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NF-κB-mediated miR-124 suppresses metastasis of non-small-cell lung cancer by targeting MYO10.

Sun Y, Ai X, Shen S, Lu S - Oncotarget (2015)

Bottom Line: Over-expression of miR-124 robustly attenuated migration and metastatic ability of the aggressive cells.Knockdown of MYO10 inhibited cell migration, whereas forced MYO10 expression markedly rescued miR-124-mediated suppression of cell metastasis.Additionally, we found an activated NF-κB-centered inflammatory loop in the highly aggressive cells leading to down-regulation of miR-124.

View Article: PubMed Central - PubMed

Affiliation: Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

ABSTRACT
Recently, dysregulation of microRNAs plays a critical role in cancer metastasis. Here, an in vivo selection approach was used to generate highly aggressive NSCLC sub-cell lines followed by comparing the microRNAs expression using microarrays. miR-124 was notably deregulated in both highly invasive sub-cell lines and node-positive NSCLC specimens. Over-expression of miR-124 robustly attenuated migration and metastatic ability of the aggressive cells. MYO10 was subsequently identified as a novel functional downstream target of miR-124, and was up-regulated in node-positive NSCLC tissues. Knockdown of MYO10 inhibited cell migration, whereas forced MYO10 expression markedly rescued miR-124-mediated suppression of cell metastasis. Additionally, we found an activated NF-κB-centered inflammatory loop in the highly aggressive cells leading to down-regulation of miR-124. These results suggest that NF-κB-regulated miR-124 targets MYO10, inhibits cell invasion and metastasis, and is down-regulated in node-positive NSCLC.

No MeSH data available.


Related in: MedlinePlus

miR-124 is down-regulated in aggressive NSCLC cells(A) Analysis of the fold regulation in the microRNAs was performed by a microRNA array. The green points indicate down-regulated miRNAs, and the red points indicate up-regulated miRNAs. (B) Relative miR-124 expression in parental and aggressive cells was determined by qRT-PCR. **p < 0.01 and ***p < 0.001 for comparing with parental cells. (C) qRT-PCR analysis of miR-124 abundance in human normal lung (n = 12) or NSCLC tumors with lymph nodes positive (n = 53) or negative (n = 65). *p < 0.05, **p < 0.01 and ***p < 0.001.
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Figure 2: miR-124 is down-regulated in aggressive NSCLC cells(A) Analysis of the fold regulation in the microRNAs was performed by a microRNA array. The green points indicate down-regulated miRNAs, and the red points indicate up-regulated miRNAs. (B) Relative miR-124 expression in parental and aggressive cells was determined by qRT-PCR. **p < 0.01 and ***p < 0.001 for comparing with parental cells. (C) qRT-PCR analysis of miR-124 abundance in human normal lung (n = 12) or NSCLC tumors with lymph nodes positive (n = 53) or negative (n = 65). *p < 0.05, **p < 0.01 and ***p < 0.001.

Mentions: Since there have only been a few reports on the associations between miRNA gene expression and NSCLC metastasis, we wonder whether miRNAs play a role in induction of a highly aggressive phenotype in our model. The miRNA expression in parental and highly aggressive cells (M3) was examined using miRNA qPCR array, and fold regulation in the miRNAs was analyzed. A panel of miRNAs with significant differential expression between parental and M3 cells was derived through a series of contrasts (Supplementary Table 1), and these miRNAs were selected for further validation and functional characterization. Among these miRNAs, the significant down-regulated expression of miR-124 was consistently observed in the two aggressive sub-cell lines (H522M3 and H1975M3) compared to parental cells (Figure 2A). These results from microarray studies were subsequently validated as demonstrated by qRT-PCR analysis that the miR-124 level was significantly down-regulated in the established aggressive cells compared with parental cells (Figure 2B). Furthermore, miR-124 expression in biopsies from normal lung or patients with lymph node-positive and -negative NSCLC was also examined with qRT-PCR. It was demonstrated that miR-124 was decreased in NSCLC compared with the normal lung tissues, and low miR-124 expression was significantly associated with lymphatic metastasis of the NSCLC (Figure 2C).


