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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.

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).

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.

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.

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.