Metabolism-Regulating Nanozyme System for Advanced Nanocatalytic Cancer Therapy.

Nanocatalytic therapy, an emerging approach in cancer treatment, utilizes nanomaterials to initiate enzyme-mimetic catalytic reactions within tumors, inducing tumor-suppressive effects. However, the targeted and selective catalysis within tumor cells is challenging yet critical for minimizing the adverse effects. The distinctive reliance of tumor cells on glycolysis generates abundant lactate, influencing the tumor's pH, which can be manipulated to selectively activate nanozymatic catalysis. Herein, small interfering ribonucleic acid (siRNA) targeting lactate transporter-mediated efflux is encapsulated within the iron-based metal-organic framework (FeMOF) and specifically delivered to tumor cells through cell membrane coating. This approach traps lactate within the cell, swiftly acidifying the tumor cytoplasm and creating an environment for boosting the catalysis of the FeMOF nanozyme. The nanozyme generates hydroxyl radical (·OH) in the reversed acidic environment, using endogenous hydrogen peroxide (H2 O2 ) produced by mitochondria as a substrate. The induced cytoplasmic acidification disrupts calcium homeostasis, leading to mitochondrial calcium overload, resulting in mitochondrial dysfunction and subsequent tumor cell death. Additionally, the tumor microenvironment is also remodeled, inhibiting migration and invasion, thus preventing metastasis. This groundbreaking strategy combines metabolic regulation with nanozyme catalysis in a toxic drug-free approach for tumor treatment, holding promise for future clinical applications.

Suppression of the long non-coding RNA LINC01279 triggers autophagy and apoptosis in lung cancer by regulating FAK and SIN3A.

Long non-coding RNAs play critical roles in the development of lung cancer by functioning as tumor suppressors or oncogenes. Changes in the expression of LINC01279 have been associated with cell differentiation and human diseases. However, the mechanism underlying LINC01279 activity in tumorigenesis is not clear. Here, we analyzed the function of LINC01279 in lung adenocarcinoma using clinical samples, xenografts, and non-small-cell lung cancer cell lines. We found that LINC01279 is highly expressed in lung adenocarcinoma and may be considered as a predictive factor for this cancer. Knockdown of LINC01279 prevents tumor growth in xenografts and in cancer cell lines by activating autophagy and apoptosis. Molecularly, we revealed that LINC01279 regulates the expression of focal adhesion kinase and extracellular-regulated kinase signaling. In addition, it complexes with and stabilizes the transcriptional co-repressor SIN3A protein. Suppression of focal adhesion kinase and SIN3A also induces apoptosis and prevents tumor progression, suggesting that they may at least in part mediate the oncogenic activity of LINC01279. These results identify LINC01279 as a possible oncogene that plays an important role in the development of lung cancer. Our findings provide insights into the mechanism underlying LINC01279-mediated oncogenesis of lung adenocarcinoma. They may help to discover potential therapeutic targets for cancer diagnosis and prognosis.

Circular RNA-mediated ceRNA network was identified in human lung adenocarcinoma by high-throughput sequencing.

OBJECTIVES: Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD). METHODS: This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second-generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected. RESULTS: We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA-microRNA (miRNA)-messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer-related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP-activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD. CONCLUSIONS: These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD.

Melatonin inhibits HCC progression through regulating the alternative splicing of NEMO.

Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tumor growth through regulating RNA alternative splicing remains largely unknown. Here we demonstrated that melatonin could inhibit the growth of HCC. Mechanistically, melatonin induced transcriptional alterations of genes, which are involved in DNA replication, DNA metabolic process, DNA repair, response to wounding, steroid metabolic process, and extracellular matrix functions. Importantly, melatonin controlled numerous cancer-related RNA alternative splicing events, regulating mitotic cell cycle, microtubule-based process, kinase activity, DNA metabolic process, GTPase regulator activity functions. The regulatory effect of melatonin on alternative splicing is partially mediated by melatonin receptor MT1. Specifically, melatonin regulates the splicing of IKBKG (NEMO), an essential modulator of NF-κB. In brief, melatonin increased the production of the long isoform of NEMO-L with exon 5 inclusion, thereby inhibiting the growth of HepG2 cells. Collectively, our study provides a novel mechanism of melatonin in regulating RNA alternative splicing, and offers a new perspective for melatonin in the inhibition of cancer progression.

