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The cell ecology and spatial niche implicated in the dynamic and sequential process of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) have not yet been elucidated. Here, we performed an integrative analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to characterize the cell atlas of the invasion trajectory of LUAD. We found that the UBE2C + cancer cell subpopulation constantly increased during the invasive process of LUAD with remarkable elevation in IAC, and its spatial distribution was in the peripheral cancer region of the IAC, representing a more malignant phenotype. Furthermore, analysis of the TME cell type subpopulation showed a constant decrease in mast cells, monocytes, and lymphatic endothelial cells, which were implicated in the whole process of invasive LUAD, accompanied by an increase in NK cells and MALT B cells from AIS to MIA and an increase in Tregs and secretory B cells from MIA to IAC. Notably, for AIS, cancer cells, NK cells, and mast cells were colocalized in the cancer region; however, for IAC, Tregs colocalized with cancer cells. Finally, communication and interaction between cancer cells and TME cell-induced constitutive activation of TGF-β signaling were involved in the invasion of IAC. Therefore, our results reveal the specific cellular information and spatial architecture of cancer cells and TME subpopulations, as well as the cellular interaction between them, which will facilitate the identification and development of precision medicine in the invasive process of LUAD from AIS to IAC.

Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed (‘hot’) tumor, as demonstrated by increased CD8+granzyme B+ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.

Cuproptosis or copper-dependent cell death is a newly identified non-apoptotic cell death pathway which plays a critical role in the development of multiple cancers. Long non-coding RNAs (lncRNAs) are increasingly recognized as crucial regulators of programmed cell death and lung adenocarcinoma (LUAD) development, and a comprehensive understanding of cuproptosis-related lncRNAs may improve prognosis prediction of LUAD. However, few studies have explored the association of cuproptosis-related lncRNAs with the prognosis of LUAD.The RNA sequencing data and corresponding clinical information of patients were extracted from The Cancer Genome Atlas (TCGA) database. Five hundred LUAD patients were randomly divided into a training (n=250) and a testing cohort (n=250). Pearson correlations were performed to identify cuproptosis-related lncRNAs, and univariate Cox regression was performed to screen prognostic lncRNAs. A cuproptosis-related lncRNAs prognostic signature (CLPS) was constructed by the least absolute shrinkage and selection operator Cox regression. Kaplan-Meier analysis, receiver operating characteristic curves, and multivariate Cox regression were performed to verify the prognostic performance of CLPS. Additionally, immune cell infiltration was estimated using the single-sample gene-set enrichment analysis. pRRophetic algorithm and Tumor Immune Dysfunction and Exclusion algorithm were used to assess the immunotherapy and chemotherapy response, respectively.CLPS was established based on 61 cuproptosis-related prognostic lncRNAs and exhibited a satisfactory performance predicting LUAD patients' survival (area under the curve at 1, 3, 5 years was 0.784, 0.749, 0.775, respectively). multivariate Cox analysis confirmed the independent prognostic effect of CLPS (hazard ratio: 1.128; 95% confidence interval: 1.071-1.189; P0.001), and a nomogram containing it exhibited robust validity in prognostic prediction. We further demonstrated a higher CLPS-risk score was associated with lower levels of signatures including immune cell infiltration, immune activation, and immune checkpoints.The CLPS serves as an effective predictor for the prognosis and therapeutic responses of LUAD patients. Our findings provide promising novel biomarkers and therapeutic targets for LUAD.

This file contains supplementary tables showing the nucleotide sequences for miRNAs, siRNA target sites and primers, as well as all antibodies used in the present study.

Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment.Significance: These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis. Cancer Res; 78(4); 962–73. ©2017 AACR.

This file contains supplementary figures showing the survival times of medulloblastoma (MB) model mice used throughout the present study (Fig. S1), a heatmap of differentially expressed genes between CGNPs and MB cells (Fig. S2), the capability of Nkx2-2as to suppress the stem-like properties of MB cells (Fig. S3), bioinformatics prediction of miRNAs potentially bound to Nkx2-2as (Fig. S4) and the candidate targets of these miRNAs (Fig. S5), a ChIP proof for the inability of Gli2 to occupy the Nkx2-2as promoter (Fig. S6), and finally the typical GAB1 staining results to distinguish Shh subtype clinical MBs (Fig. S7).

