LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans

Ho Chou Tu, Sarah Schwitalla, Zhirong Qian, Grace S. LaPier, Alena Yermalovich, Yuan Chieh Ku, Shann Ching Chen, Srinivas R. Viswanathan, Hao Zhu, Reiko Nishihara, Kentaro Inamura, Sun A. Kim, Teppei Morikawa, Kosuke Mima, Yasutaka Sukawa, Juhong Yang, Gavin Meredith, Charles S. Fuchs, Shuji Ogino, George Q. Daley

Research output: Contribution to journalArticle

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Abstract

Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc <sup>Min/+</sup> mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)1074-1086
Number of pages13
JournalGenes and Development
Volume29
Issue number10
DOIs
StatePublished - 2015

Fingerprint

Adenocarcinoma
Colorectal Neoplasms
Neoplasms
Tumor Burden
MicroRNAs
Catenins
Wnt Signaling Pathway
RNA-Binding Proteins
Genetic Models
Growth
Regeneration
Carcinogenesis
Maintenance
Mutation
Mortality

Keywords

  • Colorectal cancer
  • Invasive adenocarcinoma
  • Let-7 miRNA
  • LiN28
  • Oncogene cooperation
  • WNT

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Tu, H. C., Schwitalla, S., Qian, Z., LaPier, G. S., Yermalovich, A., Ku, Y. C., ... Daley, G. Q. (2015). LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans. Genes and Development, 29(10), 1074-1086. https://doi.org/10.1101/gad.256693.114

LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans. / Tu, Ho Chou; Schwitalla, Sarah; Qian, Zhirong; LaPier, Grace S.; Yermalovich, Alena; Ku, Yuan Chieh; Chen, Shann Ching; Viswanathan, Srinivas R.; Zhu, Hao; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Morikawa, Teppei; Mima, Kosuke; Sukawa, Yasutaka; Yang, Juhong; Meredith, Gavin; Fuchs, Charles S.; Ogino, Shuji; Daley, George Q.

In: Genes and Development, Vol. 29, No. 10, 2015, p. 1074-1086.

Research output: Contribution to journalArticle

Tu, HC, Schwitalla, S, Qian, Z, LaPier, GS, Yermalovich, A, Ku, YC, Chen, SC, Viswanathan, SR, Zhu, H, Nishihara, R, Inamura, K, Kim, SA, Morikawa, T, Mima, K, Sukawa, Y, Yang, J, Meredith, G, Fuchs, CS, Ogino, S & Daley, GQ 2015, 'LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans', Genes and Development, vol. 29, no. 10, pp. 1074-1086. https://doi.org/10.1101/gad.256693.114
Tu, Ho Chou ; Schwitalla, Sarah ; Qian, Zhirong ; LaPier, Grace S. ; Yermalovich, Alena ; Ku, Yuan Chieh ; Chen, Shann Ching ; Viswanathan, Srinivas R. ; Zhu, Hao ; Nishihara, Reiko ; Inamura, Kentaro ; Kim, Sun A. ; Morikawa, Teppei ; Mima, Kosuke ; Sukawa, Yasutaka ; Yang, Juhong ; Meredith, Gavin ; Fuchs, Charles S. ; Ogino, Shuji ; Daley, George Q. / LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans. In: Genes and Development. 2015 ; Vol. 29, No. 10. pp. 1074-1086.
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abstract = "Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc Min/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38{\%} of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.",
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AU - Tu, Ho Chou

AU - Schwitalla, Sarah

AU - Qian, Zhirong

AU - LaPier, Grace S.

AU - Yermalovich, Alena

AU - Ku, Yuan Chieh

AU - Chen, Shann Ching

AU - Viswanathan, Srinivas R.

AU - Zhu, Hao

AU - Nishihara, Reiko

AU - Inamura, Kentaro

AU - Kim, Sun A.

AU - Morikawa, Teppei

AU - Mima, Kosuke

AU - Sukawa, Yasutaka

AU - Yang, Juhong

AU - Meredith, Gavin

AU - Fuchs, Charles S.

AU - Ogino, Shuji

AU - Daley, George Q.

PY - 2015

Y1 - 2015

N2 - Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc Min/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

AB - Colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding protein paralogs that regulate biogenesis of let-7 microRNAs and influence development, metabolism, tissue regeneration, and oncogenesis. Here we demonstrate that overexpression of either LIN28 paralog cooperates with the Wnt pathway to promote invasive intestinal adenocarcinoma in murine models. When LIN28 alone is induced genetically, half of the resulting tumors harbor Ctnnb1 (β-catenin) mutation. When overexpressed in Apc Min/+ mice, LIN28 accelerates tumor formation and enhances proliferation and invasiveness. In conditional genetic models, enforced expression of a LIN28-resistant form of the let-7 microRNA reduces LIN28-induced tumor burden, while silencing of LIN28 expression reduces tumor volume and increases tumor differentiation, indicating that LIN28 contributes to tumor maintenance. We detected aberrant expression of LIN28A and/or LIN28B in 38% of a large series of human CRC samples (n = 595), where LIN28 expression levels were associated with invasive tumor growth. Our late-stage CRC murine models and analysis of primary human tumors demonstrate prominent roles for both LIN28 paralogs in promoting CRC growth and progression and implicate the LIN28/let-7 pathway as a therapeutic target.

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