Promoted Non-small Cell Lung Cancer Cell Migration Research Articles

MiR-224 enhances invasion and metastasis by targeting HOXD10 in non-small cell lung cancer cells

Increasing number of studies have indicated aberrant microRNA (miRNA) expression could affect normal biological progress in non-small cell lung cancer (NSCLC) cells. This study was performed to evaluate the biologic functions of microRNA-224 (miR-224) in NSCLC. Real-time PCR was performed to evaluate the expression of miR-224 and Homeobox D10 (HOXD10) in NSCLC cell lines and tissues. Transwell assays were performed to investigate the function of miR-224 on NSCLC cell migration and invasion. Moreover, western blotting and luciferase assays were used to investigate HOXD10 as miR-224 downstream targets. miR-224 is increased in NSCLC metastatic tissues and cell lines. Increased miR-224 expression promoted NSCLC cell migration and invasion, while low miR-224 expression suppressed NSCLC cell migration and invasion. Furthermore, HOXD10 was targeted directly by miR-224 in NSCLC cells. Moreover, we found that HOXD10 was a functional target and influenced tumour-inductive functions of miR-224 on progression of NSCLC. These findings suggest that miR-224 may be used in the treatment of NSCLC. Targeting this novel strategy, miR-224/HOXD10 axis may be helpful as promising biomarker and therapeutic method to control NSCLC cell metastasis.

The membrane bile acid receptor TGR5 drives cell growth and migration via activation of the JAK2/STAT3 signaling pathway in non-small cell lung cancer

Mounting evidence suggests that an emerging G protein-coupled receptor, TGR5, plays a crucial role ranging from metabolic diseases to cancers. However, the biological functions of TGR5 in non-small cell lung cancer (NSCLC) remain elusive. We found that TGR5 was aberrantly expressed in NSCLC and positively correlated with an advanced clinical stage in NSCLC patients. We further discovered that TGR5 knockdown prevented JAK2 and STAT3 phosphorylation and repressed the expression of STAT3 target genes, thus inhibiting cell proliferation, migration and invasion in NSCLC. Moreover, the promotive effects of TGR5 were significantly reversed by a JAK2 inhibitor or STAT3 knockdown. Additionally, we demonstrated a positive correlation between TGR5 and p-STAT3 expression in NSCLC tissue samples. Patients with both high TGR5 and p-STAT3 expression had the worst prognosis. In addition, the serum levels of deoxycholic acid (DCA), ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in NSCLC patients were much higher than those in the healthy controls and the patients with higher serum DCA levels had stronger TGR5 expression simultaneously. Moreover, DCA markedly promoted NSCLC cell migration and invasion through a TGR5-dependent way. Taken together, these results indicate that TGR5 drives cell growth and migration through JAK2/STAT3 signaling pathway in NSCLC.

Retraction Note: The microRNA-1246 promotes metastasis in non-small cell lung cancer by targeting cytoplasmic polyadenylation element-binding protein

The microRNAs present a class of non-coding RNAs which are usually implicated in tumor biology. Recent report has unraveled that a novel member of microRNA family called miR-1246. However, the functional role and molecular mechanisms of miR-1246 in non-small cell lung cancer (NSCLC) is still elusive. Using RT-PCR, luciferase reporter, mRNA microarrays, invasion and migration assays, we investigated the potential role of miR-1246 in the pathogenesis of NSCLC. In this study, we showed that miR-1246 markedly promoted NSCLC cell migration and invasion. Meanwhile, we found that cytoplasmic polyadenylation element binding protein 4 (CPEB4) might be involved and serve as a direct target of miR-1246 in NSCLC. CPEB4 knockdown substantially enhanced NSCLC migration and invasion resembling the effect of miR-1246 in NSCLC. CPEB4 is also frequently downregulated in NSCLC and decreased CPEB4 expression correlated with poor survival. These results suggested that the miR-1246 may promote cell metastasis by targeting CPEB4. Meanwhile, the level of CPEB4 could be used as a potential marker in NSCLC patients. Our findings unraveled novel functions of miR-1246 in lung cancer cells and shed light on NSCLC prognosis.

MicroRNA-92a promotes epithelial-mesenchymal transition through activation of PTEN/PI3K/AKT signaling pathway in non-small cell lung cancer metastasis.

