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A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.

Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, Flores I, Weidhaas JB, Taylor HS - EMBO Mol Med (2012)

Bottom Line: Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease.Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women.We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

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Let-7 miRNA family expression in hESC from 10 subjects without endometriosis (normal controls), 10 subjects with endometriosis carrying WT KRAS and 10 subjects with endometriosis and the variant allele of KRAS geneq-RT-PCR results show a trend towards decreased transcript levels of all let-7 miRNAs in hESC from subjects with endometriosis compared to normal hESC from subjects without endometriosis (normal control). Endometrial cells from subjects with endometriosis with the LCS6 variant in the KRAS gene showed lower levels of let-7a, b and e compared to hESC from endometriosis with non-variant KRAS (*p = 0.0047, 0.003 and 0.05, respectively). let-7a and b were also lower in KRAS-variant cells from women with endometriosis compared to normal hESC (‡p = 0.05 and 0.02, respectively).
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fig02: Let-7 miRNA family expression in hESC from 10 subjects without endometriosis (normal controls), 10 subjects with endometriosis carrying WT KRAS and 10 subjects with endometriosis and the variant allele of KRAS geneq-RT-PCR results show a trend towards decreased transcript levels of all let-7 miRNAs in hESC from subjects with endometriosis compared to normal hESC from subjects without endometriosis (normal control). Endometrial cells from subjects with endometriosis with the LCS6 variant in the KRAS gene showed lower levels of let-7a, b and e compared to hESC from endometriosis with non-variant KRAS (*p = 0.0047, 0.003 and 0.05, respectively). let-7a and b were also lower in KRAS-variant cells from women with endometriosis compared to normal hESC (‡p = 0.05 and 0.02, respectively).

Mentions: Let-7 is known to bind to the non-variant and not the variant LCS6 allele preventing KRAS protein synthesis. To assess the possibility of compensatory changes in let-7 miRNAs in the setting of the variant allele and elevated KRAS protein, we determined the level of let-7a–g miRNAs (Fig 2). Cultured endometrial stromal cells from women with endometriosis with the LCS6 variant in the KRAS gene showed lower levels of let-7a, b and e (0.26 ± 0.009, 0.07 ± 0.01 and 0.08 ± 0.02, respectively), compared to hESC from women with endometriosis with non-variant KRAS (0.21 ± 0.05, 0.29 ± 0.02, 0.21 ± 0.029, respectively; p = 0.0047, 0.003 and 0.05, respectively). let-7a and b were also lower in KRAS variant cells from endometriotic women compared to normal hESC (0.29 ± 0.188, 0.53 ± 0.23, respectively; p = 0.05 and 0.02, respectively). Compared to hESC isolated from normal endometrium, hESC from women with endometriosis exhibited lower levels of let-7 family miRNA. These alterations in let-7 in the presence of the KRAS variant allele could be a result of a feedback mechanism or due to another unidentified independent factor, but do agree with prior published findings of lower let-7 in KRAS variant-associated lesions.


A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.

Grechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, Flores I, Weidhaas JB, Taylor HS - EMBO Mol Med (2012)

Let-7 miRNA family expression in hESC from 10 subjects without endometriosis (normal controls), 10 subjects with endometriosis carrying WT KRAS and 10 subjects with endometriosis and the variant allele of KRAS geneq-RT-PCR results show a trend towards decreased transcript levels of all let-7 miRNAs in hESC from subjects with endometriosis compared to normal hESC from subjects without endometriosis (normal control). Endometrial cells from subjects with endometriosis with the LCS6 variant in the KRAS gene showed lower levels of let-7a, b and e compared to hESC from endometriosis with non-variant KRAS (*p = 0.0047, 0.003 and 0.05, respectively). let-7a and b were also lower in KRAS-variant cells from women with endometriosis compared to normal hESC (‡p = 0.05 and 0.02, respectively).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376847&req=5

fig02: Let-7 miRNA family expression in hESC from 10 subjects without endometriosis (normal controls), 10 subjects with endometriosis carrying WT KRAS and 10 subjects with endometriosis and the variant allele of KRAS geneq-RT-PCR results show a trend towards decreased transcript levels of all let-7 miRNAs in hESC from subjects with endometriosis compared to normal hESC from subjects without endometriosis (normal control). Endometrial cells from subjects with endometriosis with the LCS6 variant in the KRAS gene showed lower levels of let-7a, b and e compared to hESC from endometriosis with non-variant KRAS (*p = 0.0047, 0.003 and 0.05, respectively). let-7a and b were also lower in KRAS-variant cells from women with endometriosis compared to normal hESC (‡p = 0.05 and 0.02, respectively).
Mentions: Let-7 is known to bind to the non-variant and not the variant LCS6 allele preventing KRAS protein synthesis. To assess the possibility of compensatory changes in let-7 miRNAs in the setting of the variant allele and elevated KRAS protein, we determined the level of let-7a–g miRNAs (Fig 2). Cultured endometrial stromal cells from women with endometriosis with the LCS6 variant in the KRAS gene showed lower levels of let-7a, b and e (0.26 ± 0.009, 0.07 ± 0.01 and 0.08 ± 0.02, respectively), compared to hESC from women with endometriosis with non-variant KRAS (0.21 ± 0.05, 0.29 ± 0.02, 0.21 ± 0.029, respectively; p = 0.0047, 0.003 and 0.05, respectively). let-7a and b were also lower in KRAS variant cells from endometriotic women compared to normal hESC (0.29 ± 0.188, 0.53 ± 0.23, respectively; p = 0.05 and 0.02, respectively). Compared to hESC isolated from normal endometrium, hESC from women with endometriosis exhibited lower levels of let-7 family miRNA. These alterations in let-7 in the presence of the KRAS variant allele could be a result of a feedback mechanism or due to another unidentified independent factor, but do agree with prior published findings of lower let-7 in KRAS variant-associated lesions.

Bottom Line: Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease.Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women.We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.

Show MeSH
Related in: MedlinePlus