Mutations in driver genes contribute to the development and progression of lung adenocarcinoma (LUAD). However, in the dynamic evolutionary process from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and eventually to invasive adenocarcinoma (IAC), the role of driver genes is currently unclear. This study aimed to analyse the role of driver gene status in the progression of LUAD from preneoplasia to IAC.Patients with LUAD who underwent surgery in our centre from March 2015 to December 2019 were retrospectively analysed, and LUAD patients with tumour sizes ≤3.0 cm and pN0 were included in the final analysis. The mutation status of common driver genes, including EGFR, ALK and ROS1, was detected. According to the pathological characteristics, the patients were divided into three stages: AIS, MIA and IAC. We analysed the distribution of driver gene mutation frequencies across three stages of LUAD. In addition, we performed univariate and multivariate analyses of IAC patients to screen for relevant variables (driver genes and clinicopathological features) affecting their prognosis.Ultimately, 759 patients with LUAD were enrolled, including 135, 130, and 494 cases of AIS, MIA, and IAC, respectively. EGFR mutations were identified in 359 (61.8%) patients, and with the transition from AIS to MIA, the frequency of EGFR mutations increased from 33.3% to 50.8%, p = 0.004, whereas the frequency of EGFR mutations was comparable for MIA and IAC (50.8% vs. 50.2%, p = 0.922). Moreover, ALK and ROS1 gene fusions were identified in 17 cases (2.2%) and 2 cases (3.0‰) respectively. For AIS, neither ALK gene nor ROS1 gene fusions were observed. When the tumour progressed to MIA, the ALK fusion frequency was 2.3% (3/130), which was basically consistent with the ALK fusion frequency of 2.8% in IAC, p = 0.143. For IAC, fusions of ROS1 fell into this category. In addition, we found that 40 patients (5.3%) developed metastasis/recurrence, and 14 patients (1.8%) died of cancer-specific related diseases. Notably, for AIS, there were no recurrences and no deaths, and for MIA, only 1 patient died with LUAD. Finally, survival analysis was performed in patients with stage IA invasive adenocarcinoma, and EGFR-mutant patients showed better DFS than EGFR-wild-type patients (p = 0.036). Conversely, patients with ALK fusions showed worse DFS than those with ALK wild-type (p = 0.004), and the same results were found in OS analysis.The accumulation of EGFR driver gene mutation frequencies mediates the progression of LUAD from AIS to MIA. When the tumour progresses to stage IA invasive adenocarcinoma, multivariate analysis based on driver gene status can be used as a pivotal prognostic factor.

Background Prognostic biomarkers are promising targets for cancer prevention and treatment. Objective We try to filtrate survival-related genes for non-small cell lung cancer (NSCLC) via transcriptome analysis. Methods Transcriptome data and clinical information of Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), mainly subtypes of NSCLC, were obtained from The Cancer Genome Atlas (TCGA) program. Differentially expressed genes (DEGs) analyzed by DESeq2 package were regarded as candidate genes. For survival analysis, univariate and multivariate Cox regression were applied to select biomarkers for overall survival (OS) and progression-free survival (PFS), where univariate analysis was for preliminary filtration and multivariate analysis considering age, gender, TNM parameters and clinical stage was for ultimate determination. Gene ontology (GO) analysis and pathway enrichment were used for biological annotation. Results We ultimately acquired a series of genes closely related to prognosis. For LUAD, we determined 314 OS-related genes and 275 PFS-related genes, while 54 OS-related genes and 78 PFS-related genes were chosen for LUSC. The final biological analysis indicated important function of proliferative signaling in LUAD but for LUSC, only cornification process had statistical meaning. Conclusions We strictly determined prognostic genes of NSCLC, which would contribute to its carcinogenesis investigation and therapeutic methods improvement.

