Zhou Xue, Xie Xiaoli, Liu Ting, Chen Shengxiong, Wang Yijun, Zhang Jiuna, Wang Shuling, Wang Yongjuan, Dou Shiying, Qi Ran, Kang Ning, Zhang Dongxuan, Jin Xiaoxu, Cui Ruolin, Jiang Huiqing
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.
Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Transl Oncol. 2022 Jan;15(1):101305. doi: 10.1016/j.tranon.2021.101305. Epub 2021 Dec 7.
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.
癌胚抗原（CTAs）通常在负责肿瘤转移的癌症干细胞（CSCs）中异常表达。Rec8减数分裂重组蛋白（REC8）是CTAs的成员之一，在各种癌症中发挥着不同的作用，但其对CSCs和结直肠癌（CRC）的作用仍不清楚。我们发现，REC8的过表达促进了CRC细胞（DLD-1和SW480细胞）在体外的迁移和侵袭，并促进了CRC在体内的肝转移。此外，REC8在CRC干细胞样细胞中高表达，是维持CSC干性所必需的。机制研究表明，REC8通过激活布鲁顿酪氨酸激酶（BTK）介导。依鲁替尼抑制BTK不仅抑制了迁移和侵袭促进能力，还降低了REC8过表达后p-BTK、p-Akt、β-连环蛋白和CSC标志物的表达增加。重要的是，REC8在癌组织中的高表达与62例CRC患者的晚期临床分期和淋巴结转移相关，并且REC8在CSC标志物阳性的癌细胞中富集。总的来说，我们的结果表明，REC8通过BTK/Akt/β-连环蛋白途径增加细胞干性来促进CRC转移。
