TGF-β1-SOX9 axis-inducible COL10A1 promotes invasion and metastasis in gastric cancer via epithelial-to-mesenchymal transition

Abstract

Molecular biomarkers that predict disease progression might promote drug development and therapeutic strategies in aggressive cancers, such as gastric cancer (GC). High-throughput mRNA sequencing (RNA-seq) revealed that collagen type X alpha 1 (COL10A1) is a disease progression-associated gene. Analysis of 103 GC patients showed that high COL10A1 mRNA expression was associated with GC metastasis and reduced survival. We analyzed the COL10A1 promoter using the UCSC genome website and JASPAR database, and we found potential SOX9 binding site. Here, we demonstrated that SOX9 and COL10A1 were both up-regulated in GC. We observed a positive correlation between the expression patterns of SOX9 and COL10A1 in GC cells and tissues. The results of electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assay and promoter reporter indicated that SOX9 could directly bind to the COL10A1 gene promoter and activate its transcription. Biological function experiments showed that COL10A1 regulated the migration and invasion of GC cells. Knockdown COL10A1 inhibited lung and abdominal cavity metastasis in a nude mouse model. Moreover, transforming growth factor-β1 (TGF-β1) treatment up-regulated the phosphorylation of Smad2 and increased SOX9 and COL10A1 expression. COL10A1 was confirmed to be a potential inducer of epithelial-to-mesenchymal transition (EMT). SOX9 was essential for COL10A1-mediated EMT, and cell migration, invasion and metastasis. Co-expression of SOX9 and COL10A1 was associated with tumor progression and was strongly predictive of overall survival in GC patients. In summary, this study elucidated the mechanistic link between COL10A1 and the TGF-β1-SOX9 axis. These findings indicated that COL10A1 might play a crucial role in GC progression and serve as a potential biomarker and therapeutic target in GC patients.

Bioinformatics analysis of prognostic significance of COL10A1 in breast cancer

“…GSEA analysis revealed the function of COL10A1 enriched in TGF-β signaling pathway in breast cancer. The previous study elucidated the mechanistic link between COL10A1 and the TGF-β1-SOX9 axis in gastric cancer progression [8]. Our study is the first to reveal the potential function between COL10A1 and TGF-β signaling pathway in breast cancer.…”

“…Collagen type X alpha 1 (COL10A1), a secreted, short-chain collagen, belongs to the collagen family, which is a major interstitial matrix component [5]. COL10A1 expression is elevated in many solid tumor types, such as colon cancer, esophagus cancer, and breast cancer, and displays vital roles in many critical cellular processes such as cell proliferation, migration, invasion and tumor vasculature [6][7][8]. COL10A1 protein levels in plasma might be a potential diagnostic predictor for early breast cancer [9].…”

Integrated analysis of a ceRNA network reveals potential prognostic lncRNAs in gastric cancer

“…Modularization can simplify the complex network into several modules for further research, and cores in the modules may have important functions. Several studies have shown that the core genes of the modules, such as COL1A1 and COL10A, participate in the invasion and [45][46][47] Thrombospondin 2 (THBS2) has also been reported to inhibit tumor growth and angiogenesis and has been recommended as a potential diagnostic biomarker for several types of cancer. 48,49 In addition, karyopherin subunit alpha 2 (KPNA2) is associated with cell proliferation, migration, and apoptosis, and has been found upregulated in many cancers and is an indicator of a poor prognosis.…”

Effects of Lidocaine and Ropivacaine on Gastric Cancer Cells Through Down-regulation of ERK1/2 Phosphorylation In Vitro

“…Conventional therapeutic methods for gastric cancer are target-specific drug treatment (3), surgical excision (4), radiotherapy or chemotherapy (5). After surgery, the recurrence and metastasis of gastric cancer are pressing issues, and are complicated processes involved a series of events (6,7), such as tumor heterogeneity, and epigenetic changes (8,9). It has been confirmed that circulating tumour cells with the ability to diffuse and metastasize are a prime prognostic marker for cancer recurrence (10,11).…”