CXCL12是经典的炎性/内稳态两效趋化因子，兼具免疫调控和介导多重信号通路的作用，是极具潜力的治疗靶点。但靶向CXCL12通路药物的实际效果并不理想，其机制仍不清楚。我们发现在结直肠癌(CRC)中可变剪切事件CXCL12AT能够改变CXCL12γ/α比例，使CXCL12γ实际表达增高。预实验提示CXCL12γ具有特殊的蛋白结构，可介导NFkB选择性激活，提高CXCR4表达，并显著增强CRC细胞干性表型。此外在CRC组织中CXCL12γ与局部巨噬细胞M2型极化密切相关。因此我们推测在CRC中可变剪切体CXCL12γ可能通过促进CXCR4-NFkB正反馈及巨噬细胞M2型极化协同增强CRC细胞干性表型。为证实以上假说，本课题拟综合运用多种分子生物学手段，探讨CXCL12AT及其产物CXCL12γ在CRC细胞干性调控中的双重作用机制，为有效靶向CXCL12通路提供新的理论依据。

CXCL12 is a classic inflammatory/homeostasis two-effect chemokine, which has the functions of immune regulation and multiple signaling pathways mediation, and is a potential therapeutic target. At present, the actual effect of targeting CXCL12 is not ideal, and its mechanism is still unclear. We found that the alternative splice event CXCL12AT could change the ratio of CXCL12 γ/α and increase the expression of CXCL12γ in colorectal cancer (CRC). CXCL12γ has a special protein structure, which can mediate the selective activation of NFkB, increase the expression of CXCR4, and significantly enhance the stemness of CRC cells. In addition, the expression of CXCL12γ in CRC is closely related to M2 polarization of local macrophages. We speculated that CXCL12γ, a alternative splice in CRC, might enhance the cell stemness of CRC by promoting positive feedback of CXCR4-NFkB and M2 polarization of macrophages. In order to confirm the above hypothesis, we intend to explore the dual mechanism of CXCL12AT and its product CXCL12γ in the regulation of stemness of the CRC cell by using a variety of molecular biological methods, so as to provide a new theoretical basis for effectively targeting CXCL12 pathway.