Functions In Lung Adenocarcinoma Research Articles

WDR5 promotes theproliferation of lung adenocarcinoma by inducing SOX9 expression.

Aim: WDR5 is a coactivator of transcription factorwhich promotes the progression of several cancer types, but its function in lung adenocarcinoma (AC) is unknown. Materials & methods: We detected WDR5 expression in lung AC with quantitative real-time polymerase chain reaction and immunohistochemistry. Results: WDR5 was significantly overexpressed in ACs compared with normal lung tissues. Moreover, WDR5 was an independent prognostic biomarker of lung AC. With clinical analyzation and in vitro experiments, we proved that SOX9 was a downstream effector of WDR5 in promoting A549 proliferation, and that SOX9 was also an unfavorable prognostic biomarker of lung AC. Conclusion: WDR5 and SOX9 are both prognostic biomarkers predicting poor outcome of lung AC. WDR5 could promote proliferation of lung AC by elevating SOX9 expression.

HSD17B6 downregulation predicts poor prognosis and drives tumor progression via activating Akt signaling pathway in lung adenocarcinoma

Lung adenocarcinoma is one of the most frequent tumor subtypes, involving changes in a variety of oncogenes and tumor suppressor genes. Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) could synthetize dihydrotestosterone, abnormal levels of which are associated with progression of multiple tumors. Previously, we showed that HSD17B6 inhibits malignant progression of hepatocellular carcinoma. However, the mechanisms underlying inhibiting tumor development by HSD17B6 are not clear. Moreover, its role in lung adenocarcinoma (LUAD) is yet unknown. Here, we investigated its expression profile and biological functions in LUAD. Analysis of data from the LUAD datasets of TCGA, CPTAC, Oncomine, and GEO revealed that HSD17B6 mRNA and protein expression was frequently lower in LUAD than in non-neoplastic lung tissues, and its low expression correlated significantly with advanced tumor stage, large tumor size, poor tumor differentiation, high tumor grade, smoking, and poor prognosis in LUAD. In addition, its expression was negatively regulated by miR-31-5p in LUAD. HSD17B6 suppressed LUAD cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and radioresistance. Furthermore, HSD17B6 overexpression in LUAD cell lines enhanced PTEN expression and inhibited AKT phosphorylation, inactivating downstream oncogenes like GSK3β, β-catenin, and Cyclin-D independent of dihydrotestosterone, revealing an underlying antitumor mechanism of HSD17B6 in LUAD. Our findings indicate that HSD17B6 may function as a tumor suppressor in LUAD and could be a promising prognostic indicator for LUAD patients, especially for those receiving radiotherapy.

NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis

The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. Invivo expression of NSD2E1099K, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile invivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.

The Silence of PSMC6 Inhibits Cell Growth and Metastasis in Lung Adenocarcinoma.

The proteasome has been validated as an anticancer drug target, while the role of a subunit of proteasome, PSMC6, in lung adenocarcinoma (LUAD) has not been fully unveiled. In this study, we observed that both the RNA and protein of PSMC6 were highly upregulated in LUAD compared with the adjacent normal tissues. Moreover, a high PSMC6 expression was associated with poor prognosis. In accordance with this finding, PSMC6 was associated with poor tumor differentiation. Furthermore, the silence of PSMC6 by small interference RNAs (siRNAs) could significantly inhibit cell growth, migration, and invasion in lung cancer cell lines, suggesting that PSMC6 might serve as a promising therapeutic target in LUAD. To further explore the molecular mechanism of PSMC6 in LUAD, we observed that the proteasome subunits, such as PSMD10, PSMD6, PSMD9, PSMD13, PSMB3, PSMB1, PSMA4, PSMC1, PSMC2, PSMD7, and PSMD14, were highly correlated with PSMC6 expression. Based on the gene set enrichment analysis, we observed that these proteasome subunits were involved in the degradation of AXIN protein. The correlation analysis revealed that the positively correlated genes with PSMC6 were highly enriched in WNT signaling-related pathways, demonstrating that the PSMC6 overexpression may activate WNT signaling via degrading the AXIN protein, thereby promoting tumor progression. In summary, we systematically evaluated the differential expression levels and prognostic values of PSMC6 and predicted its biological function in LUAD, which suggested that PSMC6 might act as a promising therapeutic target in LUAD.

MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3

Tumor-infiltrating T cells are highly expressive of inhibitory receptor/immune checkpoint molecules that bind to ligand expressed by tumor cells and antigen-presenting cells, and eventually lead to T cell dysfunction. It is a hot topic to restore T cell function by targeting immune checkpoint. In recent years, immunotherapy of blocking immune checkpoint and its receptor, such as PD-L1/PD-1 targeted therapy, has made effective progress, which brings hope for patients with advanced malignant tumor. However, only a few patients benefit from directly targeting these checkpoints or their receptors by small compounds or antibodies. Since the complexity of the regulation of immune checkpoints in tumor cells, further research is needed to identify the novel endogenous regulators of immune checkpoints which can help for developing effective drug target to improve the effect of immunotherapy. Here, we verified that microRNA-326 (miR-326) repressed the gene expression of immune checkpoint molecules PD-L1 and B7-H3 in lung adenocarcinoma (LUAD). We detected that the expression of miR-326 in LUAD tissue was negatively correlated with PD-L1/B7-H3. The repression of PD-L1 and B7-H3 expression through miR-326 overexpression leads to the modification the cytokine profile of CD8+ T cells and decreased migration capability of tumor cells. Meanwhile, the downregulation of miR-326 promoted tumor cell migration. Moreover, blocking PD-L1 and B7-H3 attenuated the tumor-promoting effect induced by miR-326 inhibitor. In tumor-bearing mice, the infiltration of CD8+ T cells was significantly increased and the expression of TNF-α, and IFN-γ was significantly enhanced which contributed to tumor progression after miR-326 overexpression. Collectively, miR-326 restrained tumor progression by downregulating PD-L1 and B7-H3 expression and increasing T cell cytotoxic function in LUAD. Our findings revealed a novel perspective on the complex regulation of immune checkpoint molecules. A new strategy of using miR-326 in tumor immunotherapy is proposed.

Silencing LINC01116 suppresses the development of lung adenocarcinoma via the AKT signaling pathway.

BackgroundA growing body of evidence has proven that long noncoding ribonucleic acids (lncRNAs) are important epigenetic regulators that play crucial parts in the pathogenesis of human cancers. Previous studies have shown that long intergenic nonprotein coding RNA 01116 (LINC01116) is a carcinogen in several carcinomas; however, its function in lung adenocarcinoma (LUAD) has not been clarified. Here, we aimed to investigate the role of LINC01116 in LUAD.MethodsThe relative expression levels of LINC01116 in LUAD cell lines and tissues were detected by quantitative reverse transcription polymerase chain reaction. A Kaplan–Meier survival analysis was performed using patient information from the Gene Expression Profiling Interactive Analysis (GEPIA) database. LUAD proliferation, invasion, migration, and apoptosis were measured by performing cell counting kit‐8, colony formation, transwell, wound healing, and flow cytometric assays. A xenograft animal experiment was performed to investigate the effect of LINC01116 in vivo. Protein kinase B (AKT) signaling pathway‐related protein expressions were tested by Western blot assay.ResultsLINC01116 expression was upregulated in LUAD cells and tissues. The loss‐of‐function experiments on LUAD cells revealed that silencing LINC01116 expression could decrease cell viability both in vitro and in vivo. Furthermore, silencing LINC01116 inhibited LUAD cell invasion and migration and induced cell apoptosis. Mechanically, silencing LINC01116 significantly decreased p‐AKT protein levels, and an AKT pathway stimulator could rescue the suppressive effects of small interfering LINC011116‐specific RNAs on LUAD development.ConclusionsOur study demonstrated that silencing LINC01116 suppresses the development of LUAD via the AKT signaling pathway.

Let-7b-3p inhibits tumor growth and metastasis by targeting the BRF2-mediated MAPK/ERK pathway in human lung adenocarcinoma.

