Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation.

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.

GAS5 suppresses malignancy of human glioma stem cells via a miR-196a-5p/FOXO1 feedback loop.

Glioma stem cells (GSCs) make up highly tumorigenic subpopulations within gliomas, and aberrant expression of GSC genes is a major underlying cause of glioma pathogenesis and treatment failure. The present study characterized the expression and function of long non-coding RNA growth arrest specific 5 (GAS5) in GSCs in order to elucidate the molecular mechanisms by which GAS5 contributes to glioma pathogenesis. We demonstrate that GAS5 suppresses GSC malignancy by binding to miR-196a-5p. miR-196a-5p, an onco-miRNA, stimulates GSC proliferation, migration, and invasion, in addition to reducing levels of apoptosis. miR-196a-5p specifically downregulates the expression of forkhead box protein O1 (FOXO1) by targeting its 3' untranslated region (3'-UTR). FOXO1 upregulates expression of phosphotyrosine interaction domain containing 1 (PID1), thereby inhibiting GSC tumorigenicity and growth. FOXO1 also upregulates migration and invasion inhibitory protein (MIIP), resulting in attenuation of migration and invasion activities. Interestingly, we also show that FOXO1 promotes GAS5 transcription, thus forminga positive feedback loop. These data provide insights into potential new pathways for GSC molecular therapy and suggest that GAS5 may be an efficacious target for glioma treatments.

Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140.

The blood-tumor barrier (BTB) forms a major obstacle in brain tumor therapy by preventing the delivery of sufficient quantities of therapeutic drugs. Long non-coding RNAs (lncRNAs) play important roles in both normal development and diseases including cancer. Here, we elucidated the expression of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and defined its functional role in the regulation of BTB function as well as its possible molecular mechanisms. Our results proved that MALAT1 expression was up-regulated in brain microvessels of human glioma and glioma endothelial cells (GECs) which were obtained by co-culturing endothelial cells with glioma cells. Functionally, knockdown of MALAT1 resulted in an impairment and increased the permeability of BTB as well as decreased the expression of ZO-1, occludin and claudin-5 in GECs. Further, there was reciprocal repression between MALAT1 and miR-140, and miR-140 mediated the effects that MALAT1 knockdown exerted. Mechanistic investigations defined that nuclear factor YA (NFYA), a CCAAT box-binding transcription factor, was a direct and functional downstream target of miR-140, which was involved in the MALAT1 knockdown induced regulation of BTB function. Furthermore, NFYA could up-regulate the promoter activities and bind to the promoters of ZO-1, occludin and claudin-5 in GECs. Taken together, we have demonstrated the fact that knockdown of MALAT1 resulted in the increased permeability of BTB, which might contribute to establishing potential therapeutic strategies for human gliomas.

Gas5 Exerts Tumor-suppressive Functions in Human Glioma Cells by Targeting miR-222.

Aberrant expression of noncoding RNAs in glioma cells, including long noncoding RNAs (lncRNAs) and microRNAs, may participate in the progression of glioma. Encoded by Growth Arrest-Specific 5 (GAS5) gene, lncRNA Gas5 was reported to be a negative regulator for survival and proliferation of several cancers. Here, Gas5 is found to be downregulated in glioma specimens and U87 and U251 glioma cell lines. We showed that the introduction of Gas5 by plasmid transfection increased the expression of tumor suppressor Bcl-2-modifying factor (bmf) and Plexin C1 via directly targeting and reducing the expression of miR-222. Downregulated expression of miR-222 inhibited U87 and U251 cell proliferation and promoted the apoptosis by upregulating bmf. As downstream signaling molecules of bmf, Bcl-2 and Bax were involved in the process. Meanwhile, knockdown of miR-222 attenuated U87 and U251 cell migration and invasion by upregulating Plexin C1, and cofilin was a crucial regulator targeted by Plexin C1. Gas5 combined with the knockdown of miR-222 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. In summary, we show that Gas5 suppresses tumor malignancy by downregulating miR-222, which may serve as a promising therapy for glioma.

