Energy stress-induced circZFR enhances oxidative phosphorylation in lung adenocarcinoma via regulating alternative splicing.

BACKGROUND: Circular RNAs (circRNAs) contribute to multiple biological functions and are also involved in pathological conditions such as cancer. However, the role of circRNAs in metabolic reprogramming, especially upon energy stress in lung adenocarcinoma (LUAD), remains largely unknown. METHODS: Energy stress-induced circRNA was screened by circRNA profiling and glucose deprivation assays. RNA-seq, real-time cell analyzer system (RTCA) and measurement of oxygen consumption rate (OCR) were performed to explore the biological functions of circZFR in LUAD. The underlying mechanisms were investigated using circRNA pull-down, RNA immunoprecipitation, immunoprecipitation and bioinformatics analysis of alternative splicing. Clinical implications of circZFR were assessed in 92 pairs of LUAD tissues and adjacent non-tumor tissues, validated in established patient-derived tumor xenograft (PDTX) model. RESULTS: CircZFR is induced by glucose deprivation and is significantly upregulated in LUAD compared to adjacent non-tumor tissues, enhancing oxidative phosphorylation (OXPHOS) for adaptation to energy stress. CircZFR is strongly associated with higher T stage and poor prognosis in patients with LUAD. Mechanistically, circZFR protects heterogeneous nuclear ribonucleoprotein L-like (HNRNPLL) from degradation by ubiquitination to regulate alternative splicing, such as myosin IB (MYO1B), and subsequently activates the AKT-mTOR pathway to facilitate OXPHOS. CONCLUSION: Our study provides new insights into the role of circRNAs in anticancer metabolic therapies and expands our understanding of alternative splicing.

Construction of an m6A-related lncRNA model for predicting prognosis and immunotherapy in patients with lung adenocarcinoma.

N6-methyladenosine (m6A)-related lncRNAs could be involved in the development of multiple tumors with an unknown role in lung adenocarcinoma (LUAD). Hence, gene expression data and clinical data of LUAD patients were acquired from The Cancer Genome Atlas Database. The prognostic m6A-related lncRNAs were identified through differential lncRNA expression analysis and Spearman's correlation analysis. The least absolute shrinkage and selection operator regression was used to establish the prognostic risk model, so as to evaluate and validate the predictive performance with survival analysis and receiver operating characteristic curve analysis. The expression of immune checkpoints, immune cell infiltration and drug sensitivity of patients in different risk groups were analyzed separately. A total of 19 prognostic m6A-related lncRNAs were identified to set up the prognostic risk model. The patients were divided into high- and low-risk groups based on the median value of the risk scores. Compared with the patients in the low-risk group, the prognosis of the patients in the high-risk group was relatively worse. The receiver operating characteristic curves indicated that this model had excellent sensitivity and specificity. Multivariate Cox regression analysis demonstrated that the risk score could be supposed as an independent prognostic risk factor. We highlighted that the risk scores were correlated with immune cell infiltration and drug sensitivity for constructing a prognostic risk model in LUAD patients based on m6A-related lncRNAs.

Immunotherapy for bilateral multiple ground glass opacities: An exploratory study for synchronous multiple primary lung cancer.

