Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression.

Emerging evidence has indicated a role of the bone morphoge-netic proteins (BMP) in the pathogenesis of certain cancers. Thesignaling of BMP family members is tightly regulated by theirantagonists, including noggin and SOST, which are, in turn, posi-tively regulated by BMP, thereby forming a negative feedbackloop. Consequently, the expression of these antagonists shouldbe taken into account in studies on the prognostic significance ofBMP. In the present paper, we correlated protein and mRNAexpression levels of BMP6, noggin and SOST, alone or in combi-nation, with patient survival in various types of cancer. We foundthat BMP6 alone was not significantly correlated with esophagealsquamous cell carcinoma patient survival. Instead, a high level ofinhibitor of differentiation 1, a downstream factor of BMP6, wasassociated with shorter survival in patients whose tumors stainedstrongly for BMP6. Knockdown of noggin in esophageal cancercell line EC109, which expresses BMP6 strongly and SOST weakly,enhanced the non-adherent growth of the cells. Noggin andSOST expression levels, when analyzed alone, were not signifi-cantly correlated with patient survival. However, high BMP6activity, defined by strong BMP6 expression coupled with weaknoggin or SOST expression, was significantly associated withshorter survival in esophageal squamous cell carcinoma patients.We further confirmed that BMP6 activity could be used as a prog-nostic indicator in prostate, bladder and colorectal cancers, usingpublicly available data on BMP6, noggin and SOST mRNA expres-sion and patient survival. Our results strongly suggest thatBMP6, noggin and SOST could be used in combination as a prog-nostic indicator in cancer progression. (Cancer Sci2012; 103:1145–1154)