MiR-22-3p suppresses cell growth via MET/STAT3 signaling in lung cancer.

MiR-22-3p has been reported to be down-regulated in several cancers, but its expression pattern and roles in lung cancer is unclear. Given the crucial role of microRNAs in cancer progression, we examined the expression and function of miR-22-3p in lung adenocarcinoma. MiR-22-3p expression in lung cancer tissues and cell lines was measured by qRT-PCR. Cell proliferation was measured by WST-1 and colony formation assays were used to reveal the role of miR-22-3p in lung cancer in vitro. MiR-22-3p was notably down-regulated in lung cancer tissues as compared to normal lung tissues, but it was not associated with the clinical characteristics of tumor stage, differentiation and patient's smoking status. Colony formation ability and cell proliferation were suppressed by miR-22-3p mimics in lung cancer cell lines. Mechanistically, miR-22-3p mimics could reduce MET and STAT3 protein expression and induce apoptosis as measured by PARP protein. We conclude that miR-22-3p may play a tumor suppressor role via inhibiting MET-STAT3 signaling and have potential to be a therapeutic target and biomarker in lung adenocarcinoma.

LINC00857 promotes the proliferation of pancreatic cancer via MET, STAT3, and CREB.

BACKGROUND: Long non-coding RNA (lncRNA) LINC00857 promotes cell proliferation in various cancers and is overexpressed in pancreatic cancer (PC). However, the role of LINC00857 in PC is yet to be clarified. METHODS: In this study, we used Gene Expression Profiling Interactive Analysis (GEPIA) to investigate transcriptional data of LINC00857 in different cancers. We determined LINC00857 expression in 4 PC cell lines, and one normal pancreatic cell line by quantitative real-time reverse transcription PCR (qRT-PCR). small interfering RNA (siRNA) was employed to specifically knockdown LINC00857 in BxPc3 and PANC1 cells. Cell proliferation was evaluated using WST-1. Western blotting analysis was used to detect the expression levels of downstream proteins of LINC00857. RESULTS: We revealed that the knockdown of LINC00857 in PC cell lines inhibited the proliferation of the PC cells. We found that LINC00857 downregulation was followed by the downregulation of oncogenic proteins mesenchymal-epithelial transition (MET), signal transducer and activator of transcription 3 (STAT3), and cAMP response element-binding protein (CREB). CONCLUSIONS: Our study indicated that LINC00857 regulated the expression of STAT3 and CREB via regulating the expression of MET, and consequently promoted the growth of PC cells. The results allowed us to deepen our understanding of the pathogenesis of PC and provided a potential target for the clinical treatment of PC.

LINC00857 Interacting with YBX1 to Regulate Apoptosis and Autophagy via MET and Phosphor-AMPKa Signaling.

Long noncoding RNA (lncRNA) LINC00857 has been reported to be upregulated in lung cancer and related to poor patient survival. It can regulate cell proliferation and tumor growth in lung cancer as well as several other cancers. However, the underlying molecular mechanisms that are regulated by LINC00857 are unclear. In this study, we found that LINC00857 silencing can impair cell proliferation in 14 different genomic alterations of lung cancer cell lines. These alterations are EGFR, KRAS, TP53, MET, and LKB1 mutations. The cell apoptosis and autophagy were induced upon LINC00857 silencing in lung cancer cells. Mechanistically, LINC00857 can bind to the Y-box binding protein 1 (YBX1) protein, prevent it from proteasomal degradation, and increase its nuclear translocation. LINC00857 regulated MET expression via YBX1 at a transcriptional level. Induced cell autophagy by LINC00857 knockdown was mainly through increased phosphor-AMP-activated protein kinase (p-AMPK)a. Collectively, LINC00857-YBX1-MET/p-AMPKa signaling is critical to regulate cell proliferation, apoptosis, and autophagy, which may provide a potential clinically therapeutic target in lung cancer.

