Migration Of Non-small Cell Lung Cancer Cells Research Articles

Anisomycin sensitizes non-small-cell lung cancer cells to chemotherapeutic agents and epidermal growth factor receptor inhibitor via suppressing PI3K/Akt/mTOR.

The poor outcomes in advanced non-small-cell lung cancer (NSCLC) necessitate new treatments. Recent studies emphasize anisomycin as a promising anti-cancer drug candidate. In this work, we systematically investigated the efficacy of anisomycin alone and its combination with the standard-of-care drugs in NSCLC. We showed that anisomycin inhibited growth, migration, and survival in NSCLC cells regardless of genetic mutation status, and to a greater extent than in normal lung epithelial cells. Isobologram analysis showed that the combination of anisomycin with cisplatin, paclitaxel, or gefitinib was synergistic in NSCLC but not normal lung cells. We further demonstrated that anisomycin inhibited NSCLC growth in mice. The combination of anisomycin with cisplatin was more effective than cisplatin alone and completely arrested NSCLC growth throughout the whole duration of treatment. JNK and p38 MAPK were not required for anisomycin's action. In contrast, anisomycin inhibits PI3K/Akt/mTOR pathway. Overexpression of constitutively active Akt reversed the pro-apoptotic effect of anisomycin. Our work demonstrates the selective anti-NSCLC activity of anisomycin via suppressing PI3K/Akt/mTOR. Our findings provide preclinical evidence to initialize the clinical trial of using anisomycin to sensitize NSCLC to current therapy.

PTCH1 regulates anchorage-independent growth and bone invasion of non-small cell lung cancer cells.

Acquisition of metastatic potential by cancer cells is related to cancer stemness and anchorage-independent growth. The onset and progression of cancer are known to involve Hedgehog (HH) signaling that is activated by the binding of HH to the Patched 1 (PTCH1) receptor. However, the functions and mechanisms of action of PTCH1 in the context of bone metastasis remain to be elucidated. In this study, lentivirally-delivered shRNA was used to deplete PTCH1 levels, which resulted in the inhibition of spherical colony formation by the human non-small cell lung cancer (NSCLC) cell line; this suggested that PTCH1 promotes anchorage-independent growth. Concordantly, knockdown of PTCH1 resulted in significantly reduced migration and invasion of NSCLC cells; this was accompanied by the downregulation of MMP7 and SOX2. PTCH1 knockdown resulted in decreased bone destruction and osteoclastogenesis in a mouse bone metastasis model. These results indicate that PTCH1 may be an important regulator of bone invasion, and strongly suggest that knockdown of PTCH1 may decrease the anchorage-independent growth and metastatic potential of NSCLC.

LINC00476 Suppresses the Progression of Non-Small Cell Lung Cancer by Inducing the Ubiquitination of SETDB1.

Long non-coding RNAs are involved in the tumorigenesis of non-small cell lung cancer (NSCLC). Here we investigated whether LINC00476 affects the proliferation, invasion and migration of NSCLC cells via the SETDB1-activated Wnt/β-catenin pathway. The expression of LINC00476, SETDB1, Wnt1 and β-catenin were determined in NSCLC tumor tissues and the paired adjacent tissues, as well as in NSCLC cell lines and bronchial epithelioid cell lines. Cell proliferation, invasion and migration were determined using cell counting kit-8 assay and transwell assay. The relationship between LINC00476 and SETDB1 was elucidated using RNA pull-down, RNA immunoprecipitation and ubiquitination assays. LINC00476 was found to be significantly downregulated, while SETDB1, Wnt1 and β-catenin were upregulated in NSCLC tumor tissues and cell lines compared to the normal ones. Overexpression of LINC00476 promoted the proliferation, invasion and migration of NSCLC cells, and suppressed tumor growth in the mouse xenograft. Meanwhile, overexpression of LINC00476 induced the degradation of SETDB1 by promoting its ubiquitination. The simultaneous overexpression of LINC00476 and SETDB1 negated the inhibition of LINC00476 overexpression on the proliferation, invasion and migration of NSCLC cells. In conclusion, these findings indicate that LINC00476 acts as a tumor suppressor in NSCLC by downregulating SETDB1, which provides a novel target in the treatment of NSCLC.

LncRNA PART1 promotes cell proliferation and progression in non-small-cell lung cancer cells via sponging miR-17-5p.

