ABSTRACT
Pancreatic cancer (PC) is the seventh-leading cause of cancer-related mortality, and is associated with limited therapeutic options and poor prognosis. The extracellular matrix (ECM) represents the main component of the tumor microenvironment. Studies have found controversial roles of osteoglycin (OGN), a classical small leucine-rich proteoglycan found in the ECM in human malignancies; however, the significance of OGN in PC has not been determined. Here, the expression profiles of OGN in PC tissues and cell lines were evaluated by Gene Expression Profiling Interactive Analysis (GEPIA) database, immunohistochemistry, western blot, and quantitative PCR. OGN was found to be significantly upregulated in PC tissues and cell lines. Moreover, the expression of OGN was observed to be closely associated with TNM stage, stage III showed a higher OGN expression than that of stages I and II. Survival analysis showed that patients with PC showing high levels of OGN had low survival rates. The effects of OGN on cell proliferation and apoptosis were analyzed using MTT, CCK8, EdU and TUNEL assays. Wound-healing and invasion assays were conducted to test migratory and invasive abilities. Overexpression of OGN was demonstrated to promote proliferation, migration, and invasion, and inhibit apoptosis of PC cells. Further experiments revealed that inhibitor of DNA binding 4 (ID4) was upregulated by OGN. Silencing ID4 by small interfering RNA was shown to partially reverse the tumor-promoting effect of OGN. Collectively, our preliminary results indicate that the elevated expression of OGN may be associated with PC progression and may serve as a potential biomarker for the diagnosis and prognosis of PC. Targeting of OGN/ID4 axis may be a promising strategy in PC therapy.
Subject(s)
Intercellular Signaling Peptides and Proteins , Pancreatic Neoplasms , Cell Transformation, Neoplastic , DNA , Humans , Inhibitor of Differentiation Proteins , Pancreatic Neoplasms/genetics , RNA, Small Interfering , Small Leucine-Rich Proteoglycans , Tumor Microenvironment/genetics , Pancreatic NeoplasmsABSTRACT
This study was designed to explore the sulfation patterns of chondroitin sulfate (CS)/dermatan sulfate (DS), and keratan sulfate (KS) and the expression of carbohydrate sulfotransferases (CHSTs) in 26 pancreatic tumor and normal tissues. CS/DS and KS profiles were simultaneously determined. Pancreatic tumor tissues exhibited increased ΔDi-0S, ΔDi-4S, and ΔDi-6S levels, with absolute ΔDi-4S content being highest, followed by ΔDi-6S. However, as for the contents of KS-6S and KS-6S,6'S, there were no significant regular change. The expression levels of CHST1 and CHST4 were 37 and 15 times higher than those in normal tissues. PCA and OPLS-DA revealed that ΔDi-4S and ΔDi-6S levels could be reliably used to differentiate between healthy and cancerous tissues. The up-regulation of CHST3, CHST12, CHST13, and CHST15 was directly correlated with C-4 and C-6 sulfation. These data provide a foundation for future studies of the role of ΔDi-4S and ΔDi-6S in the progression of pancreatic cancer.
Subject(s)
Keratan Sulfate , Pancreatic Neoplasms , Chondroitin Sulfates , Dermatan Sulfate , Humans , Membrane Glycoproteins , Sulfates , Sulfotransferases/geneticsABSTRACT
Desmoplasia in the extracellular matrix (ECM) is one of the hallmarks of pancreatic cancer (PC), a virtually incurable disease. Decorin, a classical small leucine-rich proteoglycan found in the ECM, was upregulated in PC tissue samples according to the data of TCGA. However, decorin plays a protective role in the ECM. So it is necessary to study the roles of decorin in the progression of PC. A significantly upregulated expression of decorin was observed in the PC tissue samples compared with the normal tissues. However, there was no considerable difference in the level of expression of decorin during different pathological stages, which was supported by the immunoblot analysis. Western blot showed a higher expression of decorin A in the para-carcinoma tissue than in the cancerous tissue but the expression of decorin B, C, and D was elevated in the cancerous tissue. The results of the MTT and scratch wound healing assays revealed an elevated proliferation ability and migration rate in decorin B-overexpressing cells but were inhibited in the decorin A-overexpressing cells. Overexpression of decorin A significantly elevated the expression of the apoptosis-related genes and Decorin B-overexpression elevated proliferation-related genes. All the results showed that decorin B played important roles in the promoting of PC.
Subject(s)
Decorin/genetics , Disease Progression , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Decorin/metabolism , Humans , Models, BiologicalABSTRACT
Degeneration of the intervertebral discs, a natural progression of the aging process, is strongly implicated as a cause of low back pain. Aggrecan is the major structural proteoglycan in the extracellular matrix of the intervertebral disc. It is large, possessing numerous glycosaminoglycan chains and the ability to form aggregates in association with hyaluronan. The negatively charged glycosaminoglycan side chains in aggrecan in the nucleus pulposus of the intervertebral discs can bind electrostatically to polar water molecules, which are crucial for maintaining the well-hydrated state that enables the discs to undergo reversible deformation under compressive loading. A more in-depth understanding of the molecular basis of disc degeneration is essential to the design of therapeutic solutions to treat degenerative discs. Within this scope, we discuss the current knowledge concerning the structure and function of aggrecan in intervertebral disc degeneration. These data suggest that aggrecan plays a central role in the function and degeneration of the intervertebral disc, which may suggest potential aggrecan-based therapies for disc regeneration.