Background: Bilateral multiple ground glass opacities (GGOs) are observed in quite a part of patients with early-stage lung adenocarcinoma. For this so-called synchronous multiple primary lung cancer (sMPLC), targeting immune checkpoint is a favorable option in addition to surgical resection. The purpose of this study is to reveal the safety and efficacy of performing immune checkpoint inhibitors (ICIs) on patients with sMPLC and to explore the biomarkers of the efficacy. Methods: A total of 21 patients with sMPLC were enrolled and all included cases were pathologically confirmed adenocarcinoma after conducting surgical treatment for unilateral GGOs. ICIs of Sintilimab were then used to target programmed death 1 (200mg i.v., Q3W) for up to 10 cycles. Seven patients of them received the other surgery for contralateral GGOs, and multiomics assessments, including neoantigens, somatic mutations, and methylated loci, were further performed to investigate potential biomarkers. Results: Grade 1 or 2 treatment-related adverse events (AEs) occurred in most of the patients (12/21, 57.1%), and one subject withdrawn for grade 3 AEs. For the seven patients underwent twice surgeries, twelve and thirteen GGOs were achieved before and after the use of ICIs separately, and a favorable efficacy was observed among six lesions after immunotherapy (> 50% pathologic tumor regression). Tumor infiltration T-cell and B-cell were further shown to be associated with the biological activity of ICIs. According to mechanism-based multiomics analyses, MUC19- and PCDHB5- mutations were indicated to correlate with a favorable prognosis of sMPLC underwent immunotherapy, and our results suggested that immunogenetic mutation and associated promoter methylation could provide a quantitative explanation for the pathologic response of GGOs. Conclusion: Our study provides evidence that the use of ICIs contributed favorable efficacy and safety to patients with sMPLC. Immune infiltration and immunogenic biomarkers are revealed to be implications of performing ICIs on sMPLC. These preliminary findings exhibit the prospects in performing neoadjuvant or adjuvant immunotherapies on patients with sMPLC. Clinical Trial Registration: https://www.chictr.org.cn/showproj.aspx?proj=36878, identifier ChiCTR1900022159.

Circulating tumor DNA integrating tissue clonality detects minimal residual disease in resectable non-small-cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has been proven as a marker for detecting minimal residual diseases following systemic therapies in mid-to-late-stage non-small-cell lung cancers (NSCLCs) by multiple studies. However, fewer studies cast light on ctDNA-based MRD monitoring in early-to-mid-stage NSCLCs that received surgical resection as the standard of care. METHODS: We prospectively recruited 128 patients with stage I-III NSCLCs who received curative surgical resections in our Lung Cancer Tempo-spatial Heterogeneity prospective cohort. Plasma samples were collected before the surgery, 7 days after the surgery, and every 3 months thereafter. Targeted sequencing was performed on a total of 628 plasma samples and 645 matched tumor samples using a panel covering 425 cancer-associated genes. Tissue clonal phylogeny of each patient was reconstructed and used to guide ctDNA detection. RESULTS: The results demonstrated that ctDNA was more frequently detected in patients with higher stage diseases pre- and postsurgery. Positive ctDNA detection at as early as 7 days postsurgery identified high-risk patients with recurrence (HR = 3.90, P < 0.001). Our results also show that longitudinal ctDNA monitoring of at least two postsurgical time points indicated a significantly higher risk (HR = 7.59, P < 0.001), preceding radiographic relapse in 73.5% of patients by a median of 145 days. Further, clonal ctDNA mutations indicated a high-level specificity, and subclonal mutations informed the origin of tumor recurrence. CONCLUSIONS: Longitudinal ctDNA surveillance integrating clonality information may stratify high-risk patients with disease recurrence and infer the evolutionary origin of ctDNA mutations.

LncRNA LINC00525 suppresses p21 expression via mRNA decay and triplex-mediated changes in chromatin structure in lung adenocarcinoma.

BACKGROUND: Emerging evidence suggests that long noncoding RNAs (lncRNAs) play crucial roles in various cancers. In the present study, we aim to investigate the function and molecular mechanism of an up-regulated and survival-associated lncRNA, LINC00525, in lung adenocarcinoma (LUAD). METHODS: The expression level of LINC00525 in tissues was determined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and in situ hybridization (ISH). The functional role of LINC00525 in LUAD was investigated using gain-and loss-of-function approaches, both in vivo and in vitro. RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), triplex-capture assay, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were used to investigate the potential underlying mechanisms involved. RESULTS: LINC00525 is highly expressed in LUAD cells and tissues. Survival analysis indicated that upregulation of LINC00525 was associated with poor prognosis in patients with LUAD patients. Knockdown of LINC00525 inhibited cell proliferation and cell cycle progression in vitro. In xenograft models, LINC00525 knockdown suppressed tumor growth and tumorigenesis of tumor-bearing mice. Mechanistically, LINC00525 epigenetically suppressed p21 transcription by guiding Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) to the p21 promoter through an formation of RNA-DNA triplex with the p21 promoter, leading to increased trimethylation of lysine 27 on histone 3 (H3K27me3) of the p21 promoter. In addition, LINC00525 repressed p21 expression post-transcriptionally by enhancing p21 mRNA decay. LINC00525 promoted p21 mRNA decay by competitively binding to RNA Binding Motif Single Stranded Interacting Protein 2 (RBMS2). CONCLUSION: Our findings demonstrate that LINC00525 promotes the progression of LUAD by reducing the transcription and stability of p21 mRNA in concert with EZH2 and RBMS2, thus suggesting that LINC00525 may be a potential therapeutic target for clinical intervention in LUAD.

