STMN1 Promotes Tumor Metastasis in Non-small Cell Lung Cancer Through Microtubule-dependent And Nonmicrotubule-dependent Pathways.

The relationship between STMN1 and cancer metastasis is controversial. The purpose of this study was to explore the role and mechanism of STMN1 in NSCLC metastasis. In this study, we reported that STMN1 was highly expressed in NSCLC tissues and associated with poor prognosis. Both in vivo and in vitro functional assays confirmed that STMN1 promoted NSCLC metastasis. Further studies confirmed that STMN1 promoted cell migration by regulating microtubule stability. The results of Co-IP and LC‒MS/MS illustrated that STMN1 interacts with HMGA1. HMGA1 decreases microtubule stability by regulating the phosphorylation level of STMN1 at Ser16 and Ser38 after interacting with STMN1. This result suggested that STMN1 could be activated by HMGA1 to further promote NSCLC metastasis. Meanwhile, it has been found that STMN1 could promote cell migration by activating the p38MAPK/STAT1 signaling pathway, which is not dependent on microtubule stability. However, activating p38MAPK can decrease microtubule stability by promoting the dephosphorylation of STMN1 at ser16. A positive feedback loop was formed between STMN1 and p38MAPK to synergistically promote cell migration. In summary, our study demonstrated that STMN1 could promote NSCLC metastasis through microtubule-dependent and nonmicrotubule-dependent mechanisms. STMN1 has the potential to be a therapeutic target to inhibit metastasis.

Prevention of breast cancer-related lymphoedema: Quality of clinical practice guidelines and variations in recommendations.

AIM: We aimed to evaluate the quality of clinical practice guidelines (CPGs) for breast cancer related lymphoedema (BCRL) and compare the similarities and differences in recommendations. BACKGROUND: Many CPGs of BCRL have been developed; however, their recommendations and quality are controversial. METHODS: Relevant papers were retrieved from electronic databases, professional associations and guideline development organizations, from 1 January 2015 to 30 September 2021. The Appraisal of Guidelines Research and Evaluation (AGREE) II instrument was used to evaluate the quality of the guidelines. Intraclass correlation coefficient (ICC) analysis was used to evaluate the overall consistency among evaluators. RESULTS: Eight CPGs were included. The ICC values evaluation for CPGs ranged from 0.76 to 0.95, with good consensus among evaluators. The highest median score was 68.75% (61.46, 72.22%) for clarity, and the lowest was 37.50% (25.78, 51.30%) for applicability. The NICE, ACS/ACSO and APTA CPGs were rated well in most areas. Professional health education, individualized exercise programme and regular surveillance are the main methods to prevent lymphoedema. CONCLUSION: In the past 6 years, the quality of BCRL guidelines has varied greatly, especially in the domains of rigour and applicability. Interrater agreement was excellent, but recommendation showed some inconsistencies in the details.

Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib.

BACKGROUND: The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. METHODS: The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. RESULTS: Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. CONCLUSIONS: Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment.

Pharmacoepitranscriptomic landscape revealing m6A modification could be a drug-effect biomarker for cancer treatment.

RNA chemical modifications are a new but rapidly developing field. They can directly affect RNA splicing, transport, stability, and translation. Consequently, they are involved in the occurrence and development of diseases that have been studied extensively in recent years. However, few studies have focused on the correlation between chemical modifications and drug effects. Here, we provide a landscape of six RNA modifications in pharmacogene RNA (pharmacoepitranscriptomics) to fully clarify the correlation between chemical modifications and drugs. We performed systematic and comprehensive analyses on pharmacoepitranscriptomics, including basic characteristics of RNA modification and modification-associated mutations and drugs affected by them. Our results show that chemical modifications are common in pharmacogenes, especially N6-methyladenosine (m6A) modification. In addition, we found a very close relationship between chemical modifications and anti-tumor drugs. More interestingly, the results demonstrate the importance of m6A modification for anti-tumor drugs, especially for drugs in triple-negative breast cancer (TNBC), ovarian cancer, and acute myelocytic leukemia (AML). These results indicate that pharmacoepitranscriptomics could be a new source of drug-effect biomarkers, especially for m6A and anti-tumor drugs.

ECO: An Integrated Gene Expression Omnibus for Mouse Endothelial Cells In Vivo.

