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

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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.

元の言語English
ページ(範囲)1074-1086
ページ数13
ジャーナルGenes and Development
29
発行部数10
DOI
出版物ステータスPublished - 2015

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Tu, H. C., Schwitalla, S., Qian, Z., LaPier, G. S., Yermalovich, A., Ku, Y. C., Chen, S. C., Viswanathan, S. R., Zhu, H., Nishihara, R., Inamura, K., Kim, S. A., Morikawa, T., Mima, K., Sukawa, Y., Yang, J., Meredith, G., Fuchs, C. S., Ogino, S., & 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