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MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma.

Publication ,  Journal Article
Dinh, TA; Jewell, ML; Kanke, M; Francisco, A; Sritharan, R; Turnham, RE; Lee, S; Kastenhuber, ER; Wauthier, E; Guy, CD; Yeung, RS; Lowe, SW ...
Published in: Cell Mol Gastroenterol Hepatol
2019

BACKGROUND & AIMS: Fibrolamellar carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. It is characterized by a heterozygous approximately 400-kb deletion on chromosome 19 that results in a unique fusion between DnaJ heat shock protein family member B1 (DNAJB1) and the alpha catalytic subunit of protein kinase A (PRKACA). The role of microRNAs (miRNAs) in FLC remains unclear. We identified dysregulated miRNAs in FLC and investigated whether dysregulation of 1 key miRNA contributes to FLC pathogenesis. METHODS: We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atlas to identify dysregulated miRNAs in primary FLC tumors and validated the findings in 3 independent FLC cohorts. smRNA-seq also was performed on a FLC patient-derived xenograft model as well as purified cell populations of the liver to determine whether key miRNA changes were tumor cell-intrinsic. We then used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (Cas9) technology and transposon-mediated gene transfer in mice to determine if the presence of DNAJB1-PRKACA is sufficient to suppress miR-375 expression. Finally, we established a new FLC cell line and performed colony formation and scratch wound assays to determine the functional consequences of miR-375 overexpression. RESULTS: We identified miR-375 as the most dysregulated miRNA in primary FLC tumors (27-fold down-regulation; P = .009). miR-375 expression also was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell populations of the liver. Introduction of DNAJB1-PRKACA by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transposon-mediated somatic gene transfer in mice was sufficient to induce significant loss of miR-375 expression (P < .05). Overexpression of miR-375 in FLC cells inhibited Hippo signaling pathway proteins, including yes-associated protein 1 and connective tissue growth factor, and suppressed cell proliferation and migration (P < .05). CONCLUSIONS: We identified miR-375 as the most down-regulated miRNA in FLC tumors and showed that overexpression of miR-375 mitigated tumor cell growth and invasive potential. These findings open a potentially new molecular therapeutic approach. Further studies are necessary to determine how DNAJB1-PRKACA suppresses miR-375 expression and whether miR-375 has additional important targets in this tumor. Transcript profiling: GEO accession numbers: GSE114974 and GSE125602.

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Published In

Cell Mol Gastroenterol Hepatol

DOI

EISSN

2352-345X

Publication Date

2019

Volume

7

Issue

4

Start / End Page

803 / 817

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Neoplasm Invasiveness
  • MicroRNAs
  • Mice, Inbred C57BL
  • Liver Neoplasms
  • Liver
  • Humans
  • HSP40 Heat-Shock Proteins
  • Gene Expression Regulation, Neoplastic
 

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Dinh, T. A., Jewell, M. L., Kanke, M., Francisco, A., Sritharan, R., Turnham, R. E., … Sethupathy, P. (2019). MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma. Cell Mol Gastroenterol Hepatol, 7(4), 803–817. https://doi.org/10.1016/j.jcmgh.2019.01.008
Dinh, Timothy A., Mark L. Jewell, Matt Kanke, Adam Francisco, Ramja Sritharan, Rigney E. Turnham, Seona Lee, et al. “MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma.Cell Mol Gastroenterol Hepatol 7, no. 4 (2019): 803–17. https://doi.org/10.1016/j.jcmgh.2019.01.008.
Dinh TA, Jewell ML, Kanke M, Francisco A, Sritharan R, Turnham RE, et al. MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma. Cell Mol Gastroenterol Hepatol. 2019;7(4):803–17.
Dinh, Timothy A., et al. “MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma.Cell Mol Gastroenterol Hepatol, vol. 7, no. 4, 2019, pp. 803–17. Pubmed, doi:10.1016/j.jcmgh.2019.01.008.
Dinh TA, Jewell ML, Kanke M, Francisco A, Sritharan R, Turnham RE, Lee S, Kastenhuber ER, Wauthier E, Guy CD, Yeung RS, Lowe SW, Reid LM, Scott JD, Diehl AM, Sethupathy P. MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma. Cell Mol Gastroenterol Hepatol. 2019;7(4):803–817.
Journal cover image

Published In

Cell Mol Gastroenterol Hepatol

DOI

EISSN

2352-345X

Publication Date

2019

Volume

7

Issue

4

Start / End Page

803 / 817

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Signal Transduction
  • Neoplasm Invasiveness
  • MicroRNAs
  • Mice, Inbred C57BL
  • Liver Neoplasms
  • Liver
  • Humans
  • HSP40 Heat-Shock Proteins
  • Gene Expression Regulation, Neoplastic