PDF(Pubmed)
Abstract：
Over the past few decades, the worldwide incidence of cutaneous melanoma, a malignant neoplasm arising from melanocytes, has been increasing markedly, leading to the highest rate of skin cancer-related deaths. While localized tumors are easily removed by excision surgery, late-stage metastatic melanomas are refractory to treatment and exhibit a poor prognosis. Consequently, unraveling the molecular mechanisms underlying melanoma tumorigenesis and metastasis is crucial for developing novel targeted therapies. We found that the multiple endocrine neoplasia type 1 (MEN1) gene product Menin is required for the transforming growth factor beta (TGFβ) signaling pathway to induce cell growth arrest and apoptosis in vitro and prevent tumorigenesis in vivo in preclinical xenograft models of melanoma. We further identified point mutations in two MEN1 family members affected by melanoma that led to proteasomal degradation of the MEN1 gene product and to a loss of TGFβ signaling. Interestingly, blocking the proteasome degradation pathway using an FDA-approved drug and RNAi targeting could efficiently restore MEN1 expression and TGFβ transcriptional responses. Together, these results provide new potential therapeutic strategies and patient stratification for the treatment of cutaneous melanoma.
摘要：
在过去的几十年里，皮肤黑色素瘤的全球发病率，由黑素细胞引起的恶性肿瘤，明显增加，导致皮肤癌相关死亡率最高。虽然局部肿瘤很容易通过切除手术切除，晚期转移性黑色素瘤难以治疗且预后不良.因此,揭示黑素瘤肿瘤发生和转移的分子机制对于开发新型靶向治疗至关重要。我们发现，在黑色素瘤的临床前异种移植模型中，转化生长因子β（TGFβ）信号通路需要多种内分泌瘤1型（MEN1）基因产物Menin在体外诱导细胞生长停滞和凋亡并防止体内肿瘤发生。我们进一步鉴定了受黑色素瘤影响的两个MEN1家族成员中的点突变，这些点突变导致MEN1基因产物的蛋白酶体降解和TGFβ信号传导的丧失。有趣的是,使用FDA批准的药物和RNAi靶向阻断蛋白酶体降解途径可以有效恢复MEN1表达和TGFβ转录反应。一起,这些结果为皮肤黑色素瘤的治疗提供了新的潜在治疗策略和患者分层.
