Abstract Background: The STEAP family is crucial in the control of metal homeostasis. A increasing amount of data suggests the link between epigenetic alterations in the STEAP family and a range of human malignancies. Nevertheless, the STEAP family's significance in gastric cancer is unclear, and there are few relevant research.Bioinformatics analysis was carried out using R software, Kaplan-Meier Plotter, cBioPortal, TIMER, LinkedOmics, STRING, Metascape, and GSCA Lite online tools.The expression of STEAP1/2/3 was dramatically upregulated in numerous tumor tissues, in particular, gastric cancer, but STEAP4 expression was significantly downregulated. Poor treatment results and aggressiveness of cancer are associated with high STEAP1/2/3 expression.Pathway analysis of the STEAP family and its co-expressed genes using Gene Ontology (GO) and Kyodo Encyclopedia of Genes and Genomes (KEGG) revealed that numerous gene terms were related with "iron ion homeostasis," "copper ion transport," "response to iron ion," and "iron ion transport." "response to iron ion," "oxidoreductase activity acting on metal ions," and "ion transport" The pathways are associated with "iron ion homeostasis," "copper ion transport," "react to iron ion," and "oxidoreductase activity involving metal ions."Notably, there was a positive correlation between STEAP 1/2/3 expression levels and oxidative stress genes,such as NOX3 and NOX4. PPI network analysis revealed that STEAP family proteins strongly interacted with TFRC. In addition, STEAP 1/2/3 expression was linked with B-cell, CD8+ T-cell infiltrating immune lymphocytes. Interestingly, Overexpression of STEAP 1/3 was also linked to decreased susceptibility of gastric cancer cells to a number of gastric cancer-targeting or chemotherapeutic drugs, including Docetaxel and Vorinostat. STEAP family members may be prognostic indicators and novel treatment targets for patients with gastric cancer.
The nuclear matrix is very important to maintaining the nuclear structural integrity and specific genomic functions.The nuclear matrix provides structural support for several processes such as DNA replication,transcription,and RNA splicing and transport.Malignant transformation occurs during malignant changes of cells and the process of tumor cells changing from low grade to high grade malignancy.The molecular mechanisms about the morphological and biochemical changes of the cell nucleus during the process of malignant transformation have not been elucidated for many years.Recently,the studies on the aspect have made great progress.In this paper,the relationship between nuclear matrix and tumor virus and its biochemical changes during the process of malignant transformation are reviewed,which may have important biological significances in the research of the molecular mechanisms of malignant transformation.
Abstract Background To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. Methods This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. Results Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of −73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. Conclusions Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. Clinical Trial Registration ChiCTR2100046678.
Caveolae-related genes, including CAVs that encodes caveolins and CAVINs that encodes caveolae-associated proteins cavins, have been identified for playing significant roles in a variety of biological processes including cholesterol transport and signal transduction, but evidences related to tumorigenesis and cancer progression are not abundant to correlate with clinical characteristics and prognosis of patients with cancer. In this study, we investigated the expression of these genes at transcriptional and translational levels in patients with breast cancer using Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal databases, and immunohistochemistry of the patients in our hospital. Prognosis of patients with breast cancer based on the expressions of CAVs and CAVINs was summarized using Kaplan-Meier Plotter with their correlation to different subtyping. The relevant molecular pathways of these genes were further analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and Gene Set Enrichment Analysis (GSEA). Results elucidated that expression levels of CAV1, CAV2, CAVIN1, CAVIN2, and CAVIN3 were significantly lower in breast cancer tissues than in normal samples, while the expression level of CAVIN2 was correlated with advanced tumor stage. Furthermore, investigations on survival of patients with breast cancer indicated outstanding associations between prognosis and CAVIN2 levels, especially for the patients with estrogen receptor positive (ER+) breast cancer. In conclusion, our investigation indicated CAVIN2 is a potential therapeutic target for patients with ER+ breast cancer, which may relate to functions of cancer cell surface receptors and adhesion molecules.
