Abstract

Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma (PDA) patients back to an overexpressed QSOX1 parent protein. In addition to overexpression in pancreatic cancer cell lines, 29 of 37 patients diagnosed with PDA expressed QSOX1 protein in tumor cells, but QSOX1 was not detected in normal adjacent tissues or in a transformed, but nontumorigenic cell line. To begin to evaluate the advantage QSOX1 might provide to tumors, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in two pancreatic cancer cell lines. Growth, cell cycle, apoptosis, invasion, and matrix metalloproteinase (MMP) activity were evaluated. QSOX1 shRNA suppressed both short and long isoforms of the protein, showing a significant effect on cell growth, cell cycle, and apoptosis. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC-3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 plays an important role in activation of MMP-2 and MMP-9. Taken together, our results suggest that the mechanism of QSOX1-mediated tumor cell invasion is by activation of MMP-2 and MMP-9.

Highlights

  • Pancreatic ductal adenocarcinoma (PDA) is a disease that carries a poor prognosis

  • To begin to determine the frequency of expression of Quiescin sulfhydryl oxidase 1 (QSOX1) in human pancreatic ductal adenocarcinoma (PDA), QSOX1 expression was assessed in 4 different pancreatic tumor cell lines, an immortal nontumorigenic cell line, HPDE6, 37 tumor tissue sections from

  • Our results clearly show that knockdown of QSOX1 expression in tumor cells leads to a dramatic decrease in the number of pancreatic tumor cells that degrade Matrigel and migrate through the insert into nutrient-rich media

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Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) is a disease that carries a poor prognosis. It is often detected in stage III resulting in an unresectable tumor at the time of diagnosis. We found that QSOX1 is overexpressed in tumor tissue from pancreatic cancer patients but not adjacent normal tissue (Fig. 1B and C). These findings led us to hypothesize that overexpression of QSOX1 might be functionally important for tumor cells, Authors' Affiliations: 1School of Life Sciences, Arizona State University, Tempe; 2Translational Genomics Institute, Phoenix; and 3Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona

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