Abstract
BackgroundCollagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration. It was then found to be ubiquitously expressed in numerous cell types such as fibroblasts and smooth muscle cells, and aberrantly up-regulated in several malignant tumors. However, the functional role of CTHRC1 and its related mechanism in breast cancer still remains unclear.MethodsCTHRC1 expressions in breast cancer tissues and cells were assessed by qRT-PCR, western blot and immunohistochemistry. The relative expression level of miR-134, miR-155, miR-30c and miR-630 in breast cancer cells respectively was detected by qRT-PCR. Wild type (Wt) and Mutant type (Mut) CTHRC1 3’UTR sequences were cloned into a psi-CHECK2 reporter vector, and the relative luciferase activity was detected by dual-luciferase reporter assay in indicated cells. The effect of ectopic expression of miR-30c or gain and loss of CTHRC1 on cell viability, cell proliferation, cell cycle progression and apoptosis, cell invasion and migration was respectively detected by CCK-8 assay, colony formation assay, flow cytometry analysis, transwell invasion/migration assay. Protein levels of β-catenin, active β-catenin, normal and phosphorylated form of GSK-3β were detected by western blot in indicated cells. Immunofluorescence staining of β-catenin was performed to observe nuclear localization.ResultsWe found CTHRC1 was frequently up-regulated in human breast cancer cells and tissues. Then our cohort study and further meta-analysis validated high expression of CTHRC1 was associated with aggressive clinicopathological features and poor clinical outcome of breast cancer patients. In addition, CTHRC1 promoted cell proliferation, invasion and migration and suppressed cell apoptosis in breast cancer, which might be by activating GSK-3β/β-catenin signaling and inhibiting Bax/Caspase-9/Caspase-3 signaling respectively; and these biological functions of CTHRC1 could be directly negatively regulated by miR-30c.ConclusionTaken together, we identified the role of miR-30c/CTHRC1 axis in breast cancer progression and demonstrated CTHRC1 may serve as a prognostic biomarker and therapeutic target for breast cancer.
Highlights
Collagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration
We detected CTHRC1 mRNA in normal breast tissue, 5 benign breast tumor tissues and 18 paired breast cancer tissues (9 cases with regional lymph node (LN) metastasis and 9 cases without) with quantitative realtime PCR (qRT-PCR), and results were normalized with its expression in normal tissue
Results showed the expression level of CTHRC1 protein was step-increased in normal breast tissue, benign breast tumor tissue and breast cancer tissue, and its expression level in BC was frequently over-expressed in contrast with matched peri-tumor tissue of breast cancer (PBC) (Fig. 1e)
Summary
Collagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration. The functional role of CTHRC1 and its related mechanism in breast cancer still remains unclear. Collagen triple helix repeat containing-1 (CTHRC1) is a secreted 28-kDa protein, which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration [3,4,5]. CTHRC1 was found to be ubiquitously expressed in numerous cell types such as fibroblasts and smooth muscle cells, and aberrantly up-regulated in several malignant tumors, including melanoma, and cancers of gastrointestinal tract, liver, lung, ovary and so on [6,7,8]. The functional role of CTHRC1 and its mechanism in breast cancer still remains unclear
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