Izutsu Runa, Osaki Mitsuhiko, Seong HeeKyung, Ogata Sanami, Sato Reo, Hamada Jun-Ichi, Okada Futoshi
Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.
Chromosomal Engineering Research Center, Tottori University, Yonago, Tottori, Japan.
Cancer Gene Ther. 2024 Dec;31(12):1786-1795. doi: 10.1038/s41417-024-00842-z. Epub 2024 Oct 8.
In our previous studies, we identified amphoterin-inducible gene and open reading frame 2 (AMIGO2) as a driver gene for liver metastasis and found that AMIGO2 expression in cancer cells worsens the prognosis of patients with colorectal cancer (CRC). Epithelial-mesenchymal transition (EMT) is a trigger for CRC to acquire a malignant phenotype, such as invasive potential, leading to metastasis. However, the role of AMIGO2 expression in the invasive potential of CRC cells remains unclear. Thus, this study aimed to examine AMIGO2 expression and elucidate the mechanisms by which it induces EMT and promotes CRC invasion. Activation of the TGFβ/Smad signaling pathway was found involved in AMIGO2-induced EMT, and treatment with the TGFβ receptor inhibitor LY2109761 suppressed AMIGO2-induced EMT. Studies using CRC samples showed that AMIGO2 expression was highly upregulated in the invasive front, where AMIGO2 expression was localized to the nucleus and associated with EMT marker expression. These results suggest that the nuclear translocation of AMIGO2 induces EMT to promote CRC invasion by activating the TGFβ/Smad signaling pathway. Thus, AMIGO2 is an attractive therapeutic target for inhibiting EMT and metastatic CRC progression.
在我们之前的研究中，我们将双调蛋白诱导基因及开放阅读框2（AMIGO2）鉴定为肝转移的驱动基因，并发现癌细胞中AMIGO2的表达会恶化结直肠癌（CRC）患者的预后。上皮-间质转化（EMT）是CRC获得恶性表型（如侵袭潜能，进而导致转移）的一个触发因素。然而，AMIGO2表达在CRC细胞侵袭潜能中的作用仍不清楚。因此，本研究旨在检测AMIGO2的表达，并阐明其诱导EMT和促进CRC侵袭的机制。发现TGFβ/Smad信号通路的激活参与了AMIGO2诱导的EMT，并且用TGFβ受体抑制剂LY2109761处理可抑制AMIGO2诱导的EMT。使用CRC样本的研究表明，AMIGO2的表达在侵袭前沿高度上调，在那里AMIGO2的表达定位于细胞核并与EMT标志物表达相关。这些结果表明，AMIGO2的核转位通过激活TGFβ/Smad信号通路诱导EMT以促进CRC侵袭。因此，AMIGO2是抑制EMT和转移性CRC进展的一个有吸引力的治疗靶点。
