Research Papers:

Suppressive GLI2 fragment enhances liver metastasis in colorectal cancer

Ruiko Ogata, Shiori Mori, Hitoshi Ohmori, Shingo Kishi, Rina Fujiwara-Tani, Takamitsu Sasaki, Yukiko Nishiguchi, Chie Nakashima, Kei Goto, Isao Kawahara, Yi Luo _ and Hiroki Kuniyasu _

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Oncotarget. 2022; 13:122-135. https://doi.org/10.18632/oncotarget.28170

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Ruiko Ogata1, Shiori Mori1, Hitoshi Ohmori1, Shingo Kishi1, Rina Fujiwara-Tani1, Takamitsu Sasaki1, Yukiko Nishiguchi1, Chie Nakashima1, Kei Goto1, Isao Kawahara1, Yi Luo2 and Hiroki Kuniyasu1

1 Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan

2 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province 226001, China

Correspondence to:

Hiroki Kuniyasu, email: [email protected]
Yi Luo, email: [email protected]

Keywords: linoleic acid; stemness; GLI2; ubiquitination; colorectal cancer

Received: December 06, 2021     Accepted: December 20, 2021     Published: January 15, 2022

Copyright: © 2022 Ogata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Linoleic acid (LA) has been shown to cause inflammation and promote development of colorectal cancer (CRC). Moreover, many literatures show that LA is associated with cancer metastasis. Metastatic cancer cells have high stemness, suggesting that LA might affect the stemness of cancer cells. In this study, we examined the effect of LA on the hedgehog system, which affects cancer stemness. In CT26 cells, LA treatment induced the expression of sonic hedgehog (Shh); the signal transduction factor, and glioma-associated oncogene homolog (Gli) 2, whereas the expression of SRY-box transcription factor (Sox) 17 was suppressed. Furthermore, LA reduced GLI2 ubiquitination, resulting in an increase in the N-terminal fragment of GLI2, known as suppressive GLI2, produced by cleavage of GLI2. LA-induced cleaved GLI2 was also detected in Colo320 and HT29 human CRC cells. Knocking down Gli2 abrogated the LA-mediated suppression of Sox17 expression. These results suggest that LA promotes tumor cell stemness by increasing of suppressive GLI2 fragments via GLI2 modification. In mouse liver metastasis models, LA enhanced metastasis with production of the suppressive GLI2 fragments in CT26 and HT29 cells, whereas knockdown of GLI2 abrogated LA-induced metastatic activity. In human CRCs, the cases with liver metastasis showed the suppressive GLI2 fragments. This study provides mechanistic insights into LA-induced stemness in colon cancer cells. This finding suggests that dietary intake of LA might increase the stemness of cancer cells and enhance metastatic activity of the cancer.

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