Soudah Nadine, Baskin Alexey, Darash-Yahana Merav, Darlyuk-Saadon Ilona, Smorodinsky-Atias Karina, Shalit Tali, Yu Wei-Ping, Savidor Alon, Pikarsky Eli, Engelberg David
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
CREATE-NUS-HUJ Mechanisms of Liver Inflammatory Diseases, National University of Singapore, 1 CREATE WAY, Innovation Wing, Singapore, Singapore.
Oncogene. 2025 May 20. doi: 10.1038/s41388-025-03437-6.
The receptor tyrosine kinase (RTK)-Ras-Raf-MEK-Erk cascade is frequently mutated in cancer, but it is not known whether Erk is a sole mediator of the pathway's oncogenicity, and what degree of Erk activity is required for oncogenicity. Also, it is assumed that high Erk activity is required to impose and maintain oncogenicity, but the exact degree of required activity is not clear. We report that induced expression of the intrinsically active variant Erk1 in mouse liver gave rise to hepatocellular carcinoma (HCC). Intriguingly, the phosphorylated/active form of Erk1 was dramatically downregulated during HCC development, and became almost undetectable in mature tumors. Similarly, in Erk1-transformed NIH3T3 cells, the phosphorylated/active form of Erk1 was undetectable. Thus, 1) Erk1 could by itself cause HCC in mice, suggesting that it is the major or even the sole mediator of the cascade's oncogenicity. 2) Erk1-induced tumors (and other tumors) are maintained by a minimal Erk activity. 3) Erk1 is probably the driver of the malignancy in patients that carry the R84H mutation.
受体酪氨酸激酶（RTK）-Ras-Raf-MEK-Erk级联在癌症中经常发生突变，但尚不清楚Erk是否是该通路致癌性的唯一介质，以及致癌性需要何种程度的Erk活性。此外，人们认为需要高Erk活性来施加和维持致癌性，但所需活性的确切程度尚不清楚。我们报告，在小鼠肝脏中诱导表达内在活性变体Erk1会导致肝细胞癌（HCC）。有趣的是，在HCC发展过程中，Erk1的磷酸化/活性形式显著下调，在成熟肿瘤中几乎检测不到。同样，在Erk1转化的NIH3T3细胞中，也检测不到Erk1的磷酸化/活性形式。因此，1）Erk1本身可在小鼠中引发HCC，这表明它是该级联致癌性的主要甚至唯一介质。2）Erk1诱导的肿瘤（以及其他肿瘤）由最低限度的Erk活性维持。3）Erk1可能是携带R84H突变患者恶性肿瘤的驱动因素。