BackgroundLung cancer is a malignant tumor with the highest morbidity and mortality rates worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Overall, current treatments of LUAD are not satisfactory; therefore, novel targets need to be explored. Let-7b-3p is an important member of the let-7 family of microRNAs (miRNAs), and has not been studied separately in LUAD. This study aimed to investigate the role and molecular mechanism of let-7b-3p in LUAD.MethodsHerein, let-7b-3p expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) assays. MTT, colony formation assay, flow cytometry analysis, wound-healing, Transwell and in vivo experiments were conducted to assess let-7b-3p’s function in LUAD. The downstream target TFIIB-related factor 2 (BRF2) was predicted using bioinformatics analyses and confirmed by dual-luciferase reporter assay and rescue experiments. Additionally, BRF2 was found to affect the MAPK/ERK pathway through transcriptome sequencing analysis and western blot (WB) assay.ResultsLet-7b-3p is downregulated in LUAD cells and tissue samples and low let-7b-3p expression is correlated with a poor prognosis in LUAD patients. Let-7b-3p suppresses the proliferation and metastasis of LUAD cells both in vivo and in vitro by directly targeting the BRF2-mediated MAPK/ERK pathway.ConclusionsLet-7b-3p inhibits the development of LUAD and is an ideal novel therapeutic target for the treatment of LUAD.

Hypoxia-inducible lipid droplet-associated (HILPDA) facilitates the malignant phenotype of lung adenocarcinoma cells in vitro through modulating cell cycle pathways

BackgroundHypoxia-inducible lipid droplet-associated (HILPDA) is considered to have tumorigenic activity, but its function in lung adenocarcinoma (LUAD) is rarely known. This work aimed to assess the regulatory functions as well as the in-depth mechanism of HILPDA in LUAD. MethodsThe expression of HILPDA in LUAD tissues was analyzed based on TCGA database, and then qRT-PCR was performed to confirm the HILPDA expression in LUAD cell lines. Kaplan-Meier analysis was used to measure the correlation of HILPDA expression and overall survival in patients with LUAD. Then, Cell-Counting Kit-8 (CCK-8), colony formation and transwell assays were performed to detect cell proliferation, invasion and migration. Moreover, the pathways closely related to the high HILPDA expression was analyzed by Kyoto Encyclopedia of genes and Genomes (KEGG) analysis. The levels of Cell cycle pathway-related proteins were assessed using western blotting. ResultsHerein, we revealed that HILPDA was expressed at high levels in LUAD tissues and cell lines, and LUAD patients with the higher HILPDA expression presented the shorter survival time. Down-regulation of HILPDA in Calu-3 cells can retard cell proliferation, migration and invasion as well as arrest cells in the G1 phase, whereas overexpression of HILPDA in A549 cells presented a marked promotion on these phenotypes. Moreover, we surveyed that knockdown of HILPDA restrained the activation of cell cycle pathway, while up-regulation of HILPDA led to opponent outcomes. ConclusionsIn summing, HILPDA may act as an oncogenic factor in LUAD cells via modulating cell cycle pathway, which represent a novel biomarker of tumorigenesis in LUAD patients.

The interplay between ATF2 and NEAT1 contributes to lung adenocarcinoma progression

BackgroundActivating transcription factor 2 (ATF2), a member of the activator protein 1 (AP-1) transcription factor family, has been shown to be involved in the pathobiology of numerous cancers. However, the biological role and mechanism of ATF2 in lung adenocarcinoma (LUAD) remains to be elucidated.MethodsThe expression of ATF2, NEAT1 and miR-26a-5p in LUAD tissues and cell lines was detected by qRT-PCR and western blotting. The interaction between ATF2, NEAT1, and miR-26a-5p was validated by chromatin immunoprecipitation, luciferase reporter assay and RNA immunoprecipitation. Cell proliferation, invasion and tumorigenesis of LUAD cells were analyzed by using CCK8, transwell invasion assay and xenograft tumor model.ResultsWe confirmed that ATF2 expression was increased in LUAD tissues compared with normal adjacent lung tissues. Functional experiments showed that ATF2 positively regulated cell proliferation and invasion in LUAD cells. Moreover, we identified that NEAT1 expression was increased in LUAD tissues and positively correlated with ATF2 expression. Mechanistically, ATF2 could bind to the promoter of NEAT1 to promote its transcription. Rescue experiments showed that ATF2 exerted its oncogenic function in LUAD, at least, partly through NEAT1 upregulation. In turn, NEAT1 could positively regulate ATF2 expression and form a positive feedback loop in LUAD cells. Furthermore, we demonstrated that NEAT1 positively regulated ATF2 expression via sponging miR-26a-5p.ConclusionATF2 and NEAT1 form a positive feedback loop mediated by miR-26a-5p and coordinately contribute to LUAD progression.

