Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma

详细信息    查看全文

• 作者：Ruchi Shukla¹ ; ¹¹ ; Kyle R. Upton² ; ¹¹ ; Martin Mu&ntilde ; oz-Lopez³ ; Daniel J. Gerhardt² ; Malcolm E. Fisher¹ ; Thu Nguyen² ; Paul M. Brennan⁴ ; J. Kenneth Baillie¹ ; Agnese Collino⁵ ; Serena Ghisletti⁵ ; Shruti Sinha⁵ ; Fabio Iannelli⁵ ; Enrico Radaelli⁶ ; Alexandre Dos Santos⁷ ; ⁸ ; Delphine Rapoud⁷ ; ⁸ ; Catherine Guettier⁷ ; ⁸ ; Didier Samuel⁷ ; ⁸ ; Gioacchino Natoli⁵ ; Piero Carninci⁹ ; Francesca D. Ciccarelli⁵ ; Jose Luis Garcia-Perez³ ; Jamila Faivre⁷ ; ⁸ ; Geoffrey J. Faulkner¹ ; ² ; ¹⁰ ; ^{faulknergj@gmail.com}
• 刊名：Cell
• 出版年：2013
• 出版时间：28 March, 2013
• 年：2013
• 卷：153
• 期：1
• 页码：101-111
• 全文大小：981 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Summary

LINE-1 (L1) retrotransposons are mobile genetic elements comprising ¡«17 % of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19?hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1 % ) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic ¦Â-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2^?/? mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.