Overexpression of Reg4, alone or combined with MMP-7 overexpression, is predictive of poor prognosis in colorectal cancer.

Regenerating islet-derived family, member 4 (Reg4) is a secreted protein that plays a critical role in the development of colorectal cancer (CRC). In the present study, we examined the relationship between Reg4 and matrix metalloproteinase-7 (MMP-7) expression in CRC, particularly with regard to metastasis. RT-qPCR, western blotting, tissue microarray (TMA) and immunohistochemical staining were performed to detect Reg4 and MMP-7 expression in CRC tissues and paired adjacent normal tissues. As compared with normal tissues, most paired colon cancers showed a ≥2-fold increase in the Reg4 and MMP-7 mRNA levels, which was subsequently validated by the post-transcriptional levels. Immunohistochemical analysis demonstrated that Reg4 was associated with lymph node and distant metastasis, advanced American Joint Committee on Cancer (AJCC) stage, and histologic grade. Further studies showed the correlation between Reg4 and MMP-7 expression was significant in CRC with distant metastasis (r=0.555, P=0.021) and in the lymph‑node metastasis samples (r=0.557, P<0.001). Patients with tumor positivity for the two molecules showed a worse prognosis even after radical surgery (P<0.001). Multivariate analysis revealed that patients with Reg4- and MMP-7-positive tumors had extremely poor OS (HR 4.63; 95% CI 2.43-8.81; P<0.001) and DFS (HR 3.88; 95% CI 2.08-7.22; P<0.001). Reg4 expression may be useful in the prediction of colon cancer prognosis when combined with MMP-7.