Novel lncRNA UPLA1 mediates tumorigenesis and prognosis in lung adenocarcinoma

With the development of molecular biotechnology and sequencing techniques, long non-coding RNAs (lncRNAs) have been shown to play a vital role in a variety of cancers including lung cancer. In our previous study, we used RNA sequencing and high-content screening proliferation screening data to identify lncRNAs that were significantly associated with tumour biological functions such as LINC01426. Herein, based on previous work, we report a novel lncRNA UPLA1 (upregulation promoting LUAD-associated transcript-1), which has not been explored or reported in any previous studies. Our results showed that UPLA1 is highly expressed and regulates important biological functions in lung adenocarcinoma. In vitro experiments revealed that UPLA1 promoted the migration, invasion, and proliferation abilities, and is related to cell cycle arrest, in lung adenocarcinoma cells. Moreover, the upregulation of UPLA1 significantly improved the growth of tumours in vivo. We identified that UPLA1 was mainly located in the nucleus using fluorescence in situ hybridisation, and that it promoted Wnt/β-catenin signalling by binding to desmoplakin using RNA pulldown assay and mass spectrometry. Additionally, luciferase reporter assay revealed that YY1 is the transcription factor of UPLA1 and suppressed the expression of UPLA1 as a transcriptional inhibitor. This finding provides important evidence regarding the two roles of YY1 in cancer. Furthermore, in situ hybridisation assay results showed that UPLA1 was closely related to the prognosis and tumour, node, metastasis (TNM) stage of lung adenocarcinoma. In summary, our results suggest that the novel lncRNA UPLA1 promotes the progression of lung adenocarcinoma and may be used as a prognostic marker, and thus, has considerable clinical significance.

LncRNA MSC-AS1 facilitates lung adenocarcinoma through sponging miR-33b-5p to up-regulate GPAM.

Many reports have indicated that long non-coding RNAs (lncRNAs) are closely associated with the occurrence and development of various cancers. Musculin antisense RNA 1 (MSC-AS1) is a an lncRNA known to act as an oncogene in several types of human cancers; however, its specific function in lung adenocarcinoma (LUAD) is still unclear. For this study, we designed and conducted experiments to clarify the function of the lncRNA MSC-AS1 in LUAD and its underlying mechanisms. We found that the expression of MSC-AS1 was significantly higher in LUAD tissues and cells than that in normal ones. Through loss-of function assays, we confirmed that the proliferation of LUAD cells was significantly restrained by down-regulation of MSC-AS1 and the rate of cell apoptosis was accelerated. The results from our mechanistic experiments showed that MSC-AS1 interacts with microRNA-33b-5p (miR-33b-5p). Moreover, glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) was found to be a direct target gene of miR-33b-5p, and it has similar functions to MSC-AS1. Further, inhibition of miR-33b-5p or overexpression GPAM reversed the inhibitory effects of MSC-AS1 silencing on LUAD cell growth. In short, MSC-AS1 facilitates LUAD progression through sponging miR-33b-5p to up-regulate GPAM.

Silencing of long non-coding RNA SOX21-AS1 inhibits lung adenocarcinoma invasion and migration by impairing TSPAN8 via transcription factor GATA6

