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

Abstract

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.

REG4 expression was a potential marker for carcinogenesis, aggressiveness and prognosis of gastric cancer: a meta and bioinformatics analysis

“…Consistent with the data about ovarian cancer, colon cancer, glioma, pancreatic cancer, gallbladder cancer, and prostate cancer [32,[38][39][40][41][42], we found that REG4 expression was higher in gastric cancer than normal mucosa, and positively correlated with depth of invasion, lymph node metastasis, TNM staging and differentiation of gastric cancer, suggesting that REG4 overerexpression promoted gastric carcinogenesis and subsequent progression. The higher REG4 expression The bias was analyzed about risk degrees of REG4 expression in gastric mucosa (A) for gastric carcinogenesis.…”

“…Reportedly, REG4 expression was positively linked to the worse prognosis of the patients with colon cancer and adenoid cystic carcinoma [39,45]. REG4 expression might be considered as an independent factor of the worse prognosis of ovarian cancer, rectal cancer, glioma, and advanced gallbladder carcinoma as [32,40,41,46].…”

Cancer‐associated thrombosis: The search for the holy grail continues

“…Overexpression of Reg4 is associated with tumor progression, metastasis and reduced survival 62, 63, 64. As mentioned before, risk of CAT increases dramatically in patients experiencing metastasis compared to non‐metastatic cancer patients 65, 66, 67.…”

“…43 Finally, future work may demonstrate that there is a link between the expression profiles in CAT and different subtypes of colon cancer, 61 Overexpression of Reg4 is associated with tumor progression, metastasis and reduced survival. [62][63][64] As mentioned before, risk of CAT increases dramatically in patients experiencing metastasis compared to non-metastatic cancer patients. [65][66][67] Tumor cells must gain cancer stem cell properties and should undergo epithelial-to-mesenchymal transition, for successful metastasis.…”

A mutant KRAS‐induced factor REG4 promotes cancer stem cell properties via Wnt/β‐catenin signaling

“…Some studies showed conflicting results regarding the relationship between REG4 and clinical features in CRC. 24,25 Meanwhile, the Reg4-expressing deep crypt secretory cells are known to provide niche support for Lgr5 + colonic stem cells in colonic crypts, 26 and these colocalized with the Lgr5 + cells in colon adenomas of Apc min/+ mice. 13 However, the involvement of REG4 in promoting CSCs in CRC has not yet been characterized.…”