2026/02/25

CIC bioGUNE identifies two key proteins that control the growth of pediatric cancer, hepatoblastoma

A recent study, published in the journal Hepatology, reveals how two essential proteins influence the growth of childhood hepatoblastoma and provides new insights into its biology and potential future research direction.

A study published in Hepatology reports new findings on the molecular mechanisms underlying hepatoblastoma, the most common liver cancer in children. The research identifies alterations in the NEDDylation pathway, particularly involving the enzyme NEDP1 and the protein CAND1, that contribute to tumor development and progression.

Hepatoblastoma is a rare pediatric tumor, affecting approximately 1–2 children per million each year. Although current treatments have significantly improved survival, some patients experience relapse or resistance to chemotherapy. A better understanding of the biological mechanisms driving this disease may help refine future therapeutic strategies.

The study, led by Dr. María Luz Martínez-Chantar (CIBERehd) at CIC bioGUNE, member of BRTA, shows that hepatoblastoma tumors exhibit reduced levels and activity of NEDP1, a protease that regulates NEDDylation, a post-translational modification process involved in protein regulation. This reduction is associated with increased NEDDylation and elevated levels of CAND1, a protein linked to more aggressive molecular subtypes and poorer clinical outcomes.

Using patient samples to validate the dysregulation of NEDD8 pathway and employing several preclinical models, including cell lines, patient-derived xenografts, and mouse models, the researchers observed that restoring NEDP1 activity reduced tumor growth, limited metastatic potential, and altered cancer cell metabolism. In addition, high CAND1 expression was associated with adverse prognostic features and lower overall survival in patients.

“Our results indicate that alterations in the NEDP1–CAND1 axis contribute to hepatoblastoma progression”, explains Dr. Martínez-Chantar. “These findings improve our understanding of the molecular landscape of this tumor and suggest that the NEDDylation pathway may represent a potential area for further therapeutic exploration”.

Estefanía Zapata-Pavas, first author of the study, adds: “We observed that NEDP1 functions as a tumor suppressor by regulating key proteins involved in cell proliferation and metabolism. When this regulatory balance is disrupted, tumor cells acquire growth advantages”.

The study was developed within the framework of collaborative initiatives supported by the Spanish Association Against Cancer (AECC) through the coordinated project PMEd4HB (Precision Medicine for Hepatoblastoma, reference PRYCO223102ARME), led and coordinated by the Germans Trias i Pujol Research Institute (IGTP). This consortium brings together leading experts in pediatric liver cancer, including Dr. Matias Avila (CIMA), Dr. José Juan García-Marín (USAL), and Dr. Pau Sancho-Bru (IDIBAPS), fostering a multidisciplinary approach aimed at accelerating the translation of fundamental discoveries into clinically relevant advances for patients. Estefanía Zapata-Pavas and Marina Serrano-Macía are additionally funded by the Asociación Contra el Cáncer en Bizkaia.

This work provides valuable information on the mechanisms that regulate hepatoblastoma growth and how certain proteins may influence its aggressiveness. Although these are preclinical results, the study highlights the importance of investigating cancer metabolism and provides a solid foundation for exploring new strategies that, in the future, could guide the development of more targeted and better-understood therapeutic approaches.

Reference: L. Estefanía Zapata-Pavas, Marina Serrano-Macia, Miguel Ángel Merlos Rodrigo, Jon Ander Barrenechea-Barrenechea, Patricia Peña-SanFelix, Álvaro del Río-Álvarez, Clàudia Gil-Pitarch, Claudia M. Rejano-Gordillo, Naroa Goikoetxea-Usandizaga, Irene González-Recio, Hana Michalkova, Maria Mercado-Gómez, Sofia Lachiondo-Ortega, Andrea Castañeda, Maitane Asensio, Abhishek Murti, Elise Lelou, Rubén Nogueiras, Ugo Mayor, Zbynek Heger, Pau Sancho-Bru, Teresa C. Delgado, Diego F. Calvisi, Dimitris P. Xirodimas, Bruce Wang, Jose J.G. Marin, Maite G. Fernandez-Barrena, Carolina Armengol, Matías Ávila, María Luz Martínez-Chantar. NEDD8-specific protease 1 deficiency as a novel driver of hepatoblastoma development through dysregulation of the CAND1–NEDD8 pathway. Hepatology. DOI: 10.1097/HEP.0000000000001614.

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.

About BRTA

BRTA is an alliance of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE y CIC energiGUNE) and 13 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Leartiker, Lortek, Neiker, Tecnalia, Tekniker y Vicomtech) with the main objective of developing advanced technological solutions for the Basque corporate fabric.

With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three territories, the alliance seeks to promote collaboration between the research centres, strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness and outspreading the Basque scientific-technological capacity abroad.

BRTA has a workforce of 3,500 professionals, executes 22 % of the Basque Country's R&D investment, registers an annual turnover of more than 300 million euros and generates 100 European and international patents per year.

Spanish version