Bradykinin increased the permeability of BTB via NOS/NO/ZONAB-mediating down-regulation of claudin-5 and occludin.

After demonstrating bradykinin (BK) could increase the permeability of blood-tumor barrier (BTB) via opening the tight junction (TJ), and that the possible mechanism is unclear, we demonstrated that BK could increase the expressions of eNOS and nNOS and promote ZONAB translocation into nucleus. NOS inhibitors l-NAME and 7-NI could effectively block the effect of BK on increasing BTB permeability, decreasing the expressions of claudin-5 and occludin and promoting the translocation of ZONAB. Overexpression of ZONAB could significantly enhance BK-mediating BTB permeability. Meanwhile, chromatin immunoprecipitation verified ZONAB interacted with the promoter of claudin-5 and occludin respectively. This study indicated NOS/NO/ZONAB pathway might be involved in BK's increasing the permeability of BTB.

Precision targeting in oncology: The future of conjugated drugs.

Coupled drugs, especially antibody-coupled drugs (ADCs), are a hot topic in oncology. As the development of ADCs has progressed, different coupling modes have emerged, inspired by their structural design have emerged. Technological advances have led to interweaving and collision of old and new concepts of coupled drugs, and have even challenged the concepts and techniques of coupled drugs at this stage. For example, antibody-oligonucleotide conjugates are a new class of chimeric biomolecules synthesized by coupling oligonucleotides with monoclonal antibodies through linkers, offering precise targeting and improved pharmacokinetic properties. This study aimed to elucidate the mechanism of action of coupled drugs and their current development status in antitumor therapy to provide better strategies for antitumor therapy.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities.

Oncogenesis and the development of tumors affect metabolism throughout the body. Metabolic reprogramming (also known as metabolic remodeling) is a feature of malignant tumors that is driven by oncogenic changes in the cancer cells themselves as well as by cytokines in the tumor microenvironment. These include endothelial cells, matrix fibroblasts, immune cells, and malignant tumor cells. The heterogeneity of mutant clones is affected by the actions of other cells in the tumor and by metabolites and cytokines in the microenvironment. Metabolism can also influence immune cell phenotype and function. Metabolic reprogramming of cancer cells is the result of a convergence of both internal and external signals. The basal metabolic state is maintained by internal signaling, while external signaling fine-tunes the metabolic process based on metabolite availability and cellular needs. This paper reviews the metabolic characteristics of gastric cancer, focusing on the intrinsic and extrinsic mechanisms that drive cancer metabolism in the tumor microenvironment, and interactions between tumor cell metabolic changes and microenvironment metabolic changes. This information will be helpful for the individualized metabolic treatment of gastric cancers.

Breaking the mold: Overcoming resistance to immune checkpoint inhibitors.

Immune checkpoint blockade-based therapies are effective against a sorts of cancers. However, drug resistance is a problem that cannot be ignored. This review intends to elucidate the mechanisms underlying drug tolerance induced by PD-1/PD-L1 inhibitors, as well as to outline proposed mechanism-based combination therapies and small molecule drugs that target intrinsic immunity and immune checkpoints. According to the differences of patients and types of cancer, the optimization of individualized combination therapy will help to enhance PD-1/PD-L1-mediated immunoregulation, reduce chemotherapy resistance, and provide new ideas for chemotherapy-resistant cancer.

Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities.

Breast cancer is the leading cause of cancer-related deaths in females worldwide, and the liver is one of the most common sites of distant metastases in breast cancer patients. Patients with breast cancer liver metastases face limited treatment options, and drug resistance is highly prevalent, leading to a poor prognosis and a short survival. Liver metastases respond extremely poorly to immunotherapy and have shown resistance to treatments such as chemotherapy and targeted therapies. Therefore, to develop and to optimize treatment strategies as well as to explore potential therapeutic approaches, it is crucial to understand the mechanisms of drug resistance in breast cancer liver metastases patients. In this review, we summarize recent advances in the research of drug resistance mechanisms in breast cancer liver metastases and discuss their therapeutic potential for improving patient prognoses and outcomes.

