Slit2促进恶性胰岛β细胞瘤向胰岛α细胞瘤转化的作用及其机制研究

Malignant insulinoma, arising from the pancreatic insulin producing beta-cells, is a extremely rare pancreatic neuroendocrine tumor. Furthermore, the cause and metastatic mechanism of malignant insulinoma are still unclear. Slit2, a neuronal guidance factor, has a significant effect on growth and metastasis of many tumors. However, it is still unclear whether Slit2 has a significant effect on pancreatic neuroendocrine tumor. Our experiments in spontaneous insulinoma mouse models demonstrated that Slit2 overexpression promoted the growth and metastasis of insulinoma. Importantly, we further showed that the β-to-α-cell conversion can be prevented in the insulinomas of Rip1-Tag2;Slit2-Tg mice. And glucagonomas are more likely to show distant metastasis and have a much worse prognosis than inculimoma. It has been reported that misexpression of the α-cell-specific transcription factor Aristaless homeobox gene (Arx) in fetal β cells is sufficient to cause β-to-α-cell conversion. And we also found that the expression levels of Arx in the tumors of Rip1-Tag2;Slit2-Tg mice were higher than those of Rip1-Tag2 mice. Further research will be performed that Slit2 can prevent the a large repression complex formation in pancreatic β cells that includes DNMT3a, Grg3, HDAC1, Nkx2.2 and Nkx6.1, thereby inducing β-to-α-cell conversion through Arx ectopic expression in pancreatic β cells. Our results suggest that Slit2 induces the insulimoma-to-glucagonoma conversion, thereby promoting the growth and metastasis of the insulinoma. Collectively, our findings on Slit2 may offer new perspectives for inducing insulimoma-to-glucagonoma conversion and targeting this newly identified signaling represents a novel effective therapeutic approach to malignant insulinoma and glucagonoma.

恶性胰岛β细胞瘤是一种罕见的恶性度很高的胰腺神经内分泌肿瘤，其发病及转移机制仍不明了。神经导向因子Slit2，在多种肿瘤中发挥重要作用，但在胰腺神经内分泌肿瘤中的作用尚未见报道。我们发现Slit2在自发胰岛β细胞瘤小鼠的肿瘤中表达明显增高；利用Slit2过表达转基因鼠与自发肿瘤小鼠杂交后发现明显促进了肿瘤生长和全身转移；最重要的是Slit2高表达造成了β细胞瘤向恶性程度更高、更具高转移性的α细胞瘤转化；此作用可能与Slit2诱导α细胞标志物Arx在β细胞中异位表达有关。我们推测胰岛β细胞或其他细胞分泌的Slit2可能通过抑制Arx启动子区Dnmt3a-Grg3等复合物形成，促进了β细胞向α细胞的转化，从而造成肿瘤恶化。本项目以基因工程小鼠疾病模型为主要研究体系，结合临床肿瘤标本，阐明Slit2对恶性胰岛β细胞瘤和α细胞瘤的作用及其机制，从而为恶性胰腺神经内分泌肿瘤的防治寻找新途径和新策略。

恶性胰岛β细胞瘤是一种罕见的恶性度很高的胰腺神经内分泌肿瘤，其发病及转移机制仍不明了。神经导向因子Slit2，在多种肿瘤中发挥重要作用，但在胰腺神经内分泌肿瘤中的作用尚未见报道。我们发现Slit2在自发胰岛β细胞瘤小鼠的肿瘤中表达明显增高，用Slit2-Tg表达转基因鼠与自发胰岛β细胞瘤小鼠杂交，发现Slit2显著促进了胰岛β细胞瘤的生长和全身转移；最重要的是，Slit2高表达诱导了胰岛β细胞瘤向恶性程度更高、更具高转移性的α细胞瘤的转化；而且Slit2/Robo1信号的阻断剂R5通过阻断胰岛β细胞瘤向胰岛α细胞瘤的转化，进而显著抑制了Rip1-Tag2;Slit2-Tg小鼠肿瘤的生长和转移。进一步研究发现Slit2通过抑制Arx启动子区Dnmt3a-Grg3等复合物形成，诱导α细胞标志物Arx在β细胞中异位表达，促进了恶性胰岛β细胞向α细胞的转化，从而造成胰岛β细胞瘤恶化。为恶性胰腺神经内分泌肿瘤的防治寻找到了新的途径和新的策略。