Complex aberrant expression of planar nuclear polarity factors in intraductal papillary mucinous neoplasm of the pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are classified into low grade (LG), high grade (HG), and invasive carcinoma-associated (IC) groups, each requiring different clinical therapeutic strategies. Loss of planar nuclear polarity (PNP) in IPMNs is a key factor in tumor progression. We studied 29 IPMN cases (8 LG, 10 HG, and 11 IC) using targeted next-generation sequencing and immunohistochemistry to elucidate the complex molecular dynamics of PNP factors in tumor progression. We analyzed the mRNA expression of 61 PNP-related factors, including those associated with the cell membrane, epithelial-mesenchymal transition (EMT), the Hippo pathway, cytoskeletal network, and nuclear envelope, in the IPMN cases. The Kruskal-Wallis test identified 15 PNP factors (ITGB1, CLDN4, CLDN7, ANO1, TWIST1, SRSF1, LATS2, TOP2A, MAPK1, TGFBR1, PCNT, FSCN1, RHOA, CDC42, and SYNE3) with significantly higher mRNA expression in IC compared with LG and HG. Multinomial logistic regression identified three PNP factors (CLDN7, FSCN1, and TOP2A) with significantly higher mRNA expression and stronger or more frequent immunohistochemical positivity in both LG versus IC and LG versus HG comparisons. Overall, our study indicates that the molecular mechanisms underlying disturbed PNP in IPMNs are not mediated by a single pathway but involve multiple interconnected pathways. Our findings may contribute to elucidation of the molecular mechanisms regulating PNP in IPMNs, enhancing our understanding of tumor progression and contributing to more accurate pathological diagnosis.