It has been demonstrated in previous studies that lncPART1 is dysregulated in non-small cell lung cancer (NSCLC). However, the function of lncPART1 in NSCLC is unclear. Therefore, this experimental design was based on LncPART1 to explore the pathogenesis of NSCLC. Real-time polymerase chain reaction was used to detect the expression of lncPART1 and miR-17-5p in NSCLC. Cell Counting Kit -8, colony formation, and transwell assays were used to examine the effects of lncPART1 and miR-17-5p on NSCLC cell proliferation and migration invasiveness. Target gene prediction, luciferase reporter assays were used to validate downstream target genes for lncPART1 and miR-17-5p. Western blot analysis was used to detect the expression of TGFBETAR2. LncPART1 was highly expressed in NSCLC. LncPART1 significantly promoted cell proliferation of NSCLC cells. miR-17-5p was down-expressed in NSCLC. miR-17-5p overexpression inhibited cell proliferation and migration invasion in NSCLC cells. LncPART1 was able to inhibit miR-17-5p expression and upregulate the expression level of TGFBETAR2. The results of in vivo animal models confirmed that lncPART1 promoted NSCLC progression by miR-17-5p/TGFBETAR2 axis. LncPART1 promoted the progression of NSCLC by miR-17-5p/TGFBETAR2 axis.

Hsa_circ_0016760 exacerbates the malignant development of non‑small cell lung cancer by sponging miR‑145‑5p/FGF5.

Hsa_circ_0016760 expression has been reported to be increased in non-small cell lung cancer (NSCLC). The present study was designed to explore the role and mechanism of hsa_circ_0016760 in regulating NSCLC progression. In total, 60NSCLC patients were followed-up for 60 months after surgery. Hsa_circ_0016760 expression in tumor tissues and adjacent non-tumor tissues of NSCLC patients was explored by reverse transcription quantitative polymerase chain reaction (RT-qPCR). NSCLC cell proliferation was monitored by CCK-8 assay and EdU experiment. Transwell assays were used for the detection of NSCLC cell migration and invasion. The target of hsa_circ_0016760 (or miR-145-5p) was validated by luciferase reporter gene assay and RNA immunoprecipitation experiment. A xenograft model was studied with nude mice. Immunohistochemical staining was applied for the detection of Ki67 expression in xenograft tumors. Hsa_circ_0016760/miR-145-5p/FGF5 expression in tissues and cells was investigated by RT-qPCR and western blotting. Hsa_circ_0016760 was aberrantly upregulated in NSCLC, which was associated with poor prognosis of patients (P<0.05). Hsa_circ_0016760 silencing suppressed NSCLC cell proliferation, migration and invasion in vitro (P<0.01). Hsa_circ_0016760 facilitated FGF5 expression via sponging miR-145-5p. The miR-145-5p upregulation or FGF5 downregulation reversed the promoting effect of hsa_circ_0016760 on NSCLC cell proliferation, migration and invasion in vitro (P<0.01). In addition, hsa_circ_0016760 silencing inhibited tumor growth in vivo (P<0.01), and decreased Ki67 expression in xenograft tumors. In conclusion, hsa_circ_0016760 exacerbated the malignant development of NSCLC by sponging miR-145-5p/FGF5.

Angio-associated migratory cell protein (AAMP) interacts with cell division cycle 42 (CDC42) and enhances migration and invasion in human non-small cell lung cancer cells.

Angio-associated migratory cell protein (AAMP) is considered a pro-tumor protein, which contributes to angiogenesis, proliferation, adhesion, and other biological activities. Although AAMP is known to facilitate the motility of breast cancer cells and smooth muscle cells by regulating ras homolog family member A (RHOA) activity, the function of AAMP in the metastasis of non-small cell lung cancer (NSCLC) cells still remains unknown. In the present study, AAMP was upregulated in non-small cell lung carcinoma, and was found to promote migration and invasion in NSCLC cells. Further experiments demonstrated that AAMP interacted with cell division cycle 42 (CDC42) and promoted its activation, resulting in the formation of cellular protrusions. Subsequently, we found that AAMP enhanced CDC42 activation by impairing the combination of rho GTPase activating protein 1 (ARHGAP1) and CDC42. Taken together, we revealed and elucidated the critical role of AAMP in the migration and invasion of NSCLC cells and presented a new potential target for lung cancer therapy.

TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-β-catenin signaling.