NF-κB-mediated miR-124 suppresses metastasis of non-small-cell lung cancer by targeting MYO10.

Sun Y, Ai X, Shen S, Lu S - Oncotarget (2015)

miR-124 is down-regulated in aggressive NSCLC cells(A) Analysis of the fold regulation in the microRNAs was performed by a microRNA array. The green points indicate down-regulated miRNAs, and the red points indicate up-regulated miRNAs. (B) Relative miR-124 expression in parental and aggressive cells was determined by qRT-PCR. **p < 0.01 and ***p < 0.001 for comparing with parental cells. (C) qRT-PCR analysis of miR-124 abundance in human normal lung (n = 12) or NSCLC tumors with lymph nodes positive (n = 53) or negative (n = 65). *p < 0.05, **p < 0.01 and ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480748&req=5

Figure 2: miR-124 is down-regulated in aggressive NSCLC cells(A) Analysis of the fold regulation in the microRNAs was performed by a microRNA array. The green points indicate down-regulated miRNAs, and the red points indicate up-regulated miRNAs. (B) Relative miR-124 expression in parental and aggressive cells was determined by qRT-PCR. **p < 0.01 and ***p < 0.001 for comparing with parental cells. (C) qRT-PCR analysis of miR-124 abundance in human normal lung (n = 12) or NSCLC tumors with lymph nodes positive (n = 53) or negative (n = 65). *p < 0.05, **p < 0.01 and ***p < 0.001.
Mentions: Since there have only been a few reports on the associations between miRNA gene expression and NSCLC metastasis, we wonder whether miRNAs play a role in induction of a highly aggressive phenotype in our model. The miRNA expression in parental and highly aggressive cells (M3) was examined using miRNA qPCR array, and fold regulation in the miRNAs was analyzed. A panel of miRNAs with significant differential expression between parental and M3 cells was derived through a series of contrasts (Supplementary Table 1), and these miRNAs were selected for further validation and functional characterization. Among these miRNAs, the significant down-regulated expression of miR-124 was consistently observed in the two aggressive sub-cell lines (H522M3 and H1975M3) compared to parental cells (Figure 2A). These results from microarray studies were subsequently validated as demonstrated by qRT-PCR analysis that the miR-124 level was significantly down-regulated in the established aggressive cells compared with parental cells (Figure 2B). Furthermore, miR-124 expression in biopsies from normal lung or patients with lymph node-positive and -negative NSCLC was also examined with qRT-PCR. It was demonstrated that miR-124 was decreased in NSCLC compared with the normal lung tissues, and low miR-124 expression was significantly associated with lymphatic metastasis of the NSCLC (Figure 2C).

Bottom Line: Over-expression of miR-124 robustly attenuated migration and metastatic ability of the aggressive cells.Knockdown of MYO10 inhibited cell migration, whereas forced MYO10 expression markedly rescued miR-124-mediated suppression of cell metastasis.Additionally, we found an activated NF-κB-centered inflammatory loop in the highly aggressive cells leading to down-regulation of miR-124.

View Article: PubMed Central - PubMed

Affiliation: Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

ABSTRACT
Recently, dysregulation of microRNAs plays a critical role in cancer metastasis. Here, an in vivo selection approach was used to generate highly aggressive NSCLC sub-cell lines followed by comparing the microRNAs expression using microarrays. miR-124 was notably deregulated in both highly invasive sub-cell lines and node-positive NSCLC specimens. Over-expression of miR-124 robustly attenuated migration and metastatic ability of the aggressive cells. MYO10 was subsequently identified as a novel functional downstream target of miR-124, and was up-regulated in node-positive NSCLC tissues. Knockdown of MYO10 inhibited cell migration, whereas forced MYO10 expression markedly rescued miR-124-mediated suppression of cell metastasis. Additionally, we found an activated NF-κB-centered inflammatory loop in the highly aggressive cells leading to down-regulation of miR-124. These results suggest that NF-κB-regulated miR-124 targets MYO10, inhibits cell invasion and metastasis, and is down-regulated in node-positive NSCLC.

No MeSH data available.


Related in: MedlinePlus