Endothelial cell (EC) plays critical roles in vascular physiological and pathological processes. With the development of high-throughput technologies, transcriptomics analysis of EC has increased dramatically and a large amount of informative data have been generated. The dynamic patterns of gene expression in ECs under various conditions were revealed. Unfortunately, due to the lack of bioinformatics infrastructures, reuse of these large-scale datasets is challenging for many scientists. Here, by systematic re-analyzing, integrating, and standardizing of 203 RNA sequencing samples from freshly isolated mouse ECs under 71 conditions, we constructed an integrated mouse EC gene expression omnibus (ECO). The ECO database enables one-click retrieval of endothelial expression profiles from different organs under different conditions including disease models, genetic modifications, and clinically relevant treatments in vivo. The EC expression profiles are visualized with user-friendly bar-plots. It also provides a convenient search tool for co-expressed genes. ECO facilitates endothelial research with an integrated tool and resource for transcriptome analysis. The ECO database is freely available at https://heomics.shinyapps.io/ecodb/.

Pretreatment HDL-C and ApoA1 are predictive biomarkers of progression-free survival in patients with EGFR mutated advanced non-small cell lung cancer treated with TKI.

BACKGROUND: We aimed to explore the correlation between blood lipids (high density lipoprotein cholesterol [HDL-C] and apolipoprotein A1 [ApoA1]) and epidermal growth factor receptor (EGFR) T790M mutation, as well as its predictive role in clinical efficacy and progression-free survial (PFS) in advanced non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKI). METHODS: We retrospectively collected information of 153 patients with advanced NSCLC harboring exon EGFR mutation and receiving EGFR-TKI. RESULTS: The best cutoff value for HDL-C and ApoA1 was determined to be 1.15 and 1.14 mmol/l. The overall response rate (ORR) was 67.7% in the high HDL-C group and 46.6% in the low HDL-C group, respectively. The ORR of the high ApoA1 group showed a significant increase than that of the low ApoA1 group (68.1% vs. 38.5%). The mean ApoA1 level of the EGFR T790M mutation-positive group was significantly higher than that of the EGFR T790M mutation-negative group (1.13 g/l vs. 1.01 g/l). Patients with high ApoA1 levels were related to the EGFR T790M mutation (r = 0.324). (3) The median progression-free survival (PFS) of the high HDL-C group and low HDL-C group were 13.00 months and 10.20 months. The median PFS of the high ApoA1 group and the low ApoA1 group were 12.10 and 10.00 months, respectively. Multivariate Cox stepwise regression model analysis demonstrated ECOG PS, pathological type and HDL-C were confirmed as critical and independent predictors of PFS. CONCLUSIONS: Patients with EGFR T790M mutations often show higher ApoA1 levels. Peripheral serum HDL-C and ApoA1 before treatment can be used as potential significant factors for predicting clinical efficacy and PFS in advanced NSCLC patients treated with EGFR-TKI.

Molecular Characteristics of the Uncommon EGFR Exon 21 T854A Mutation and Response to Osimertinib in Patients With Non-Small Cell Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) T854A is an uncommon exon 21 mutation in patients with non-small cell lung cancer (NSCLC). It was first reported in samples collected after first generation EGFR tyrosine kinase inhibitor (TKI) treatment as an acquired resistant mutation to first generation EGFR-TKI. The efficacy of osimertinib, a third generation EGFR-TKI, in these patients was not clear. METHODS: In this study, a total of 8932 NSCLC patients with NGS data were retrospectively analyzed to investigate the molecular characteristics and clinical outcomes of patients with EGFR T854A mutation. RESULTS: Eight of 8932 patients (0.09%) had EGFR T854A mutation, and 5 of them (62.5%) were treatment-naïve. Interestingly, all EGFR T854A mutations were co-occurred with EGFR L858R mutation in cis. TP53 was the most common concomitant mutation and no other driver mutation was found. Five of the 8 patients received treatment of osimertinib. Four patients achieved partial response, and one had stable disease, resulting in an overall objective response rate of 80% and disease control rate of 100%. The median progression-free survival of patients who received osimertinib was 10 months. Moreover, EGFR C797S mutation was detected in 1 patient after resistant to osimertinib treatment. CONCLUSION: Presence of EGFR T854A mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that osimertinib may be an effective treatment to improve survival outcomes in patients with EGFR T854A.

Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma.

Glioblastoma (GBM) is the most aggressive type of brain tumor. Microvascular proliferation and abnormal vasculature are the hallmarks of the GBM, aggravating disease progression and increasing patient morbidity. Here, we uncovered a key role of ETS1 on vascular abnormality in glioblastoma. ETS1 was upregulated in endothelial cells from human tumors compared to endothelial cells from paired control brain tissue. Knockdown of Ets1 in mouse brain endothelial cells inhibited cell migration and proliferation, and suppressed expression of genes associated with vascular abnormality in GBM. ETS1 upregulation in tumor ECs was dependent on TGFß signaling, and targeting TGFß signaling by inhibitor decreased tumor angiogenesis and vascular abnormality in CT-2A glioma model. Our results identified ETS1 as a key factor regulating tumor angiogenesis, and suggested that TGFß inhibition may suppress the vascular abnormality driven by ETS1.

A Five Autophagy-Related Long Non-Coding RNA Prognostic Model for Patients with Lung Adenocarcinoma.

PURPOSE: Lung adenocarcinoma is the most common pathological type among non-small cell lung cancer. Although huge progress has been made in terms of early diagnosis and precision treatment in recent years, the overall 5-year survival rate of a patient remains low. In our study, we try to construct an autophagy-related lncRNA prognostic signature that may guide clinical practice. METHODS: The mRNA and lncRNA expression matrix of lung adenocarcinoma patients were retrieved from the TCGA database. Next, we constructed a co-expression network of lncRNAs and autophagy-related genes. Lasso regression and multivariate Cox regression were then applied to establish a prognostic risk model. Subsequently, a risk score was generated to differentiate the high and low risk groups and a ROC curve and nomogram to visualize the predictive ability of the current signature. Finally, gene ontology and pathway enrichment analysis were executed via GSEA. RESULTS: A total of 1,703 autophagy-related lncRNAs were screened and five autophagy-related lncRNAs (LINC01137, AL691432.2, LINC01116, AL606489.1, and HLA-DQB1-AS1) were finally included in our signature. Judging from univariate (HR=1.075, 95% CI=1.046-1.104) and multivariate (HR=1.088, 95% CI=1.057-1.120) Cox regression analysis, the risk score is an independent factor for LUAD patients. Further, the AUC value based on the risk score for 1-year, 3-years, and 5-years, was 0.735, 0.672, and 0.662, respectively, indicating a reliable model. Drug sensitivity analysis revealed low risk patients were more sensitive to Gemcitabine and Gefitinib, while high risk patients had a better response to Paclitaxel and Erlotinib. Moreover, the lncRNAs included in our signature were primarily enriched in the autophagy process, metabolism, p53 pathway, and JAK/STAT pathway. Finally, a multi-omics analysis of correlated genes showed CFLAR overexpressed in the tumor sample, while GAPDH and MLST8 had a slightly higher expression in the normal sample. CONCLUSION: Overall, our study indicated that the prognostic model we generated had certain predictability for LUAD patients' prognosis and the related genes might be potential biomarkers and therapeutic targets.

An Autophagy-Related Long Non-Coding RNA Prognostic Signature for Patients with Lung Squamous Carcinoma Based on Bioinformatics Analysis.

PURPOSE: Lung cancer is the most common and deadly cancer type affecting humans. Although huge progress has been made on early diagnosis and precision treatment, the overall 5 year survival rate remains low. In this study, we constructed an autophagy-related long non-coding RNA (lncRNA) prognostic signature for guiding clinical practice. METHODS: From The Cancer Genome Atlas, we retrieved mRNA and lncRNA expression matrices of patients with lung squamous carcinoma. We then established a prognostic risk model using Lasso regression and multivariate Cox regression. The model generated a risk score to differentiate high- and low-risk groups. An ROC curve and nomogram were used to visualize the predictive ability of the current signatures. Finally, we used Gene Set Enrichment Analysis to determine gene ontology and pathway enrichment. RESULTS: After screening 1248 autophagy-related lncRNAs, we selected seven lncRNAs (LUCAT1, AC022150.2, AL035425.3, AC138976.2, AC106786.1, GPRC5D-AS1 and AP006545.2) for our signature. Univariate (hazard ratio [HR] = 2.147, 95% confidence interval [CI]: 1.681-2.743, P < 0.001) and multivariate (HR = 2.096, 95% CI: 1.652-2.658, P < 0.001) Cox regression analyses revealed that the risk score is an independent predictive factor for LUSC patients. Further, areas under the receiver operating characteristic curve were 0.622, 0.699, and 0.721, respectively, for the 1 year, 3 year, and 5 year risk scores-indicating a reliable model. Selected lncRNAs were primarily enriched in autophagy, metabolism, MAPK pathway, and JAK/STAT pathway. Further drug sensitivity analysis revealed that low-risk patients were more sensitive to Cisplatin, Docetaxel, Vinblastine, and Vinorelbine. Finally, a multi-omics analysis found that lncRNA-linked proteins IKBKB and SQSTM1 were expressed at low levels and significantly correlated in tumor samples, compared with normal tissue. CONCLUSION: Our prognostic model successfully predicted patient prognosis in lung cancer.

