tiRNA-Gly-GCC-001 in major depressive disorder: Promising diagnostic and therapeutic biomarker.

BACKGROUND AND PURPOSE: In major depressive disorder (MDD), exploration of biomarkers will be helpful in diagnosing the disorder as well as in choosing a treatment and predicting the treatment response. Currently, tRNA-derived small ribonucleic acids (tsRNAs) have been established as promising non-invasive biomarker candidates that may enable a more reliable diagnosis or monitoring of various diseases. Herein, we aimed to explore tsRNA expression together with functional activities in MDD development. EXPERIMENTAL APPROACH: Serum samples were obtained from patients with MDD and healthy controls, and small RNA sequencing (RNA-Seq) was used to profile tsRNA expression. Dysregulated tsRNAs in MDD were validated by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic utility of specific tsRNAs and the expression of these tsRNAs after antidepressant treatment were analysed. KEY RESULTS: In total, 38 tsRNAs were significantly differentially expressed in MDD samples relative to healthy individuals (34 up-regulated and 4 down-regulated). qRT-PCR was used to validate the expression of six tsRNAs that were up-regulated in MDD (tiRNA-1:20-chrM.Ser-GCT, tiRNA-1:33-Gly-GCC-1, tRF-1:22-chrM.Ser-GCT, tRF-1:31-Ala-AGC-4-M6, tRF-1:31-Pro-TGG-2 and tRF-1:32-chrM.Gln-TTG). Interestingly, serum tiRNA-Gly-GCC-001 levels exhibited an area under the ROC curve of 0.844. Moreover, tiRNA-Gly-GCC-001 is predicted to suppress brain-derived neurotrophic factor (BDNF) expression. Furthermore, significant tiRNA-Gly-GCC-001 down-regulation was evident following an 8-week treatment course and served as a promising baseline predictor of patient response to antidepressant therapy. CONCLUSION AND IMPLICATIONS: Our current work reports for the first time that tiRNA-Gly-GCC-001 is a promising MDD biomarker candidate that can predict patient responses to antidepressant therapy.

Novel synergistic treatment for depression: involvement of GSK3ß-regulated AMPA receptors in the prefrontal cortex of mice.

Previous evidence has suggested a vital role of glycogen synthase kinase 3ß-mediated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors trafficking in depression. Considering the antidepressant effect of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors activation in the prefrontal cortex, we hypothesized that glycogen synthase kinase 3ß-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors function in the prefrontal cortex participate in depression. Herein, we confirmed that the levels of phosphorylated glycogen synthase kinase 3ß and GluA1, the latter being a subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, were decreased in the prefrontal cortex of the chronic social defeat stress model mice presenting with depressive-like behaviors. We then found that a glycogen synthase kinase 3ß (p.S9A) point mutation downregulated GluA1 and induced depressive-like behaviors in mice, whereas an agonist of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, PF-4778574 (2 mg/kg) did not reversed the molecular changes. On the other hand, the antidepressant effect of PF-4778574 was dose dependent, and the single administration of PF-4778574 at a lower dose (0.5 mg/kg) or of the glycogen synthase kinase 3ß inhibitor SB216763 (5 and 10 mg/kg) did not evoke an antidepressant effect. In contrast, co-treatment with PF-4778574 (0.5 mg/kg) and SB216763 (10 mg/kg) led to antidepressant effects similar to those of PF-4778574 (2 mg/kg). Our results suggest that glycogen synthase kinase 3ß-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors dysfunction in the prefrontal cortex is one of the key mechanisms of depression, and the combination of a lower dose of PF-4778574 with SB216763 shows potential as a novel synergistic treatment for depression.

The diagnostic potential of a circRNA-miRNA network in non-small cell lung cancer.