The role and application of vesicles in triple-negative breast cancer: Opportunities and challenges.

Extracellular vesicles (EVs) carry DNA, RNA, protein, and other substances involved in intercellular crosstalk and can be used for the targeted delivery of drugs. Triple-negative breast cancer (TNBC) is rich in recurrent and metastatic disease and lacks therapeutic targets. Studies have proved the role of EVs in the different stages of the genesis and development of TNBC. Cancer cells actively secrete various biomolecules, which play a significant part establishing the tumor microenvironment via EVs. In this article, we describe the roles of EVs in the tumor immune microenvironment, metabolic microenvironment, and vascular remodeling, and summarize the application of EVs for objective delivery of chemotherapeutic drugs, immune antigens, and cancer vaccine adjuvants. EVs-based therapy may represent the next-generation tool for targeted drug delivery for the cure of a variety of diseases lacking effective drug treatment.

Chemotherapy- and Immune-Related Gene Panel in Prognosis Prediction and Immune Microenvironment of SCLC.

Small-cell lung cancer (SCLC) is a highly proliferative, invasive lung cancer with poor prognosis. Chemotherapy is still the standard first-line treatment for SCLC, but many patients relapse due to chemoresistance. Along with advances in immunology, it is essential to investigate potential indicators of the immune response and the prognosis of SCLC. Using bioinformatics analysis, we identified 313 differentially expressed genes (DEGs) in SCLC and normal lung samples, and we found that four upregulated genes (TOP2A, CDKN2A, BIRC5, and MSH2) were associated with platinum resistance, while immune-related genes (HLA family genes) were downregulated in SCLC. Then, a prognostic prediction model was constructed for SCLC based on those genes. Immune cell infiltration analysis showed that antigen presentation was weak in SCLC, and TOP2A expression was negatively correlated with CD8+ T cells, while HLA-ABC expression was positively correlated with M1 macrophages, memory B cells, and CD8+ T cells. We also found that TOP2A was related to poor prognosis and inversely correlated with HLA-ABC, which was verified with immunohistochemical staining in 151 SCLC specimens. Our study findings indicated that TOP2A may be a potential prognosis indicator and a target to reverse the immunosuppressive tumor microenvironment of SCLC.

Research Progress on Circular RNA in Glioma.

The discovery of circular RNA (circRNA) greatly complements the traditional gene expression theory. CircRNA is a class of non-coding RNA with a stable cyclic structure. They are highly expressed, spatiotemporal-specific and conservative across species. Importantly, circRNA participates in the occurrence of many kinds of tumors and regulates the tumor development. Glioma is featured by limited therapy and grim prognosis. Cancer-associated circRNA compromises original function or creates new effects in glioma, thus contributing to oncogenesis. Therefore, this article reviews the biogenesis, metabolism, functions and properties of circRNA as a novel potential biomarker for gliomas. We elaborate the expression characteristics, interaction between circRNA and other molecules, aiming to identify new targets for early diagnosis and treatment of gliomas.

circATP2B1 Promotes Aerobic Glycolysis in Gastric Cancer Cells Through Regulation of the miR-326 Gene Cluster.

