Chronic pancreatitis triggers factors promoting pancreatic cancer development in genetically engineered mouse model

丝氨酸蛋白酶抑制因子1(SPINK1)基因突变与慢性胰腺炎(CP)相关。我们之前的研究表明，SPINK1的小鼠同源基因Spink3的缺失会导致小鼠发生胰腺炎样变化。本研究的目的是通过产生Spink3-/-小鼠来挽救Spink3-/-表型。(方法)将CAG-SPINK1基因(SP1)定位于X染色体。X染色体失活是雌性哺乳动物体内存在的两个X染色体副本中的一个被灭活的过程。通过利用X失活，我们能够创造出SPINK1水平部分但不是完全降低的小鼠。结果Spink3-/-XSP1/+小鼠出生时胰腺内既有正常的腺泡细胞，也有变性的腺泡细胞，并有大量的自噬空泡堆积。Spink3-/-XSP1/+小鼠出现了人类CP的病理特征，包括腺泡细胞丢失和星状细胞活化的纤维化。老年小鼠腺泡导管上皮化生，原癌基因EGFR、Her2和RAS显著表达。(结论)CP可触发促进胰腺癌发生的因素。

The mutations of serine protease inhibitor Kazal type 1(SPINK1) are associated with chronic pancreatitis(CP). We previously showed that deletion of Spink3, the mouse homologue of SPINK1, causes pancreatitis-like changes in the mouse. The aim of this study was to rescue the Spink3-/-phenotype by generating Spink3-/-mice with knockin SPINK1.(Methods) We placed CAG-SPINK1 gene(SP1) into X chromosome. X-inactivation is a process whereby one of the two copies of the X chromosome present in female mammals is inactivated. By utilizing X-inactivation, we were able to create mice in which SPINK1 level was partially, but not completely, reduced. The SP1 knockin mice were crossed to Spink3+/-mice.(Results) The pancreas of Spink3-/-XSP1/+mice at birth contained both normal and degenerated acinar cells, with accumulation of autophagic vacuoles. The Spink3-/-XSP1/+mice developed pathologic features of human CP, including loss of acinar cells and fibrosis with activated stellate cells. Older mice displayed acinar-ductal metaplasia and prominent expression of proto-oncogenes Egfr, Her2, and Ras.(Conclusions) The results indicate that CP trigger factors promoting pancreatic cancer development.