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miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer.

Du L, Zhao Z, Ma X, Hsiao TH, Chen Y, Young E, Suraokar M, Wistuba I, Minna JD, Pertsemlidis A - Oncogene (2013)

Bottom Line: The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types.Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function.We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA.

View Article: PubMed Central - PubMed

Affiliation: 1] Greehey Children's Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center at San Antonio, San Antonio, TX, USA.

ABSTRACT
The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types. The role of DAB2 in lung tumorigenesis, however, is not fully characterized, and the mechanisms of DAB2 dysregulation in lung cancer are not defined. Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function. We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA. Using in vitro and in vivo approaches, we demonstrate that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by downregulating DAB2 expression. Our clinical investigations further indicate that high tumor levels of miR-93 are correlated with poor survival of lung cancer patients. The correlations of both low DAB2 and high miR-93 expression levels with poor patient survival strongly support the critical role of the miR-93/DAB2 pathway in determining lung cancer progression.

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Related in: MedlinePlus

Over-expression of miR-93 promotes lung cancer cell proliferation in vitroH1993 cells were transfected with either the miR-93 expression construct, miR-93 inhibitor, miR-93 sponge vector, or corresponding controls. A, Expression levels of miR-93 measured by qRT-PCR. B, BrdU incorporation as a function of miR-93 over-expression or knockdown. C–D, Colony formation and quantification of colonies as function of miR-93 over-expression. **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.
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Figure 4: Over-expression of miR-93 promotes lung cancer cell proliferation in vitroH1993 cells were transfected with either the miR-93 expression construct, miR-93 inhibitor, miR-93 sponge vector, or corresponding controls. A, Expression levels of miR-93 measured by qRT-PCR. B, BrdU incorporation as a function of miR-93 over-expression or knockdown. C–D, Colony formation and quantification of colonies as function of miR-93 over-expression. **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.

Mentions: We and others have previously shown that miR-93 is over-expressed in lung cancers (19, 26), further suggesting that aberrant over-expression of miR-93 contributes to the repression of DAB2 expression in lung cancer. We first examined the function of miR-93 in regulating lung cancer proliferation by over-expressing or knocking down miR-93 in lung cancer cells in vitro. Figure 4A–B shows that miR-93 over-expression increases cell proliferation, whereas miR-93 knockdown with either a miR-93 inhibitor (Dharmacon) or a miR-93 sponge decreases cell proliferation. The results demonstrate the growth-promoting function of miR-93 in lung cancer cells. Figure 4C–D further shows that miR-93 over-expression in lung cancer cells significantly promotes long-term cell growth as measured by colony formation assay.


miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer.

Du L, Zhao Z, Ma X, Hsiao TH, Chen Y, Young E, Suraokar M, Wistuba I, Minna JD, Pertsemlidis A - Oncogene (2013)

Over-expression of miR-93 promotes lung cancer cell proliferation in vitroH1993 cells were transfected with either the miR-93 expression construct, miR-93 inhibitor, miR-93 sponge vector, or corresponding controls. A, Expression levels of miR-93 measured by qRT-PCR. B, BrdU incorporation as a function of miR-93 over-expression or knockdown. C–D, Colony formation and quantification of colonies as function of miR-93 over-expression. **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281941&req=5

Figure 4: Over-expression of miR-93 promotes lung cancer cell proliferation in vitroH1993 cells were transfected with either the miR-93 expression construct, miR-93 inhibitor, miR-93 sponge vector, or corresponding controls. A, Expression levels of miR-93 measured by qRT-PCR. B, BrdU incorporation as a function of miR-93 over-expression or knockdown. C–D, Colony formation and quantification of colonies as function of miR-93 over-expression. **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.
Mentions: We and others have previously shown that miR-93 is over-expressed in lung cancers (19, 26), further suggesting that aberrant over-expression of miR-93 contributes to the repression of DAB2 expression in lung cancer. We first examined the function of miR-93 in regulating lung cancer proliferation by over-expressing or knocking down miR-93 in lung cancer cells in vitro. Figure 4A–B shows that miR-93 over-expression increases cell proliferation, whereas miR-93 knockdown with either a miR-93 inhibitor (Dharmacon) or a miR-93 sponge decreases cell proliferation. The results demonstrate the growth-promoting function of miR-93 in lung cancer cells. Figure 4C–D further shows that miR-93 over-expression in lung cancer cells significantly promotes long-term cell growth as measured by colony formation assay.

Bottom Line: The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types.Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function.We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA.

View Article: PubMed Central - PubMed

Affiliation: 1] Greehey Children's Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center at San Antonio, San Antonio, TX, USA.

ABSTRACT
The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types. The role of DAB2 in lung tumorigenesis, however, is not fully characterized, and the mechanisms of DAB2 dysregulation in lung cancer are not defined. Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function. We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA. Using in vitro and in vivo approaches, we demonstrate that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by downregulating DAB2 expression. Our clinical investigations further indicate that high tumor levels of miR-93 are correlated with poor survival of lung cancer patients. The correlations of both low DAB2 and high miR-93 expression levels with poor patient survival strongly support the critical role of the miR-93/DAB2 pathway in determining lung cancer progression.

Show MeSH
Related in: MedlinePlus