MicroRNAs (miRNAs) have important roles in various cancers, including non-small cell lung cancer (NSCLC). Although several miRNAs have reported to be involved in the development of NSCLC, understanding the regulatory roles of other miRNAs in NSCLC is essential. Therefore, the aim of the current study was to explore the roles and mechanisms of screened miRNAs in NSCLC. First, the differentially expressed miRNAs that were screened based on GSE29248 microarray data retrieved from Gene Expression Omnibus (GEO). The expression of miR-92a, acted as an oncogene in many cancers, was validated using quantitative real-time PCR (qRT-PCR), and then its association with overall survival was analyzed. The efficacy of miR-92a to promote cell proliferation, invasion and metastasis was evaluated invitro, and invivo. Then, the role of miR-92a in epithelial-mesenchymal transition (EMT), a key step of the progression of tumor cell metastasis, was investigated in NSCLC cells. The association of miR-92a and its downstream target was investigated in both cell line and clinical specimens. Furthermore, gain- and loss-of-function studies of the phosphatase and tensin homolog (PTEN) were performed to assess whether the effect of miR-92a promoted growth and metastasis of NSCLC cells were via targeting PTEN. Our results showed that miR-92a was significantly upregulated in NSCLC tissues and NSCLC cell lines, and was positively associated with poor prognosis of NSCLC patients. The overexpression of miR-92a enhanced EMT-relatived protein levels, promoted NSCLC cell migration and invasion invitro, and increased tumor growth invivo. Bioinformatic prediction and function assay suggested that PTEN, a negative regulator of PI3K/AKT pathway, was a direct target of miR-92a. It was found that PTEN expression was inversely correlated with miR-92a in NSCLC tissues. In addition, miR-92a could activate the PI3K/AKT pathway by inhibiting PTEN expression. Notably, Transwell and wound healing assays demonstrated that altering PTEN expression abrogated the promotive effects of miR-92a on NSCLC cell migration and invasion. Taken together, these results demonstrated that miR-92a induced EMT and regulated cell migration and invasion in the NSCLC cells through regulating PI3K/AKT signaling pathway by targeting PTEN, indicating that miR-92a may be an attractive target and prognostic marker for NSCLC.

MicroRNA-138 inhibits migration and invasion of non-small cell lung cancer cells by targeting LIMK1.

MicroRNA (miR)-138 has previously been demonstrated to have a suppressive role in numerous types of human cancer, including non-small cell lung cancer (NSCLC). LIM domain kinase1 (LIMK1) is a serine/threonine kinase that regulates actin polymerization via phosphorylation and inactivation of cofilin. Previous studies have reported that LIMK1 is associated with NSCLC; however, the underlying regulatory mechanism of LIMK1, and the association between LIMK1 and miR‑138 in NSCLC cells, remains largely unknown. The present study aimed to reveal the regulatory roles of miR‑138 and LIMK1 in NSCLC cell migration and invasion. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to examine the mRNA and protein expression levels. Transwell and wound healing assays were conducted to determine cell invasion and migration. A luciferase reporter assay was used to determine the target association between miR‑138 and LIMK1. The present study demonstrated that miR‑138 was markedly downregulated in NSCLC tissues and cell lines, whereas the expression levels of LIMK1 were significantly upregulated. LIMK1 was further identified as a direct target of miR‑138 in NSCLCH460 cells. Furthermore, overexpression of miR‑138 significantly inhibited the protein expression of LIMK1, whereas knockdown of miR‑138 upregulated the protein expression of LIMK1 in H460 cells. In addition, overexpression of miR‑138 significantly inhibited the migration and invasion of NSCLC cells; however, overexpression of LIMK1 significantly promoted NSCLC cell migration and invasion. An investigation into the underlying molecular mechanism revealed that overexpression of miR‑138 significantly decreased cofilin signaling activity, whereas knockdown of miR‑138 notably enhanced cofilin signaling activity. In conclusion, the present study suggests that miR‑138 may inhibit the migration and invasion of NSCLC cells by targeting the LIMK1/cofilin signaling pathway. Therefore, miR-138/LIMK1/cofilin may be considered a potential therapeutic target for the treatment of NSCLC.

MicroRNA-133b inhibits the migration and invasion of non small cell lung cancer cells via targeting FSCN1.

MicroRNA (miR)-133b has been reported to act as a tumor suppressor in multiple types of human cancers, including non small cell lung cancer (NSCLC). However, the underlying mechanism by which miR-133b inhibits NSCLC metastasis remains largely unclear. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect messenger RNA and protein expression. A wound healing assay and transwell assay were used to examine the cell migration and invasion. The expression level of miR-133b was found to be significantly downregulated in NSCLC cell lines compared with normal lung epithelial BEAS-2B cells. Further investigation identified fascin1 (FSCN1) as a direct target of miR-133b in NSCLC cells. The expression of FSCN1 was significantly increased in NSCLC cell lines compared with BEAS-2B cells, and its protein expression was negatively regulated by miR-133b in NSCLC A549 cells. Further investigation showed that the upregulation of miR-133b notably inhibited NSCLC cell migration and invasion, while the overexpression of FSCN1 significantly promoted NSCLC cell migration and invasion. Furthermore, the overexpression of FSCN1 reversed the suppressive effect of miR-133b overexpression on NSCLC cell migration and invasion. Accordingly, the present study suggests that miR-133b inhibits the migration and invasion of NSCLC cells via directly targeting FSCN1, and thus may be used for the treatment of NSCLC metastasis.