The Clinical Characteristics and Prognosis of Different Age Patients with Lung Cancer.

OBJECTIVE: Cancer is closely related to age, and the incidence of cancer increases with age. However, there are few studies on the relationship between age and clinical characteristics of lung cancer. PATIENTS AND METHODS: We collected all the consecutive lung cancer cases from 2012 to 2017 in our hospital and divided them into 6 groups according to their ages: ≤40 y/o, 41~50 y/o, 51~60 y/o, 61~70 y/o, 71~80 y/o and >80 y/o. The clinical characteristics and prognosis of these patients were evaluated. RESULTS: There were 1143 cases diagnosed in our hospital from 2012 to 2017. There were more non-smokers (p<0.01), stage IV (p<0.01) and anaplastic lymphoma kinase (ALK) fusion (p<0.01) patients but less stage I patients in ≤40 y/o group compared with other age groups. It seemed that older patients were more likely had co-exist driver gene mutations (p=0.04). There was no significant difference in overall survival (OS) among these 6 age groups. However, the age may be an independent prognostic factor compared with the patients in ≤40 y/o group, the patients in >80 y/o group were associated with a higher mortality risk, while the patients in other groups had the similar mortality risk. CONCLUSION: There are some differences in clinical characteristics and prognosis among different age groups. The reasons behind the phenomenon are largely unclear. The age should be taken into account when we develop clinical trials.

Lnc-MAP6-1:3 knockdown inhibits osteosarcoma progression by modulating Bax/Bcl-2 and Wnt/ß-catenin pathways.

Osteosarcoma (OS) is the most common type of malignant bone tumor that affects children and adolescents. Still, the cellular and molecular mechanisms driving the development of this disease remain poorly understood. In this study, numerous dysregulated lncRNAs were identified by RNA-seq. As a result, we were able to find a novel lncRNA Lnc-MAP6-1:3 which is highly expressed in osteosarcoma. Using a set of approaches including gene knockdown, RT-PCR, oncogenic function assay and western blotting, we observed that knockdown of Lnc-MAP6-1:3 expression suppressed cell proliferation and colony formation, and promoted apoptosis in vitro. For the first time, we have identified that Lnc-MAP6-1:3 potentially influence the malignant behavior of osteosarcoma via Bax/Bcl-2 and Wnt/ß-catenin signaling pathways. Henceforth, Lnc-MAP6-1:3 may provide a new molecular route of research and therapeutic applications for the diagnosis and treatment of osteosarcoma.

Concomitant genetic alterations are associated with response to EGFR targeted therapy in patients with lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered to be more effective than chemotherapy in the treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, in addition to EGFR-sensitive mutations, the genetic factors that affect the prognosis of patients who receive TKI treatment are not yet clear. METHODS: The clinical data of 36 NSCLC patients with EGFR mutation who received TKI treatment were retrospectively analyzed. Liquid re-biopsy with next generation sequencing (NGS) analysis was performed to analyze genetic alterations and potential resistance mechanisms. RESULTS: All of the patients harbored actionable sensitive EGFR mutations by NGS, with the major types being 19del or 21L858R (52.78%, 19/36 and 55.56%, 20/36, respectively). The 3 most frequent accompanying somatic mutations were TP53 (12, 48.4%), KRAS (7, 19.44%) and PIK3CA (3, 8.33%). Concomitant mutations were present in 16 patients (44.44%). The occurrence of co-mutation was found to be significantly related to a history of smoking [87.5% (7 of 8) vs. 32.14% (9 of 28); Pearson chi-square, P=0.005]. Patients who received EGFR-TKIs treatment (P=0.0079) or third-generation EGFR-TKIs only (P=0.0468) had better progression-free survival (PFS). Concomitant mutations were significantly related to lower objective response rates (43.75% vs. 80.0%; P=0.024) and poorer PFS (P<0.001). Patients with concomitant genetic alterations had a worse response after receiving EGFR-TKIs treatment (P=0.0033). CONCLUSIONS: Our research underscores the importance of using multiple molecular profiles. Concomitant genetic alterations were significantly associated with response to EGFR targeted therapy in NSCLC. Therefore, research on multi-drug or sequential therapy to address the covariation that drives drug resistance is urgently needed.

Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer.

The role of circular RNA in cancer is emerging. A newly reported circular RNA HIPK3 (circHIPK3) is critical in cell proliferation of various cancer types, although its role in non-small cell lung cancer (NSCLC), has yet to be elucidated. Our results provided evidence that silencing of circHIPK3 significantly impaired cell proliferation, migration, invasion and induced macroautophagy/autophagy. Mechanistically, we uncovered that autophagy was induced upon loss of circHIPK3 via the MIR124-3p-STAT3-PRKAA/AMPKa axis in STK11 mutant lung cancer cell lines (A549 and H838). STAT3 abrogation as well as transfection with a MIR124-3p mimic, recapitulated the induction of autophagy. We also demonstrated antagonistic regulation on autophagy between circHIPK3 and linear HIPK3 (linHIPK3). We therefore propose that the ratio between circHIPK3 and linHIPK3 (C:L ratio) may reflect autophagy levels in cancer cells. We observed that a high C:L ratio (>0.49) was an indicator of poor survival, especially in advanced-stage NSCLC patients. These results support that circHIPK3 is a key autophagy regulator in a subset of lung cancer and has potential clinical use as a prognostic factor. The circular RNA HIPK3 (circHIPK3) functions as an oncogene and autophagy regulator may potential use as a prognostic marker and therapeutic target in lung cancer.Abbreviations 3-MA: 3-methyladenine; AMPK: AMP-activated protein kinase; ATG7: autophagy related 7; Baf-A: bafilomycin A1; BECN1: beclin 1; circHIPK3: circular HIPK3; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HIPK3: homeodomain interacting protein kinase 3; IL6R: interleukin 6 receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NSCLC: non-small cell lung cancer; RFP: red fluorescent protein; RPS6KB1/S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; STK11: serine/threonine kinase 11.

Validation of a serum 4-microRNA signature for the detection of lung cancer.

BACKGROUND: Our previous studies have identified a serum-based 4-microRNA (4-miRNA) signature that may help distinguish patients with lung cancer (LC) from non-cancer controls (NCs). Here, we used an extended independent cohort of 398 subjects to further validate the diagnostic ability of this 4-miRNA signature. METHODS: Using quantitative reverse transcription polymerase chain reaction (qRT-PCR), expression of the 4-miRNAs was assessed in a total of 398 sera that included 213 LC patients and 185 NCs. A logistic regression model using training-test sets, receiver operating characteristic (ROC) curve analysis and t-test were used to test the impact of varying expression of these miRNAs on its diagnostic accuracy for LC. The cell proliferation and colony formation affected by these miRNAs, as well as gene ontology (GO) analysis of miRNA target genes were performed. RESULTS: The levels of the 4-miRNAs were significantly higher in the serum of patients with LCs as compared to NCs. Using a logistic regression prediction model based on training and test sets analysis, we obtained the area under the curve (AUC) of 0.921 [95% confidence interval (CI), 0.876-0.966] on the test set with specificity 90.6%, sensitivity 77.9%, accuracy 84.1%, positive predictive value (PPV) 89.8% and negative predictive value (NPV) 79.5%. CONCLUSIONS: We have verified that this serum 4-miRNA signature could provide a promising noninvasive biomarker for the prediction of LC, particularly in patients with indeterminate lung nodules on screening CT scans.

LncRNA MIR22HG abrogation inhibits proliferation and induces apoptosis in esophageal adenocarcinoma cells via activation of the STAT3/c-Myc/FAK signaling.