Increasing studies demonstrate the significant contributions of circRNA-related competitive endogenous RNA (ceRNA) regulatory networks to tumorigenesis and cancer progression. Here, we aimed to construct a non-small cell lung cancer (NSCLC)-specific circRNA-miRNA network and evaluate its diagnostic potential in NSCLC. MiRNA deep sequencing was performed to screen differentially-expressed serum miRNAs in NSCLC. Four bioinformatics databases (TargetScan, miRanda, starBase, and RNAhybrid) were used to analyze the integrated circRNA-miRNA interaction network. The circRNA-miRNA network, including hsa-miR-4482-3p, hsa-miR-146a-3p, hsa_circ_0008167 and hsa_circ_0003317 was constructed based on their interactions and preliminary testing in NSCLC cells. The relative levels of the selected non-coding RNAs (ncRNAs) were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) in the healthy, pneumonia, benign lung tumor and NSCLC cohorts. The diagnostic power of the circRNA-miRNA network was evaluated using receiver operating characteristic (ROC) analyses. The serum levels of hsa-miR-4482-3p, hsa-miR-146a-3p, hsa_circ_0008167, and hsa_circ_0003317 were dysregulated in NSCLC. The combination of the four ncRNAs showed the highest diagnostic value to discriminate between benign lung tumors and NSCLC. Additionally, the upregulated levels of hsa_circ_0008167 were correlated to more aggressive features of NSCLC, such as lymph node metastasis, distant metastasis, and higher stage. Furthermore, the combination of hsa_circ_0008167 + hsa-miR-4482-3p, and hsa_circ_0008167 + hsa-miR-4482-3p + hsa-miR-146a-3p had the greatest diagnostic power to differentiate between lymph node +/- metastases and higher/lower stages, respectively, compared to circRNAs or miRNAs alone, and traditional tumor markers. In conclusion, we identified a specific circRNA-miRNA network with higher sensitivity and specificity to diagnose NSCLC, thereby providing a new strategy for further development of ceRNA-related tumor markers in other cancers. KEY MESSAGES: Serum miR-4482-3p, miR-146a-3p, circ_0008167 and circ_0003317 are dysregulated in NSCLC. Higher levels of serum circ_0008167 are associated with more malignant NSCLC. Multiple combinations of circRNAs and miRNAs show higher value to diagnose NSCLC.

The molecular pathophysiology of depression and the new therapeutics.

Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long-lasting antidepressant effects in treatment-resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects.

The Therapeutic Potential of tRNA-derived Small RNAs in Neurodegenerative Disorders.

Gene expressions and functions at various levels, namely post-transcriptional, transcriptional, and epigenetic, can be regulated by transfer RNA (tRNA)-derived small RNAs (tsRNAs), which are as well-established as tRNA fragments or tRFs. This regulation occurs when tsRNAs are created through the special endonuclease-mediated cleavage of mature or precursor tRNAs. However, tsRNAs are newly discovered entities, and molecular functions associated with tsRNAs are still not clearly understood. There is increasingly robust evidence suggesting that specific tsRNAs perform fundamental tasks in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders. Indeed, the patterns of tsRNA expression are uncertain and could be altered in patients suffering from Parkinson's disease, pontocerebellar hypoplasia, amyotrophic lateral sclerosis, Alzheimer's disease, and other neurodegenerative disorders. In the present article, a review is conducted of recent domestic and international progress in research on the potential cellular and molecular mechanisms of tsRNA biogenesis. We also describe endogenous tsRNAs during neuronal development and neurodegenerative disorders, thereby providing theoretical support and guidance for further revealing the therapeutic potential of tsRNAs in neurodegenerative disorders.

PLA2G10 incorporated in exosomes could be diagnostic and prognostic biomarker for non-small cell lung cancer.