The discovery of circular RNA (circRNA) enormously complimented the repertoire of traditional gene expression theory. As a type of endogenous noncoding RNA, circRNA participates in the occurrence of many kinds of tumors in addition to regulating their development. The Warburg effect (aerobic glycolysis is taken with priority for cancer cells instead of oxidative phosphorylation) is one of the most important factors involved in the excessive proliferation of gastric cancer cells. Our data showed that circRNA circATP2B1 (also called hsa_circ_000826) was overexpressed in gastric cancer tissues instead of linear ATP2B1 mRNA, and it promoted aerobic glycolysis in gastric cancer cells. Bioinformatic Gene Ontology analysis showed that the potential downstream targets of circATP2B1 include the microRNA miR-326 gene cluster (miR-326-3p/miR-330-5p), which is functionally focused on cell growth and metabolic processes. The expressions of miR-326-3p/miR-330-5p were downregulated in gastric cancer, and circATP2B1 functionally targeted miR-326-3p/miR-330-5p in an RNA-induced silencing complex (RISC) dependent manner. Dual-luciferase reporter assays demonstrated that pyruvate kinase M2 (PKM2) was one of the targets of miR-326-3p/miR-330-5p. As a rate-limiting enzyme in the aerobic glycolytic pathway, PKM2 accelerated gastric cancer cells' glucose uptake and increased cell viability. Taken together, circATP2B1 captured miR-326-3p/miR-330-5p and decreased the suppression of PKM2 by miR-326-3p/miR-330-5p, thus aiding the aerobic glycolysis and proliferation of gastric cancer cells. This study identified a novel molecular pathway in gastric cancer that may provide more targets for reversing cancer metabolic reprogramming, as well as a potential strategy for targeted therapy of gastric cancer.

Identification of Aberrantly Expressed Genes in Murine Glioblastoma During Radiotherapy via Bioinformatic Data Mining.

OBJECTIVE: Glioblastoma (GBM) is an aggressive tumor with a fast growth rate. Radioresistance of GBM can lead to high recurrence. In general, due to the protection of the blood-brain barrier, the immune environment of the central nervous system is unique. The immune response induced by radiotherapy is weak in GBM. In the present study, aberrantly expressed genes during radiotherapy were assessed in murine models based on microarray RNA data. METHODS: The microarray data were extracted from the Intergovernmental Group on Earth Observations and differentially expressed genes (DEGs) screened out. Gene expression profiles of 115 samples in GSE56113 were analyzed and 104 genes were identified as aberrantly expressed based on GEO2R 8 d after radiotherapy. Then, the Database for Annotation, Visualization, and Integrated Discovery was used to analyze Genome Kyoto Encyclopedia of Gene pathways and Gene Ontology (GO) terms. The 20 core candidate genes were identified using protein-protein interaction network analysis and Cytoscape software with Molecular Complex Detection plug-in. RESULTS: Post-irradiated tumor tissues expressed significantly more immune-associated genes than contralateral brain tissues. GO and pathway analyses showed core DEGs were mainly enriched in the chemokine signaling and IL-6 signaling pathways, which could lead to immunosuppressive inflammatory monocyte infiltration and radioresistance. Chemokine signaling and IL-6 signaling pathway-associated genes were increased in the irradiated U87 cell strain. CONCLUSION: Chemokine signaling and IL-6 signaling pathways were activated after radiation in murine glioma and human glioma cell lines which could lead to changes in the immune microenvironment and treatment failure. The results of the present study could provide potential therapeutic targets especially when immune therapy and radiotherapy are combined to treat GBM patients.

Effects of lifestyle and diet on bone health in young adult Chinese women living in Hong Kong and Beijing.

