LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans
| Autor: | Sun A. Kim, Gavin Meredith, Shann Ching Chen, Yuan Chieh Ku, Reiko Nishihara, Juhong Yang, Ho-Chou Tu, Zhi Rong Qian, Srinivas R. Viswanathan, Kentaro Inamura, George Q. Daley, Charles S. Fuchs, Yasutaka Sukawa, Kosuke Mima, Alena Yermalovich, Teppei Morikawa, Hao Zhu, Grace S. LaPier, Sarah Schwitalla, Shuji Ogino |
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| Rok vydání: | 2015 |
| Předmět: |
animal structures
Colorectal cancer Adenocarcinoma Biology medicine.disease_cause Mice Genetic model microRNA Genetics medicine Animals Humans Gene silencing Neoplasm Invasiveness Regulation of gene expression fungi Wnt signaling pathway RNA-Binding Proteins medicine.disease Gene Expression Regulation Neoplastic Wnt Proteins Immunology Cancer research Colorectal Neoplasms Carcinogenesis Research Paper Signal Transduction Developmental Biology |
| Zdroj: | Genes & Development. 29:1074-1086 |
| ISSN: | 1549-5477 0890-9369 |
| Popis: | 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 ApcMin/+ 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. |
| Databáze: | OpenAIRE |
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