BACKGROUND: Exosomal cargos such as nucleic acids and proteins have been attracting major interest as promising diagnostic biomarkers of cancers. The aim of this study was to characterize the mRNA profiles of serum exosomes and to identify non-small cell lung cancer (NSCLC) related mRNAs with higher sensitivity and specificity to diagnose and predict prognosis of NSCLC. METHODS: mRNA microarray analysis was conducted to screen differentially expressed mRNAs in the serum exosomes of NSCLC patients. Selected exosomal mRNA candidate PLA2G10 and PLA2G10 protein were quantified by RT-qPCR and ELISA assay, respectively, in the sample cohorts of healthy, benign lung tumor and NSCLC. Receiver operating characteristic (ROC) analyses were performed to evaluate the diagnostic power of exosomal PLA2G10 mRNA and protein. Kaplan-Meier plots were used to estimate patients' overall and disease-free survival. RESULTS: Serum exosomal PLA2G10 mRNA levels were elevated in NSCLC patients, and were closely related to more aggressive characteristics (higher stages, lymphatic node metastasis and distant metastasis) and poor overall and disease-free survival of NSCLC patients. Intriguingly, PLA2G10 protein was proved to be incorporated in exosomes, and its expression patterns and relationship with clinical pathological factors were similar to exosomal PLA2G10 mRNA. Additionally, the levels of exosomal PLA2G10 mRNA and protein were positively correlated and their combination could improve the diagnostic power to discriminate less and more malignance of NSCLC. CONCLUSIONS: Increased levels of serum exosomal PLA2G10 mRNA and protein were associated with more aggressive features of NSCLC, suggesting their potential as diagnostic and prognostic biomarkers of NSCLC.

Serum exosomal hsa_circ_0069313 has a potential to diagnose more aggressive non-small cell lung cancer.

BACKGROUND: Circular RNAs (circRNAs) derived from exosomes are involved in the carcinogenesis and development of non-small cell lung cancer (NSCLC), showing great potential to be diagnostic biomarkers for NSCLC. METHODS: Serum exosomes were isolated with an exosome isolation kit, and verified by western blot, transmission electron microscopy and a potentiometric analyzer. Five differentially expressed exosomal circRNAs, including hsa_circ_0069313, hsa_circ_0063526, hsa_circ_0010522, hsa_circ_0048677 and hsa_circ_0001946, were selected based on the circRNA array analyses and the published documents in Pubmed. The serum and serum exosomal levels of the above five circRNAs were quantified by qRT-PCR. The diagnostic power of serum and serum exosomal hsa_circ_0069313 was evaluated by receiver operating characteristic (ROC) test. RESULTS: The levels of hsa_circ_0069313 in serum exosomes were statistically lower than those in the matched serum samples. In contrast, the levels of hsa_circ_0063526, hsa_circ_0010522, hsa_circ_0048677 and hsa_circ_0001946 showed no statistical difference in the sera and serum exosomes of healthy donors. The levels of serum and serum exosomal hsa_circ_0069313 were notably elevated in the NSCLC group compared to the healthy, pneumonia and benign lung tumor groups. Furthermore, serum and serum exosomal hsa_circ_0069313 could differ benign lung tumor and NSCLC with AUC values of 0.803 and 0.749, respectively. Intriguingly, the higher levels of serum exosomal hsa_circ_0069313 were associated with stage III-IV, lymph node metastasis and distant metastasis of NSCLC. CONCLUSIONS: Serum and serum exosomal hsa_circ_0069313 have the potential to discriminate NSCLC and benign lung tumor. The higher levels of serum exosomal hsa_circ_0069313 are linked to more aggressive pathological features of NSCLC.

Mechanism of bio-electrokinetic remediation of pyrene contaminated soil: Effects of an electric field on the degradation pathway and microbial metabolic processes.

In this study, the mechanism of bio-electrokinetic (BIO-EK) remediation to improve the degradation of pyrene was evaluated based on an analysis of the intermediate products and the microbial community. The results show that BIO-EK remediation has a higher pyrene degradation efficiency on pyrene and its intermediate products than the bioremediation and electrokinetic (EK) remediation processes. A series of intermediate products were detected. According to the type of the intermediate products, two degradation pathways, biological metabolism and electrochemical oxidation, are proposed in the BIO-EK remediation of pyrene. Furthermore, the primary microbial taxa involved in the pollutant degradation changed, which led to variations in the functional gene components. The abundant and functional genes related to metabolism were specifically analyzed. The results indicate that the electric field promotes the expression of metabolisms associated with 14 carbohydrates, 13 lipids, 13 amino acids, five energies, and in particular, 11 xenobiotics. These results suggest that in addition to the promotion effect on the microbial metabolism caused by the electric field, BIO-EK remediation can promote the degradation of pollutants due to the coexistence of a microbial metabolic pathway and an electrochemical oxidation pathway.

LncRNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 and predicts poor prognosis in lung cancer patients.

OBJECTIVE: The purpose of this study was to explore the function and gene expression regulation of the newly identified lncRNA DPP10-AS1 in lung cancer, and its potential value as a prognostic biomarker. METHODS: qRT-PCR and Western blot were conducted to detect the expression of DDP10-AS1 and DPP10 in lung cancer cell lines and tissues. The effects of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry, and xenograft animal experiments. RESULTS: The novel antisense lncRNA DPP10-AS1 was found to be highly expressed in cancer tissues (P < 0.0001), and its upregulation predicted poor prognosis in patients with lung cancer (P = 0.0025). Notably, DPP10-AS1 promoted lung cancer cell growth, colony formation, and cell cycle progression, and repressed apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitated lung tumor growth via upregulation of DPP10 protein in a xenograft mouse model. Importantly, DPP10-AS1 positively regulated DPP10 gene expression, and both were coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 was found to associate with DPP10 mRNA but did not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributed to their coordinate upregulation in lung cancer. CONCLUSIONS: These findings indicated that the upregulation of the antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10. DPP10-AS1 may serve as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

Inflammatory cytokines derived from peripheral blood contribute to the modified electroconvulsive therapy-induced cognitive deficits in major depressive disorder.

Little is known about the pathophysiology of memory deficits in patients with major depressive disorder (MDD) treated with modified electroconvulsive therapy (MECT). This study examined the profiles of cytokines, the memory function, and their association in MECT-treated MDD patients. Forty first-episode, drug-free MDD patients and 40 healthy controls were recruited. MECT was started with antidepressant treatment at a stable initial dose. The Wechsler Memory Scale (WMS) and Hamilton Rating Scale for Depression 17 (HRSD-17) were used to assess the cognitive function. MDD patients were divided into the memory impairment group (WMS < 50) and the non-memory impairment group (WMS ≥ 50) based on the total WMS scores after MECT. The levels of NOD-like receptor 3 (NLRP3) inflammasome, interleukin-18 (IL-18) and nuclear factor kappa-B (NF-κB) in the serum were measured. MDD patients showed significantly higher levels of NLRP3 inflammasome, IL-18 and NF-κB than that in the controls prior to MECT, and the levels also significantly increased after MECT. In MDD patients, the serum levels of these inflammatory cytokines were negatively associated with the total WMS scores and likely contributed to the scores independently. The receiver operating characteristic curve showed that the serum levels of these inflammatory cytokines may predict the cognitive impairment risk in MDD patients receiving MECT. Abnormal levels of NLRP3 inflammasome, IL-18 and NF-κB reflecting the disturbed balance of pro-inflammatory and anti-inflammatory mechanisms likely contribute to the MECT-induced cognitive deficits in MDD patients.

lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/ß-catenin signaling.

BACKGROUND: MicroRNAs (miRNAs) and Twist1-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination are well established, but the involvement of long noncoding RNAs (lncRNAs) in Twist1-mediated signaling remains largely unknown. METHODS: RT-qPCR and western blotting were conducted to detect the expression levels of lncRNA JPX and Twist1 in lung cancer cell lines and tissues. The impact of JPX on Twist1 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by western blotting, rescue experiments, colony formation assay, flow cytometry, and xenograft animal experiment. RESULTS: We observed that lncRNA JPX was upregulated in lung cancer metastatic tissues and was closely correlated with tumor size and an advanced stage. Functionally, JPX promoted lung cancer cell proliferation in vitro and facilitated lung tumor growth in vivo. Additionally, JPX upregulated Twist1 by competitively sponging miR-33a-5p and subsequently induced EMT and lung cancer cell invasion. Interestingly, JPX and Twist1 were coordinately upregulated in lung cancer tissues and cells. Mechanically, the JPX/miR-33a-5p/Twist1 axis participated in EMT progression by activating Wnt/ß-catenin signaling. CONCLUSIONS: These findings suggest that lncRNA JPX, a mediator of Twist1 signaling, could predispose lung cancer cells to metastasis and may serve as a potential target for targeted therapy.

