Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRAS^G12D; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRAS^G12D; Pdx1-Cre; Crmp4^−/− (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN.

胰腺上皮内瘤变（PanIN）是胰腺最常见的癌前病变，是浸润性胰腺导管腺癌（PDAC）的组织学明确定义的前体。然而，尚未完全阐明PanIN进展的分子机制。以前，我们证明了PDAC中胶原蛋白反应介导蛋白4（CRMP4）的表达与不良预后有关。在胰腺炎小鼠模型中，CRMP4的表达也增加了。但是，CRMP4在PanIN病变进展中的作用仍不确定。在本研究中，我们使用基因工程小鼠模型研究了CRMP4表达与PanIN病变进展之间的关系。腹腔注射胆囊收缩素类似物caerulein可诱导PanIN病变。LSL-KRAS ^G12D ; Pdx1-Cre（KC - Crmp4野生型，WT）小鼠和LSL-KRAS ^G12D；Pdx1-Cre ; Crmp4 ^-/-（KC- Crmp4基因敲除，KO）小鼠。我们分析了这些小鼠的胰腺组织切片，并通过苏木精和曙红染色评估了PanIN等级。使用针对CRMP4，CD3和α平滑肌肌动蛋白（SMA）的抗体，通过免疫组织化学检查CRMP4的表达并评估其细胞成分。高档帕宁在KC-发生Crmp4野生型小鼠明显高于KC-更高Crmp4KO动物。CRMP4不仅在PanIN病变的基质区域的上皮细胞中表达，而且在αSMA阳性细胞中表达。WT小鼠间质区域的CRMP4表达与PanIN等级相关。这些结果表明，CRMP4在基质细胞中的表达可能是PanIN发生或发展的基础。