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MicroRNA-375 May Be Therapeutic Strategy in Fibrolamellar Carcinoma

Key clinical point: Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma.

Major finding: MicroRNA-375 is down-regulated 27-fold in primary fibrolamellar carcinoma tumors (P = .009).

Study details: A genomic study involving patient tumors, cell lines, and mouse models.

Disclosures: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.

Citation:

Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.

Commentary:

For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity. Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA.

Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators. In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.

Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.