Wnt signaling is activated in many cancer types, yet targeting the canonical Wnt pathway has been challenging for cancer therapy. The pathway might be effectively targeted at many levels depending on the mechanism by which it has become hyperactive. Recently, mouse genetic screens have found that R-spondins (RSPOs) act as oncogenes. Evidence includes recurrent genomic rearrangements that led to increased RSPO2 or RSPO3 expression in human colorectal adenocarcinomas, exclusive of APC mutations. RSPOs modulate Wnt signaling to promote epithelial cell proliferation and survival. These secreted proteins modulate Wnt signaling by binding to G-coupled receptors LGR4/5/6, ultimately inhibiting frizzled membrane clearance by RNF43 and ZNRF3. They also exert their function independent of leucine-rich repeat-containing, G protein-coupled receptors (LGRs) by binding to ZNRF3 and RNF43. This results in increased β-catenin concentration that, after translocation to the nucleus, acts as a transcriptional coactivator of genes necessary for proliferation and cell survival. In this article, we aimed to identify the role of RSPOs in colon and breast cancers by using in silico and in vitro studies. We found that expression of RSPO2 and RSPO3 at high levels characterized a subset of colorectal cancers (CRCs). RSPO2 expression was found to characterize a subset of triple-negative breast cancers. In both instances, increased expression of RSPOs was associated with an activated Wnt signaling gene expression profile. Furthermore, knockdown of RSPO2 decreased Wnt signaling and proliferation in human breast cancer cells. Our findings show and confirm that RSPO2 and RSPO3 expression is upregulated in a subset of colorectal adenocarcinomas and breast cancers and that both are attractive druggable oncoprotein targets against such cancers. We also describe novel fusion transcripts that occur in CRC.

中文翻译：

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R-Spondins 2 和 3 在人类结肠癌和乳腺癌的亚群中过度表达


Wnt 信号传导在许多癌症类型中被激活，但针对经典 Wnt 通路一直是癌症治疗的挑战。该通路可能在许多层面上被有效地靶向，具体取决于它变得过度活跃的机制。最近，小鼠遗传筛选发现 R-spondins (RSPO) 是癌基因。证据包括导致人类结直肠腺癌中RSPO2或RSPO3表达增加的反复基因组重排（不包括APC突变）。 RSPO 调节 Wnt 信号传导以促进上皮细胞增殖和存活。这些分泌蛋白通过与 G 偶联受体 LGR4/5/6 结合来调节 Wnt 信号传导，最终抑制 RNF43 和 ZNRF3 的卷曲膜清除。它们还通过与 ZNRF3 和 RNF43 结合来发挥其功能，不依赖于富含亮氨酸重复序列的 G 蛋白偶联受体 (LGR)。这导致 β-连环蛋白浓度增加，在转位到细胞核后，充当增殖和细胞存活所需基因的转录共激活因子。在本文中，我们旨在通过计算机和体外研究来确定RSPO在结肠癌和乳腺癌中的作用。我们发现RSPO2和RSPO3高水平表达是结直肠癌 (CRC) 的一个亚型的特征。 RSPO2表达被发现是三阴性乳腺癌的一个子集的特征。在这两种情况下， RSPO表达的增加都与激活的 Wnt 信号基因表达谱相关。此外，敲低RSPO2会降低人乳腺癌细胞中的 Wnt 信号传导和增殖。 我们的研究结果表明并证实， RSPO2和RSPO3表达在结直肠腺癌和乳腺癌的子集中上调，并且两者都是针对此类癌症的有吸引力的可药物癌蛋白靶点。我们还描述了 CRC 中出现的新型融合转录本。