State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Int J Cancer. 2021 Jun 15;148(12):3060-3070. doi: 10.1002/ijc.33494. Epub 2021 Mar 6.
The HOX genes are a group of highly conserved Homeobox-containing genes that control the body plan organization during development. However, their contributions to tumorigenesis and tumor progression remain uncertain and controversial. Here we provided evidence of tumor-suppressive activity of HOXD13 in prostate cancer. HOXD13 depletion contributes to more aggressiveness of prostate cancer cells in vitro and in vivo. These effects were corroborated in a metastatic mice model, where we observed more bone metastatic lesions formed by prostate cancer cells with HOXD13 ablation. Mechanistically, HOXD13 prevents BMP4-induced epithelial-mesenchymal transition (EMT) by inhibiting mothers against decapentaplegic homolog 1 (SMAD1) transcription. Both bioinformation and our tissue microarray cohort data show that HOXD13 expression inversely correlated in advanced prostate cancer patient specimens. Our findings establish HOXD13 as a negative regulator of prostate cancer progression and metastasis by preventing BMP4/SMAD1 signaling, and potentially suggest new strategies for targeting metastatic prostate cancer.
HOX 基因是一组高度保守的同源盒基因，它们在发育过程中控制着身体形态的组织。然而，它们在肿瘤发生和肿瘤进展中的作用仍不确定和有争议。在这里，我们提供了 HOXD13 在前列腺癌中具有肿瘤抑制活性的证据。HOXD13 的缺失有助于前列腺癌细胞在体外和体内的侵袭性增加。这些效应在转移性小鼠模型中得到了证实，我们观察到具有 HOXD13 缺失的前列腺癌细胞形成了更多的骨转移病灶。在机制上，HOXD13 通过抑制母系抗 decapentaplegic 同源物 1（SMAD1）转录来阻止 BMP4 诱导的上皮间质转化（EMT）。生物信息学和我们的组织微阵列队列数据都表明，HOXD13 的表达在晚期前列腺癌患者标本中呈负相关。我们的研究结果确立了 HOXD13 通过阻止 BMP4/SMAD1 信号转导作为前列腺癌进展和转移的负调节剂，并且可能为靶向转移性前列腺癌提供了新的策略。