CRL3-SPOP ubiquitin ligase complex suppresses the growth of diffuse large B-cell lymphoma by negatively regulating the MyD88/NF-κB signaling.

Recurrent oncogenic mutations of MyD88 have been identified in a variety of lymphoid malignancies. Gain-of-function mutations of MyD88 constitutively activate downstream NF-κB signaling pathways, resulting in increased cellular proliferation and survival. However, whether MyD88 activity can be aberrantly regulated in MyD88-wild-type lymphoid malignancies remains poorly understood. SPOP is an adaptor protein of CUL3-based E3 ubiquitin ligase complex and frequently mutated genes in prostate and endometrial cancers. In this study, we reveal that SPOP binds to and induces the nondegradative ubiquitination of MyD88 by recognizing an atypical SPOP-binding motif in MyD88. This modification blocks Myddosome assembly and downstream NF-κB activation. SPOP is mutated in a subset of lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). Lymphoid malignancies-associated SPOP mutants exhibited impaired binding to MyD88 and suppression of NF-κB activation. The DLBCL-associated, SPOP-binding defective mutants of MyD88 escaped from SPOP-mediated ubiquitination, and their effect on NF-κB activation is stronger than that of wild-type MyD88. Moreover, SPOP suppresses DLBCL cell growth in vitro and tumor xenograft in vivo by inhibiting the MyD88/NF-κB signaling. Therefore, SPOP acts as a tumor suppressor in DLBCL. Mutations in the SPOP-MyD88 binding interface may disrupt the SPOP-MyD88 regulatory axis and promote aberrant MyD88/NF-κB activation and cell growth in DLCBL.

Circulating lncRNA XLOC_009167 serves as a diagnostic biomarker to predict lung cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been proven to be involved in carcinogenesis and to be released into peripheral blood. Our objective was to develop a circulating lncRNA as a novel biomarker to predict lung cancer. METHODS: We analyzed the lncRNA expression profile in lung cancer patients by lncRNA array and identified lncRNA XLOC_009167 as a circulating biomarker using qRT-PCR in whole blood of lung cancer patients. The diagnostic value of was analyzed by area under curve (AUC) and the receiver operating characteristic (ROC) test. RESULTS: LncRNA XLOC_009167 was screened as a candidate biomarker for lung cancer and was up-regulated in both lung cancer tissues and cell lines. Notably, lncRNA XLOC_009167 in whole blood of lung cancer patients was highly expressed as compared with that in healthy controls or in patients with pneumonia. The values of AUC of lung cancer vs. healthy controls, and that of lung cancer vs. pneumonia were 0.7398 (95%CI = 0.6493 to 0.8303) and 0.7005 (95%CI = 0.5771 to 0.8240), respectively. Intriguingly, the ROC showed lncRNA XLOC_009167 was a better diagnostic potential compared to the traditional biomarkers (CYFR21-1, NSE and CA72-4), and the circulating lncRNA XLOC_009167 was found to be stable in whole blood under different conditions. CONCLUSIONS: LncRNA XLOC_009167 could serve as a novel diagnostic biomarker to distinguish lung cancer from benign lung disease and healthy controls.

[Circulating long noncoding RNAs as biomarkers in tumor diagnosis].

Long noncoding RNAs (lncRNAs) are involved in vital life processes of gene expression, epigenetic regulation and X-chromosome inactivation. lncRNAs are also closely associated with tumor initiation and progression. Moreover, lncRNAs may enter human circulation system in the form of microvesicle or exosome, or in combination with RNA binding protein. Interestingly, the circulating lncRNAs are widely existed in body fluids, such as blood and urine. We review the origin of circulating lncRNAs, and the detection methods as potential biomarkers. We focus on the early diagnosis value of circulating lncRNAs as tumor biomarkers in lung, breast, gastric, liver, colorectal and prostate cancers. Compared with the traditional biomarkers, the circulating lncRNAs show the unique advantages and clinical values as novel biomarkers.

