Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are Show more
Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are known. We performed whole-exome sequencing for a primary IPMN tissue, which uncovered somatic mutations in KCNF1, DYNC1H1, PGCP, STAB1, PTPRM, PRPF8, RNASE3, SPHKAP, MLXIPL, VPS13C, PRCC, GNAS, KRAS, RBM10, RNF43, DOCK2, and CENPF. We further analyzed GNAS mutations in archival cases of 118 IPMNs and 32 pancreatic ductal adenocarcinomas (PDAs), which revealed that 48 (40.7%) of the 118 IPMNs but none of the 32 PDAs harbored GNAS mutations. G-protein alpha-subunit encoded by GNAS and its downstream targets, phosphorylated substrates of protein kinase A, were evidently expressed in IPMN; the latter was associated with neoplastic grade. These results indicate that GNAS mutations are common and specific for IPMN, and activation of G-protein signaling appears to play a pivotal role in IPMN. Show less
DUSP6/MKP-3 is a dual specificity phosphatase exclusively specific to MAPK1/ERK2 for its substrate recognition and dephosphorylating activity. DUSP6 is demonstrated to play a negative regulatory role Show more
DUSP6/MKP-3 is a dual specificity phosphatase exclusively specific to MAPK1/ERK2 for its substrate recognition and dephosphorylating activity. DUSP6 is demonstrated to play a negative regulatory role in MAPK1 in a feedback loop manner; however, the regulation mechanisms of its expression in human cells have been largely unknown. We previously found that human pancreatic cancer cells frequently lost DUSP6 expression, which could induce constitutively active MAPK1, and the loss was associated with hypermethylation of the CpG cluster region of intron 1 of DUSP6. In this study, we investigated the promoter activity of intron 1 of DUSP6 in human cells. We demonstrated that the intron indeed had promoter activity and this activity was associated with MAPK1 activity. Moreover, promoter activity depended on a consensus binding sequence of ETS transcription factors and ETS2 was specifically associated with the intron. Because ETS2 is a direct target of MAPK, these results indicate that intron 1 of DUSP6 plays a crucial role in transcriptional regulation of DUSP6 in a feedback loop manner responding to MAPK1 via ETS2 in human cells. Show less