Down-regulation of SOSTDC1 mediates tumorigenesis and metastasis in gastric cancer

Abstract

Gastric cancer (GC), with high incidence rate among Eastern Asian population, is usually diagnosed at an advanced stage and is accompanied by metastasis. Metastasis of gastric tumor cells to distant organs is the main cause of gastric cancer-related deaths. Achieving a detailed molecular understanding of gastric cancer genetic aberrations is crucial for improving patients’ outcomes. Currently, although extensive research revealed numerous novel regulators in cell malignancy progression, much remains unclear due to the complexity and systemic nature of cancer. ii With the aim to uncover new gastric cancer-associated genes as potential therapeutic targets, transcriptome sequencing for four cases of gastric cancer samples, each case composed of adjacent non-tumor tissue, matched primary tumor tissue and lymph node metastasis, was conducted. Following screening and validation, we proposed 16 candidates whose expression levels were declined stepwise with the increase of extent of malignancy. Among these genes, sclerostin domain containing 1 (SOSTDC1) was selected for further studies. It is a member of the sclerostin family and encodes a secreted protein with a C-terminal cystine knot-like domain. This protein is highly likely critical in cancer biology since it is an antagonist of bone morphogenetic protein (BMP) pathway, which controls essential embryogenesis and development processes. Clinically, downregulation of SOSTDC1 was frequently detected in gastric tumors and metastasis (p<0.0001) and depletion of it was significantly associated with poorer overall survival (p=0.0123) in the tissue microarray. Considering the great potential of SOSTDC1, functional studies were conducted, and results suggested that SOSTDC1 displays strong tumor suppressive features. Ectopic overexpression of it could inhibit proliferation and cell motility both in vitro and in vivo, which are essential capacities of disseminated cancer cells to form metastatic colonies. Short hairpin RNA mediated silencing of SOSTDC1, however, accelerated cell growth and promote the formation of lung metastatic lesions in the tail vein injection mouse model. These findings demonstrated the cells with depletion of SOSTDC1 conferred strong tumorigenic and metastatic advantages in gastric cancer. iii Belonging to a BMP antagonist family, SOSTDC1 is most likely to execute its functions through the regulation of BMP pathway. Thus, we first detected the alterations of the levels of key players in the canonical Smad-dependent BMP signaling upon SOSTDC1 restoration. Despite of the observations that SOSTDC1 only modulated the activation of Smad1/5/8 in a minor way, it could convincingly restrain the phosphorylation of c-Jun and the transcription of its downstream targets in the noncanonical BMP signaling. Treatment of a c-Jun N-terminal kinase inhibitor, SP600125, could attenuate cell proliferative and migrative advantages of SOSTDC1 knockdown cell lines, indicating that SOSTDC1 may modulate cancer progression predominantly via inactivation of c-Jun signaling. In this study, we reported the identification of a novel gene, SOSTDC1 from transcriptome profiles and the characterization of its inhibitory role in tumorigenesis and metastasis in gastric cancer via inactivation of c-Jun signaling axis.