Metastatic prostate cancer (mPCa) is a leading cause of mortality, partly due to its resistance to anti-androgens like enzalutamide. Snail can promote this resistance by increasing full-length AR and AR-V7. High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein upstream of Snail, is crucial in proliferation and epithelial–mesenchymal transition (EMT). This study examines HMGA2’s role in enzalutamide resistance. LNCaP and 22Rv1 cells overexpressing wild-type HMGA2, but not truncated HMGA2, showed EMT. Both variants led to a decreased sensitivity to enzalutamide but not alisertib compared to Neo control cells. The overexpression of HMGA2 did not alter AR expression. Enzalutamide-resistant C4-2B cells (C4-2B MDVR) had higher HMGA2 and AR/AR variant expression than enzalutamide-sensitive C4-2B cells but remained sensitive to alisertib. The HMGA2 knockdown in C4-2B MDVR cells increased sensitivity to both enzalutamide and alisertib without changing AR expression. A clinical analysis via cBioPortal revealed HMGA2 alterations in 3% and AR alterations in 59% of patients. The HMGA2 changes were linked to treatments like enzalutamide, abiraterone, or alisertib, with amplifications more prevalent in bone, lymph node, and liver metastases. Conclusively, HMGA2 is a potential biomarker for enzalutamide resistance in mPCa, independent of Snail and AR signaling, and alisertib may be an effective treatment for mPCa that expresses HMGA2.
转移性前列腺癌（mPCa）是导致死亡的主要原因之一，部分原因在于其对恩杂鲁胺等抗雄激素药物的耐药性。Snail可通过增加全长雄激素受体（AR）及AR-V7的表达促进此类耐药。高迁移率族蛋白AT-hook 2（HMGA2）作为Snail上游的DNA结合蛋白，在细胞增殖和上皮-间质转化（EMT）过程中起关键作用。本研究探讨HMGA2在恩杂鲁胺耐药中的作用机制。过表达野生型HMGA2（而非截短型HMGA2）的LNCaP和22Rv1细胞表现出EMT特征。与Neo对照组相比，两种HMGA2变异体均导致细胞对恩杂鲁胺敏感性降低，但对阿利塞特的敏感性未受影响。HMGA2过表达未改变AR表达水平。恩杂鲁胺耐药细胞株C4-2B MDVR较敏感株C4-2B表现出更高的HMGA2及AR/AR变异体表达，但对阿利塞特仍保持敏感性。敲低C4-2B MDVR细胞中的HMGA2可增强其对恩杂鲁胺和阿利塞特的敏感性，且不改变AR表达。通过cBioPortal进行的临床数据分析显示，3%患者存在HMGA2基因改变，59%存在AR基因改变。HMGA2改变与恩杂鲁胺、阿比特龙或阿利塞特治疗相关，其扩增在骨、淋巴结和肝转移灶中更为普遍。结论表明，HMGA2可作为mPCa恩杂鲁胺耐药的潜在生物标志物，其作用独立于Snail和AR信号通路，而阿利塞特可能成为治疗HMGA2阳性mPCa的有效方案。
肿瘤(癌症)患者之家