Long non-coding RNAs (lncRNAs) have involved in human malignancies and played an important role in gene regulations. The dysregulation of lncRNA MIR22HG has been reported in several cancers. However, the role of MIR22HG in esophageal adenocarcinoma (EAC) is poorly understood. Loss of function approaches were used to investigate the biological role of MIR22HG in EAC cells. The effects of MIR22HG on cell proliferation were evaluated by WST-1 and colony formation assays. The effects of MIR22HG on cell migration and invasion were examined using transwell assays. QRT-PCR and Western blot were used to evaluate the mRNA and protein expression of related genes. In this study, abrogation of MIR22HG inhibited cell proliferation, colony formation, invasion and migration in EAC 3 cell lines (OE33, OE19 and FLO-1). Mechanistically, MIR22HG silencing decreased the expression of STAT3/c-Myc/p-FAK proteins and induced apoptosis in EAC cell lines. These results delineate a novel mechanism of MIR22HG in EAC, and may provide potential targets by developing lncRNA-based therapies for EAC.

Serum microRNA Signature Is Capable of Early Diagnosis for Non-Small Cell Lung Cancer.

Despite decades of efforts, non-small-cell lung cancer (NSCLC) remains the leading cause of cancer mortality globally primarily due to the challenge in early detection of the cancer. Being an important player in cancer development, the dysregulated miRNAs have been shown promising values as non-invasive diagnostic and prognostic biomarkers for NSCLC. The aim of our study is to access the efficacy and reliability of a potential circulating miRNA panel in early diagnosis of NSCLC. We first selected eight candidate miRNAs, miR-146b, miR-205, miR-29c, miR-31, miR-30b, miR-337, miR-411, and miR-708, which have been shown frequently aberrant in primary NSCLC patients based on our previous studies and other reports. The serum level of each of these miRNAs was evaluated by quantitative real-time PCR (qRT-PCR) in training and testing sets. We found that 5 out of 8 miRNAs (miR-146b, miR-205, miR-29c, miR-30b, and miR-337) were significantly up-regulated in NSCLCs patients compared to healthy or cancer-free controls in both training and testing sets. Based on the logistic regression model, a 4-miRNAs set (miR-146b, miR-205, miR-29c and miR-30b) was picked out of the 5 miRNAs owing to its excellent diagnostic power for NSCLC patients in the training set (AUC=0.99, accuracy=95.00%), the testing set (AUC=0.93, accuracy=89.69%), and the training-testing combined set ( AUC=0.96, accuracy=92.00%). When pathological subtypes of NSCLC are compared, this 4-miRNA panel carried a relatively higher prediction power and higher sensitivity for adenocarcinoma (AC) (AUC=0.98, sensitivity=99.10%) than for squamous cell carcinoma (SCC) (AUC=0.93, sensitivity=90.32%). Additionally, this panel demonstrated a comparable diagnostic capacity for stage I (AUC=0.96) and stage II-III (AUC=0.95) of NSCLC, suggesting its role in reflecting the tumor load. Importantly, the high levels of miR-146b and miR-29c in serum were significantly associated with poor 5-year overall survival (OS) (both p=0.04). Further survival analysis showed that high level of miR-146b in serum is specifically correlated with poor survival rate in SCC patients (p=0.0035) but not in AC patients (p=0.83), consistent with our previous finding that the high tissue expression of miR-146b in lung cancer specimen is indicative of a poor prognosis for SCC patients. Altogether, our study demonstrated that the 4-miRNA panel is a novel, sensitive and non-invasive serum marker for the early diagnosis of NSCLC.

LINC00857 knockdown inhibits cell proliferation and induces apoptosis via involving STAT3 and MET oncogenic proteins in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is one of the leading causes of cancer-related death worldwide, and the molecular biology of this cancer remains poorly understood. Recent evidence indicates that long non-coding RNAs are dysregulated in a variety of cancers including EAC. In this study, siRNA mediated gene knockdown, Western blot, RT-PCR, as well as oncogenic function assay were performed. We found that the cell proliferation, colony formation, invasion and migration were decreased after LINC00857 knockdown in EAC cell lines. We also found that knockdown LINC00857 could induce apoptosis. Mechanistically, we found that the MET, STAT3, c-Myc and p-CREB proteins were decreased after LINC00857 knockdown. Our study suggests that LINC00857 may play an important oncogenic role in EAC via STAT3 and MET signaling.

