R-spondins是近年来发现的一类新的Wnt信号激活蛋白。因其对经典Wnt/β-catenin通路的激活作用被认为是潜在原癌基因。之前我们已经报道该家族的RSPO2蛋白在肠癌形成中起到抑癌基因的作用，RSPO2与LGR5相互作用形成负反馈机制抑制Wnt/β-catenin信号。进一步研究中我们发现RSPO2还具有不依赖于经典Wnt/β-catenin的抑制肠癌转移侵袭的能力。本项目将对此进行深入研究，以期：①在体内外确定RSPO2蛋白对肠癌转移扩散能力的影响，评估将其用于临床前研究的可能性；②阐明RSPO2以ERK/JNK为主要通路影响肠癌转移的分子机制；③确定RSPO2对非经典Wnt信号通路的影响并揭示相关作用机制；④确定RSPO2是否可通过调控EGFR/Ras通路影响肠癌发生发展。后续研究结果既对Wnt信号通路的研究具有重要理论意义，也将为肠癌治疗研究提供新靶点。

R-spondins are a novel family of Wnt activators discovered in recent years. Given the crucial role of canonical Wnt signaling in tumorigenesis, R-spondins have been considered as potential oncogenes. Previously, we reported that one of the family members, R-spondin-2 (RSPO2), functions as a tumor suppressor in human colon cancer and RSPO2 interacts with LGR5 to create a negative feedback loop of Wnt/β-catenin signaling that exerts a net growth-suppressive effect on colon cancer cells (Nature Communications, 2014). In the follow-up study we found that RSPO2 suppresses colon cancer metastasis and this inhibition is independent of canonical Wnt/β-catenin signaling. To fully understand the mechanisms involved in this process, further investigations will be undertaken to i) clarify the roles of RSPO2 protein in colon cancer metastasis both in vitro and in vivo and evaluate its potential for preclinical research; ii) elucidate the mechanism of RSPO2 regulating colon cancer metastasis through ERK/JNK pathway; iii) illuminate the regulatory function of RSPO2 in noncanonical Wnt/β-catenin signaling; and iv) confirm whether RSPO2 can regulate colon tumorigenesis and development via EGFR/Ras pathway. The findings of this study will shed a new light on the mechanics of Wnt signaling and may also provide novel targets for colon cancer therapy.