Abstract
BackgroundOesophageal cancer is one of the most common malignancies worldwide,and oesophageal squamous cell carcinoma (ESCC) is the predominant histological type both globally and in China. Collagen triple helix repeat containing 1 (CTHRC1) has been found to be upregulated in ESCC. However, its role in tumourigenesis and progression of ESCC remains unclear.MethodsUsing our previous ESCC mRNA profiling data, we screened upregulated genes to identify those required for proliferation. Immunohistochemistry was performed to determine the level of CTHRC1 protein expression in 204 ESCC patients. Correlations between CTHRC1 expression and clinicopathological characteristics were assessed. In addition, pyrosequencing and 5-aza-dC treatment were performed to evaluate methylation status of CTHRC1 promoter. In vitro and in vivo analyses were also conducted to determine the role of CTHRC1 in ESCC cell proliferation, migration and invasion, and RNA sequencing and molecular experiments were performed to study the underlying mechanisms.ResultsBased on mRNA profiling data, CTHRC1 was identified as one of the most significantly upregulated genes in ESCC tissues (n = 119, fold change = 20.5, P = 2.12E-66). RNA interference screening also showed that CTHRC1 was required for cell proliferation. Immunohistochemistry confirmed markedly high CTHRC1 protein expression in tumour tissues, and high CTHRC1 expression was positively correlated with advanced T stage (P = 0.043), lymph node metastasis (P = 0.023), TNM stage (P = 0.024) and poor overall survival (P = 0.020). Promoter hypomethylation at cg07757887 may contribute to increased CTHRC1 expression in ESCC cells and tumours. Forced overexpression of CTHRC1 significantly enhanced cell proliferation, migration and invasion, whereas depletion of CTHRC1 suppressed these cellular functions in three ESCC cell lines and xenografts. CTHRC1 was found to activate FRA-1 (Fos-related antigen 1, also known as FOSL1) through the MAPK/MEK/ERK cascade, which led to upregulation of cyclin D1 and thus promoted cell proliferation. FRA-1 also induced snail1-mediated MMP14 (matrix metallopeptidase 14, also known as MT1-MMP) expression to facilitate ESCC cell invasion, migration, and metastasis.ConclusionsOur data suggest that CTHRC1 may act as an oncogenic driver in progression and metastasis of ESCC, and may serve as a potential biomarker for prognosis and personalized therapy.
Highlights
Oesophageal cancer is one of the most common malignancies worldwide,and oesophageal squamous cell carcinoma (ESCC) is the predominant histological type both globally and in China
Among the top 500 upregulated genes in tumor tissues, we selected Collagen triple helix repeat containing 1 (CTHRC1), neural EGFL like 2 (NELL2), DLG associated protein 5 (DLGAP5), DEP domain containing 1 (DEPDC1), Zic family member 2 (ZIC2) and centrosomal protein 55 (CEP55) for this study (Additional file 3: Figure S1); these genes were significantly upregulated in an independent gene expression profiling dataset [15]
CTHRC1 facilitates Oesophageal squamous cell carcinoma (ESCC) cells aggressiveness primarily via activation of the MAPK/MEK/ERK pathway We explored the downstream signalling pathways responsible for CTHRC1-mediated ESCC cell aggressiveness using RNA sequencing with KYSE510 cells carrying ShCTHRC1 or the empty vector
Summary
Oesophageal cancer is one of the most common malignancies worldwide,and oesophageal squamous cell carcinoma (ESCC) is the predominant histological type both globally and in China. A germline mutation in CTHRC1 gene was identified to be associated with Barrett’s oesophagus and oesophageal adenocarcinoma [13], and high CTHRC1 expression in ESCC was revealed by expression profiling studies involving a small number of cases [14, 15]. These findings should be confirmed in studies including larger groups and the cellular function and clinical implications of CTHRC1 in ESCC need to be resolved
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