Association Between Pretreatment Serum Apolipoprotein A1 and Prognosis of Solid Tumors in Chinese Population: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Serum apolipoprotein A1 (apoA1) has been reported to be abnormally expressed in several malignancies. However, the prognostic role of apoA1 in solid tumors is still controversial. We conducted this meta-analysis to obtain a more accurate evaluation of prognostic significance of apoA1 in Chinese patients with solid tumors. METHODS: A comprehensive literature search of electronic databases was carried out up to August 2018. We included studies investigating the association between pretreatment serum apoA1 level and clinicopathological features, including survival outcomes, in solid tumors. Hazard ratios (HRs) and odds ratio (ORs) with 95% confidence intervals (CIs) were applied as effect size estimates. RESULTS: A total of 13 studies and 8052 patients were included in our meta-analysis. Elevated level of pretreatment serum apoA1 was markedly associated with an improved OS (pooled HR = 0.608, 95% CI = 0.557 - 0.665, P < 0.001). The statistical significances were observed in all cancer types, including digestive system malignancies (pooled HR = 0.633; 95% CI = 0.550-0.727; P < 0.001), urinary system cancers (pooled HR = 0.471; 95% CI = 0.352-0.630; P < 0.001), nasopharyngeal cancer (pooled HR = 0.642; 95% CI = 0.538-0.766; P < 0.001) and non-small cell lung cancer (pooled HR = 0.526; 95% CI = 0.329-0.841; P = 0.007), but not in breast cancer (pooled HR = 0.573; 95% CI = 0.266-1.246; P = 0.155). Meanwhile, cancer patients with a low level of serum apoA1 suffered an unfavorable DFS (pooled HR = 0.714, 95% CI = 0.603 - 0.845, P < 0.001). Moreover, abnormal serum apoA1 was significantly correlated to tumor size (pooled OR = 0.640, 95% CI = 0.475 - 0.863, P = 0.003), tumor differentiation (pooled HR = 0.724, 95% CI = 0.565 - 0.929, P = 0.011), and tumor stage (pooled HR = 0.493, 95% CI = 0.384 - 0.633, P < 0.001). CONCLUSION: Elevated level of pretreatment serum apoA1 was significantly associated with longer survival in patients with solid tumors. Pretreatment serum apoA1 could serve as a novel positive factor for malignant patient prognosis in Chinese population.

Target-initiated synthesis of fluorescent copper nanoparticles for the sensitive and label-free detection of bleomycin.

Fluorescent copper nanoparticles (CuNPs) have received great attention due to their distinct characteristics of facile synthesis, tunable fluorescence emission, high photostability, and biological compatibility, and they have been widely used for chemical and biological analyses. Bleomycins (BLMs) are widely used antitumor agents for the clinical treatment of various cancers. Here, we develop a sensitive and label-free fluorescence method for the quantitative detection of BLM on the basis of BLM-initiated enzymatic polymerization-mediated synthesis of fluorescent CuNPs. We design two hairpin DNAs: one (Hp1) for the recognition of BLM and the other (Hp2) for signal amplification. In the presence of BLM, it may recognize and cleave the 5'-GC-3' site of the Hp1 stem, releasing the 8-17 DNAzyme fragment. The resultant 8-17 DNAzyme fragments may bind with the loop of Hp2 to form a partial double-stranded DNA (dsDNA) duplex, initiating the cyclic cleavage of Hp2 in the presence of Zn2+-dependent DNAzymes and generating numerous new DNA fragments with the free 3'-OH terminal, which can induce the formation of a poly(thymine) (poly-T) sequence with the assistance of terminal deoxynucleotidyl transferase (TdTase). Subsequently, the ploy-T sequence may function as the template for the synthesis of CuNPs with strong fluorescence emission. This method shows good selectivity and high sensitivity with a detection limit as low as 8.1 × 10-16 M, and it exhibits good performance in serum samples. Moreover, this method has distinct advantages of simplicity and low cost, holding great potential in clinical diagnosis and biomedical research.