FAM83H-AS1 is a noncoding oncogenic driver and therapeutic target of lung adenocarcinoma.

BACKGROUND: Little is known about noncoding oncogenes of lung adenocarcinoma (LUAD), and these potential drivers might provide novel therapeutic targets. METHODS: Since abnormally overexpression of oncogenic drivers is induced by genomic variation, we here utilized genomic, transcriptomic, and clinical prognosis data of The Cancer Genome Atlas (TCGA) LUAD datasets to discover novel drivers from long noncoding RNAs. We further used zebrafish models to validate the biological function of candidates in vivo. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends assay. RNA pull-down, RNA immunoprecipitation, quantitative mass spectrometry, and RNA sequencing assays were conducted to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) method and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1. RESULTS: The results suggest that FAM83H-AS1 is a potential oncogenic driver due to chromosome 8q24 amplification. Upregulation of FAM83H-AS1 results in poor prognosis of LUAD patients in both Jiangsu Cancer Hospital (JSCH) and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds HNRNPK to enhance the translation of antiapoptotic oncogenes RAB8B and RAB14. Experiments using CRISPRi-mediated xenografts and PDTX models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo. CONCLUSIONS: Our work demonstrates that FAM83H-AS1 is a noncoding oncogenic driver that inhibits LUAD apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis, which highlights the importance and potential roles that FAM83H-AS1 may serve as a novel therapeutic target for LUAD.

Long non-coding RNAs in lung cancer: implications for lineage plasticity-mediated TKI resistance.

The efficacy of targeted therapy in non-small-cell lung cancer (NSCLC) has been impeded by various mechanisms of resistance. Besides the mutations in targeted oncogenes, reversible lineage plasticity has recently considered to play a role in the development of tyrosine kinase inhibitors (TKI) resistance in NSCLC. Lineage plasticity enables cells to transfer from one committed developmental pathway to another, and has been a trigger of tumor adaptation to adverse microenvironment conditions including exposure to various therapies. More importantly, besides somatic mutation, lineage plasticity has also been proposed as another source of intratumoural heterogeneity. Lineage plasticity can drive NSCLC cells to a new cell identity which no longer depends on the drug-targeted pathway. Histological transformation and epithelial-mesenchymal transition are two well-known pathways of lineage plasticity-mediated TKI resistance in NSCLC. In the last decade, increased re-biopsy practice upon disease recurrence has increased the recognition of lineage plasticity induced resistance in NSCLC and has improved our understanding of the underlying biology. Long non-coding RNAs (lncRNAs), the dark matter of the genome, are capable of regulating variant malignant processes of NSCLC like the invisible hands. Recent evidence suggests that lncRNAs are involved in TKI resistance in NSCLC, particularly in lineage plasticity-mediated resistance. In this review, we summarize the mechanisms of lncRNAs in regulating lineage plasticity and TKI resistance in NSCLC. We also discuss how understanding these themes can alter therapeutic strategies, including combination therapy approaches to overcome TKI resistance.

circ5615 functions as a ceRNA to promote colorectal cancer progression by upregulating TNKS.

