School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou 450001, China.
School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Cell Rep. 2021 Jul 27;36(4):109431. doi: 10.1016/j.celrep.2021.109431.
Colorectal cancer (CRC) is one of the most common cancers worldwide, in which adenomatous polyposis coli (APC) mutations are frequently and uniquely observed. Here we find that cis-HOX (circular RNA stabilizing HOXC10) is robustly expressed in colorectal tumor-initiating cells (TICs). cis-HOX knockout decreases colorectal TIC numbers and impairs the self-renewal, tumorigenesis, and metastatic capacities of TICs, whereas cis-HOX overexpression drives colorectal TIC self-renewal and metastasis. Mechanistically, cis-HOX binds to HOXC10 mRNA to attenuate its decay through blocking the K-homology splicing regulatory protein (KSRP)-binding sequence of HOXC10 3' UTR. HOXC10 is highly expressed in colorectal tumors and TICs and triggers Wnt/β-catenin activation by activating FZD3 expression. HOXC10 inhibitor salinomycin exerts efficient therapeutic effects in APC-wild-type colorectal tumors, but not in tumors with APC nonsense mutations. Therefore, the cis-HOX-HOXC10 pathway drives colorectal tumorigenesis, stemness, and metastasis and serves as a potential therapeutic target for APC-wild-type colorectal tumors.
结直肠癌（CRC）是全球最常见的癌症之一，其中常观察到腺瘤性结肠息肉病（APC）突变。在这里，我们发现顺式-HOX（环状 RNA 稳定 HOXC10）在结直肠肿瘤起始细胞（TICs）中强烈表达。顺式-HOX 敲除可减少结直肠 TIC 的数量，并损害 TIC 的自我更新、致瘤和转移能力，而顺式-HOX 过表达则驱动结直肠 TIC 的自我更新和转移。在机制上，顺式-HOX 与 HOXC10 mRNA 结合，通过阻止 HOXC10 3'UTR 的 K-homology 剪接调节蛋白（KSRP）结合序列来减弱其衰减。HOXC10 在结直肠肿瘤和 TICs 中高表达，并通过激活 FZD3 表达来触发 Wnt/β-catenin 激活。HOXC10 抑制剂硫酸黏菌素在 APC 野生型结直肠肿瘤中具有有效的治疗效果，但在 APC 无义突变的肿瘤中没有效果。因此，顺式-HOX-HOXC10 通路驱动结直肠肿瘤发生、干性和转移，是 APC 野生型结直肠肿瘤的潜在治疗靶点。
