and nomogram for predicting the survival probability of patients with breast cancer. MRPL12, MRPL13 and POP1 might act as oncogenes in maintaining cellular viability and accelerating metastasis of breast cancer cells, implying the possibility of which to be designed as biomarkers and/or therapeutic targets for breast cancer.

Clinical Significance of ZNF711 in Human Breast Cancer.

PURPOSE: To investigate the clinicopathologic and prognostic significance of the zinc-finger protein 711 (ZNF711) in breast cancer (BCa). MATERIALS AND METHODS: The relevance of ZNF711 in BCa was analyzed using bioinformatics. The expression of ZNF711 was detected by immunohistochemistry in paraffin blocks of BCa. To evaluate its clinical significance, the correlation between the expression of ZNF711 and BCa clinical indicators, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2), was analyzed. Finally, the Kaplan-Meier method was applied to explore the prognostic value of ZNF711. RESULTS: ZNF711 expression was decreased in BCa and was negatively correlated with ER expression (P < 0.05) and positively correlated with HER-2 expression (P < 0.01), but there was no significant correlation between ZNF711 and PR expression. ZNF711 expression was not correlated with age, tumor diameter, or lymph node metastasis; however, ZNF711 expression was correlated with staging in BCa. Survival analysis results showed that the ZNF711-positive group patients had a poorer prognosis compared with the ZNF711-negative group. CONCLUSION: The expression of ZNF711 was deceased in BCa and closely related to ER and HER-2 expression. Therefore, ZNF711 could not only serve as a predictor of BCa with poor prognosis but also as a potential biomarker for targeted therapy.

Clinicopathological significance of TM4SF5 expression in human hepatocellular carcinoma tissues.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Recent studies have indicated that transmembrane 4 L six family member 5 (TM4SF5) serves a vital role in tumor progression and metastasis in human cell lines and mouse models. However, little is known about the association between TM4SF5 expression and clinicopathological factors. The aim of the current study was to investigate this association and evaluate overall survival (OS) of patients. Immunohistochemistry and clinical record analysis revealed that TM4SF5 expression was significantly downregulated in HCC tissues. In addition, TM4SF5 expression was significantly associated with tumor size, vascular invasion, tumor differentiation, and tumor-node-metastasis stage. The survival analysis also demonstrated that low TM4SF5 expression resulted in shorter OS. In conclusion, the association between TM4SF5 expression and clinicopathologic factors was established, and prognostic significance of TM4SF5 as a potential biomarker was evaluated using human HCC formalin-fixed paraffin-embedded tissue samples. The results of the present study demonstrated that low TM4SF5 expression was associated with tumor malignant progression and may be a good prognostic biomarker for OS in HCC.

Prognostic genes of hepatocellular carcinoma based on gene coexpression network analysis.

Hepatocellular carcinoma (HCC) is the most common subtype in liver cancer whose prognosis is affected by malignant progression associated with complex gene interactions. However, there is currently no available biomarkers associated with HCC progression in clinical application. In our study, RNA sequencing expression data of 50 normal samples and 374 tumor samples was analyzed and 9225 differentially expressed genes were screened. Weighted gene coexpression network analysis was then conducted and the blue module we were interested was identified by calculating the correlations between 17 gene modules and clinical features. In the blue module, the calculation of topological overlap was applied to select the top 30 genes and these 30 genes were divided into the green group (11 genes) and the yellow group (19 genes) through searching whether these genes were validated by in vitro or in vivo experiments. The genes in the green group which had never been validated by any experiments were recognized as hub genes. These hub genes were subsequently validated by a new data set GSE76427 and KM Plotter Online Tool, and the results indicated that 10 genes (FBXO43, ARHGEF39, MXD3, VIPR1, DNASE1L3, PHLDA1, CSRNP1, ADR2B, C1RL, and CDC37L1) could act as prognosis and progression biomarkers of HCC. In summary, 10 genes who have never been mentioned in HCC were identified to be associated with malignant progression and prognosis of patients. These findings may contribute to the improvement of the therapeutic decision, risk stratification, and prognosis prediction for HCC patients.

A novel SWIM domain protein ZSWIM5 inhibits the malignant progression of non-small-cell lung cancer.

