SMOC2, an intestinal stem cell marker, is an independent prognostic marker associated with better survival in colorectal cancers

Abstract

We aimed to investigate the expression profile of SPARC-related modular calcium-binding protein 2 (SMOC2) during colorectal cancer (CRC) progression and assess its prognostic impact in CRC patients. In our study, we showed that SMOC2 transcript level was higher in CRC samples than in normal mucosa ( P = 0.017); this level was not associated with candidate cancer stem cell markers ( CD44, CD166, CD133, and CD24) or intestinal stem cell markers ( LGR5, ASCL2, and EPHB2) except for OLFM4 ( P = 0.04). Immunohistochemical analysis showed that SMOC2-positive cells were confined to the crypt bases in the normal intestinal mucosa, hyperplastic polyps, and sessile serrated adenomas, whereas traditional serrated adenomas and conventional adenomas exhibited focal or diffuse distribution patterns. In total, 28% of 591 CRCs were positive for SMOC2, but SMOC2 positivity had negative correlations with lymphatic invasion ( P = 0.002), venous invasion ( P = 0.002), and tumor stage ( P < 0.001). However, a positive association with nuclear β-catenin expression was seen. Furthermore, while upregulated SMOC2 expression was maintained during the adenoma-carcinoma transition, it decreased in cancer cells at the invasive front but did not decline further during lymph node metastasis. SMOC2 positivity showed no correlations with molecular abnormalities, including microsatellite instability, CpG island methylator phenotype, and mutations of KRAS and BRAF. In addition, we showed comprehensively that SMOC2 positivity is an independent prognostic marker for better clinical outcomes in a large cohort of CRC patients ( P = 0.006). In vitro studies also demonstrated that induced SMOC2 expression in DLD1 cells exerts a suppressive role in tumor growth as well as in migration, colony, and sphere formation abilities. Taken together, our results suggest SMOC2 as a candidate tumor suppressor in CRC progression.