title: Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA19-9 ≥ 1,000 U/mL.
abstract: Patients with pancreatic ductal adenocarcinoma (PDAC) and preoperative CA19-9 ≥ 1,000 U/mL that does not decrease postresection have the worst prognosis, but the mechanism is unclear. Here, we elucidated the relationship between this signature and driver-gene mutations, and the cavins/caveolin-1 axis. Four major driver-genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4) that are associated with PDAC and five critical molecules (cavin-1/-2/-3/-4 and caveolin-1) in the cavins/caveolin-1 axis were screened by immunohistochemistry in tumor tissue microarrays. Additionally, six pancreatic cancer cell lines and a spleen subcapsular inoculation nude mouse model were also used. Overexpression of mutant p53 was the major mutational event in patients with the CA19-9 signature. Cavin-1 was also overexpressed, and mutant p53 correlated directly with high cavin-1 expression in pancreatic cancer cell lines and tumor specimens (P < 0.01). Furthermore, mutant p53(R172H) upregulated cavin-1 and promoted invasiveness and metastasis of pancreatic cancer cells in vitro and in vivo. Finally, combination of mutant p53 and high cavin-1 density indicated the shortest survival for patients with PDAC after resection (P < 0.001). Mutant p53-driven upregulation of cavin-1 represents the major mechanism of poor outcome for PDAC patients with the CA19-9 signature after resection, indicating that inhibition of cavin-1 may improve the long-term efficacy of pancreatectomy.
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Xiang
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.|Fudan University Shanghai Cancer Center, Collaborative Innovation Center for Cancer Medicine, Shanghai, China.
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Wang
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Hua-Xiang
authors.initials: HX
authors.lastname: Xu
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Chun-Tao
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Medicine, Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Jing-Xuan
authors.initials: JX
authors.lastname: Yang
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Zi-Hao
authors.initials: ZH
authors.lastname: Qi
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Ya-Qi
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Quan-Xing
authors.initials: QX
authors.lastname: Ni
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.|The Vivian L. Smith Department of Neurosurgery, University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University; Pancreatic Cancer Institute, Fudan University, Shanghai, China.|Fudan University Shanghai Cancer Center, Collaborative Innovation Center for Cancer Medicine, Shanghai, China.
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Yu