Background: Esophageal cancer is still a leading cause of death among all tumors in males, with unsatisfactory responses to novel immunotherapies such as anti-PD-1 agents. Herein, we explored the role of CD155 in esophageal squamous cell cancer (ESCA) and its underlying molecular mechanisms. Methods: Publicly available datasets were used for differential gene expression and immune infiltration analyses, and their correlation with patient survival. A total of 322 ESCA and 161 paracancer samples were collected and evaluated by performing immunohistochemistry and the H score was obtained by performing semiquantitative analysis. In vitro transfection of ESCA cell lines with lentivirus vectors targeting CD155 was performed to knockdown the protein. These cells were analyzed by conducting RNA sequencing, and the effects of CD155 knockdown on cell cycle and apoptosis were verified with flow cytometry and Western blotting. In addition, in vivo experiments using these engineered cell lines were performed to determine the role of CD155 in tumor formation. A small interfering RNA-mediated knockdown of Nectin3 was used to determine whether it phenocopied the profile of CD155 knockdown. Results: CD155 is highly expressed in ESCA tissues and is positively associated with PD1, PDL1, CD4, IL2RA, and S100A9 expression. Furthermore, CD155 knockdown inhibited ESCA cells’ proliferation by impairing the cell cycle and inducing cell apoptosis. Bioinformatics analysis of the gene expression profile of these engineered cells showed that CD155 mainly contributed to the regulation of PI3K/Akt and MAPK signals. The downregulation of Nectin3 expression phenocopied the profile of CD155 knockdown. Discussion: CD155 may cooperate with PD-1/PD-L1 to support ESCA proliferation in ways other than regulating its underlying immune mechanisms. Indeed, CD155 downregulation can impair ESCA cell pro-cancerous behavior via the inhibition of the PI3K/Akt and MAPK signaling pathways. Moreover, Nectin3 may be a ligand of CD155 and participate in the regulation of ESCA cells’ proliferation. Hence, the inhibition of CD155 may enhance the therapeutic effect of anti-PD-1 immunotherapies in ESCA.

Background: In the past 10 years, the identification of new mutant genes involved in the pathogenesis of melanoma and the discovery of key immune checkpoints have promoted the development of targeted therapy and immunotherapy. There is no doubt that an important breakthrough has been made in the treatment of advanced or metastatic melanoma. However, the treatment of melanoma also faces many challenges. In addition to resistance to existing targeted therapies or immunotherapy, most patients do not respond to immunotherapy or have serious adverse reactions. At present, the value of existing biomarkers to predict treatment response and toxicity is still limited. Therefore, there is an urgent need to establish a convenient and reliable immunotherapy response prediction model in order to preliminarily clarify the population benefiting from immunotherapy.Results: We established a predictive model based on the expression values of five genes for patients with melanoma with an anti-PD1 immunotherapy response score. This model showed better predictive ability compared with other common immunotherapy predictors. Differences were found in the number of immune cells and the expression of common immune checkpoint genes between the high- and low-score groups. The model played a pivotal role in predicting renal cell carcinoma anti-PD1 immunotherapy response. Conclusions: The anti-PD1 immunotherapy response score prediction model for patients with melanoma showed good predictive power, thus having far-reaching significance for identifying people who benefited from anti-PD1 immunotherapy and reducing the potential toxicity of insensitive patients.