Overexpression of BCCIP predicts an unfavorable prognosis and promotes the proliferation and migration of lung adenocarcinoma.

BACKGROUND: Lung cancer accounts for the highest rate of cancer-related diagnosis and mortality. Lung adenocarcinoma (LUAD) is the most common histopathological type. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein. In different cancers, BCCIP plays different roles. The role of BCCIP in LUAD is still unknown. METHODS: The expression and prognostic value of BCCIP was analyzed using public databases, including LCE, GEPIA, TCGA, and clinical specimens. Bioinformatic analysis and vitro experiments were conducted to explore the biological functions of BCCIP in LUAD. By using the GEPIA and TIMER databases, we investigated the correlations between LUAD expression and immune infiltration in LUAD. RESULTS: Compared with normal tissue, LUAD tissue had a higher expression level of BCCIP and high expression level of BCCIP was detrimental to LUAD patient survival. The suppression of BCCIP inhibited LUAD cell proliferation, migration and resulted in G1/S phase arrest in vitro. Bioinformatic analysis demonstrated that BCCIP could be associated with cell cycle, DNA repair and E2F transcription factor family. There were significant correlations between BCCIP expression and immune infiltrates, including B cell, CD4+ T cell, macrophage, neutrophil and dendritic cells. Furthermore, BCCIP expression showed strong correlations with diverse immune marker sets in LUAD, such as B cell, macrophage and DC. CONCLUSIONS: Overexpression of BCCIP predicts an unfavorable prognosis and promotes the proliferation and migration of lung adenocarcinoma cells. BCCIP is correlated with immune infiltration in LUAD. Suppression of BCCIP may be a potential approach in the prevention and treatment of LUAD.

Uncovering a Distinct Gene Signature in Endothelial Cells Associated With Contrast Enhancement in Glioblastoma.

PURPOSE: Glioblastoma (GBM) is the most aggressive and lethal type of brain tumors. Magnetic resonance imaging (MRI) has been commonly used for GBM diagnosis. Contrast enhancement (CE) on T1-weighted sequences are presented in nearly all GBM as a result of high vascular permeability in glioblastomas. Although several radiomics studies indicated that CE is associated with distinct molecular signatures in tumors, the effects of vascular endothelial cells, the key component of blood brain barrier (BBB) controlling vascular permeability, on CE have not been thoroughly analyzed. METHODS: Endothelial cell enriched genes have been identified using transcriptome data from 128 patients by a systematic method based on correlation analysis. Distinct endothelial cell enriched genes associated with CE were identified by analyzing difference of correlation score between CE-high and CE-low GBM cases. Immunohistochemical staining was performed on in-house patient cohort to validate the selected genes associated with CE. Moreover, a survival analysis was conducted to uncover the relation between CE and patient survival. RESULTS: We illustrated that CE is associated with distinct vascular molecular imprints characterized by up-regulation of pro-inflammatory genes and deregulation of BBB related genes. Among them, PLVAP is up-regulated, whereas TJP1 and ABCG2 are down-regulated in the vasculature of GBM with high CE. In addition, we found that the high CE is associated with poor prognosis and GBM mesenchymal subtype. CONCLUSION: We provide an additional insight to reveal the molecular trait for CE in MRI images with special focus on vascular endothelial cells, linking CE with BBB disruption in the molecular level. This study provides a potential new direction that may be applied for the treatment optimization based on MRI features.

Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing.

Passage of systemically delivered pharmacological agents into the brain is largely blocked by the blood-brain-barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). Tumor vessels in glioblastoma (GBM), the most common malignant brain tumor in humans, are abnormally permeable, but this phenotype is heterogeneous and may differ between the tumor's center and invasive front. Here, through single-cell RNA sequencing (scRNA-seq) of freshly isolated ECs from human glioblastoma and paired tumor peripheral tissues, we have constructed a molecular atlas of human brain ECs providing unprecedented molecular insight into the heterogeneity of the human BBB and its molecular alteration in glioblastoma. We identified 5 distinct EC phenotypes representing different states of EC activation and BBB impairment, and associated with different anatomical locations within and around the tumor. This unique data resource provides key information for designing rational therapeutic regimens and optimizing drug delivery.

CircPVT1 promotes proliferation of lung squamous cell carcinoma by binding to miR-30d/e.

BACKGROUND: Circular RNAs (circRNAs) are a new type of extensive non-coding RNAs that regulate the activation and progression of different human diseases, including cancer. However, information on the underlying mechanisms and clinical significance of circRNAs in lung squamous cell carcinoma (LUSC) remains scant. METHODS: The expression profile of RNAs in 8 LUSC tissues, and 9 healthy lung tissues were assayed using RNA sequencing (RNA-seq) techniques. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to profile the expression of circPVT1 and its relationship with the prognosis of LUSC, i.e., survival analysis. Moreover, in vitro and in vivo experiments were performed to evaluate the impacts of circPVT1 on the growth of tumors. RNA pull-down tests, mass spectrometry, dual-luciferase reporter assessment, and RNA immune-precipitation tests were further conducted to interrogate the cross-talk between circPVT1, HuR, or miR-30d/e in LUSC. RESULTS: Our data showed that circPVT1 was upregulated in LUSC tissues, serum, and cell lines. LUSC patients with higher circPVT1 expression exhibited shorter survival rates. The in vivo and in vitro data revealed that circPVT1 promotes the proliferation of LUSC cells. Additionally, mechanistic analysis showed that HuR regulated circPVT1. On the other hand, circPVT1 acted as a competing endogenous RNA (ceRNA) of miR-30d and miR-30e in alleviating the suppressive influences of miR-30d and miR-30e on its target cyclin F (CCNF). CONCLUSION: CircPVT1 promotes LUSC progression via HuR/circPVT1/miR-30d and miR-30e/CCNF cascade. Also, it acts as a novel diagnostic biomarker or treatment target of individuals diagnosed with LUSC.

Erratum: Long non-coding RNA LINC01116 is overexpressed in lung adenocarcinoma and promotes tumor proliferation and metastasis.

[This corrects the article on p. 4302 in vol. 12, PMID: 32913506.].

An investigation to identify tumor microenvironment-related genes of prognostic value in lung squamous cell carcinoma based on The Cancer Genome Atlas.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a prevalent and lethal malignancy with a poor clinical prognosis. Major constituents of the tumor microenvironment (TME) include infiltrating immune cells and stromal cells, which play a pivotal role in the progression and growth of the disease. To improve the understanding of the prognostic influence of immune and stromal cell-related genes for patients with the disease, we performed a comprehensive bioinformatics analysis to identify TME-relevant biomarkers, and investigated the potential role of these candidate signatures in LUSC. METHODS: Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) assessed the samples of LUSC obtained from The Cancer Genome Atlas (TCGA). The samples were grouped according to their immune/stromal scores (high or low). Multivariate cox regression and receiver operating characteristic curves (ROC) were implemented to construct the risk assessment model for prognosis prediction. The co-upregulated differentially expressed genes (DEGs) in the immune and stromal groups were used for further analyses. Overall survival (OS) curves were used to determine the prognostic value of the DEGs, and the TME-related DEGs were verified with Gene Expression Omnibus (GEO) datasets. The functional assessments were performed include Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses. RESULTS: The immune/stromal scores calculated by ESTIMATE showed significant associations with OS (log-rank P<0.05). In addition, the prognostic risk score model based on immune and stromal scores also showed significant correlations with OS. A total of 94 TME-related genes were obviously related to poor OS. Among them, BHMT2, FES, HSPB7, NOVA2, LPAP2, and SEMA3B (BFHNLS) were confirmed using GSE4573 and GSE17710 datasets. The functional assessments exhibited those TME-related genes mostly participate in immune response, cytokine-cytokine receptor interaction, and metabolic pathways, which elucidated the probable correlation of TME with tumorigenesis in LUSC. CONCLUSIONS: In this study, 6 potential biomarkers named BFHNLS were identified as TME-related genes with prognostic value based on immune and stromal scores of LUSC patients of TCGA, and were verified using GEO datasets, which might serve as therapeutic targets.