The Wnt/β-catenin pathway plays vital roles in diverse biological processes, including cell differentiation, proliferation, migration, and insulin sensitivity. A recent study reported that the DNA-binding transcriptional factor SIX3 is essential during embryonic development in vertebrates and capable of downregulating target genes of the Wnt/β-catenin pathway in lung cancer, indicating negative regulation of Wnt/β-catenin activation. However, regulation of the SIX3-Wnt/β-catenin pathway axis remains unknown. We measured the expression of TRIM27 and SIX3 as well as investigated whether there was a correlation between them in lung cancer tissue samples. Herein, we found that the E3 ubiquitin ligase, TRIM27, ubiquitinates, and degrades SIX3. TRIM27 induces non-small cell lung cancer (NSCLC) cell proliferation and metastasis, and the expression of β-catenin, S100P, TGFB3, and MMP-9 were significantly inhibited by SIX3. Furthermore, XAV939 is a selective β-catenin-mediated transcription inhibitor that inhibited TRIM27- and SIX3-mediated NSCLC cell proliferation, migration, and invasion. Clinically, lung tissue samples of cancer patients showed increased TRIM27 expression and decreased SIX3 expression. Taken together, these data demonstrate that TRIM27 acts as an oncogene regulating cell proliferation and metastasis in NSCLC through SIX3-β-catenin signaling.

Long Noncoding RNA LINC01426 Sequesters microRNA-519d-5p to Promote Non-Small Cell Lung Cancer Progression by Increasing ETS1 Expression.

PurposeRecent studies have identified important roles for long intergenic non-protein coding RNA 1426 (LINC01426) in glioma and clear cell renal cell carcinoma. The present study evaluated the expression profile of LINC01426 in non-small cell lung cancer (NSCLC) tissues and cell lines. Furthermore, the function of LINC01426 in NSCLC and the molecular mechanisms involved were extensively studied.MethodsThe abundance of LINC01426 in NSCLC tissues and cell lines was determined using quantitative reverse transcription–polymerase chain reaction. The cell counting kit-8 assay, flow cytometry, transwell experiments for migration and invasion, and xenograft tumor model were used to assess the function of LINC01426 in NSCLC cells. Mechanistic studies were performed using the luciferase reporter assay and RNA immunoprecipitation.ResultsSignificant LINC01426 upregulation was observed in NSCLC tissues and cell lines. Silencing LINC01426 inhibited proliferation, migration, and invasion of NSCLC cells and facilitated cell apoptosis in vitro. Furthermore, interference of LINC01426 restricted tumor growth of NSCLC cells in vivo. In addition, LINC01426 showed the ability to directly bind to microRNA-519d-5p (miR-519d-5p) and act as a molecular sponge for miR-519d-5p in NSCLC cells. Furthermore, the ETS proto-oncogene 1 (ETS1) was identified as a direct target of miR-519d-5p and LINC01426 could indirectly upregulate ETS1 expression by sponging miR-519d-5p. Moreover, the cancer-inhibiting activities of LINC01426 knockdown in NSCLC cells were partially offset by miR-519d-5p inhibition.ConclusionLINC01426 increases ETS1 expression by sequestering miR-519d-5p, thereby aggravating the malignant progression of NSCLC. The LINC01426/miR-519d-5p/ETS1 competing endogenous RNA pathway may provide a target for designing therapeutic agents for NSCLC treatment.

SphK1 promotes development of non‑smallcell lungcancer through activation of STAT3.

Sphingosine kinase1 (SphK1) is an oncogenic enzyme that regulates tumor cell apoptosis, proliferation and survival. SphK1 has been reported to promote the development of non‑small cell lung cancer (NSCLC), although the underlying mechanism remains to be determined. The aim of the present study was to examine the expression and function of SphK1 in NSCLC and to explore the underlying molecular mechanism. The results of the present study demonstrated that SphK1 expression was upregulated in NSCLC tissues and cell lines. Overexpression of SphK1 increased the proliferation and migration of NSCLC cells. Additionally, overexpression of SphK1 induced expression of antiapoptotic and migration‑associated genes, such as Bcl‑2, matrix metallopeptidase 2 and cyclin D1. Of note, signal transducer and activator of transcription 3 (STAT3) was also activated in the SphK1‑overexpressing cells. By treatment with a STAT3 inhibitor, it was demonstrated that the SphK1‑induced changes in expression of target genes, as well as the increase in proliferation and migration of NSCLC cells were mediated by STAT3. In conclusion, the effects of SphK1 overexpression on the development of NSCLC were demonstrated to be mediated by the activation of STAT3. These results suggested that inhibition of the SphK1‑STAT3 axis may be a potential strategy for the treatment of NSCLC.