This study highlights aspects of the latest clinical research conducted on the relationship between immune checkpoints and tumor metastasis. The overview of each immune checkpoint is divided into the following three sections: 1) structure and expression; 2) immune mechanism related to tumor metastasis; and 3) clinical research related to tumor metastasis. This review expands on the immunological mechanisms of 17 immune checkpoints, including TIM-3, CD47, and OX-40L, that mediate tumor metastasis; evidence shows that most of these immune checkpoints are expressed on the surface of T cells, which mainly exert immunomodulatory effects. Additionally, we have summarized the roles of these immune checkpoints in the diagnosis and treatment of metastatic tumors, as these checkpoints are considered common predictors of metastasis in various cancers such as prostate cancer, non-Hodgkin lymphoma, and melanoma. Moreover, certain immune checkpoints can be used in synergy with PD-1 and CTLA-4, along with the implementation of combination therapies such as LIGHT-VTR and anti-PD-1 antibodies. Presently, most monoclonal antibodies generated against immune checkpoints are under investigation as part of ongoing preclinical or clinical trials conducted to evaluate their efficacy and safety to establish a better combination treatment strategy; however, no significant progress has been made regarding monoclonal antibody targeting of CD28, VISTA, or VTCN1. The application of immune checkpoint inhibitors in early stage tumors to prevent tumor metastasis warrants further evidence; the immune-related adverse events should be considered before combination therapy. This review aims to elucidate the mechanisms of immune checkpoint and the clinical progress on their use in metastatic tumors reported over the last 5 years, which may provide insights into the development of novel therapeutic strategies that will assist with the utilization of various immune checkpoint inhibitors.

Transcription factor AP-2α (TFAP2A) was previously regarded as a critical regulator during embryonic development, and its mediation in carcinogenesis has received intensive attention recently. However, its role in lung adenocarcinoma (LUAD) has not been fully elucidated. Here, we tried to investigate TFAP2A expression profiling, clinical significance, biological function and molecular underpinnings in LUAD. We proved LUAD possessed universal TFAP2A high expression, indicating a pervasively poorer prognosis in multiple independent datasets. Then we found TFAP2A was not indispensable for LUAD proliferation, and exogenous overexpression even caused repression. However, we found TFAP2A could potently promote LUAD metastasis possibly by triggering epithelial–mesenchymal transition (EMT) in vitro and in vivo. Furthermore, we demonstrated TFAP2A could transactivate Pregnancy-specific glycoprotein 9 (PSG9) to enhance transforming growth factor β (TGF-β)-triggering EMT in LUAD. Meanwhile, we discovered suppressed post-transcriptional silencing of miR-16 family upon TFAP2A partly contributed to TFAP2A upregulation in LUAD. In clinical specimens, we also validated cancer-regulating effect of miR-16 family/TFAP2A/PSG9 axis, especially for lymph node metastasis of LUAD. In conclusion, we demonstrated that TFAP2A could pivotally facilitate LUAD progression, possibly through a novel pro-metastasis signaling pathway (miR-16 family/TFAP2A/PSG9/ TGF-β).

Background: Immunotherapy has dramatically changed the treatment landscape of cancer. Immunotherapies targeting the programmed death 1/programmed death ligand 1 pathway have been shown to lead to durable responses in patients with a variety of cancers. However, combination approaches are required to extend this benefit beyond a subset of patients. Studies have suggested that anti-angiogenic therapy can elicit or enhance tumor immunity response.Therefore, we hypothesised that combining immunotherapy with anti-angiogenic treatment may have a synergistic effect and may enhance the efficacy of both treatments.Methods: We evaluated the combination of bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) and pembrolizumab (anti-programmed death 1 monoclonal antibody) in two mouse models of human non-small cell lung cancer cell lines (H1299 and A549). We monitored tumour growth and examined changes in the tumour vasculature, along with the frequency and phenotype of tumour-infiltrating lymphocytes.Results: The combination of bevacizumab and pembrolizumab synergistically inhibited tumour growth in vivo without overt toxicity in both cell lines. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T cell infiltration, thereby turning tumours with different phenotypes into inflamed (‘hot’) tumours. This is potentially mediated by vascular normalisation and endothelial cell activation, as demonstrated by a reduction in the number of microvessels and an increase in adhesion molecules.Conclusions: Taken together, our preclinical studies demonstrate that the combination of bevacizumab and pembrolizumab had a synergistic anti-tumour effect and provides a theoretical basis for translating basic research into clinical applications.

