microRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C.

Recent studies have indicated that microRNAs (miRNAs) are important gene regulators that play critical roles in biological processes and function as either tumour suppressors or oncogenes. Therefore, the expression levels of miRNAs can be important and reliable biomarkers for cancer detection and prognostic prediction, and potentially serve as targets for cancer therapy. In this study, we showed that the expression level of miR-128 was significantly downregulated in non-small cell lung cancer (NSCLC) tissues and cancer cells, and was significantly correlated with NSCLC differentiation, pathological stage and lymph node metastasis. Ectopic miR-128 overexpression significantly suppressed in vitro proliferation, colony formation, immigration and invasion, and induced G1 arrest and apoptosis of NSCLC cells. Interestingly, ectopic miR-128 overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-C expression and reduce the activity of a luciferase reporter containing the VEGF-C 3'-untranslated region. In addition, overexpression of miR-128 in NSCLC cells and human umbilical vein endothelial cells (HUVECs) cells led to decreased expression of VEGF-A, vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3, critical factors responsible for cancer angiogenesis and lymphangiogenesis, and subsequently decreased phosphorylation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (AKT) and p38 signalling pathways. Furthermore, in vivo restoration of miR-128 significantly suppressed tumourigenicity of A549 cells in nude mice and inhibited both angiogenesis and lymphangiogenesis of tumour xenografts. These findings suggest that miR-128 could play a role in NSCLC tumourigenesis at least in part by modulation of angiogenesis and lymphangiogenesis through targeting VEGF-C, and could simultaneously block ERK, AKT and p38 signalling pathways. Therapeutic strategies to restore miR-128 in NSCLC could be useful to inhibit tumour progression.

Hu J ，Cheng Y ，Li Y ，Jin Z ，Pan Y ，Liu G ，Fu S ，Zhang Y ，Feng K ，Feng Y ... -  《-》

RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways.

Vascular endothelial growth factor C (VEGF-C) expression is associated with the malignant tumour phenotype making it an attractive therapeutic target. We investigated the biological roles of VEGF-C in tumour growth, migration, invasion and explored the possibility of VEGF-C as a potential therapeutic target for the treatment of non-small cell lung cancer (NSCLC). A lentivirus-mediated RNA interference (RNAi) technology was used to specifically knockdown the expression of VEGF-C in A549 cells. Quantitative reverse transcriptase-polymerase chain reaction, flow cytometry, Western blot, immunohistochemistry, cellular growth, migration, invasion and ELISA assays were used to characterise VEGF-C expression in vitro. A lung cancer xenograft model in nude mice was established to investigate whether knockdown of VEGF-C reduced tumour growth in vivo. Silencing of VEGF-C suppressed tumour cell growth, migration and invasion in vitro; suppressed tumour growth, angiogenesis and lymphangiogenesis by tail vein injection of lentivirus encoded shRNA against VEGF-C in vivo. More importantly, silencing of VEGF-C also trapped the VEGFR-2, VEGFR-3, CXCR4, CCR7-dependent axes, and down-regulated the AKT, ERK and p38 signalling pathways. These results suggest that VEGF-C has a multifaceted role in NSCLC growth, migration and invasion; that VEGF-C-mediated autocrine loops with their cognate receptors and chemokine receptors are significant factors affecting tumour progression; and that RNAi-mediated silencing of VEGF-C represents a powerful therapeutic approach for controlling NSCLC growth and metastasis.

Feng Y ，Hu J ，Ma J ，Feng K ，Zhang X ，Yang S ，Wang W ，Zhang J ，Zhang Y ... -  《-》

MiR-182-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-C.

MicroRNAs (miRNAs) are gene modulators essential for biological processes. However, the precise functions of miRNAs in growth and development of colon cancer are still elusive. To clarify their role, here we analyzed a miRNA microarray of colon cancer. MiR-182-5p was found markedly downregulated in colon cancer tissues and cells, and strongly correlated with pathological stage, differentiation, and lymphatic metastasis. In vitro, miR-182-5p overexpression repressed colon cancer cell proliferation, colony formation, migration, and invasion, and triggered G1 arrest and apoptosis. MiR-182-5p overexpression also downregulated vascular endothelial growth factor (VEGF)-C and inhibited the activity of a luciferase reporter containing the VEGF-C 3'-untranslated region. Moreover, miR-182-5p overexpression in colon cancer cells and human umbilical vein endothelial cells (HUVECs) downregulated VEGF-A as well as VEGF receptor (VEGFR)-2 and VEGFR-3, thereby inhibiting the phosphorylation of ERK and AKT. In vivo, miR-182-5p overexpression strikingly suppressed oncogenicity of SW620 cells as well as angiogenesis and lymphangiogenesis of xenograft tumors in nude mice. These data indicate that miR-182-5p regulates colon cancer tumorigenesis partially through modulating angiogenesis and lymphangiogenesis by targeting VEGF-C, and inhibiting ERK and AKT signaling pathways.

Yan S ，Wang H ，Chen X ，Liang C ，Shang W ，Wang L ，Li J ，Xu D ... -  《-》

MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14).

Wang R ，Wang ZX ，Yang JS ，Pan X ，De W ，Chen LB ... -  《-》

miR-99a suppresses the metastasis of human non-small cell lung cancer cells by targeting AKT1 signaling pathway.

MicroRNAs (miRNAs) play an important role in the development and progression of non-small cell lung cancer (NSCLC). Recently, several studies have shown that miR-99a is downregulated in various cancers, which can affect tumor initiation and maintenance. Herein, we found that miR-99a was downregulated in NSCLC tissues and suppressed tumor metastasis of NSCLC cells. Down-regulation of miR-99a is significantly associated with last-stage and tumor metastasis in NSCLC patients. Further functional experiments found that overexpression of miR-99a inhibit cell proliferation, migration, and invasion of NSCLC cells in vitro and tumor metastasis of NSCLC in vivo. In addition, we also found that AKT1 is directly involved in miR-99a-mediated tumor suppression. Restored the expression of AKT1 partially abolished the suppressive effects miR-99a on proliferation and invasion of NSCLC cells. Collectively, our data suggest that miR-99a plays an important role in the tumorigenesis and metastasis of NSCLC and may serve as a therapeutic target to avoid dissemination of NSCLC cells.

Yu SH ，Zhang CL ，Dong FS ，Zhang YM ... -  《-》