The microRNA-1246 promotes metastasis in non-small cell lung cancer by targeting cytoplasmic polyadenylation element-binding protein 4.

BackgroundThe microRNAs present a class of non-coding RNAs which are usually implicated in tumor biology. Recent report has unraveled that a novel member of microRNA family called miR-1246. However, the functional role and molecular mechanisms of miR-1246 in non-small cell lung cancer (NSCLC) is still elusive.MethodsUsing RT-PCR, luciferase reporter, mRNA microarrays, invasion and migration assays, we investigated the potential role of miR-1246 in the pathogenesis of NSCLC.ResultsIn this study, we showed that miR-1246 markedly promoted NSCLC cell migration and invasion. Meanwhile, we found that cytoplasmic polyadenylation element binding protein 4 (CPEB4) might be involved and serve as a direct target of miR-1246 in NSCLC. CPEB4 knockdown substantially enhanced NSCLC migration and invasion resembling the effect of miR-1246 in NSCLC. CPEB4 is also frequently downregulated in NSCLC and decreased CPEB4 expression correlated with poor survival.ConclusionsThese results suggested that the miR-1246 may promote cell metastasis by targeting CPEB4. Meanwhile, the level of CPEB4 could be used as a potential marker in NSCLC patients. Our findings unraveled novel functions of miR-1246 in lung cancer cells and shed light on NSCLC prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-015-0366-1) contains supplementary material, which is available to authorized users.

Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung cancer and promotes cell invasion via epithelial-to-mesenchymal transition

Discoidin domain receptors (DDRs) are a novel class of receptor tyrosine kinases that respond to several collagens and facilitate cell adhesion. DDR1 is highly expressed in a variety of human cancers, and it is clear that DDR1 is primarily expressed in epithelial cells including lung, colon and brain. Moreover, DDR1 expression can be stimulated by collagen types I, II, III, IV, V, VIII and XI, and aberrant signaling induced by DDR1 dysregulated expression is involved in various steps of tumorigenesis. However, the molecular mechanism underlying the role of DDR1 in cancer development is not well documented. In this study, we found that the expression of DDR1 is upregulated in non-small cell lung cancer (NSCLC) tissues and cells when compared with counterpart normal tissues and cells. Furthermore, collagen I could induce DDR1 expression, and activated DDR1 promoted NSCLC cell migration and invasion, while knockdown of DDR1 by transfection with siRNA resulted in a significant decrease in cell migrativeness and invasiveness. Enhanced DDR1 expression mediated by collagen I could activate MMP-2, N-cadherin and vimentin expression, but reduce E-cadherin expression; however, inhibition of DDR1 expression could suppress MMP-2, N-cadherin and vimentin expression and induce E-cadherin activation. In conclusion, our findings indicated that upregulation of DDR1 induced by collagen I may contribute to the development and progression of NSCLC and this effect may be associated with increased invasiveness, at least in part, via promoting epithelial-to-mesenchymal transition.

ADAM10 overexpression in human non-small cell lung cancer correlates with cell migration and invasion through the activation of the Notch1 signaling pathway

A disintegrin and metalloproteinase 10 (ADAM10) was identified as a key protease in the ectodomain shedding of various substrates, such as Notch1 protein, ErbB2 and E-cadherin, which are important in the development of non-small cell lung cancer (NSCLC). The aim of this study was to investi-gate the role of ADAM10 in NSCLC metastasis.We characterized the expression of ADAM10 and Notch1 in human NSCLC tissues in vivo. Immunohistochemical analysis indicated that ADAM10 expression was significantly increased in the NSCLC tissues, particularly in the metastatic tissues. Futhermore, ADAM10 overexpression positively correlated with Notch1 expression in the NSCLC tissues. The in vitro downregulation of ADAM10 expression using ADAM10 short hairpin RNA (shRNA) reduced the migration and invasion of NSCLC cells. We present further evidence that ADAM10 promotes NSCLC cell migration and invasion via the activation of the Notch1 signaling pathway. Taken together, our results suggest that ADAM10 may serve as a potential target for the therapeutic intervention of NSCLC metastasis. The data provided in this study may aid in the further understanding of the function of ADAM10 in the progression of NSCLC and open new perspectives for the diagnosis and treatment of NSCLC.