ADFP promotes cell proliferation in lung adenocarcinoma via Akt phosphorylation.

Previously, we identified differentially expressed proteins, including ADFP, between lung adenocarcinoma (LAC) tissue and paired normal bronchioloalveolar epithelium. In this study, we investigated the role of ADFP in LAC. ADFP levels in the serum of patients with lung cancer and benign diseases were measured by enzyme-linked immunosorbent assays (ELISA). shRNA was used to knock-down or overexpress ADFP in A549 and NCI-H1299 cells. The biological function of ADFP and its underlying mechanisms was evaluated in vivo and in vitro. ADFP was highly expressed in the serum of lung cancer patients, especially those with LAC. ADFP promoted cell proliferation and up-regulated the p-Akt/Akt ratio in A549 and NCI-H1299 cells in vitro. Furthermore, in nude mice, ADFP promoted tumour formation with high levels of p-Akt/Akt, Ki67 and proliferating cell nuclear antigen (PCNA). Similar to the effect of ADFP knock-down, MK-2206 (a phosphorylation inhibitor of Akt) reduced A549 and NCI-H1299 cell proliferation. In ADFP-overexpressing A549 and NCI-H1299 cells, proliferation was suppressed by MK-2206 and returned to the control level. ADFP did not regulate invasion, migration or adhesion in LAC cells. Together, these results suggest that ADFP promotes LAC cell proliferation in vitro and in vivo by increasing Akt phosphorylation level.

Leflunomide Suppresses the Growth of LKB1-Inactivated Tumors in the Immune-Competent Host and Attenuates Distant Cancer Metastasis.

Liver kinase B1 (LKB1)-inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77-1726, inhibits dihydroorotate dehydrogenase, which is essential for de novo pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors in vivo, and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models. We also generated a mouse tumor-derived cancer cell line, WRJ388, that could metastasize to the lung within a month after subcutaneous implantation in all animals. This model was used to assess the ability of leflunomide to control distant metastasis. Leflunomide treatment shrank a HeLa xenograft and attenuated the growth of an H460 xenograft, a patient-derived xenograft, and lung adenocarcinoma in the immune-competent genetically engineered mouse models. Interestingly, leflunomide suppressed tumor growth through at least three different mechanisms. It caused apoptosis in HeLa cells, induced G1 cell-cycle arrest in H460 cells, and promoted S-phase cell-cycle arrest in WRJ388 cells. Finally, leflunomide treatment prevented lung metastasis in 78% of the animals in our novel lung cancer metastasis model. In combination, these results demonstrated that leflunomide utilizes different pathways to suppress the growth of LKB1-inactivated tumors, and it also prevents cancer metastasis at distant sites. Therefore, leflunomide should be evaluated as a therapeutic agent for tumors with LKB1 inactivation.

Long non-coding RNA LINC01116 is overexpressed in lung adenocarcinoma and promotes tumor proliferation and metastasis.

Long non-coding RNA LINC01116 is involved in the occurrence and progression of a variety of cancers. However, the specific role of LINC01116 in lung adenocarcinoma (LUAD) remains unclear. In this work, we found that LINC01116 was overexpressed in LUAD tissues and cell lines and that increased expression was significantly associated with worse prognoses in patients with LUAD. Univariate and multivariate Cox regression analyses indicated that LINC01116 was an independent risk factor for the prognosis of patients with LUAD. Downregulation of LINC01116 significantly inhibited cell proliferation and migration, promoted cell apoptosis, and prevented cell progression from G1 to S phase. In addition, downregulation of LINC01116 significantly inhibited the epithelial-mesenchymal transition, leading to an increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. In summary, our results suggest that LINC01116 may act as an oncogene in LUAD and may be a valuable prognostic biomarker for patients with LUAD.