Long non-coding RNA LSAMP-1 is down-regulated in non-small cell lung cancer and predicts a poor prognosis.

BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as master regulators for gene expression and thus play a vital role in human tumorigenesis and progression. But the involvement of novel lncRNAs in non-small cell lung cancer (NSCLC) remains largely unelucidated. METHODS: A total of 170 NSCLC and their adjacent non-tumor tissues were enrolled to detect the expression of Lnc-LSAMP-1 by RT-qPCR. The effects of Lnc-LSAMP-1 on cell proliferation, migration, invasion and drug-sensitivity were determined by in vitro and in vivo experiments. The proteins that interact with Lnc-LSAMP-1were confirmed by RNA pull-down assay. RNA-sequencing were used to identify the potential targets of Lnc-LSAMP-1 in NSCLC. RESULTS: We found that Lnc-LSAMP-1 was significantly down-regulated in 170 cases of NSCLC tissues when compared to their adjacent non-cancerous tissues. Loss expression of Lnc-LSAMP-1 was notably correlated with unfavorable prognosis of NSCLC patients. The ectopic expression of Lnc-LSAMP-1 drastically inhibited lung cancer cell proliferation, viability, invasion and migration ability, arrested cell cycle and facilitated apoptosis. Chemotherapy sensitization experiments showed that over-expressed Lnc-LSAMP-1 enhanced the inhibition of cell proliferation induced by TKI. Mechanistically, Lnc-LSAMP-1-LSAMP formed a complex which could protect the degradation of LSAMP gene, and thus exerted crucial roles in NSCLC progression and TKI targeted treatment. CONCLUSIONS: Consequently, our findings highlight the function and prognostic value of Lnc-LSAMP-1 in NSCLC and provide potential novel therapeutic targets and prognostic biomarkers for patients with NSCLC.

Discovery of a novel linc01125 isoform in serum exosomes as a promising biomarker for NSCLC diagnosis and survival assessment.

A non-invasive method to distinguish potential lung cancer patients would improve lung cancer prevention. We employed the RNA-sequencing analysis to profile serum exosomal long non-coding RNAs (lncRNAs) from non-small cell lung cancer (NSCLC) patients and pneumonia controls, and then determined the diagnostic and prognostic value of a promising lncRNA in four datasets. We identified 90 dysregulated lncRNAs for NSCLC and found the most significant lncRNA was a novel isoform of linc01125. Serum exosomal linc01125 could distinguish NSCLC cases from disease-free and tuberculosis controls, with the area under the curve values as 0.662 [95% confidence interval (CI) = 0.614-0.711] and 0.624 (95% CI = 0.522-0.725), respectively. High expression of exosomal linc01125 was also correlated with an unfavorable overall survival of NSCLC (hazard ratio = 1.48, 95% CI = 1.05-2.08). Clinic treatment decreased serum exosomal linc01125 in NSCLC patients (P = 0.036). Linc01125 functions to inhibit cancer growth and metastasis via acting as a competing endogenous RNA to up-regulate tumor necrosis factor alpha-induced protein 3 (TNFAIP3) expression by sponging miR-19b-3p. Notably, the oncogenic transformation of 16HBE led to decreased linc01125 in cells but increased linc01125 in cell-derived exosomes. The expression of linc01125 in total exosomes was highly correlated with that in tumor-associated exosomes in serum. Moreover, lung cancer cells were capable of releasing linc01125 into exosomes in vitro and in vivo. Our analyses suggest serum exosomal linc01125 as a promising biomarker for non-invasively diagnosing NSCLC and predicting the prognosis of NSCLC.

Analysis of Survival-Related lncRNA Landscape Identifies A Role for LINC01537 in Energy Metabolism and Lung Cancer Progression.

Many long non-coding RNAs (lncRNAs) have emerged as good biomarkers and potential therapeutic targets for various cancers. We aimed to get a detailed understanding of the lncRNA landscape that is associated with lung cancer survival. A comparative analysis between our RNA sequencing (RNA-seq) data and TCGA datasets was conducted to reveal lncRNAs with significant correlations with lung cancer survival and then the association of the most promising lncRNA was validated in a cohort of 243 lung cancer patients. Comparing RNA-seq data with TCGA ones, 84 dysregulated lncRNAs were identified in lung cancer tissues, among which 10 lncRNAs were significantly associated with lung cancer survival. LINC01537 was the most significant one (p = 2.95 × 10-6). Validation analysis confirmed the downregulation of LINC01537 in lung cancer. LINC01537 was observed to inhibit tumor growth and metastasis. It also increased cellular sensitivity to nilotinib. PDE2A (phosphodiesterase 2A) was further identified to be a target of LINC01537 and it was seen that LINC01537 promoted PDE2A expression via RNA-RNA interaction to stabilize PDE2A mRNA and thus echoed effects of PDE2A on energy metabolism including both Warburg effect and mitochondrial respiration. Other regulators of tumor energy metabolism were also affected by LINC01537. These results elucidate a suppressed role of LINC01537 in lung cancer development involving tumor metabolic reprogramming, and we believe that it might be a biomarker for cancer survival prediction and therapy.

Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer.

Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16-1.74) and validation cohort (HR = 1.42, 95%CI: 1.13-1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664-0.693) and 0.686 (95%CI: 0.670-0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (P interaction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC.

Identification of Three Circular RNA Cargoes in Serum Exosomes as Diagnostic Biomarkers of Non-Small-Cell Lung Cancer in the Chinese Population.