Additional file 1: Figure S1. qRT-PCR analysis of CASC15 RNA levels in A549 and H1299 cells, which were treated with si-Control or si-CASC15 for 48 hours. Figure S2. Western blot analysis of SOX4 protein levels in A549 and H1299 cells, which were treated with si-Control or si-SOX4 for 48 hours. Figure S3. Tumor volume in nude mice injected with A549 and H129 cells with stable knockdown of CASC15, or concurrent overexpression of SOX4. Figure S4. Representative IHC staining of HIF-1α and ISH staining of CASC15 in A549-shControl and A549-shHIF1A xenograft tissues. Figure S5. Western blot analysis of SOX4 protein levels in CASC15-overexpressing H1299 cells and control cells. Figure S6. RNA-IP assay detecting potential interactions between CASC15 RNA and WDR5 protein in A549 and H1299 cells. U1 snRNA, which was reported not binding to WDR5, was used as a negative control. Table S1. The characteristics of 35 NSCLC patients included in the tissue microarray in our study. Table S2. Primer sequences for qRT-PCR.

Background Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive. Methods Firstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples. Results CASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients. Conclusions HIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC.

Background Lung adenocarcinoma (LUAD) remains a crucial factor endangering human health. Gene-based clinical predictions could be of great help for cancer intervention strategies. Here, we tried to build a gene-based survival score (SS) for LUAD via analyzing multiple transcriptional datasets. Methods We first acquired differentially expressed genes between tumors and normal tissues from intersections of four LUAD datasets. Next, survival-related genes were preliminarily unscrambled by univariate Cox regression and further filtrated by LASSO regression. Then, we applied PCA to establish a comprehensive SS based on survival-related genes. Subsequently, we applied four independent LUAD datasets to evaluate prognostic prediction of SS. Moreover, we explored associations between SS and clinicopathological features. Furthermore, we assessed independent predictive value of SS by multivariate Cox analysis and then built prognostic models based on clinical stage and SS. Finally, we performed pathway enrichments analysis and investigated immune checkpoints expression underlying SS in four datasets. Results We established a 13 gene-based SS, which could precisely predict OS and PFS of LUAD. Close relations were elicited between SS and canonical malignant indictors. Furthermore, SS could serve as an independent risk factor for OS and PFS. Besides, the predictive efficacies of prognostic models were also reasonable (C-indexes: OS, 0.7; PFS, 0.7). Finally, we demonstrated enhanced cell proliferation and immune escape might account for high clinical risk of SS. Conclusions We built a 13 gene-based SS for prognostic prediction of LUAD, which exhibited wide applicability and could contribute to LUAD management.

Mining disease-related genes contributes momentously to handling lung adenocarcinoma (LUAD). But genetic complexity and tumor heterogeneity severely get in the way. Fortunately, new light has been shed by dramatic progress of bioinformatic technology in the past decades. In this research, we investigated relationships between gene expression and clinical features of LUAD via integrative bioinformatic analysis. First, we applied limma and DESeq2 packages to analyze differentially expressed genes (DEGs) of LUAD from GEO database and TCGA project (tumor tissues versus normal tissues), and acquired 180 down-regulated DEGs and 52 up-regulated DEGs. Then, we investigated genetic and biological assignment of theses DEGs by Bioconductor packages and STRING database. We found these DEGs were distributed dispersedly among chromosomes, enriched observably in extracellular matrix-related processes, and weighted hierarchically in interaction network. Finally, we established DEGs-based statistical models for evaluating TNM stage and survival status of LUAD. And these models (logistic regression models for TNM parameter and Cox regression models for survival probability) all possessed fine predictive efficacy (C-indexes: T, 0.740; N, 0.687; M, 0.823; overall survival, 0.678; progression-free survival, 0.611). In summary, we have successfully established gene expression-based models for assessing clinical characteristics of LUAD, which will assist its pathogenesis investigation and clinical intervention.

Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio‐characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.