Circular RNAs (circRNAs), non-coding RNAs generated by precursor mRNA back-splicing of exons, have been reported to fulfill multiple roles in cancer. However, the role of quite a lot circRNAs in colorectal cancer (CRC) remains mostly unknown. Herein, we explored the expression profiles of circRNAs in 5 paired samples of CRC patients by microarray and noted a circRNA, hsa_circ_0005615 (circ5615), was significantly upregulated in CRC tissues. Circ5615 was derived from exon 2 of NFATC3 and its upregulation was tightly correlated with higher T stage and poor prognosis in CRC patients. Studies in vitro and in vivo demonstrated that knockdown of circ5615 in cancer cells inhibited proliferation and cell cycle acceleration, while overexpression promoted malignant phenotypes. Mechanistically, RNA immunoprecipitation, biotin-coupled probe pull-down and luciferase reporter assays revealed circ5615 effectively bound to miR-149-5p and might play a role like miR-149-5p sponge. Additionally, tankyrase (TNKS), regulator of ß-catenin stabilization, was identified as circ5615 downstream and the potential miR-149-5p targets by RNA-seq and bioinformatics analysis. We further verified the upregulation of ß-catenin and cyclin D1 induced by circ5615. Our results indicated that circ5615 exerted oncogenic function as competing endogenous RNA (ceRNA) of miR-149-5p to release TNKS and activated Wnt/ß-catenin pathway.

Four transcription profile-based models identify novel prognostic signatures in oesophageal cancer.

Oesophageal cancer (ESCA) is a clinically challenging disease with poor prognosis and health-related quality of life. Here, we investigated the transcriptome of ESCA to identify high risk-related signatures. A total of 159 ESCA patients of The Cancer Genome Atlas (TCGA) were sorted by three phases. In the discovery phase, differentially expressed transcripts were filtered; in the training phase, two adjusted Cox regressions and two machine leaning models were used to construct and estimate signatures; and in the validation phase, prognostic signatures were validated in the testing dataset and the independent external cohort. We constructed two signatures from three types of RNA markers by Akaike information criterion (AIC) and least absolute shrinkage and selection operator (LASSO) Cox regressions, respectively, and all candidate markers were further estimated by Random Forest (RFS) and Support Vector Machine (SVM) algorithms. Both signatures had good predictive performances in the independent external oesophageal squamous cell carcinoma (ESCC) cohort and performed better than common clinicopathological indicators in the TCGA dataset. Machine learning algorithms predicted prognosis with high specificities and measured the importance of markers to verify the risk weightings. Furthermore, the cell function and immunohistochemical (IHC) staining assays identified that the common risky marker FABP3 is a novel oncogene in ESCA.

Long Noncoding RNA SBF2-AS1 Is Critical for Tumorigenesis of Early-Stage Lung Adenocarcinoma.

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are deeply involved in the development of various cancers. This study identified that SBF2-AS1, an early-stage-specific lncRNA, is critical for the tumorigenesis of lung adenocarcinoma (LUAD). We first analyzed LUAD transcriptome data from The Cancer Genome Atlas and the GEO database by weighted gene co-expression network analysis (WGCNA). Five early LUAD-specific lncRNAs were filtered out, and only SBF2-AS1 was upregulated in LUAD. High expression of SBF2-AS1 indicates poor survival of LUAD, especially the early-stage LUAD, but not lung squamous cell carcinoma. SBF2-AS1 promotes LUAD cells proliferation in vitro, and RNA-sequencing data shows that many cell-cycle-related genes were downregulated after SBF2-AS1 knockdown. Mechanically, SBF2-AS1 could competitively bind with miR-338-3p and miR-362-3p to increase E2F1 expression. Finally, we show that the SBF2-AS1-miR-338-3p/362-3p-E2F1 axis could promote LUAD tumorigenesis in vitro and in vivo. Our study demonstrates that SBF2-AS1, an early-stage-specific lncRNA, promotes LUAD tumorigenesis by sponging miR-338-3p and miR-362-3p and increasing E2F1 expression. The SBF2-AS1-miR-338-3p/362-3p-E2F1 regulatory axis may serve as a prognostic marker and potential therapeutic target for LUAD.

[Cyclic RNA Molecule circ_0007766 Promotes the Proliferation of Lung Adenocarcinoma Cells by Up-regulating the Expression of Cyclin D1/CyclinE1/CDK4].

