Upregulated Collagen COL10A1 Remodels the Extracellular Matrix and Promotes Malignant Progression in Lung Adenocarcinoma

Abstract

Collagens are major components of the ECM in various organs, including the lungs. Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM). However, it remains largely unexplored whether collagens are involved in the tumor progression of lung adenocarcinoma (LUAD). Analysis of three LUAD transcriptional expression profiles showed that COL10A1 mRNA expression was up-regulated and associated with poor prognosis. Gain- and loss-of-function studies were performed to observe that up-regulated COL10A1 promotes LUAD cell proliferation and invasion in vitro and in vivo. In molecular mechanism study, we found that COL10A1 interacts with DDR2 and affects the downstream FAK signaling pathway to regulate LUAD cell progression. The expression of COL10A1 on tissue microarray (TMA) was also measured to explore the association between COL10A1 expression and patient outcome. The results addressed that COL10A1 is up-regulated and positively correlated with lymph node metastasis in lung adenocarcinoma, and the COL10A1 expression is also an independent prognostic factor. In summary, the up-regulated COL10A1 remodels the ECM and the COL10A1/DDR2/FAK axis regulates the proliferation and metastasis of LUAD cells, implying that COL10A1 is a promising therapeutic target and prognostic marker for LUAD patients.

HypDB: A functionally annotated web-based database of the proline hydroxylation proteome

“…Since Hyp promotes the structural stability of collagens, such changes likely indicated a significantly increase in stability for collagen X and decrease in stability for collagen IV and VI in lung cancer tissue compared to the normal tissue. Our finding agreed well with a very recent publication indicating a pro-metastatic role of up-regulated collagen X in lung cancer progression [ 61 ]. In addition, we also identified significant up-regulation of Hyp on glycolysis enzymes pyruvate kinase (PKM), enolase (ENO1), and autophagy protein Parkin (PARK7) in tumor tissue ( Fig 7D ).…”

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

“…Since proline hydroxylation promotes the structural stability of collagens, such changes likely indicated a signficantly increase in stability for Collagen X and decrease in stability for Collagen IV and VI in lung cancer tissue compared to the normal tissue. Our finding agreed well with a very recent publication indicating a pro-metastatic role of upregulated Collagen X in lung cancer progression [21]. In addition, we also identified significant upregulation of proline hydroxylation on glycolysis enzymes pyruvate kinase (PKM) and enolase (ENO1), heat-shock protein HSPA5 as well as autophagy protein Parkin (PARK7) (Figure 7D).…”

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib

“…Functionally, DDR2 activity and downstream signalling has been associated with cell proliferation, survival, adhesion, spreading and differentiation [ 60 ]. Activated DDR2 has been shown to signal through a number of pathways including ERK, MAPK, PI3K and possibly FAK [ 61 , 62 ] Induction of EMT in a variety of model systems has been demonstrated to correlate with a switch from the expression of the more epithelial DDR1 to the more mesenchymal DDR2 [ 60 , 63 ]. In a human mammary epithelial cell line, the expression of EMT inducers, such as Snail, Slug and TGF-ß induced an “EMT core signature” which included an upregulation of DDR2 expression concomitant to a down regulation of DDR1 [ 64 ].…”