REC8 enhances stemness and promotes metastasis of colorectal cancer through BTK/Akt/β-catenin signaling pathway

Xue Zhou; Xiaoli Xie; Ting Liu; Shengxiong Chen; Yijun Wang; Jiuna Zhang; Shuling Wang; Yongjuan Wang; Shiying Dou; Ran Qi; Ning Kang; Dongxuan Zhang; Xiaoxu Jin; Ruolin Cui; Huiqing Jiang

doi:10.1016/j.tranon.2021.101305

REC8 enhances stemness and promotes metastasis of colorectal cancer through BTK/Akt/β-catenin signaling pathway

Transl Oncol. 2022 Jan;15(1):101305. doi: 10.1016/j.tranon.2021.101305. Epub 2021 Dec 7.

Authors

Xue Zhou¹, Xiaoli Xie¹, Ting Liu¹, Shengxiong Chen², Yijun Wang¹, Jiuna Zhang¹, Shuling Wang¹, Yongjuan Wang¹, Shiying Dou³, Ran Qi⁴, Ning Kang¹, Dongxuan Zhang¹, Xiaoxu Jin¹, Ruolin Cui¹, Huiqing Jiang⁵

Affiliations

¹ Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China.
² Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
³ Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
⁴ Department of General Practice, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
⁵ Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China. Electronic address: jianghq@aliyun.com.

Abstract

Cancer/testis antigens (CTAs) are often aberrantly expressed in cancer stem cells (CSCs) which are responsible for tumor metastasis. Rec8 meiotic recombination protein (REC8), a member of CTAs, shares distinct roles in various cancers, while its contribution to CSCs and colorectal cancer (CRC) remains unclear. We found that overexpression of REC8 facilitated the migration and invasion of CRC cells (DLD-1 and SW480 cells) in vitro and promoted the liver metastasis of CRC in vivo. Moreover, REC8 is highly expressed in CRC stem-like cells and is required for the maintenance of CSC stemness. Mechanistic studies suggested that REC8 mediated through the activation of Bruton tyrosine kinase (BTK). Inhibition of BTK by ibrutinib not only suppressed the migration and invasion-promoting ability, but also declined the increased expression of p-BTK, p-Akt, β-catenin, and CSC markers upon REC8 overexpression. Importantly, high expression of REC8 in cancerous tissues was related to advanced clinical stage and lymph node metastasis of 62 CRC patients, and REC8 was enriched in the cancerous cells positive for CSC markers. Collectively, our results indicate that REC8 promotes CRC metastasis by increasing cell stemness through BTK/Akt/β-catenin pathway.

Keywords: Cancer stem cell; Colorectal cancer; Metastasis; Rec8 meiotic recombination protein; Stemness.