BACKGROUND: Cyclic RNA (circRNA) is a new type of non-coding RNA (ncRNA) which is different from traditional linear RNA. More and more studies suggest that circRNA can be used as a biological marker of many malignant tumors and becomes a potential target for treatment. Therefore, searching for new molecular targets of lung adenocarcinoma from the circRNA will help to reveal the new mechanism of the occurrence and development of lung adenocarcinoma, and provide new ideas for clinical diagnosis and treatment. In this study, the biological function of circ_0007766, a highly expressed circRNA found in a screen of lung adenocarcinoma tissue, was verified and analyzed in vitro, so as to preliminarily explore the mechanism of circ_0007766 in promoting the proliferation of lung adenocarcinoma. METHODS: The expression level of circ_0007766 in lung adenocarcinoma cells was detected by qPCR. Then siRNA was used to knock down the expression of circ_0007766. The effects of knockdown of circ_0007766 on proliferation, cell cycle and apoptosis of lung adenocarcinoma cells were detected by CCK8, scratch test, PI staining and Annexin V/PI double staining. In addition, the biological mechanism of circ_0007766 in lung adenocarcinoma was preliminarily studied by qPCR and Western blots. RESULTS: The expression of circ_0007766 in lung adenocarcinoma cell lines was detected by qPCR. The expression of circ_0007766 was interfered in SPCA-1 cells. The proliferation and migration abilities of cells were inhibited. The cell cycle was arrested in G0/G1 phase, but the apoptosis was not affected. The deletion of circ_0007766 did not affect the expression of ERBB2, but influenced the mRNA and protein expression of Cyclin D1/Cyclin E1/CDK4. CONCLUSIONS: In vitro functional studies have shown that circ_0007766 may promote the proliferation and migration of lung adenocarcinoma cells. Further molecular mechanism studies have found that circ_0007766 can up-regulate the expression of Cyclin D1/Cyclin E1/CDK4, which are the key proteins of cell cycle, and thus promote the malignant proliferation of lung adenocarcinoma. From the perspective of circRNA, this study will provide new clues for the pathogenesis, development and prognosis of lung adenocarcinoma, and provide new target for clinical treatment.

H3K27 trimethylation and H3K9 dimethylation as poor prognostic markers for patients with esophageal squamous cell carcinoma.

BACKGROUND: Esophageal cancer (EC) is the fourth most commonly diagnosed cancer in males and the fifth in females in China. Dysregulation methylation of histone is now considered a biomarker for cancer prognosis. METHODS: In this study, we focused on exploring the expression patterns of two repressor histone methylation marks, H3K9 dimethylation (H3K9me2) and H3K27 trimethylation (H3K27me3), to provide potential biomarkers for diagnosis and therapies in esophageal squamous cell carcinoma (ESCC). RESULTS: After analyzing the relationship between the expression pattern of H3K27me3 and the clinic-pathological features of ESCC tissues, we found that upregulated H3K27me3 correlated with advanced T stage and N stage. A multivariate Cox regression analysis showed H3K27me3 expression, T stage and N stage were all independent factors for the poor prognosis of ESCC. Therefore, H3K27me3 can be considered an independent factor for predicting the prognosis of ESCC. CONCLUSIONS: Chromatin remodeling, especially the methylation of H3, plays a vital role in ESCC development and is a potential therapeutic target.

Long noncoding RNA AFAP1-AS1 is upregulated in NSCLC and associated with lymph node metastasis and poor prognosis.

