Gastric cancer is a deadly disease and remains the third leading cause of cancer-related death worldwide. The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%, whereas that of patients with distant metastasis is less than 5%. Surgical resection is the best option for early-stage gastric cancer, while chemotherapy is mainly used in the middle and advanced stages of this disease, despite the frequently reported treatment failure due to chemotherapy resistance. Therefore, there is an unmet medical need for identifying new biomarkers for the early diagnosis and proper management of patients, to achieve the best response to treatment. Long non-coding RNAs (lncRNAs) in body fluids have attracted widespread attention as biomarkers for early screening, diagnosis, treatment, prognosis, and responses to drugs due to the high specificity and sensitivity. In the present review, we focus on the clinical potential of lncRNAs as biomarkers in liquid biopsies in the diagnosis and prognosis of gastric cancer. We also comprehensively discuss the roles of lncRNAs and their molecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastric cancer precision medicine.
BackgroundResistance to trastuzumab has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Cell behavior can be modulated by long non-coding RNAs (lncRNAs), but the contribution of lncRNAs in trastuzumab resistance to breast cancer is largely unknown. To this end, the involvement and regulatory function of lncRNA AGAP2-AS1 in human breast cancer are yet to be investigated.MethodsTrastuzumab-resistant SKBR-3 and BT474 cells were obtained by continuous culture with 5 mg/mL trastuzumab for 6 months. RT-qPCR assay was used to determine the expression of AGAP2-AS1 in tissues and cells. RNA fluorescence in situ hybridization was used to investigate the subcellular location of AGAP2-AS1 in breast cancer cells. Bioinformatic analysis, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), western blotting, and immunofluorescence were carried out to verify the regulatory interaction of AGAP2-AS1, CREB-binding protein (CBP), and MyD88. In addition, a series of in vitro assays and a xenograft tumor model were used to analyze the functions of AGAP2-AS1 in breast cancer cells.ResultsAGAP2-AS1 was upregulated and transcriptionally induced by SP1 in breast cancer. Overexpression of AGAP2-AS1 promoted cell growth, suppressed apoptosis, and caused trastuzumab resistance, whereas knockdown of AGAP2-AS1 showed an opposite effect. MyD88 was identified as a downstream target of AGAP2-AS1 and mediated the AGAP2-AS1-induced oncogenic effects. Mechanistically, the RIP assay revealed that AGAP2-AS1 could bind to CBP, a transcriptional co-activator. ChIP assays showed that AGAP2-AS1-bound CBP increased the enrichment of H3K27ac at the promoter region of MyD88, thus resulting in the upregulation of MyD88. Gain- and loss-of-function assays confirmed that the NF-κB pathway was activated by MyD88 and AGAP2-AS1. Furthermore, high AGAP2-AS1 expression was associated with poor clinical response to trastuzumab therapy in breast cancer patients.ConclusionAGAP2-AS1 could promote breast cancer growth and trastuzumab resistance by activating the NF-κB signaling pathway and upregulating MyD88 expression. Therefore, AGAP2-AS1 may serve as a novel biomarker for prognosis and act as a therapeutic target for the trastuzumab treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0875-3) contains supplementary material, which is available to authorized users.
Currently, resistance to trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor, has become one major obstacle for improving the clinical outcome of patients with advanced HER2+ breast cancer. While cell behaviour can be modulated by long non‐coding RNAs (lncRNAs), the contributions of lncRNAs in progression and trastuzumab resistance of breast cancer are largely unknown. To this end, the involvement and regulatory functions of lncRNA SNHG14 in human breast cancer were investigated. RT‐qPCR assay showed that SNHG14 was up‐regulated in breast cancer tissues and associated with trastuzumab response. Gain‐ and loss‐of‐function experiments revealed that overexpression of SNHG14 promotes cell proliferation, invasion and trastuzumab resistance, whereas knockdown of SNHG14 showed an opposite effect. PABPC1 gene was identified as a downstream target of SNHG14, and PABPC1 mediates the SNHG14‐induced oncogenic effects. More importantly, ChIP assays demonstrated that lncRNA SNHG14 may induce PABPC1 expression through modulating H3K27 acetylation in the promoter of PABPC1 gene, thus resulting in the activation of Nrf2 signalling pathway. These data suggest that lncRNA SNHG14 promotes breast cancer tumorigenesis and trastuzumab resistance through regulating PABPC1 expression through H3K27 acetylation. Therefore, SNHG14 may serve as a novel diagnostic and therapeutic target for breast cancer patients.
The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.
The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.
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