MicroRNA-877 contributes to decreased non-small cell lung cancer cell growth via the PI3K/AKT pathway by targeting tartrate resistant acid phosphatase 5 activity

ABSTRACT Non-small cell lung cancer (NSCLC) is a leading cause of cancer death in both men and women. microRNAs (miRs) can exert important functions in cancer development. However, the role of miR-877 in NSCLC as it relates to tartrate resistant acid phosphatase 5 (ACP5) is unknown. For this study, the gain-and-loss-of-function experiments were performed to explore the effects of miR-877 and ACP5 on NSCLC. miR-877 expression in LC and paracancerous tissues, lung epithelial cell line and NSCLC cell lines was detected, and the association between miR-877 expression and clinical features of LC patients was analyzed. The levels of ACP5, epithelial-mesenchymal transition (EMT) markers and apoptosis-related proteins were measured. In vivo experiments were conducted for further validation. Consequently, we found that miR-877 expression was lowered in LC tissues and cell lines, and correlated with clinical stage, differentiation, lymph node metastasis and prognosis of NSCLC patients. Additionally, miR-877 was determined to inhibit ACP5 activity, and miR-877 downregulated the PI3K/AKT pathway by silencing ACP5. Furthermore, overexpression of miR-877 inhibited the viability, migration, invasion and EMT of NSCLC cells, but promoted cell apoptosis. In conclusion, miR-877 overexpression inhibited malignant biological behaviors of NSCLC cells by downregulating ACP5 and inactivating the PI3K/AKT pathway.

Platelet isoform of phosphofructokinase promotes aerobic glycolysis and the progression of non‑small cell lung cancer.

The platelet isoform of phosphofructokinase (PFKP) is a rate-limiting enzyme involved in glycolysis that serves an important role in various types of cancer. The aim of the present study was to explore the specific regulatory relationship between PFKP and non-small cell lung cancer (NSCLC) progression. PFKP expression in NSCLC tissues and corresponding adjacent tissues was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical analysis. PFKP expression in human bronchial epithelial cells (16HBE) and NSCLC cells (H1299, H23 and A549) was also detected using RT-qPCR. Cell proliferation was detected by Cell Counting Kit-8 and colony formation assays. Transwell invasion and wound healing assays, and flow cytometry were used to detect cell invasion, migration and apoptosis, respectively. The expression levels of glycolysis-associated enzymes (hexokinase-2, lactate dehydrogenase A and glucose transporter-1), epithelial-mesenchymal transition-related proteins (N-cadherin, vimentin and E-cadherin) and apoptosis-related proteins (caspase-3 and B-cell lymphoma-2) were detected by western blotting. Glucose uptake, lactate production and the adenosine trisphosphate/adenosine diphosphate ratio were measured using the corresponding kits. The results of the present study demonstrated that PFKP expression was upregulated in NSCLC tissues and cells, and PFKP expression was related to lymph node metastasis and histological grade. In addition, overexpression of PFKP inhibited cell apoptosis, and promoted proliferation, migration, invasion and glycolysis of H1299 cells, whereas knockdown of PFKP had the opposite effects. In conclusion, PFKP inhibited cell apoptosis, and promoted proliferation, migration, invasion and glycolysis of NSCLC cells; these findings may lay the foundation for novel treatments of NSCLC.

