The BMP antagonist, SOSTDC1, restrains gastric cancer progression via inactivation of c-Jun signaling.

Gastric cancer is commonly diagnosed at an advanced stage when metastasis is almost inevitable. Despite numerous novel regulators have been identified in driving gastric cancer progression, much remains unclear due to the complex nature of cancer. Comparison of the transcriptome profiles of gastric primary tumor tissue, with its matched non-tumor and lymph node metastasis revealed frequent stepwise down-regulation of sclerostin domain containing 1 (SOSTDC1) related with tumor progression. Clinically, deficiency of this gene is associated with shortened survival of patients. Our results suggest that SOSTDC1 confers tumor-suppressive features in gastric cancer and silencing of it accelerates tumor growth and promotes the formation of lung metastasis. Although SOSTDC1 displayed limited inhibition of canonical SMAD-dependent bone morphogenetic proteins (BMP) pathway, it remarkably restrained the c-Jun activation and transcription of c-Jun downstream targets in the noncanonical BMP signaling pathway. Furthermore, c-Jun N-terminal kinase (JNK) blockage attenuated cell proliferative and migrative advantages of SOSTDC1 knockdown cell lines. Our study comprehensively elucidated the role of SOSTDC1 in gastric cancer progression and the results translate into potential therapy for gastric cancer.