Jianhong Ding, Qian Du, Biguang Tuo,Rui Xie, Jingyu Xu

Department of Gastroenterology,Affiliated Hospital,Zunyi. Medical University,Zunyi 563003,China.

Background/Aims: The specific mechanism of liver cancer migration and invasion is still unclear. Studies have shown that the chemokine CCL21 play a crucial role in the development of tumors. Our research shows that CCL21 causes the increase of intracellular calcium ([Ca2+]i) and promotes the migration and invasion of liver cancer, indicating that the relevant ion channels involved in the regulation of [Ca2+]i activation. IRBIT is a binding protein for the IP3 receptor and the dissociated IRBIT can activate various ion channels. Moreover, our research shows that CCL21 can induce the up-regulation of IRBIT expression. Therefore, this study aims to explore the potential mechanism of CCL21-mediated IRBIT in liver cancer, in order to seek new drug targets for the treatment of liver cancer.

Methods: Immunohistochemistry, Western blot, CCK8 assays, wound healing assay, Transwell assays with matrigel, and high-speed calcium imaging were used to reveal the role of CCL21-mediated IRBIT in the malignant biological behavior of liver cancer.

Results:The expression of IRBIT in liver cancer tissues and cells is significantly increased. After IRBIT silenced in Huh7 cells, the proliferation, migration and invasion abilities were significantly reduced compared to control cells. CCL21 culture increased the migration and invasion ability and the expression of IRBIT. 200uM CCL21 can induce the concentration of [Ca2+]i increase. Inhibitor KB-R7943 can inhibit the increase of [Ca2+]i and decrease the expression of NCX1 induced by CCL21, and can inhibit the migration and invasion ability.

Conclusion: This study reveals for the first time a new mechanism for the chemokine CCL21 to promote the malignant biological behavior of liver cancer through the IRBIT/NCX1/Ca2+ pathway axis, providing a new theoretical basis for the treatment or prevention of liver cancer recurrence and metastasis.

Keywords: liver carcinoma, malignant biological behavior, metastasis, chemokine, invasion