Long noncoding RNA (lncRNA) has been indicated to have an important role in various types of malignant tumors; however, only a small number of lncRNAs have been entirely elucidated. In the present study, a novel lncRNA, actin filament associated protein 1 antisense RNA 1 (AFAP1-AS1), was investigated, which is highly expressed in non-small cell lung cancer (NSCLC). Reverse transcription-quantitative polymerase chain reaction and in situ hybridization were performed to detect AFAP1-AS1 expression in frozen tissues and tissue microarrays, respectively. The results revealed that the expression level of AFAP1-AS1 was significantly increased in tumor tissues, compared with the paired non-cancerous tissues. It was also determined that the AFAP1-AS1 expression level was higher in patients with lymph node metastasis than those without lymph node metastasis (P=0.014). Kaplan-Meier analysis was conducted to evaluate the overall survival of patients with NSCLC and different expression levels of AFAP1-AS1, and the results indicated that patients with high AFAP1-AS1 expression had a reduced survival time, compared with those with low AFAP1-AS1 expression (P=0.011). Cox regression analysis was also performed to analyze the prognostic value of lncRNA AFAP1-AS1. The obtained data demonstrated that lncRNA AFAP1-AS1 was an unfavorable prognostic biomarker for NSCLC (HR: 3.12, 95% CI (1.05-9.25), P=0.040). In conclusion, it was demonstrated that lncRNA AFAP1-AS1 is overexpressed in NSCLC and an unfavorable biomarker for patients with NSCLC.

Profiling expression of coding genes, long noncoding RNA, and circular RNA in lung adenocarcinoma by ribosomal RNA-depleted RNA sequencing.

Noncoding RNA play important roles in various biological processes and diseases, including cancer. The expression profile of circular RNA (circRNA) has not been systematically investigated in lung adenocarcinoma (LUAD). In this study, we performed genomewide transcriptome profiling of coding genes, long noncoding RNA (lncRNA), and circRNA in paired LUAD and nontumor tissues by ribosomal RNA-depleted RNA sequencing. The detected reads were first mapped to the human genome to analyze expression of coding genes and lncRNA, while the unmapped reads were subjected to a circRNA prediction algorithm to identify circRNA candidates. We identified 1282 differentially expressed coding genes in LUAD. Expression of 19 023 lncRNA was detected, of which 244 lncRNAs were differentially expressed in LUAD. AFAP1-AS1, BLACAT1, LOC101928245, and FENDRR were most differentially expressed lncRNAs in LUAD. Also identified were 9340 circRNA candidates with ≥ 2 backspliced, including 3590 novel circRNA transcripts. The median length of circRNA was ~ 530 nt. CircRNA are often of low abundance, and more than half of circRNAs we identified had < 10 reads. Agarose electrophoresis and Sanger sequencing were used to confirm that four candidate circRNA were truly circular. Our results characterized the expression profile of coding genes, lncRNA, and circRNA in LUAD; 9340 circRNAs were detected, demonstrating that circRNA are widely expressed in LUAD. Database: The raw RNA sequencing data have been submitted to Gene Expression Omnibus (GEO) database and can be accessed with the ID GEO: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104854.

Upregulated long non-coding RNA SBF2-AS1 promotes proliferation in esophageal squamous cell carcinoma.

Esophageal cancer is one of the most common types of malignant tumors located within the digestive system, with >50% of esophageal cancer cases worldwide occurring in China. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are frequently dysregulated in cancer; however, few lncRNAs have been characterized in esophageal squamous cell carcinoma (ESCC). In the present study, a novel lncRNA, SET-binding factor 2 (SBF2) antisense RNA1 (SBF2-AS1) was exhibited in ESCC. Expression levels of SBF2-AS1 in ESCC and adjacent non-cancerous tissues were detected using the reverse transcription-quantitative polymerase chain reaction. SBF2-AS1 was knocked down, and proliferation, migration, invasion, apoptosis and the cell cycle were examined in ESCC cells. Results identified that SBF2-AS1 was significantly upregulated in ESCC compared with adjacent non-cancerous tissues (fold increase, 8.82; P=0.023). The SBF2-AS1 expression level was significantly increased in patients who had a smoking (9.927 vs. 4.507; P=0.030) and/or drinking (10.938 vs. 4.232; P=0.032) history. Patients with a large tumor size exhibited increased SBF2-AS1 expression (≥4 vs. <4 cm, 14.898 vs. 5.435; P=0.018). Patients with advanced ESCC exhibited increased upregulation of SBF2-AS1 [tumor-node-metastasis (TNM) I-II vs. TNM III-IV, 1.302 vs. 15.475; P<0.01]. SBF2-AS1 was also silenced using small interfering RNA. Cell proliferative and invasive ability were significantly inhibited (P<0.05) following SBF2-AS1 silencing, the cell cycle was arrested in the G2 phase; however, there was no significant difference in the proportion of apoptotic cells. Gene Set Enrichment Analysis revealed that genes associated with cell cycle biological processes, including the cancer suppressor gene cyclin-dependent kinase 1A (CDKN1A), were significantly associated with SBF2-AS1 in ESCC tissues. Further validation confirmed that CDKN1A expression levels were increased in ECA-109 cells following SBF2-AS1 silencing. The results of the present study demonstrate that SBF2-AS1 is significantly upregulated in ESCC, and that silencing of SBF2-AS1 inhibits the proliferative and invasive ability of ESCC cells. SBF2-AS1 may be a novel biomarker and therefore a potential therapeutic target for ESCC.

