Department of Medical Bioscience, Umeå University, