Hao Qinggang, Bai Yan, Guan Ruiqi, Dong Rui, Bai Weiyu, Hamdy Hayam, Wang Liqiong, Meng Mingyao, Sun Yan, Shen Junling, Sun Jianwei
Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, 650504, China.
Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, 650051, China.
Sci China Life Sci. 2025 May 8. doi: 10.1007/s11427-024-2884-2.
Retromer is a conserved endosomal trafficking complex responsible for recycling transmembrane protein cargoes. Membrane-type I matrix metalloproteinase (MT1-MMP), a well-studied membrane-type metalloprotease, is highly expressed in metastatic melanomas. Previously, we reported that inducing MT1-MMP perinuclear localization and inhibiting MT1-MMP membrane localization significantly reduce melanoma metastasis. However, the regulation of MT1-MMP subcellular localization and recycling is still largely unknown. Here, we performed target gene shRNA screening and found that shRNA targeting the Retromer complex subunit vacuolar protein sorting 35 (VPS35) inhibited MT1-MMP membrane localization and induced its perinuclear localization. We found that inhibiting VPS35/Retromer decreased MT1-MMP recycling and increased MT1-MMP-lysosome localization, which significantly affected the stability of MT1-MMP. Furthermore, our results indicated that VPS35/Retromer regulates the transcription of MT1-MMP by activating interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) inflammatory signaling pathway. Tissue microarray analysis indicated that VPS35/Retromer positively correlated with MT1-MMP levels and distant metastasis. Xenograft experiments showed that targeting VPS35/Retromer significantly inhibited melanoma lung metastasis, which is dependent on MT1-MMP. Our results implicate the importance of VPS35/Retromer in metastatic dissemination. Our study suggests that targeting the VPS35/Retromer-MT1-MMP axis will contribute to inhibiting the metastasis of melanoma.
回收体是一种保守的内体运输复合物，负责跨膜蛋白货物的回收。膜型I基质金属蛋白酶（MT1-MMP）是一种研究充分的膜型金属蛋白酶，在转移性黑色素瘤中高度表达。此前，我们报道诱导MT1-MMP核周定位并抑制MT1-MMP膜定位可显著减少黑色素瘤转移。然而，MT1-MMP亚细胞定位和回收的调控在很大程度上仍不清楚。在此，我们进行了靶基因shRNA筛选，发现靶向回收体复合物亚基液泡蛋白分选35（VPS35）的shRNA抑制了MT1-MMP膜定位并诱导其核周定位。我们发现抑制VPS35/回收体会减少MT1-MMP的回收，并增加MT1-MMP-溶酶体定位，这显著影响了MT1-MMP的稳定性。此外，我们的结果表明VPS35/回收体通过激活白细胞介素-6（IL-6）/信号转导和转录激活因子3（STAT3）炎症信号通路来调节MT1-MMP的转录。组织微阵列分析表明VPS35/回收体与MT1-MMP水平和远处转移呈正相关。异种移植实验表明，靶向VPS35/回收体可显著抑制依赖于MT1-MMP的黑色素瘤肺转移。我们的结果表明VPS35/回收体在转移性播散中的重要性。我们的研究表明，靶向VPS35/回收体-MT1-MMP轴将有助于抑制黑色素瘤的转移。