The recent discovery of circular RNAs (circRNAs) in serum exosomes suggests a novel and potentially useful tool for noninvasive cancer diagnosis. However, there are currently no substantial studies addressing this topic. RNA-sequencing analysis was performed between three pairs of non-small-cell lung cancer (NSCLC) patients and controls. The diagnostic values of exosomal circRNAs were assessed in a training set, validation set 1, and validation set 2. A total of 46 abnormally expressed circRNAs were identified. Among these, circ_0047921, circ_0056285, and circ_0007761 were found to display significant diagnostic validity for NSCLC. In distinguishing NSCLC cases from healthy controls, the panel of aforementioned circRNAs exhibited area under the curve (AUC) values of 0.926 (95% CI, 0.895-0.956) in the training set and 0.919 (95% CI, 0.877-0.962) in validation set 1. Circ_0047921 could distinguish NSCLC cases from chronic obstructive pulmonary disease controls (AUC, 0.890; 95%CI, 0.831-0.948), whereas the circ_0056285 and circ_0007761 combination could distinguish NSCLC cases from tuberculosis controls (AUC, 0.820; 95% CI, 0.739-0.902). For an early NSCLC diagnosis, similar results were observed for these circRNAs in distinguishing early-stage NSCLC cases from healthy controls, chronic obstructive pulmonary disease controls, or tuberculosis controls. Circ_0056285 expression was correlated with clinical stages and lymph node metastasis. The exosomal circRNAs, circ_0047921, circ_0056285, and circ_0007761, are promising biomarkers for NSCLC diagnosis in the Chinese population.

Long non-coding RNA AGER-1 inhibits colorectal cancer progression through sponging miR-182.

OBJECTIVE: Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Ectopic expression of a novel lncRNA, termed lnc-AGER-1, has been discovered in cancers, and this lncRNA was reported to exert an anti-tumor effect. However, its biological mechanism remains unelucidated in colorectal cancer. METHODS: A total of 159 paired colorectal cancer specimens and adjacent tissues was applied to detect the expression of lnc-AGER-1 by the quantitative Real-time PCR (qRT-PCR), and a series of functional assays was executed to uncover the role of this lncRNA on colorectal cancer. RESULTS: We found that the expression of lnc-AGER-1 in the tumor tissues was significantly down-regulated, while compared with adjacent normal tissues (0.0115 ± 0.0718 vs. 0.0347 ± 0.157; P < 0.0001). Also, lnc-AGER-1 was observably associated with clinical T status (r = -0.184, P = 0.024). Patients with advanced T status exerted a significantly lower level of lnc-AGER-1 than those with early T status (20.0% vs. 40.7%, P = 0.021). Over-expression of lnc-AGER-1 inhibited cell proliferation and migration efficiency, and induced cell cycle arrest at the G0/G1 phase, and promoted cell apoptosis. Further research proved that lnc-AGER-1 altered the expression of its neighbor gene, AGER, through acting as a competing endogenous RNA for miR-182 in colorectal cancer. CONCLUSION: lnc-AGER-1 has a suppressive role in colorectal cancer development via modulating AGER, which may serve as a target for colorectal cancer diagnosis and treatment.

Upregulation of LncRNA FEZF-AS1 is associated with advanced clinical stages and family history of cancer in patients with NSCLC.

Antisense RNA (AS) is a type of long non-coding RNAs that functions as a post-transcriptional regulatory element on regulating parental coding gene expression via directly binding to complementary mRNA sequences. We aimed to investigate the effect of the AS to FEZF1 gene on non-small cell lung cancer (NSCLC) development. The expression level of lncRNA FEZF-AS1 and FEZF1 was determined by the quantitative Real-time PCR in 160 cases of NSCLC tissues and their adjacent non-tumour tissues. We found that lncRNA FEZF-AS1 was significantly up-regulated in tumour tissues when compared to the adjacent non-cancerous tissues (P = 0.001), and it's high expression correlated with advanced stages (P = 0.002) and Tumour Family History (P = 0.029). Meanwhile, In 58 cases of NSCLC tissues the expression of lncRNA FEZF-AS1 was positively associated with that of FEZF1expression (r = 0.8810, p = 1.6575E-20). By GEPIA database analysis, we also found that the expression of lncRNA FEZF-AS1 and FEZF1 were significantly higher in tumour tissues than those of the adjacent non-cancerous tissues in 969 NSCLC patients (P < 0.05), and lncRNA FEZF-AS1 was positively correlated with FEZF1 (r = 0.90, P < 0.001). These results suggest that lncRNA FEZF-AS1 relate to the progression of lung cancer patients and it may be a potential target for cancer therapy.

Long Noncoding RNA PRRG4-4 Promotes Viability, Cell Cycle, Migration, and Invasion in Lung Cancer Cells.

There is a perception that long noncoding RNA (lncRNA) has relationship with carcinogenesis. Many studies have previously identified and validated that the section of chromosome 11p13 is associated with high incidence of tumor. In this study, we investigated a new lncRNA, named lncPRRG4-4, mapped to 11p13 and suspected that lncPRRG4-4 was a potential lung cancer-related gene. To explore its role in carcinogenesis, we first demonstrated that lncPRRG4-4 was upregulated in lung cancer tissues compared with adjacent nontumor tissues and functioned as an oncogene in lung cancer cells. The lncPRRG4-4 was significantly upregulated in lung cancer tissues compared with adjacent normal counterparts (mean ± standard deviation: 0.12 ± 0.84 vs. 0.05 ± 0.22; p < 0.001). Patients with metastasis exhibited high levels of lncPRRG4-4 expression than those without metastasis in both the southern samples (p = 0.045) and eastern samples (p = 0.030), total samples (p = 0.004). In addition, downregulation of lncPRRG4-4 expression inhibited lung cancer proliferation, viability, migration, and invasion ability, arrested cell cycle, facilitated apoptosis, and vice versa. Taken together, these observations suggested that the lncPRRG4-4 functions as an oncogene in lung cancer cells.