Cancer cells display altered metabolism distinct from non-transformed cells, which is correlated closely with malignant biocharacteristics. Flexibility remains the central feature of metabolic alteration, enabling cancer cells to survive and thrive in the challenge of inner and outer environments. In this review, we summarise how cancer reprogrammes its metabolism nimbly and adaptively. To begin with, cancer cells adapt metabolism cunningly to supply sufficient materials and energy for infinite proliferation. Further, cancer cells harness metabolism to maintain appropriate cellular redox status, providing survival benefit rather than impairment on tumor growth. Moreover, cancer can switch between different metabolic types flexibly to handle harsh conditions like hypoxia, nutrient deficiency and metabolic inhibition on the journey for expansion. Last but not least, cancer coordinates metabolism of cancerous or stromal cells well to gain support and escape immune destruction. In a word, metabolic flexibility confers indomitable viability on cancer. Exploring such plasticity will help us gain new insights into cancer pathogenesis and cancer therapy.

Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment. Significance: These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis. Cancer Res; 78(4); 962–73. ©2017 AACR.

In non-small cell lung cancer (NSCLC), success of targeted therapy has promoted researches explicitly orientated based on genetic background. Although PTEN deficiency is common in NSCLC, carcinogenesis about such genetic type has not been fully explored. Here, we have found that classical tumor suppressor P53 could be modulated by deacetylase sirtuin-3 (SIRT3) depending on the PTEN condition in NSCLC, which may be a novel breakpoint for handling PTEN deficiency NSCLC. First, we examined SIRT3 and P53 expression files in PTEN-deficient NSCLC clinical samples and investigated their correlation. Second, we built SIRT3 high or low expression models in different PTEN conditions by plasmid overexpression or si-RNA interference in NSCLC cell lines and explored the effect of SIRT3 upon P53. Furthermore, we investigated the influence of SIRT3 upon the ubiquitin–proteasome dependent degradation pathway of P53 in PTEN-deficient NSCLC cell lines. Finally, we probed into the deacetylation modification of P53 via SIRT3. We found that SIRT3 expression was strongly positive and P53 expression was almost negative in PTEN-deficient NSCLC clinical samples. Further, we demonstrated that SIRT3 promoted degradation of P53 in PTEN-deficient NSCLC cell lines via the ubiquitin–proteasome pathway. Finally, we demonstrated that SIRT3 could deacetylate P53 at lysines 320 and 382, which may account for the observed degradation of P53 in PTEN-deficient tumor cells. We have identified a novel mechanism by which P53 was inactivated via SIRT3 in PTEN-deficient cells. This may shed light on the mechanisms underlying the malignancy of PTEN-deficient NSCLC.

The mitochondrial deacetylase SIRT3 plays a pivotal role in the initiation and the progression of certain cancers acting as an oncogene. However, in others it acts anti-oncogenically. Its conflicting action is possibly due to the different key proteins it modifies depending on the context of active intracellular signaling pathways in different cancers. SIRT3 is thus a novel target for preventing and treating cancer. In the present study, we explored the function of SIRT3 in non-small cell lung cancer (NSCLC) with the aim of elucidating the underlying mechanisms. We first determined the SIRT3 expression levels by real-time PCR, western blotting and immunohistochemistry on tissue microarrays of paired samples of NSCLC tissue and adjacent normal tissue from 70 patients with associated clinicopathological data. Levels of SIRT3 protein and mRNA were significantly increased in NSCLC tissue, compared with normal tissue (P

Purpose High metastasis is a leading risk factor for the survival of non-small cell lung cancer (NSCLC) and epithelial-mesenchymal transition (EMT) is a vital step of metastasis. The expression of novel oncogene with kinase domain (NOK) has been observed in some human malignancies, including non-small cell lung cancer (NSCLC); however, the biological function of NOK in NSCLC remains unclear. In the study, we explored the function of NOK in NSCLC, with an aim to elucidate the relevant underlying mechanisms. Patients and methods We investigate the expression of NOK, p-Akt, p-GSK-3β, E-cadherin and N-cadherin expression by immunohistochemical analysis using tissue microarrays of 72 paired NSCLC samples of cancerous and adjacent normal tissues. The associations between NOK expression and clinicopathological factors, overall survival, other proteins were assessed. Immunofluorescence analysis of NSCLC tissues was performed to study the location of NOK, Akt and GSK-3β. Up or down-regulated of NOK were conducted in two NSCLC cell lines to analyze its impact on AKT/GSK3β pathway. Results Statistical analysis revealed NOK expression increased in NSCLC tissues compared with normal tissues (P