Here, we revealed the novel role of long non-coding RNAs (lncRNAs) SOX21 antisense RNA 1 (SOX21-AS1)/TSPAN8/GATA6 in progression of lung adenocarcinoma. SOX21-AS1 expression was quantified in lung adenocarcinoma tissues and cells by RT-qPCR. Then, gain- and loss-of-function experiments were conducted in lung adenocarcinoma cells. Expression of GATA6, TSPAN8 and extracellular signal-regulated kinase (ERK) signaling pathway-related genes was determined in lung adenocarcinoma cells by western blot analysis. The interaction and relationship among SOX21-AS1, GATA6 and TSPAN8 were predicted and verified respectively by RNA pull down, RIP, ChIP, and dual-luciferase reporter assays. Next, lung adenocarcinoma cell proliferation, colony formation, invasion and migration were assessed by 5-ethynyl-2′-deoxyuridine staining, colony formation assay and Transwell assay. Xenograft tumors were established in nude mice and the tumor growth was observed and recorded. SOX21-AS1 was observed to be highly expressed in lung adenocarcinoma tissues. The overexpression of SOX21-AS1, GATA6 or TSPAN8 obviously enhanced cell biological functions in lung adenocarcinoma. Meanwhile, SOX21-AS1 interacted with GATA6 which bound to TSPAN8 promoter and promoted TSPAN8 expression, which further enhanced cell colony formation, proliferation and invasion, and also activated ERK signaling pathway. Silencing of SOX21-AS1 and inhibiting its binding to GATA6 downregulate TSPAN8 and thereby exert anti-oncogenic effects in lung adenocarcinoma.

Integrated analysis of miRNAs and DNA methylation identifies miR‐132‐3p as a tumor suppressor in lung adenocarcinoma

BackgroundAberrant miRNA expression and DNA methylation are two major epigenetic events in lung adenocarcinoma (LUAD). We conducted a combined analysis of the molecular changes in LUAD.MethodsWe analyzed differentially expressed miRNAs and methylated CpG loci in 489 LUAD tissues versus 49 normal lung tissues of the Cancer Genome Atlas (TCGA). The results were validated in cell lines and xenograft mouse models and additional pairs of 36 LUAD and 36 normal lung tissues.ResultsA total of 125 differentially expressed miRNAs and 145 differentially methylated CpG loci were identified in the LUAD versus normal lung tissues of TCGA data. Expression of the 22 miRNAs was inversely correlated with the 47 differentially methylated sites located in the miRNAs. Molecular and cellular function analysis showed that the abnormally methylated miRNAs were mainly involved in cell‐to‐cell signaling and interaction in airway cells. The DNA methylation status and altered expressions of miRNAs and their target genes were confirmed in 36 pairs of lung tumor and noncancerous lung tissues. Furthermore, aberrant miRNA expressions or DNA methylations alone could be involved in tumorigenesis of LUAD via different pathways. In addition, elevated miR‐132‐3p expression, reduced expression of its targeted gene (ZEB2), and decreased cell proliferation was observed in lung cancer cells treated with DNA methyltransferase inhibitor. Moreover, in vitro and in vivo analyses showed that miR‐132‐3p‐3p downregulation via DNA methylation promoted tumorigenicity of lung cancer by directly regulating ZEB2.ConclusionsThe interaction between two epigenetic aberrations could have important functions in LUAD. miR‐132‐3p might act as a tumor suppressor in the tumorigenicity of LUAD.Key pointsSignificant findings of the study Systemically investigating relationship between aberrant miRNA expression and DNA methylation in lung cancer could improve understanding of lung tumorigenesis and develop diagnostic and therapeutic targets. What this study adds Three forms of relationships between the two epigenetic changes are defined.miR‐132‐3p is further identified as a tumor suppressor in lung cancer.

FAM83A Is a Prognosis Signature and Potential Oncogene of Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common subtype of nonsmall cell lung cancer, and 5-year survival rate is only 15% in recent years. This study aimed to explore the FAM83A expression and its potential functions in LUAD. Data of LUAD were downloaded from The Cancer Genome Atlas database. Expression level of FAM83A was compared between LUAD samples and adjacent normal samples. The association between FAM83A expression and clinic-pathological parameters was analyzed, as well as copy number variation and methylation status. Kaplan-Meier curve was used to visualize the relationship of FAM83A expression with survival outcomes. Finally, gene set enrichment analysis was used to identify potential signaling pathways in LUAD specimens. FAM83A expression was significantly correlated with four clinical factors in LUAD specimens, age, gender, smoking, and overall survival status (all p < 0.05). High expression level of FAM83A was negatively correlated with methylation level. Moreover, patients in low expression groups exhibited a better prognosis than those in high expressed groups, which was independent of gender (p < 0.001). Histidine metabolism pathway was significantly upregulated in FAM83A-high expressed samples than FAM83A-low expressed samples according to functional enrichment analysis. High expression of FAM83A predicted a poor prognosis in LUAD patients. Our study demonstrated that FAM83A might be a potential biomarker and meaningful therapeutic target in LUAD.

