Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration and Tumor Growth in Zebrafish and Mice

Irene Portolés; Jordi Ribera; Esther Fernandez-Galán; Elena Lecue; Gregori Casals; Pedro Melgar-Lesmes; Guillermo Fernández-Varo; Loreto Boix; Marco Sanduzzi; Veenu Aishwarya; Maria Reig; Wladimiro Jiménez; Manuel Morales-Ruiz

doi:10.20944/preprints202401.0766.v1

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preprints.org > medicine and pharmacology > gastroenterology and hepatology > doi: 10.20944/preprints202401.0766.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration and Tumor Growth in Zebrafish and Mice

Irene Portolés

Jordi Ribera

Esther Fernandez-Galán

Elena Lecue

Gregori Casals

Pedro Melgar-Lesmes

Guillermo Fernández-Varo

Version 1 : Received: 9 January 2024 / Approved: 10 January 2024 / Online: 10 January 2024 (08:16:11 CET)

A peer-reviewed article of this Preprint also exists.

Portolés, I.; Ribera, J.; Fernandez-Galán, E.; Lecue, E.; Casals, G.; Melgar-Lesmes, P.; Fernández-Varo, G.; Boix, L.; Sanduzzi, M.; Aishwarya, V.; et al. Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice. International Journal of Molecular Sciences 2024, 25, 3716, doi:10.3390/ijms25073716. Portolés, I.; Ribera, J.; Fernandez-Galán, E.; Lecue, E.; Casals, G.; Melgar-Lesmes, P.; Fernández-Varo, G.; Boix, L.; Sanduzzi, M.; Aishwarya, V.; et al. Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice. International Journal of Molecular Sciences 2024, 25, 3716, doi:10.3390/ijms25073716.

Abstract

Background: RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology and pathology. Methods: Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. FANA Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Results: Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with FANA Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. Conclusion: Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients and has a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

Keywords

RNA helicase; hepatocellular carcinoma; liver regeneration; liver organogenesis; glucose metabolism

Subject

Medicine and Pharmacology, Gastroenterology and Hepatology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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