Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide, with metastasis representing the leading cause of treatment failure and poor patient survival. Although the RNA-editing enzyme ADAR1 has long been implicated in liver cancer progression, the specific contribution of its individual isoforms to metastatic disease has remained unclear.

A new study published in Genes & Diseases by a collaborative scientific team from Chongqing Medical University, Shenzhen Bay Laboratory, Southern University of Science and Technology, Hubei University of Medicine, Southern Medical University, The University of Hong Kong and Sun Yat-sen University Cancer Center identifies the constitutively expressed ADAR1 isoform, ADAR1p110, as a key driver of HCC metastasis and uncovers a previously unrecognized mechanism through which it promotes tumor dissemination by regulating microRNA biogenesis.

The researchers first demonstrated that ADAR1p110 is the predominant ADAR1 isoform expressed in hepatocellular carcinoma and that elevated expression is strongly associated with unfavorable clinical outcomes. Using hepatocyte-specific ADAR1p110 knock-in mice together with multiple human HCC cell models, the study showed that ADAR1p110 overexpression markedly enhances tumor cell migration, invasion, and metastatic spread without substantially affecting primary tumor growth. These findings establish ADAR1p110 as a specific regulator of metastatic potential rather than a general promoter of tumor proliferation.

Mechanistic investigations revealed that ADAR1p110 promotes metastasis through post-transcriptional regulation of the microRNA miR-451a, a well-established tumor suppressor. Instead of altering RNA editing activity, ADAR1p110 directly binds to the primary miR-451a transcript (pri-miR-451a), competitively preventing its recognition and processing by the Drosha–DGCR8 microprocessor complex. This blockade suppresses miR-451a maturation, resulting in a substantial reduction of functional mature miR-451a within tumor cells.

Loss of miR-451a subsequently releases repression of its downstream target TUBA1A, a microtubule-associated protein that plays a critical role in cytoskeletal organization and cellular motility. Increased TUBA1A expression enhances the migratory and invasive properties of HCC cells, providing a direct molecular link between ADAR1p110 activity and metastatic behavior. Rescue experiments further confirmed this regulatory pathway, as restoring miR-451a expression or suppressing TUBA1A effectively attenuated the pro-metastatic effects induced by ADAR1p110 overexpression.

Importantly, the study demonstrates that this regulatory mechanism operates independently of the canonical RNA-editing function traditionally attributed to ADAR1, revealing a non-canonical RNA-binding role for ADAR1p110 in controlling microRNA biogenesis. This expands the current understanding of ADAR1 biology and highlights how RNA-binding proteins can regulate cancer progression through mechanisms beyond RNA editing.

Collectively, these findings establish the ADAR1p110–miR-451a–TUBA1A signaling axis as a critical molecular pathway driving hepatocellular carcinoma metastasis. By uncovering an alternative mechanism through which ADAR1p110 promotes tumor dissemination, this work identifies new opportunities for therapeutic intervention aimed at restoring tumor-suppressive microRNA activity and limiting metastatic progression in patients with advanced liver cancer.

Reference

Title of Original Paper: ADAR1p110 promotes hepatocellular carcinoma metastasis via the miR-451a/TUBA1A axis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101770

Funding Information

The National Natural Science Foundation of China (No. 82372768, No. 82073127)
Guangdong Provincial Natural Science Fund (China) (No. 2022A1515012284)
Shenzhen Science and Technology Innovation grant (China) (No. JCYJ20220530115204011)

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