title: Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer.
abstract: Caveolin-1 exhibits a stage-dependent, functional fluctuation during pancreatic cancer development, but the underlying mechanisms remain unclear. Here, we report that cavin-1, a structural protein of caveolae, modulates the oncogenic function of caveolin-1 and cooperates with caveolin-1 to enhance pancreatic cancer aggressiveness. Cavin-1 expression is associated with caveolin-1 in pancreatic cancer tissue samples and cell lines, and predicts the metastatic potential of pancreatic cancer. Interactome analyses further revealed the physical interaction of cavin-1 and caveolin-1 and their colocalization in pancreatic cancer cells. Cavin-1 stabilizes caveolin-1 expression or activity by inhibiting its internalization and subsequent lysosomal degradation. More in-depth functional experiments showed that caveolin-1-enhanced aggressiveness of pancreatic cancer cells is dependent on the presence of cavin-1. In contrast, cavin-1 depletion inhibited the invasion and metastasis of pancreatic cancer cells, which could not be restored by caveolin-1-rescue construct. Tissue microarray analyses in two independent clinic cohorts also supported the augment of cavin-1 on the prognostic potency of caveolin-1, and showed that combination of cavin-1 with caveolin-1 predicted worse survival in pancreatic cancer patients. Of note, the phenotypes because of cavin-1 could not be achieved by other cavins such as cavin-2, and the tumor-promoting role of cavin-1 in pancreatic cancer was found to be largely dependent on caveolin-1 expression, which highlights the critical role of cavin-1/caveoin-1 in pancreatic cancer progression, and suggests that the interruption of cavin-1/caveolin-1 interaction is a promising therapeutic strategy for pancreatic cancer.
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: H-X
authors.initials: HX
authors.lastname: Xu
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: W-Q
authors.initials: WQ
authors.lastname: Wang
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: C-T
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Long
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Y-F
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Q-X
authors.initials: QX
authors.lastname: Ni
authors.affiliation: 1] Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] The Vivian L. Smith Department of Neurosurgery, University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Pancreatic Cancer Institute, Fudan University; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Yu
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C495540:CAV1 protein, human; C497835:CAVIN1 protein, human; D051242:Caveolin 1; D016601:RNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases