MUC4 potentiates invasion and metastasis of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1.
MUC4 is a type-1 transmembrane mucin differentially expressed in multiple cancers and has previously been shown to potentiate progression and metastasis of pancreatic cancer. In this study, we investigated the molecular mechanisms associated with the MUC4-induced invasion and metastasis in pancreatic cancer. Stable silencing of MUC4 in multiple pancreatic cancer cells resulted in the downregulation of N-cadherin and its interacting partner fibroblast growth factor receptor 1 (FGFR1) through downregulation of partly by pFAK, pMKK7, pJNK and pc-Jun pathway and partly through PI-3K/Akt pathway. The downregulation of FGFR1 in turn led to downregulation of pAkt, pERK1/2, pNF-κB, pIkBα, uPA, MMP-9, vimentin, N-cadherin, Twist, Slug and Zeb1 and upregulation of E-cadherin, Occludin, Cytokeratin-18 and Caspase-9 in MUC4 knockdown BXPC3 and Capan1 cells compared with scramble vector transfected cells. Further, downregulation of FGFR1 was associated with a significant change in morphology and reorganization of the actin-cytoskeleton, leading to a significant decrease in motility (P < 0.00001) and invasion (P < 0.0001) in vitro and decreased tumorigenicity and incidence of metastasis in vivo upon orthotopic implantation in the athymic mice. Taken together, the results of the present study suggest that MUC4 promotes invasion and metastasis by FGFR1 stabilization through the N-cadherin upregulation.
Department of Biochemistry and Molecular Biology, University of Nebraska MedicalCenter, Omaha, NE 68198-5870, USA.
Satyanarayana
S
Rachagani
Muzafar A
MA
Macha
Moorthy P
MP
Ponnusamy
Dhanya
D
Haridas
Sukhwinder
S
Kaur
Maneesh
M
Jain
Surinder K
SK
Batra
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055264:Mucin-4 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D015820:Cadherins; D055264:Mucin-4; D034741:RNA, Small Interfering; D051496:Receptor, Fibroblast Growth Factor, Type 1