Human RECQL5 promotes metastasis and resistance to cisplatin in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) patients have a lower 5-year survival rate, and the distant tumor metastasis and drug resistance are the main reasons for the high mortality. RECQL5, a member of RecQ helicases family, has been linked to tumorigenesis of various cancers expect NSCLC. In the current study, analysis with the Cancer Genome Atlas (TCGA) dataset showed that the level of RECQL5 was elevated in LUAD (Lung Adenocarcinoma) and LUSC (lung squamous carcinomas), two major subtypes of NSCLC, which was confirmed by immunohistochemistry staining on Tissue array slides. The level of RECQL5 was also elevated in NSCLC cell lines. Further, Kaplan-Meier analysis of TCGA dataset suggested that the up-regulated RECQL5 was associated with poor prognosis of LUAD, but not with that of LUSC. Knockdown of RECQL5 significantly inhibited the invasion and migration of NSCLC cells, and suppressed epithelial-mesenchymal transition (EMT) as indicated by the changes of EMT-related proteins, while overexpression of RECQL5 displayed reverse effects. Lung metastasis was also suppressed by RECQL5 knockdown. Additionally, the addition of Akt inhibitor LY294002 reversed the effects of RECQL5 overexpression on cell migration, invasion and EMT. Moreover, knockdown of RECQL5 increased the apoptosis of cisplatin-resistant A549 cell line (A549/DDP) caused by cisplatin treatment. In summary, RECQL5 contributed to the metastasis of NSCLC and assisted NSCLC cells incompletely response to cisplatin therapy, and could be considered as a biomarker or clinical target for NSCLC.

Inhibition of histamine receptor H3 suppresses the growth and metastasis of human non-small cell lung cancer cells via inhibiting PI3K/Akt/mTOR and MEK/ERK signaling pathways and blocking EMT.

Recent evidence shows that the expression levels of histamine receptor H3 (Hrh3) are upregulated in several types of cancer. However, the role of Hrh3 in non-small cell lung cancer (NSCLC) has not been elucidated. In the present study, we showed that the expression levels of Hrh3 were significantly increased in NSCLC samples, and high levels of Hrh3 were associated with poor overall survival (OS) in NSCLC patients. In five human NSCLC cell lines tested, Hrh3 was significantly upregulated. In NSCLC cell lines H1975, H460, and A549, Hrh3 antagonist ciproxifan (CPX, 10-80 μM) exerted moderate and concentration-dependent inhibition on the cell growth and induced apoptosis, whereas its agonist RAMH (80 μM) reversed these effects. Furthermore, inhibition of Hrh3 by CPX or siRNA retarded the migration and invasion of NSCLC cells through inhibiting epithelial-mesenchymal transition (EMT) progression via reducing the phosphorylation of PI3K/Akt/mTOR and MEK/ERK signaling pathways. In nude mice bearing H1975 cell xenograft or A549 cell xenograft, administration of CPX (3 mg/kg every other day, intraperitoneal) significantly inhibited the tumor growth with increased E-cadherin and ZO-1 expression and decreased Fibronectin expression in tumor tissue. In conclusion, this study reveals that Hrh3 plays an important role in the growth and metastasis of NSCLC; it might be a potential therapeutic target against the lung cancer.

TOPK mediates hypoxia-induced epithelial-mesenchymal transition and the invasion of nonsmall-cell lung cancer cells via the HIF-1α/snail axis

Hypoxia has been suggested to induce epithelial-mesenchymal transition (EMT) in various cancer types via the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). Here, we demonstrated that TOPK upregulates EMT and the invasion of H460 nonsmall-cell lung cancer cells through the induction of the HIF-1α/Snail axis and hypoxic signaling. The expression of endogenous TOPK, phosphorylated TOPK, HIF-1α and Snail was significantly increased upon hypoxia exposure, but TOPK depletion markedly abrogated the induced mRNA and protein levels of HIF-1α and Snail. Interestingly, TOPK knockdown restored the hypoxia-induced suppression of E-cadherin and diminished hypoxia-induced N-cadherin expression. In addition, Snail depletion suppressed hypoxia-induced N-cadherin expression, which was attenuated by TOPK knockdown. Moreover, knockdown of Snail decreased hypoxia-induced nonsmall-cell lung cancer cell migration and invasion, which were suppressed by TOPK depletion. In summary, we conclude that TOPK positively regulates HIF-1α expression through hypoxia signaling and thereby promotes Snail expression, leading to EMT and the invasion of nonsmall-cell lung cancer cells. These findings suggest that TOPK plays a critical role as a novel mediator of hypoxia signaling that regulates nonsmall-cell lung cancer development.

ILT3 promotes tumor cell motility and angiogenesis in non-small cell lung cancer.

