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.

Jin-Feng Xiang,Zi-Hao Qi,Quan-Xing Ni,Chen Liu,Min Li,Wen-Quan Wang,Liang Liu,Jiang Long,Chun-Tao Wu,Jing-Xuan Yang,Hua-Xiang Xu,Xian-Jun Yu,Jin Xu,Ya-Qi Wang

doi:10.1038/srep19222

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 p53R172H 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.

Highlights

RETRACTED a preoperative serum signature of CEA+/CA125+/CA19-9 ≥ 1,000 U/mL that predicted extremely poor outcome after pancreatectomy for patients with PDAC9
We found that overexpression of mutant p53, rather than complete loss of p53 expression, was the major genetic alteration in pancreatic ductal adenocarcinoma (PDAC) for patients with preoperative CA19-9 ≥ 1,000 U/mL that did not decrease postresection
We identified overexpression of mutant p53, rather than complete loss of p53 expression, and high expression of cavin-1 in PDAC patients with a preoperative serum signature of CA19-9 ≥ 1,000 U/mL that did not decrease postresection

Summary

Introduction

RETRACTED a preoperative serum signature of CEA+/CA125+/CA19-9 ≥ 1,000 U/mL that predicted extremely poor outcome after pancreatectomy for patients with PDAC9. Four major genes, including KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4, are the most frequently mutated genes in the landscape of the human PDAC genome as revealed by whole-exome sequencing[10] Mutations of these driver-genes have been strongly associated with malignant behavior of the tumor and may assist in making an optimal therapeutic selection[6,7,8,11,12,13]. It has long been recognized that the serum CA19-9 level reflects the tumor burden in PDAC and could be used to predict patient survival[15,16,17] It remains ambiguous whether there is a direct correlation between CA19-9 and driver-gene mutations. Tanase et al.[24] found that overexpression of caveolin-1 correlates with tumor progression biomarkers, such as TP53 mutation and CA19-9 level, in PDAC, suggesting that specific driver-gene mutations might regulate the cavin-1/caveolin-1 axis. We investigated how mutant p53 regulated cavin-1/caveolin-1, thereby affecting the invasion and metastasis of pancreatic cancer cells

Methods

Results

Conclusion