Long noncoding RNA SNHG14 exerts oncogenic functions in lung adenocarcinoma through acting as a sponge to miR-613.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Long noncoding RNA SNHG14 exerts oncogenic functions in lung adenocarcinoma through acting as a sponge to miR-613, by Z.-N. Xu, Z.-X. Wang, L. Xu, H.-X. Yu, K. Chao, L.-L. Yang, X.-L. Han, H.-B. Sun, published in Eur Rev Med Pharmacol Sci 2019; 23 (24): 10810-10817-DOI: 10.26355/eurrev_201912_19784-PMID: 31858549" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19784.

Long noncoding RNA SNHG14 exerts oncogenic functions in lung adenocarcinoma through acting as a sponge to miR-613.

Lung adenocarcinoma is one of the most ordinary malignant tumors. Recent researches have proved that long noncoding RNAs (lncRNAs) are vital factors in many diseases. In this work, lncRNA SNHG14 was studied to identify its function in the development of lung adenocarcinoma. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to detect SNHG14 expression in paired lung adenocarcinoma patients' tissue samples and cells. Then, the function of SNHG14 was detected through MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, colony formation assay, and transwell assay in vitro. Besides, mechanism assays and the interaction between SNHG14 and miR-613 were conducted. SNHG14 was remarkably higher-expressed in lung adenocarcinoma tissues than in adjacent samples. Moreover, cell proliferation and invasion of lung adenocarcinoma were promoted via overexpression of SNHG14, while cell proliferation and invasion of lung adenocarcinoma were inhibited via silence of SNHG14. Moreover, RT-qPCR results revealed that miR-613 was downregulated via overexpression of SNHG14, while miR-613 was upregulated via knockdown of SNHG14. Further experiments showed that miR-613 was also a direct target of SNHG14 in lung adenocarcinoma. Our study suggests that SNHG14 enhances lung adenocarcinoma cell proliferation and invasion via targeting miR-613, which indicates that SNHG14 may be a potential therapeutic target in lung adenocarcinoma.

LINC00958 Accelerates Cell Proliferation and Migration in Non-Small Cell Lung Cancer Through JNK/c-JUN Signaling

Non-small cell lung cancer (NSCLC) denotes the most common type of lung cancers with high mortality globally. Long non-coding RNAs (lncRNAs) with differential expression have been indicated to be participants in the pathogenesis and development of cancer. However, the precise role of lncRNAs in NSCLC is still largely obscure. In this study, we explored a newly discovered intergenic lncRNA LINC00958 in NSCLC. First of all, the online databases suggested that LINC00958 was slightly expressed in human normal lung tissues but upregulated in LUSC tissues. Besides, the upregulation of LINC00958 in both lung adenocarcinoma (LUAD) and LUSC cell lines was easily found when compared with the normal BEAS-2B cells. In addition, we elucidated that knockdown of LINC00958 led to impaired proliferation, induced apoptosis, and hampered migration in LUAD cells. Moreover, a typical oncogenic pathway, JNK signaling, was verified to be involved in LINC00958-contributed LUAD development. Of note, we explained that LINC00958 exerted the tumor-promoting function in LUAD by enhancing the transactivation of p-c-JUN through activating JNK signaling. Meanwhile, we also revealed that LINC00958 was transcriptionally regulated by c-JUN. In addition, earlier findings were also suitable for LUSC cells. By and large, our work illustrated that LINC00958 facilitates tumorigenesis in NSCLC by activating the JNK/c-JUN signaling pathway, indicating a new road for diagnosis and treatment of both LUAD and LUSC.

Clinical Significance And Integrative Analysis Of Kinesin Family Member 18B In Lung Adenocarcinoma.