Abstract Gli proteins are transcription factors that mediate Hedgehog (HH) signaling in cells. Previously, we reported that Gli2 binds to the androgen receptor (AR) protein in prostate cancer (PCa) cells and further upregulates expression of genes under AR control. This “co-activator” effect allows the growth of Gli2 overexpressing LNCaP cells in androgen-depleted medium, mimicking the behavior of castrate resistant variants of PCa. We report here our success in localizing the specific binding domains between Gli2 and AR proteins. Outcomes of GST-pulldown and co-immunoprecipitation studies showed that Gli2 binds to AR via a limited domain (aa628-aa897) within the C-terminal region and this recognizes the tau5/AF5 domain (aa 392-558) within the N-terminal region of the AR protein. Because tau5/AF5 is conserved in truncated (splice variant) ARs, we also showed that Gli2 recognizes and co-activates the transcriptional activity of a truncated variant AR (AR-V7). To further define Gli2 regulatory functions on AR transcriptional activity in CRPC, we overexpressed Gli2ΔN (a constitutive-active form of Gli2) in LNCaP-AI (androgen-independent) cells and examined its effects on AR target gene expressions. Surprisingly, we found that Gli2Δ overexpression coincided with significant downregulated expression of genes considered “traditional” AR targets (i.e., KLK3 and KLK2), while increasing the expression of M-phase check-point genes, such as UBE2C, CDK1 and CDC20. In contrast, treatment of unmodified LNCaP-AI cells with the Gli-inhibitor, GANT61, significantly increased expression of KLK2 and KLK3 while downregulating UBE2C, CDC20 and CDK1. Our outcomes now imply that Gli2 differentially affects the AR transcriptional program in androgen-dependent (LNCaP) vs androgen-independent (LNCaP-AI) cells. In androgen-dependent cells, Gli2 co-activates expression of the traditional AR target genes while suppressing expression of genes involved in the CRPC transcriptional program whereas in androgen-independent cells, Gli2 co-activates expression of CRPC program genes while downregulating expression of traditional AR target genes. This dichotomy suggests that Gli2 participates in the decisions through which AR transcriptional activity is redirected in castration resistant disease. Supported by the DOD PCRP (W81XH-10-1-0493, to RB) Citation Format: Na Li, Ralph Buttyan, Sarah Truong, Yue Yu, Mengqian Chen. Gli2 protein and the AR operational switch to the castration resistant prostate cancer transcription program. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5574. doi:10.1158/1538-7445.AM2014-5574
Abstract Background Breast cancer has become the most frequently diagnosed cancer worldwide. Increasing evidence indicated that zinc finger proteins (ZNFs), the largest family of transcription factors, contribute to cancer development and progression. Although ZNF384 is overexpressed in several types of human cancer, the role of ZNF384 in breast cancer remains unknown. Therefore, our research focused on ZNF384 regulation of the malignant phenotype of breast cancer and the underlying molecular mechanisms. Methods CCK-8 and colony formation assays were used to evaluate cell proliferation. Transwell and scratch assays were used to evaluate the cell migration and invasion. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were used to confirm the target relationship between ZNF384 and zinc finger E-box binding homeobox 1 (ZEB1). Xenografts were used to monitor the targets in vivo effects. Results We noted that ZNF384 was significantly overexpressed in breast cancer and highlighted the oncogenic mechanism of ZNF384. ZNF384 transactivated ZEB1 expression and induced an epithelial and mesenchymal-like phenotype, resulting in breast cancer metastasis. Furthermore, ZNF384 may be a target of miR-485-5p, and ZEB1 can up-regulate ZNF384 expression by repressing miR-485-5p expression. Together, we unveiled a feedback loop of ZNF384–ZEB1 in breast cancer metastasis. Conclusions The findings suggest that ZNF384 can serve as a prognostic factor and a therapeutic target for breast cancer patients.
Thyroid cancer (TC) tends to be a common malignancy worldwide and results in various outcomes due to its different subtypes. The tumor microenvironment (TME) was demonstrated to play crucial roles in various malignancies, including thyroid cancer. This study combined the ESTIMATE and CIBERSORT algorithms, identified four TME-related genes, and evaluated their correlation with clinical characteristics. These findings revealed the malignant performance of TME in TC, and the TME-related DEGs might serve as prognostic biomarkers, which can be utilized for the prediction of immunotherapy effects in patients with TC.
SUMMARY PI3K/AKT signaling is known to regulate cancer metabolism but whether metabolic pathway feedbacks and regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal cross-talks between the PI3K/AKT signal and PPP branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of PPP, by inhibiting a newly identified E3 ligase TIRM21, and promotes PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of an AKT inhibitor PHLDA3. Knockout TRIM21 or PHLDA3 promotes the cross-talks and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of these reciprocal cross-talks may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.
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