Pecanex functions as a competitive endogenous RNA of S-phase kinase associated protein 2 in lung cancer.

Investigating the RNA-RNA interactions involving in the initiation and progression of non-small cell lung cancer (NSCLC) may provide promising diagnostic and targeted therapeutic strategies. Here, we showed that pecanex (PCNX) positively regulates the mRNA and protein expressions of S-phase kinase associated protein 2 (Skp2) in miRNA- and 3' UTR-dependent manners. And miR-26, miR-182, miR-340 and miR-506 were verified as the common miRNAs shared by Skp2 and PCNX. Intriguingly, we initially uncovered that PCNX-3' UTR promotes cell growth, proliferation and cell cycle progression, and suppresses apoptosis of lung cancer cells, which is consistent with the oncogenic activity of Skp2-3' UTR. Consequently, PCNX was identified as a competitive endogenous RNA (ceRNA) of Skp2. Moreover, knockdown of PCNX inhibits EGF-induced Akt phosphorylation, which can be reversed by the silencing of Dicer. Finally, we further discovered that Skp2 and PCNX are coordinately upregulated in lung cancer tissues compared with the adjacent non-tumor tissues. Our study establishes for the first time the oncogenic property of PCNX-3' UTR and Skp2-3' UTR, and the PCNX-miRNA-Skp2 regulatory pattern, which may offer a molecular basis for the diagnosis and targeted therapy in NSCLC.

Long and short noncoding RNAs in lung cancer precision medicine: Opportunities and challenges.

The long and short noncoding RNAs have been involved in the molecular diagnosis, targeted therapy, and predicting prognosis of lung cancer. Utilizing noncoding RNAs as biomarkers and systemic RNA interference as an innovative therapeutic strategy has an immense likelihood to generate novel concepts in precision oncology. Targeting of RNA interference payloads such as small interfering RNAs, microRNA mimetic, or anti-microRNA (antagomirs) into specific cell types has achieved initial success. The clinical trials of noncoding RNA-based therapies are on the way with some positive results. Many attempts are done for developing novel noncoding RNA delivery strategies that could overcome systemic or local barriers. Furthermore, it precipitates concerted efforts to define the molecular subtypes of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and reveal mechanisms of sensitivity and resistance to targeted therapies. These efforts contribute a visible effect now in lung cancer precision medicine: patients receive molecular testing to determine whether their tumor harbors an actionable come resistance to the first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Thus, ongoing and future efforts to find new vulnerabilities of lung cancers unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve the outcome of lung cancer patients.

Long Noncoding RNAs Regulate Cell Growth, Proliferation, and Apoptosis.

The revolutionary findings in nonprotein-coding part of human genome analysis have revealed a large number of RNA transcripts longer than 200 nucleotides that lack coding protein function, termed long noncoding RNAs (lncRNAs). Recently, accumulating shreds of evidence suggest that lncRNAs are widely distributed in human genome and deeply involved in cellular activities such as cell growth, proliferation, and apoptosis. Generally, lncRNAs regulate cell behaviors by targeting cell cycle-associated cyclins, cyclin-dependent kinases (CDKs), and/or CDK inhibitors. Specifically, lncRNAs serve as scaffolds or guides for chromatin-modifying complexes and act as signals in response to DNA damage. In addition, lncRNAs function as protein decoys and microRNA decoys, as well as interveners in cell division by modulating oncogenes and/or tumor suppressors. In this review, we mainly focus on the current understanding of the molecular mechanisms, how lncRNAs influence cellular processes and cancer progression. Finally, we also prospect the limitations of lncRNAs in cell behaviors and the novel roles of lncRNAs in epigenetic regulations.