BACKGROUND: Dietary and lifestyle variations may be too small to detect possible associations with bone mineral density (BMD) within a community. Pooled data from communities with different diets and lifestyle but of the same ethnicity may help explore these associations. OBJECTIVE: To examine the effects of dietary and lifestyle factors on BMD in young Chinese women. METHODS: Baseline data were analyzed from 441 women aged 20 to 35 years in Hong Kong and Beijing who were participating in a longitudinal study evaluating the effect of milk supplementation on bone health. Data on demographic characteristics, lifestyle, use of oral contraceptives, diet, physical activity, and BMD of total hip, femoral neck, and total spine measured by dual-energy x-ray absorptiometry were pooled for analysis. RESULTS: Hong Kong subjects had significantly lower BMD and higher body-size-adjusted dietary intakes of protein, fat, fiber, vitamins, potassium, sodium, and selenium than Beijing subjects. Multivariate regression of pooled data showed that body mass index was the most important determinant of BMD at all sites. Age was negatively associated and use of oral contraceptives was positively associated with femoral neck BMD. Carbohydrate intake was positively associated with total hip BMD. Fiber intake was negatively associated with BMD at total hip and total spine. Increased vitamin E intake was associated with greater total spine BMD. None of the nutrients were associated with BMD at the femoral neck. CONCLUSIONS: Diet, lifestyle, and BMD differed greatly between young women from Hong Kong and Beijing. Body mass index was the most important determinant of BMD in young Chinese women, whereas age, use of oral contraceptives, and diet had less pronounced effects.

Milk supplementation and bone health in young adult chinese women.

BACKGROUND: Milk is potentially beneficial for bone health, particularly for Chinese populations where consumption of dairy products is low. There are few data about milk consumption by Chinese women aged 20-35 years. This study examines whether milk supplement over 2 years caused increased bone mineral density (BMD) in Chinese women aged 20-35 years. METHODS: Four hundred forty-one community-living women living in Hong Kong SAR (221) and Beijing (220) China were randomized to receive milk supplement or nothing. The supplement consisted of two sachets of milk powder (1000 mg calcium, 80 microg vitamin K(1)), for 24 months. BMD at total hip, total spine, and whole body was measured at baseline and at 6, 12, 18, and 24 months; blood specimens were analyzed at baseline and at 3 and 24 months for biochemical indices of bone turnover and vitamin K. Urine samples also were collected. Analysis was by intention to treat as well as per protocol. Differences in change from baseline between the milk and control groups were analyzed using the mixed models approach to repeated measures, including the baseline value as a covariate. RESULTS: Both groups had an increase in BMD and a decrease in bone turnover markers over time, as an indicator of the process of attainment of peak bone mass during this period. Apart from a higher total spine BMD at 6 months in the milk group using per protocol analysis, there was little significant difference observed between the milk group and the control group. CONCLUSIONS: Age-related bone metabolism and lack of compliance most likely explain the lack of consistent changes in BMD or bone biochemical measures in response to milk supplementation for 2 years in Chinese women aged 20-35 years.

Hypoxia Promotes Gastric Cancer Malignancy Partly through the HIF-1α Dependent Transcriptional Activation of the Long Non-coding RNA GAPLINC.

Hypoxia-inducible factor (HIF) activates the transcription of genes involved in cancer progression. Recently, HIF was reported to regulate the transcription of non-coding RNAs. Here, we show that the transcription of a long non-coding RNA (lncRNA), Gastric Adenocarcinoma Associated, Positive CD44 Regulator, Long Intergenic Non-Coding RNA (GAPLINC), is directly activated by HIF-1α in gastric cancer (GC). GAPLINC was overexpressed in GC tissues and promoted tumor migration and invasive behavior. GAPLINC overexpression was associated with poor prognosis in GC patients. Luciferase reporter assays and chromatin immunoprecipitation assays confirmed that HIF-1α binds to the promoter region of GAPLINC and activates its transcription. GAPLINC knockdown inhibited hypoxia-induced tumor proliferation in vivo. Taken together, our results identified a novel role for HIF transcriptional pathways in GC tumorigenesis mediated by the regulation of the lncRNA GAPLINC, and suggest GAPLINC as a novel therapeutic target for reversing chemoradioresistance and prolonging survival.

Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis.

The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV) side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR) of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49-2.78), letrozole and anastrozole was 1.80 (95% CI =0.40-3.92), and letrozole and exemestane was 1.46 (95% CI =0.34-3.4). OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence.