Abstract
Protease-activated receptor 4 (PAR4), a member of G-protein coupled receptors family, was recently reported to exhibit decreased expression in gastric cancer and esophageal squamous cancer, yet increased expression during the progression of prostate cancer. Trefoil factor 2 (TFF2), a small peptide constitutively expressed in the gastric mucosa, plays a protective role in restitution of gastric mucosa. Altered TFF2 expression was also related to the development of gastrointestinal cancer. TFF2 has been verified to promote cell migration via PAR4, but the roles of PAR4 and TFF2 in the progress of colorectal cancer are still unknown. In this study, the expression level of PAR4 and TFF2 in colorectal cancer tissues was measured using real-time PCR (n = 38), western blotting (n=38) and tissue microarrays (n = 66). The mRNA and protein expression levels of PAR4 and TFF2 were remarkably increased in colorectal cancer compared with matched noncancerous tissues, especially in positive lymph node and poorly differentiated cancers. The colorectal carcinoma cell LoVo showed an increased response to TFF2 as assessed by cell invasion upon PAR4 expression. However, after intervention of PAR4 expression, PAR4 positive colorectal carcinoma cell HT-29 was less responsive to TFF2 in cell invasion. Genomic bisulfite sequencing showed the hypomethylation of PAR4 promoter in colorectal cancer tissues and the hypermethylation in the normal mucosa that suggested the low methylation of promoter was correlated to the increased PAR4 expression. Taken together, the results demonstrated that the up-regulated expression of PAR4 and TFF2 frequently occurs in colorectal cancer tissues, and that overexpression of PAR4 may be resulted from promoter hypomethylation. While TFF2 promotes invasion activity of LoVo cells overexpressing PAR4, and this effect was significantly decreased when PAR4 was knockdowned in HT-29 cells. Our findings will be helpful in further investigations into the functions and molecular mechanisms of Proteinase-activated receptors (PARs) and Trefoil factor factors (TFFs) during the progression of colorectal cancer.
Highlights
The progression of colorectal cancer is a multistep process involved in polygenetic alterations in prooncogenes and/or tumor suppressor genes, and aberrant epigenetic gene regulation can lead to abnormal growth of malignant tumors [1,2]
The difference expression of Protease-activated receptor 4 (PAR4) and Trefoil factor 2 (TFF2) was detected in various tumors, such as the pancreas cancer, lung cancer and gastric cancer, and this difference expression was associated with tumor cell growth, migration, invasion and angiogenesis [11,22,23,24]
We presented some fundamental data that the expression levels of PAR4 and TFF2 were significantly increased in colorectal cancer tissues when compared to the matched noncancerous tissues, especially in the metastatic positive lymph nodes and poorly differentiated tumors
Summary
The progression of colorectal cancer is a multistep process involved in polygenetic alterations in prooncogenes and/or tumor suppressor genes, and aberrant epigenetic gene regulation can lead to abnormal growth of malignant tumors [1,2]. As having the ability of degradation of extracellular matrix proteins, PARs serve as signal molecules involved in tumor cell migration, invasion and metastasis [4]. PAR1, which was widely expressed in cancers, promoted tumor genesis and invasion of breast cancer cells and colorectal cells [5,6]. PAR2, overexpressed in prostate cancer, promoted prostate cancer cell migration [7]. PAR2 showed a tumor-protective role in skin carcinogenesis [8]. The expression and potential roles of PAR4 in tumorigenesis are still unknown. PAR4 expression was absent in normal colon mucosa, but appeared obvious staining in the dysplastic and colorectalous mucosa. PAR4 mRNA was found in 10 out of 14 (71%) human colorectal carcinoma cell lines [12]
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