分泌捲曲性相關蛋白(SFRPs)已被廣泛認為是一主要透過降低Wnt訊息傳遞活性之胞外調控因子與腫瘤抑制子。在我們所建立CRISPR/Cas9系統研究中發現細胞核內的SFRPs會與-catenin交互作用以致促進或抑制TCF4的引誘。除此之外，SFRPs會利用其氨基端或羧基端與-catenin相互反應,然而此不同結合位置會有不同的結果，氨基端結合所抑制Wnt訊息傳遞的反應會大於羧基端結合的促進反應；而當細胞處於高活化態Wnt訊息傳遞時，SFRPs與-catenin僅會利用其羧基端結合，導致-catenin轉錄活性的上升與癌幹細胞基因的高度表現。不僅如此我們也發現SFRPs半胱氨酸區域(CRD)的雙硫鍵結與導素區域(NTR)的蘇氨酸磷酸化作用對於SFRPs雙調節作用是必須的。除此之外,我們分析了臨床組織樣本亦證實了細胞核內的SFRPs/Twist1/CD133的表現可以用來當作癌症病患的檢測指標。在此研究基礎上我們預測SFRPs在Wnt所引起的癌症幹細胞特性有別於胞外的作用,其亦可在胞內扮演雙調節子的功能,而我們的研究也證明了CRISPR/Cas9標靶癌幹細胞特性基因表現的應用可當作人類腫瘤治療上的一種方式。

Secreted frizzled-related proteins (SFRPs) are mainly known for their role as extracellular modulators and tumor suppressors that down-regulate the Wnt signaling pathway. Using the established (CRISPR/Cas9 targeting promoters of SFRPs and targeting SFRPs transcript) system, we found that nuclear SFRPs interact with β-catenin and either promote or suppress TCF4 recruitment. SFRPs bound with β-catenin on both their N and C termini. The repressive effects caused by SFRP-β-catenin-N-terminus binding overpowered the promoting effects of their binding at the C terminus. By high Wnt activity, β-catenin and SFRPs only bound with their C termini, which resulted in the up-regulation of β-catenin transcriptional activity and cancer stem cell (CSC)-related genes. Furthermore, we identified disulfide bonds of the CRD domain and two threonine phosphorylation events of the NTR domain of SFRPs that are essential for their role as biphasic modulators. In addition, using clinical tumor samples, we confirmed that the nuclear SFRPs/Twist1/CD133 signature was a predictor of patient outcome. On the basis of these results, we propose that SFRPs are biphasic modulators of Wnt signaling-elicited CSC properties beyond extracellular control and provide evidences for applying of CRISPR/Cas9 targeting CSC-related genes as a new treatment strategy in human cancer therapy.

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