Quiescin Sulfhydryl Oxidase 1 Promotes Invasion of Pancreatic Tumor Cells Mediated by Matrix Metalloproteinases

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. Mol Cancer Res; 9(12); 1621-31. Ó2011 AACR.

The Emerging Role of QSOX1 in Cancer

“…Model for QSOX1-mediated tumor cell invasion. QSOX1 activates matrix metalloproteinases (MMPs) that are capable of digesting basement membranes (46) and incorporates laminin into fibroblasts, which facilitates the migration of tumor cells into the fibroblast layer (44). The production of H 2 O 2 by QSOX1 may also elicit vascular endothelial growth factor (VEGF) production by tumor cells, stimulating blood vessel growth into the tumor (62).…”

“…In 2011 and 2013, we reported that QSOX1 plays a role in pancreatic and breast tumor cell growth and invasion in vitro (46,47). We also demonstrated that QSOX1 affects the proteolytic activity of matrix metalloproteins (MMP-2 and -9) FIG.…”

“…In this study, knockdown of QSOX1 using short hairpin RNA resulted in an increase in endothelial cell sprouting. If Hellebreker's findings are correct, an unanswered question is how QSOX1 expression is connected to the suppression of angiogenesis, especially when QSOX1 appears to be involved in invasion (44,46,47). It is likely that different mechanisms are required for invasion and growth at a metastatic site, so one explanation could be as follows.…”

HIF1 Contributes to Hypoxia-Induced Pancreatic Cancer Cells Invasion via Promoting QSOX1 Expression

“…The biological function of QSOX1 is to oxidate sulfhydryl members during protein folding to generate disulfide bonds in proteins, thus ultimately reducing the transformation from oxygen to hydrogen peroxide [8,9,10]. Recently, QSOX1 has been identified over-expressed in pancreatic and breast cancers and plays an important role in pancreatic and breast cancer cells invasion via activating MMP-2 and MMP-9 [11,12,13,14]. However, the regulation mechanism of QSOX1 remains largely elucidated.…”

A Proteomic Analysis of the Malignant Mesothelioma Secretome Using iTRAQ

“…In MM cells, inhibition of HSP90 by 17-AAG results in cell cycle arrest and apoptosis (31). Quiescin sulfhydryl oxidase 1 (QSOX1) is involved in protecting cells from ROS induced apoptosis by preserving mitochondrial polarity (32) and in the activation of matrix metalloproteinases (MMP) 2 and 9 (33).…”