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Let-7 Represses Carcinogenesis and a Stem Cell Phenotype in the Intestine via Regulation of Hmga2.

Madison BB, Jeganathan AN, Mizuno R, Winslow MM, Castells A, Cuatrecasas M, Rustgi AK - PLoS Genet. (2015)

Bottom Line: Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2.In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b.In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Washington University School of Medicine, Saint Louis, Missouri, United States of America; Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.

ABSTRACT
Let-7 miRNAs comprise one of the largest and most highly expressed family of miRNAs among vertebrates, and is critical for promoting differentiation, regulating metabolism, inhibiting cellular proliferation, and repressing carcinogenesis in a variety of tissues. The large size of the Let-7 family of miRNAs has complicated the development of mutant animal models. Here we describe the comprehensive repression of all Let-7 miRNAs in the intestinal epithelium via low-level tissue-specific expression of the Lin28b RNA-binding protein and a conditional knockout of the MirLet7c-2/Mirlet7b locus. This ablation of Let-7 triggers the development of intestinal adenocarcinomas concomitant with reduced survival. Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2. Functional studies in 3-D enteroids revealed that Hmga2 is necessary and sufficient to mediate many characteristics of Let-7 depletion, namely accelerating cell cycle progression and enhancing a stem cell phenotype. In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b. In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2.

No MeSH data available.


Related in: MedlinePlus

Hmga1 and Hmga2 proteins are increased in invasive areas of adenocarcinomas.Immunohistochemical staining for Hmga2 (A-C, G, H) and Hmga2 (D-F, I, J), in sections from WT small intestine (S.I.) (A, D), Lin28bLo/Let7IEC-KO S.I. (B, E), Lin28bLo/Let7IEC-KO adenoma (C, F), and Lin28bLo/Let7IEC-KO adenocarcinoma (AdenoCA) (G-J). An enlargement of a region containing invasive HMGA1-positive tumor cells from G (dotted yellow box) is pictured in H, while a region containing invasive HMGA2-positive tumor cells from I is likewise displayed in J. Pictures in A-F, H, and J are at same magnification (200x), with scale bar = 100 μm, while pictures in G and I are both at 40x, with scale bar = 250 μm.
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pgen.1005408.g003: Hmga1 and Hmga2 proteins are increased in invasive areas of adenocarcinomas.Immunohistochemical staining for Hmga2 (A-C, G, H) and Hmga2 (D-F, I, J), in sections from WT small intestine (S.I.) (A, D), Lin28bLo/Let7IEC-KO S.I. (B, E), Lin28bLo/Let7IEC-KO adenoma (C, F), and Lin28bLo/Let7IEC-KO adenocarcinoma (AdenoCA) (G-J). An enlargement of a region containing invasive HMGA1-positive tumor cells from G (dotted yellow box) is pictured in H, while a region containing invasive HMGA2-positive tumor cells from I is likewise displayed in J. Pictures in A-F, H, and J are at same magnification (200x), with scale bar = 100 μm, while pictures in G and I are both at 40x, with scale bar = 250 μm.

Mentions: To gain insight into the association of several Let-7 targets with tumorigenesis in vivo, we examined Hmga1, Hmga2, Arid3a, and Hif3a protein expression by immunostaining adenomas and adenocarcinomas, as well as adjacent normal tissue, from Lin28bLo/Let7IEC-KO mice. These targets exhibited little or modest up-regulation in normal small intestine epithelia of Lin28bLo/Let7IEC-KO mice, but dramatic increases in tumors (Fig 3A–3J and S3A–S3H Fig). Pathological assessment of the staining pattern revealed that Hmga1 and Hmga2 staining was most intense in areas of invasive adenocarcinoma (Fig 3G, 3H and 3I).


Let-7 Represses Carcinogenesis and a Stem Cell Phenotype in the Intestine via Regulation of Hmga2.

