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MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma.

Wang LK, Hsiao TH, Hong TM, Chen HY, Kao SH, Wang WL, Yu SL, Lin CW, Yang PC - PLoS ONE (2014)

Bottom Line: The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines.In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells.Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

ABSTRACT
Non-small cell lung cancers (NSCLCs) cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R), TGF-beta receptor type-1 (TGFBR1), and epidermal growth factor receptor (EGFR), are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.

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The miR-133a tumor suppressor modulates cell invasive capacity in lung cancer.(A) The expression levels of miR-133a in 434 tumor tissues and 46 normal tissues from the TCGA lung adenocarcinoma database were examined. (B) The expression level of endogenous miR-133a in BEAS-2B, EKVX, H23, H441, A549 and H1299 cell lines. MiR-133a expression level (C, left panel), as measured by real time RT-PCR, and cell morphology (C, right panel) in BEAS-2B cells were examined 72 hours after transfection of the anti-miR-133a inhibitor. (D)The number of invasive cells was counted 24 hours after seeding cells that post-treated anti-miR-133a inhibitor (100 nM) for 48 hours in a transwell containing matrigel. (E) The endogenous level of miR-133a in CL1-0, CL1-1, CL1-5 and CL1-5F4 cells. (F) Measurement of the invasion in CL1-5 and A549 cells transiently infected with the AS2-Neo (Ctl) or AS2-Neo-miR-133a-expressing viruses (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel) (G) 48 hours after transient transfection of the anti-miR-133a inhibitor, the invasive capacity of CL1-1 cells was determined (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel).
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pone-0096765-g001: The miR-133a tumor suppressor modulates cell invasive capacity in lung cancer.(A) The expression levels of miR-133a in 434 tumor tissues and 46 normal tissues from the TCGA lung adenocarcinoma database were examined. (B) The expression level of endogenous miR-133a in BEAS-2B, EKVX, H23, H441, A549 and H1299 cell lines. MiR-133a expression level (C, left panel), as measured by real time RT-PCR, and cell morphology (C, right panel) in BEAS-2B cells were examined 72 hours after transfection of the anti-miR-133a inhibitor. (D)The number of invasive cells was counted 24 hours after seeding cells that post-treated anti-miR-133a inhibitor (100 nM) for 48 hours in a transwell containing matrigel. (E) The endogenous level of miR-133a in CL1-0, CL1-1, CL1-5 and CL1-5F4 cells. (F) Measurement of the invasion in CL1-5 and A549 cells transiently infected with the AS2-Neo (Ctl) or AS2-Neo-miR-133a-expressing viruses (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel) (G) 48 hours after transient transfection of the anti-miR-133a inhibitor, the invasive capacity of CL1-1 cells was determined (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel).

Mentions: In the TCGA lung adenocarcinoma database (https://tcga-data.nci.nih.gov/tcga/tcgaHome2.jsp), we found significantly reduced expression levels of miR-133a in 434 tumor tissues compared with 46 normal lung tissues (Figure 1A). To further evaluate the role of miR-133a during lung cancer progression, the expression level of miR-133a in transformed normal bronchial epithelium cells (BEAS-2B cells) and five lung cancer cell lines with different invasive capacities was examined. We found that the expression levels of miR-133a were higher in BEAS-2B cells and in cells with low invasiveness (EKVX and H23) [23] than in those with high invasive ability (A549, H441 and H1299) [24] (Figure 1B). These data suggest that miR-133a is dysregulated in lung cancer and that the expression of miR-133a negatively correlates with cell invasiveness.


MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma.

Wang LK, Hsiao TH, Hong TM, Chen HY, Kao SH, Wang WL, Yu SL, Lin CW, Yang PC - PLoS ONE (2014)

The miR-133a tumor suppressor modulates cell invasive capacity in lung cancer.(A) The expression levels of miR-133a in 434 tumor tissues and 46 normal tissues from the TCGA lung adenocarcinoma database were examined. (B) The expression level of endogenous miR-133a in BEAS-2B, EKVX, H23, H441, A549 and H1299 cell lines. MiR-133a expression level (C, left panel), as measured by real time RT-PCR, and cell morphology (C, right panel) in BEAS-2B cells were examined 72 hours after transfection of the anti-miR-133a inhibitor. (D)The number of invasive cells was counted 24 hours after seeding cells that post-treated anti-miR-133a inhibitor (100 nM) for 48 hours in a transwell containing matrigel. (E) The endogenous level of miR-133a in CL1-0, CL1-1, CL1-5 and CL1-5F4 cells. (F) Measurement of the invasion in CL1-5 and A549 cells transiently infected with the AS2-Neo (Ctl) or AS2-Neo-miR-133a-expressing viruses (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel) (G) 48 hours after transient transfection of the anti-miR-133a inhibitor, the invasive capacity of CL1-1 cells was determined (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel).
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pone-0096765-g001: The miR-133a tumor suppressor modulates cell invasive capacity in lung cancer.(A) The expression levels of miR-133a in 434 tumor tissues and 46 normal tissues from the TCGA lung adenocarcinoma database were examined. (B) The expression level of endogenous miR-133a in BEAS-2B, EKVX, H23, H441, A549 and H1299 cell lines. MiR-133a expression level (C, left panel), as measured by real time RT-PCR, and cell morphology (C, right panel) in BEAS-2B cells were examined 72 hours after transfection of the anti-miR-133a inhibitor. (D)The number of invasive cells was counted 24 hours after seeding cells that post-treated anti-miR-133a inhibitor (100 nM) for 48 hours in a transwell containing matrigel. (E) The endogenous level of miR-133a in CL1-0, CL1-1, CL1-5 and CL1-5F4 cells. (F) Measurement of the invasion in CL1-5 and A549 cells transiently infected with the AS2-Neo (Ctl) or AS2-Neo-miR-133a-expressing viruses (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel) (G) 48 hours after transient transfection of the anti-miR-133a inhibitor, the invasive capacity of CL1-1 cells was determined (right panel). The expression level of miR-133a was normalized to that of RNU48, which was used as an internal control (left panel).
Mentions: In the TCGA lung adenocarcinoma database (https://tcga-data.nci.nih.gov/tcga/tcgaHome2.jsp), we found significantly reduced expression levels of miR-133a in 434 tumor tissues compared with 46 normal lung tissues (Figure 1A). To further evaluate the role of miR-133a during lung cancer progression, the expression level of miR-133a in transformed normal bronchial epithelium cells (BEAS-2B cells) and five lung cancer cell lines with different invasive capacities was examined. We found that the expression levels of miR-133a were higher in BEAS-2B cells and in cells with low invasiveness (EKVX and H23) [23] than in those with high invasive ability (A549, H441 and H1299) [24] (Figure 1B). These data suggest that miR-133a is dysregulated in lung cancer and that the expression of miR-133a negatively correlates with cell invasiveness.

Bottom Line: The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines.In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells.Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

ABSTRACT
Non-small cell lung cancers (NSCLCs) cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R), TGF-beta receptor type-1 (TGFBR1), and epidermal growth factor receptor (EGFR), are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.

Show MeSH
Related in: MedlinePlus