Silencing of Long Noncoding RNA MIR22HG Triggers Cell Survival/Death Signaling via Oncogenes YBX1, MET, and p21 in Lung Cancer.

The long noncoding RNA (lncRNA) MIR22HG has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from RNA-Seq data and report that MIR22HG plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that MIR22HG was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival. MIR22HG bound and stabilized the YBX1 protein. Silencing of MIR22HG triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this MIR22HG network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers. MIR22HG played a tumor-suppressive role as indicated by inhibition of multiple cell cycle-related genes in human primary lung tumors. These data show that MIR22HG has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer.Significance: The lncRNA MIR22HG functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer. Cancer Res; 78(12); 3207-19. ©2018 AACR.

Overexpression of LINC00152 correlates with poor patient survival and knockdown impairs cell proliferation in lung cancer.

We employed RNA sequencing analysis to reveal dysregulated lncRNAs in lung cancer utilizing 461 lung adenocarcinomas and 156 normal lung tissues from 3 separate cohorts. We found that LINC00152 was highly overexpressed in lung tumors as compared to their adjacent normal tissues. Patients with high LINC00152 expression demonstrate a significantly poorer survival than those with low expression. We verified the diagnostic/prognostic potential of LINC00152 expression in an independent cohort of lung tumor tissues using quantitative RT-PCR. After knockdown of LINC00152 using siRNAs in lung cancer cell lines, both cell proliferation and colony formation were decreased. Cell fractionation and qRT-PCR analysis indicated that LINC00152 is found mainly in the cytoplasm. Treatment with Trichostatin A in cell lines having low LINC00152 expression indicated that histone acetylation may be one mechanism underlying LINC00152 overexpression in NSCLC. Western blot analyses indicated that p38a, STAT1, STAT3, CREB1, CCNE1 and c-MYC proteins were decreased after LINC00152 siRNA treatment. Our study indicates LINC00152 plays an important role in lung tumor growth and is potentially a diagnostic/prognostic marker. Further characterization of LINC00152 in regulating its target proteins may provide a novel therapeutic target of lung cancer.

Overexpression of FAM83H-AS1 indicates poor patient survival and knockdown impairs cell proliferation and invasion via MET/EGFR signaling in lung cancer.

Whole transcriptome analyses of next generation RNA sequencing (RNA-Seq) data from human cancer samples reveled thousands of uncharacterized non-coding RNAs including long non-coding RNA (lncRNA). Recent studies indicated that lncRNAs are emerging as crucial regulators in cancer processes and potentially useful as biomarkers for cancer diagnosis and prognosis. To delineate dysregulated lncRNAs in lung cancer, we analyzed RNA-Seq data from 461 lung adenocarcinomas (LUAD) and 156 normal lung tissues. FAM83H-AS1, one of the top dysregulated lncRNAs, was found to be overexpressed in tumors relative to normal lung and significantly associated with worse patient survival in LUAD. We verified this diagnostic/prognostic potential in an independent cohort of LUAD by qRT-PCR. Cell proliferation, migration and invasion were decreased after FAM83H-AS1 knockdown using siRNAs in lung cancer cells. Flow cytometry analysis indicated the cell cycle was arrested at the G2 phase after FAM83H-AS1 knockdown. Mechanistically, we found that MET/EGFR signaling was regulated by FAM83H-AS1. Our study indicated that FAM83H-AS1 plays an important role in lung tumor progression and may be potentially used as diagnostic/prognostic marker. Further characterization of this lncRNA may provide a novel therapeutic target impacting MET/EGFR signaling.