LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy
Pavlos Missios, … , David T. Ting, George Q. Daley
Pavlos Missios, … , David T. Ting, George Q. Daley
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e145142. https://doi.org/10.1172/JCI145142.
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Research Article Oncology

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy

Abstract

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7–independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Authors

Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley

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Figure 2

LIN28B mediates metastasis of MYCN-amplified neuroblastoma cells.

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LIN28B mediates metastasis of MYCN-amplified neuroblastoma cells. (A) Sc...
(A) Schematic of kidney capsule injection protocol and tumor tracking (primary and metastatic [Met]) using an in vivo imaging system (IVIS). (B) Representative bioluminescence image of mice 3 weeks after injection of BE2C cells (CTRL) or BE2C cells lacking LIN28B expression (KO) under the capsule of the left kidney. Red arrow pointing to metastatic site. (C) Representative bioluminescence images of explanted livers 3 weeks after injection of BE2C cells under the kidney capsule of NSG mice. (D) Quantitative analysis of bioluminescence of livers of indicated groups (n = 4 mice for BE2C CTRL and n = 3 mice for BE2C-KO cells). (E) Representative bioluminescence images of explanted livers 5 weeks after injection of Kelly cells under the kidney capsule of NSG mice. (F) Quantitative analysis of bioluminescence of livers of indicated groups (n = 6 mice/group). (G) Representative bioluminescence image of explanted livers 4 weeks after orthotopic injection of LIN28B-expressing patient derived xenograft (PDX) cells. (H) Quantitative analysis of bioluminescence of livers of indicated groups (n = 5 mice/group). All statistical data were assessed using 2-tailed Student’s t test (D, F, and H) and are presented as mean ± SEM. *P < 0.05; **P < 0.01.