Immunoglobulin-like transcript (ILT) 3 is an immunosuppressive molecule that negatively regulates myeloid cell activation. ILT3 overexpression in tumor cells induces immune escape of solid tumors and facilitates invasion of monocytic acute myeloid leukemia cells. However, the expression and function of ILT3 in non-small cell lung cancer (NSCLC) cells remain elusive. Herein, we found that ILT3 was enriched in human NSCLC cells, and predicted advanced disease and poor overall survival. ILT3 overexpression enhanced the migration and invasion of NSCLC cells and tubule formation of human umbilical vein endothelial cells by upregulating and interacting with its ligand apolipoprotein E (ApoE) in vitro. Mechanistically, ILT3 recruited SHP2 and SHIP1, and subsequently activated ERK1/2 signaling mediating epithelial-mesenchymal transition (EMT) and increasing vascular endothelial growth factor (VEGF)-A expression in NSCLC cells, which are responsible for tumor cell motility and angiogenesis, respectively. Using murine metastasis models, we further confirmed ILT3 promoted NSCLC metastasis and explored the exact correlation of ILT3 with ApoE, EMT, and VEGF-A in vivo. These results unraveled novel mechanisms for ILT3-induced tumor progression and proposed ILT3 as a potential therapeutic target and prognostic biomarker for NSCLC patients.

LINC00518 Interference Inhibits Non-Small Cell Lung Cancer by Upregulating miR216b-5p Expression.

IntroductionNon–small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases, and effective treatment for this disease is still lacking. This study aimed to explore the potential role of LINC00518 and miR216b-5p on cell proliferation and tumor growth in NSCLC.MethodsThe expression of LINC00518, miR216b-5p, MMP7, and MMP9 in NSCLC cell lines was determined by RT-qPCR analysis, which was also used to confirm the transfection effects. After transfection, proliferation, clone-formation ability, migration, and invasion of NSCLC cells were detected by CCK8, clone-formation, wound-healing, and transwell assays, respectively. Western blot analysis was used to detect the expression of MMP7, MMP9, Ki67, and PCNA. A xenograft model was constructed by subcutaneous injection of transfected NSCLC cells into nude mice.ResultsThe results indicated that LINC00518 expression was increased and miR216b-5p expression decreased in NSCLC cell lines, and A549 cells were chosen for the next experiments. LINC00518 interference inhibited proliferation, invasion, and migration of A549 cells, together with the progression of NSCLC in vivo. In addition, LINC00518 directly targeted miR216b-5p. Downregulation of miR216b-5p weakened the inhibitory effect of LINC00518 interference on proliferation, invasion, and migration of A549 cells, as well as progression of NSCLC in vivo.DiscussionIn conclusion, LINC00518 interference inhibits NSCLC, which is partially reversed by downregulation of miR216b-5p expression.

CircSEC31A Promotes the Malignant Progression of Non-Small Cell Lung Cancer Through Regulating SEC31A Expression via Sponging miR-376a.

BackgroundCircular RNAs (circRNAs) have recently been shown as important regulators in the pathogenesis of non-small cell lung cancer (NSCLC). The purpose of this work was to explore the precise parts played by circRNA SEC31 homolog A (circSEC31A, hsa_circ_0001421) in NSCLC malignant progression.MethodsThe expression levels of circSEC31A, miR-376a and SEC31 homolog A (SEC31A) were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Subcellular fractionation assay was used to determine the subcellular localization of circSEC31A, and RNase R assay was performed to assess the stability of circSEC31A. Cell migration and invasion were detected by transwell assay, and cell apoptosis was evaluated using flow cytometry. Measurement of glucose consumption, lactate production and adenosine triphosphate (ATP) level were done using corresponding assay kits. The targeted interactions among circSEC31A, miR-376a and SEC31A were confirmed by the dual-luciferase reporter and RNA pull-down assays. Animal studies were performed to observe the role of circSEC31A in tumor growth in vivo.ResultsOur data indicated that circSEC31A and SEC31A were upregulated in NSCLC tissues and cells. CircSEC31A knockdown suppressed NSCLC cell migration, invasion, glycolysis and promoted apoptosis in vitro, as well as hindered tumor growth in vivo. Mechanistically, circSEC31A directly interacted with miR-376a, and circSEC31A depletion regulated NSCLC cell malignant progression by miR-376a. Moreover, SEC31A was a functional target of miR-376a, and it mediated the regulatory impact of miR-376a overexpression on NSCLC cell progression. Furthermore, circSEC31A controlled SEC31A expression through acting as a miR-376a sponge.ConclusionOur findings first identified that the knockdown of circSEC31A suppressed NSCLC malignant progression at least partly through modulating SEC31A expression by acting as a miR-376a sponge, providing a novel molecular target of NSCLC therapy.