BackgroundKinesin family member 18B (KIF18B) is a member of the kinesin-8 superfamily, and functions as an oncogene in human cancers. However, its expression profile and role in lung adenocarcinoma (LUAD) remain unclear.Materials and methodsWe examined the expression profile of KIF18B using quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry in fresh clinical samples. Using data downloaded from the Cancer Genome Atlas database and Gene Expression Omnibus, we explored the clinical significance of KIF18B, potential mechanisms of its dysregulation and its underlying biological function in LUAD.ResultsKIF18B was significantly over-expressed in LUAD tissues relative to normal tissues. High KIF18B expression was associated with smoking history, positive nodal invasion, advanced clinical stage, death status and poorer prognosis. Cox regression analyses revealed that KIF18B overexpression was an independent prognostic biomarker for poor overall survival (OS) and recurrence-free survival in LUAD. In addition, KIF18B mutation was observed in 2.2% of LUAD cases. DNA copy number variation was correlated with upregulated expression of KIF18B in LUAD tissues and cell lines. The methylation level of some KIF18B DNA CpG sites was negatively associated with its mRNA expression. KIF18B was predictively targeted by miR-125a-5p, which was downregulated in LUAD tissues, inversely correlated with KIF18B mRNA expression and significantly associated with poor OS. Furthermore, gene set enrichment analysis revealed that genes positively co-expressed with KIF18B were mainly enriched in cell cycle signaling pathways.ConclusionOur results indicate that KIF18B is a promising prognostic biomarker for LUAD. DNA amplification, hypomethylation as well as miR-125a-5p downregulation may be involved in the mechanism of KIF18B dysregulation in LUAD. KIF18B might function as a novel oncogene through cell cycle regulation pathways in LUAD.

Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression.

Metabolic alterations that are critical for cancer cell growth and metastasis are one of the key hallmarks of cancer. Here, we show that thymidine kinase 1 (TK1) is significantly overexpressed in tumor samples from lung adenocarcinoma (LUAD) patients relative to normal controls, and this TK1 overexpression is associated with significantly reduced overall survival and cancer recurrence. Genetic knockdown of TK1 with short hairpin RNAs (shRNAs) inhibits both the growth and metastatic attributes of LUAD cells in culture and in mice. We further show that transcriptional overexpression of TK1 in LUAD cells is driven, in part, by MAP kinase pathway in a transcription factor MAZ dependent manner. Using targeted and gene expression profiling-based approaches, we then show that loss of TK1 in LUAD cells results in reduced Rho GTPase activity and reduced expression of growth and differentiation factor 15 (GDF15). Furthermore, ectopic expression of GDF15 can partially rescue TK1 knockdown-induced LUAD growth and metastasis inhibition, confirming its important role as a downstream mediator of TK1 function in LUAD. Collectively, our findings demonstrate that TK1 facilitates LUAD tumor and metastatic growth and represents a target for LUAD therapy.

MicroRNA-218 regulates the epithelial-to-mesenchymal transition and the PI3K/Akt signaling pathway to suppress lung adenocarcinoma progression by directly targeting BMI-1.

To investigate the role of miR-218 in the development of lung adenocarcinoma (LA) and its underlying mechanism. Fifty-two pairs of human LA samples and adjacent para-carcinoma tissue samples were collected from our hospital between June 2015 and March 2017. Meanwhile, one normal human pulmonary epithelial cell line BEAS-2B and four human LA cell lines (H1299, PC-9, A549, and SPC-A1) were cultured. The cells' ability of proliferation and migration was detected by MTT assays and Transwell assays, respectively. The target gene was clarified by dual-luciferase reporter assay. The related protein and mRNA expression levels were detected by immunohistochemistry (IHC), Western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. At last, the tumor xenograft model was made for further exploring the mechanism. MiR218 expressions were notably reduced in LA tissues in comparison with controls. In addition, the declined miR218 expressions were correlated with the poor OS and worse clinicopathological parameters of LA patients. Furthermore, miR218 overexpression could suppress the proliferation, migration and invasion capacities of LA cells via regulation of PI3K/Akt signaling pathway and epithelial-mesenchymal transition (EMT) respectively. Results in the current study also revealed that miR-218 upregulation could suppress the tumor growth rate and tumor size of LA mice. B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was confirmed to be a direct target for miR-218 and upregulated in LA tissues, which indicated the poor prognosis of LA patients. MiR-218 exerted anti-tumor functions in LA partially via the regulation of BMI-1, suggesting that BMI-1/miR-218 axis may provide a novel insight into tumorigenesis and the basis for the development of miRNA-targeting therapies against LA.