PURPOSE: Zinc finger SWIM-type containing 5 (ZSWIM5) is a newly discovered protein, which contains a novel zinc-chelating domain SWIM (CxCxnCxH), and is predicted to interact with DNA or proteins. Currently, the knowledge of functions of ZSWIM5 remains limited. In this study, we aimed to elucidate the biological functions of ZSWIM5 and their mechanisms. PATIENTS AND METHODS: We detected the expression of ZSWIM5 in samples from 139 cases of non-small-cell lung cancer (NSCLC) patients and six cell lines using immunohistochemistry and Western blot. Moreover, we explored the biological functions of ZSWIM5 in lung cancer cells by siRNA interference and cDNA transfection of ZSWIM5. RESULTS: The results showed that compared with adjacent non-tumor lung tissues, ZSWIM5 expression was significantly decreased in NSCLC tissues (P=0.0199) and that the ZSWIM5-positive rate in non-tumor tissues (76.67%) was notably higher than that in NSCLC tissues (40.29%). ZSWIM5 expression in human normal bronchial epithelial cells was also much higher than that in lung cancer lines (P<0.001). ZSWIM5-negative expression was significantly related to TNM stage (P<0.001), lymph node metastasis (P=0.002), and poor prognosis (P<0.001) of NSCLC patients. MTT and colony formation assays showed that ZSWIM5 could inhibit the proliferation and colony formation abilities of lung cancer cells. Meanwhile, the results of transwell and wound healing assays showed that ZSWIM5 could suppress the invasion and migration of lung cancer cells. Further investigation revealed that ZSWIM5 could downregulate cyclin D1, cyclin E, cyclin A2, MMP2, and MMP9 expression, which affected the proliferation, invasion, and migration abilities of lung cancer cells. CONCLUSION: ZSWIM5 could inhibit the malignant progression of NSCLC by affecting the expression of cyclins and MMPs.

Transcriptomic analysis reveals the underlying pro-malignant functions of Gankyrin for colorectal cancer via affecting tumor necrosis factor pathway.

BACKGROUND: Recently increasing evidence had indicated Gankyrin play an important role for the development and progression of colorectal cancer (CRC). However, its function mechanisms remain unclear. The goal of this study was to further illuminate the roles of Gankyrin in CRC using microarray data. METHODS: The microarray data of CRC was extracted from the Gene Expression Omnibus (GEO) database under the accession number GSE44029. Differentially expressed genes (DEGs) were identified using the LIMMA method, and then protein-protein interaction (PPI) network was constructed to screen crucial genes associated with Gankyrin. GO and KEGG pathway enrichment analysis were performed to investigate the underlying functions of DEGs using DAVID tool. RESULTS: A total of 712 genes were identified as DEGs, including 15 upregulated genes and 697 downregulated genes. Go enrichment analysis indicated that Gankyrin was involved in tumor necrosis factor-mediated signaling pathway. A PPI network including 586 nodes and 654 edges was constructed, in which BIRC3 and PSMB9 were demonstrated to be the hub genes associated with Gankyrin. CONCLUSION: Our present study preliminarily revealed that the pro-malignant effects of Gankyrin in CRC cells may be mediated by affecting TNF signaling pathway via changing the expression of the crucial enriched genes (BIRC3 and PSMB9).

Nonfunctional pancreatic neuroendocrine tumor masked as anemia: A case report.

After a series of clinical relevant examinations. The patient was dignosed as pancreatic tomor in the pancreatic tail accompanied with the symptom of anenmia and dizziness.Until now surgery is the best treatment strategy for pancreatic tumors.So we take a joint multiple organ removal surgery.Before surgery, the main concerns of patient is whether the operation can relieve the anemia-related symptoms and improve the quality of life.The patient was dignosed as nonfunctional pancreatic neuroendocrine tumor.A joint multiple organ removal surgery including pancreaticbody and tail, spleen, part of the stomach wall, left adrenal gland,and portal splenic vein thrombosis and lymphadenectomy were performed on this patient.After surgery, the concentration of hemoglobin gradually increased and remained stable (88 g/L) on the postoperative day7. Furthermore, complete resolution of the symptom of anemia was achieved on postoperative day 30. There was no recurrence of the tumor or the symptom of anemia during the 3-month follow-up.We conclude that NF-PNETs can manifest as anemia at the time of diagnosis, and if the tumor is resectable, surgical resection is a safe and curative form of therapy not only for the anemia but also for the original tumor.