Serum exosomal miR-1269a serves as a diagnostic marker and plays an oncogenic role in non-small cell lung cancer.

BackgroundEarly diagnosis improves the prognosis for non‐small cell lung cancer (NSCLC); therefore, there is a pressing need for effective diagnostic methods for NSCLC. Increasing evidence indicates that serum exosomal micro RNAs (miRNAs) represent promising diagnostic and prognostic markers for multiple cancers. Here, we explored a panel of miRNAs for NSCLC diagnosis and functionally characterized miR‐1269a in the pathogenesis of NSCLC. Methods: First, we analyzed high‐throughput data from The Cancer Genome Atlas (TCGA) to identify differentially expressed miRNAs between NSCLC patients and healthy controls. We examined the expression profiles of the identified miRNAs using qRT‐PCR. Results: We found that four micro‐RNAs (hsa‐miR‐9‐3p, hsa‐miR‐205‐5p, hsa‐miR‐210‐5p, and hsa‐miR‐1269a) were more abundant in serum exosomes from NSCLC patients. A logistic regression model validated the diagnostic efficacy of the four‐microRNA panel, allowing us to distinguish NSCLC patients from healthy controls with AUCs of 0.915 and 0.878 for the training and validation sets, respectively. Functionally, NSCLC cell proliferation, migration, and invasion were affected by the aberrant expression of hsa‐miR‐1269a in culture. Reduced expression of miR‐1269a resulted in reduced proliferation, migration, and invasion through targeting the forkhead box O1 gene (FOXO1). Conclusions: Taken together, our study identified a panel of four serum exosomal miRNAs as a potential noninvasive diagnostic biomarker for NSCLC. The interactions between FOXO1 and miR‐1269a represent novel potential targets for NSCLC therapy.

The high expression of MTH1 and NUDT5 promotes tumor metastasis and indicates a poor prognosis in patients with non-small-cell lung cancer

MutT Homolog 1 (MTH1) is a mammalian 8-oxodGTPase for sanitizing oxidative damage to the nucleotide pool. Nudix type 5 (NUDT5) also sanitizes 8-oxodGDP in the nucleotide pool. The role of MTH1 and NUDT5 in non-small-cell lung cancer (NSCLC) progression and metastasis remains unclear. In the present study, we reported that MTH1 and NUDT5 were upregulated in NSCLC cell lines and tissues, and higher levels of MTH1 or NUDT5 were associated with tumor metastasis and a poor prognosis in patients with NSCLC. Their suppression also restrained tumor growth and lung metastasis in vivo and significantly inhibited NSCLC cell migration, invasion, cell proliferation and cell cycle progression while promoting apoptosis in vitro. The opposite effects were observed in vitro following MTH1 or NUDT5 rescue. In addition, the upregulation of MTH1 or NUDT5 enhanced the MAPK pathway and PI3K/AKT activity. Furthermore, MTH1 and NUDT5 induce epithelial–mesenchymal transition both in vitro and in vivo. These results highlight the essential role of MTH1 and NUDT5 in NSCLC tumor tumorigenesis and metastasis as well as their functions as valuable markers of the NSCLC prognosis and potential therapeutic targets.

SETD8 is a prognostic biomarker that contributes to stem-like cell properties in non-small cell lung cancer

SETD8 is a lysine methyltransferase containing an SET domain and has been reported to regulate various biological processes, including carcinogenesis. However, its prognostic value and mechanisms of action in non-small cell lung cancer (NSCLC) have not been extensively studied. Here, we assessed SETD8 expression and its relationship with clinicopathological parameters, cancer stemness proteins, and cell cycle-regulating proteins in NSCLC. SETD8 expression in NSCLC tissues was correlated with primary tumor stage, lymph node metastases, and clinical stage. Moreover, SETD8 was an independent predictor of poor overall survival in NSCLC. A Cox regression analysis showed that SETD8 was a potential biomarker of unfavorable clinical outcomes in patients with NSCLC. SETD8 overexpression was associated with cancer stemness-related genes and cell cycle-related genes in NSCLC tissue samples. SETD8 silencing significantly reduced the expression of cancer stemness-associated genes (CD44, LGR5, and SOX2) and inhibited NSCLC cell proliferation, spheroid formation, invasion, and migration. Our findings demonstrate that SETD8 may be a novel cancer stemness-associated protein and a potential prognostic biomarker in NSCLC.