Madison BB, Jeganathan AN, Mizuno R, Winslow MM, Castells A, Cuatrecasas M, Rustgi AK - PLoS Genet. (2015)

Hmga1 and Hmga2 proteins are increased in invasive areas of adenocarcinomas.Immunohistochemical staining for Hmga2 (A-C, G, H) and Hmga2 (D-F, I, J), in sections from WT small intestine (S.I.) (A, D), Lin28bLo/Let7IEC-KO S.I. (B, E), Lin28bLo/Let7IEC-KO adenoma (C, F), and Lin28bLo/Let7IEC-KO adenocarcinoma (AdenoCA) (G-J). An enlargement of a region containing invasive HMGA1-positive tumor cells from G (dotted yellow box) is pictured in H, while a region containing invasive HMGA2-positive tumor cells from I is likewise displayed in J. Pictures in A-F, H, and J are at same magnification (200x), with scale bar = 100 μm, while pictures in G and I are both at 40x, with scale bar = 250 μm.
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Related In: Results  -  Collection

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Show All Figures
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pgen.1005408.g003: Hmga1 and Hmga2 proteins are increased in invasive areas of adenocarcinomas.Immunohistochemical staining for Hmga2 (A-C, G, H) and Hmga2 (D-F, I, J), in sections from WT small intestine (S.I.) (A, D), Lin28bLo/Let7IEC-KO S.I. (B, E), Lin28bLo/Let7IEC-KO adenoma (C, F), and Lin28bLo/Let7IEC-KO adenocarcinoma (AdenoCA) (G-J). An enlargement of a region containing invasive HMGA1-positive tumor cells from G (dotted yellow box) is pictured in H, while a region containing invasive HMGA2-positive tumor cells from I is likewise displayed in J. Pictures in A-F, H, and J are at same magnification (200x), with scale bar = 100 μm, while pictures in G and I are both at 40x, with scale bar = 250 μm.
Mentions: To gain insight into the association of several Let-7 targets with tumorigenesis in vivo, we examined Hmga1, Hmga2, Arid3a, and Hif3a protein expression by immunostaining adenomas and adenocarcinomas, as well as adjacent normal tissue, from Lin28bLo/Let7IEC-KO mice. These targets exhibited little or modest up-regulation in normal small intestine epithelia of Lin28bLo/Let7IEC-KO mice, but dramatic increases in tumors (Fig 3A–3J and S3A–S3H Fig). Pathological assessment of the staining pattern revealed that Hmga1 and Hmga2 staining was most intense in areas of invasive adenocarcinoma (Fig 3G, 3H and 3I).

Bottom Line: Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2.In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b.In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Washington University School of Medicine, Saint Louis, Missouri, United States of America; Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.

ABSTRACT
Let-7 miRNAs comprise one of the largest and most highly expressed family of miRNAs among vertebrates, and is critical for promoting differentiation, regulating metabolism, inhibiting cellular proliferation, and repressing carcinogenesis in a variety of tissues. The large size of the Let-7 family of miRNAs has complicated the development of mutant animal models. Here we describe the comprehensive repression of all Let-7 miRNAs in the intestinal epithelium via low-level tissue-specific expression of the Lin28b RNA-binding protein and a conditional knockout of the MirLet7c-2/Mirlet7b locus. This ablation of Let-7 triggers the development of intestinal adenocarcinomas concomitant with reduced survival. Analysis of both mouse and human intestinal cancer specimens reveals that stem cell markers were significantly associated with loss of Let-7 miRNA expression, and that a number of Let-7 targets were elevated, including Hmga1 and Hmga2. Functional studies in 3-D enteroids revealed that Hmga2 is necessary and sufficient to mediate many characteristics of Let-7 depletion, namely accelerating cell cycle progression and enhancing a stem cell phenotype. In addition, inactivation of a single Hmga2 allele in the mouse intestine epithelium significantly represses tumorigenesis driven by Lin28b. In aggregate, we conclude that Let-7 depletion drives a stem cell phenotype and the development of intestinal cancer, primarily via Hmga2.

No MeSH data available.


Related in: MedlinePlus