The NAD-dependent protein deacetylase sirtuin 3 (SIRT3) is an enzyme localized primarily in the mitochondrion, where it modulates cellular functions such as nutrient metabolism, ATP balance, antioxidant machinery, and other mechanisms fundamental to mitochondria. SIRT3 is closely associated with the pathogenesis of diverse disorders. In particular, it plays a dual role in the development and progression of cancer. In many cancers, SIRT3 acts as an oncogene by promoting or maintaining the malignant phenotypes of neoplastic cells, including uncontrolled proliferation, resistance to apoptosis, and increased motility or invasiveness; however, SIRT3 suppresses these phenotypes in certain types of malignancy. The underlying mechanisms involve depletion of intracellular reactive oxygen species, modulation of metabolic reprogramming, and regulation of intracellular signaling responsible for cell growth and death. This review summarizes recent findings concerning the characteristics and substrates/interacting partners of SIRT3, with particular emphasis on emerging mechanisms responsible for fine-tuning cellular behaviors that potentially underlie its conflicting roles in carcinogenesis.

// Yanlu Xiong 1, * , Tao Wang 1, * , Mingxing Wang 1 , Jinbo Zhao 1 , Xiaofei Li 1 , Zhipei Zhang 1 , Yongsheng Zhou 3 , Jiabao Liu 3 , Lintao Jia 2 and Yong Han 1 1 Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China 2 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China 3 Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China * These authors contributed equally to this work Correspondence to: Yong Han, email: hanyong_td@163.com Lintao Jia, email: jialth@fmmu.edu.cn Keywords: lncRNA; NSCLC; biomarker; prognosis; malignancy Received: July 13, 2017 Accepted: November 14, 2017 Published: January 04, 2018 ABSTRACT Objectives: Non-small cell lung cancer (NSCLC) is associated with high morbidity and mortality, leading the understanding the pathogenesis paramount. Recent studies suggest that long non-coding RNAs (lncRNAs) play an important role in NSCLC. We conducted a systematic review to examine the relationship between lncRNAs and NSCLC. Materials and Methods: We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate overall survival (OS), and odds ratios (ORs) and 95% CIs to assess clinicopathological parameters. Also, pooled sensitivity and specificity values were used to measure the diagnostic value of lncRNAs for NSCLC. Finally, we summarized the molecular mechanisms underlying the activity of lncRNAs in NSCLC. Results: We found that high expression of oncogenic lncRNAs was associated with a poor prognosis (OS: HR, 1.18; 95% CI, 1.14–1.22) and poor clinicopathological characteristics (tumor size: OR, 2.74 or 2.04; 95% CI, 1.66–4.52 or 1.09–3.79 based on the two classification criterias; lymph node metastasis: OR, 3.30; 95% Cl, 2.42–4.49), Also, high expression of tumor-suppressor lncRNAs was correlated with longer survival times (OS: HR, 0.54; 95% CI, 0.44–0.66) and improved clinical characteristics (tumor size: OR, 0.33 or 0.28; 95% CI, 0.14–0.75 or 0.18–0.45; lymph node metastasis: OR, 0.37; 95% Cl, 0.26–0.52). Furthermore, we found that lncRNAs could be used as serum biomarkers of NSCLC (sensitivity: 0.81; 95% CI, 0.72–0.87; specificity: 0.83; 95% CI, 0.73–0.90). Finally, lncRNAs regulated expression of key proteins, thereby mediating development of a malignant phenotype. Conclusions: lncRNAs have significant clinical value in NSCLC and could function as novel predictors of disease and/or as therapeutic targets.