The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma.

Somatic copy number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma, we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in lung adenocarcinoma tissues, in part due to amplification of the 3q26.2 locus, and promoted proliferation and tumorigenesis of lung adenocarcinoma. circPRKCI functioned as a sponge for both miR-545 and miR-589 and abrogated their suppression of the protumorigenic transcription factor E2F7 Intratumor injection of cholesterol-conjugated siRNA specifically targeting circPRKCI inhibited tumor growth in a patient-derived lung adenocarcinoma xenograft model. In summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in patients with lung adenocarcinoma.Significance: These findings reveal high expression of the circular RNA circPRKCI drives lung adenocarcinoma tumorigenesis. Cancer Res; 78(11); 2839-51. ©2018 AACR.

Stereotactic ablative radiotherapy versus lobectomy for stage I non-small cell lung cancer: A systematic review.

BACKGROUND: There is debate regarding the use of stereotactic ablative radiotherapy (SABR) or surgery for patients with early stage non-small cell lung cancer (NSCLC). This meta-analysis compared the clinical efficacy of SABR and lobectomy in stage I NSCLC patients. METHODS: An online search identified eight eligible articles (including 2 trials and 7 cohort studies) for inclusion. The odds ratio (OR) was used as a summary statistic. Overall survival (OS), cause-specific survival (CSS), and recurrence-free survival (RFS) were selected to calculate ORs with 95% confidence intervals (CI). Fixed-effects or random-effects models were conducted according to study heterogeneity. RESULTS: There were no significant differences between SABR and lobectomy in terms of one-year OS or CSS. Significant benefits of surgery were observed in three-year OS (OR 2.11, 95% CI 1.55-2.86), three-year CSS (OR 1.94, 95% CI 1.05-3.57), three-year RFS (OR 1.63, 95% CI 1.12-2.36), and five-year OS (OR 2.40, 95% CI 1.71-3.36). In addition, lobectomy demonstrated a beneficial trend in one-year RFS, five-year RFS, and CSS. CONCLUSION: Meta-analyses of current evidence suggested that lobectomy provides better long-term survival outcomes for stage I NSCLC patients.

Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number.

BACKGROUND: Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS). METHODS: Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation. RESULTS: OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n ≤ 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n ≤ 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n ≤ 3). CONCLUSIONS: In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n ≤ 3).

Roles of RNA methylation by means of N6-methyladenosine (m6A) in human cancers.

Reversible methylation by means of N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian mRNA. This RNA chemical mark is created by proteins that are m6A "writers" and can be reversed by proteins that are m6A "erasers" (i.e., demethylases). Some other proteins serving as "readers" can recognize m6A-containing mRNA and regulate downstream molecular mechanisms accordingly. Although m6A bases in RNA perform critical functions in important biological processes, their roles in cancer biology and cancer stem cells remain largely unknown. In this review, we focus on the m6A-associated mechanisms and modification landscapes in several major malignant tumors. Global and detailed analyses were both conducted on relevant high-throughput sequencing data. Possible interventions against m6A demethylases are also explored in this review, which may be advantageous for the treatment of m6A related cancers.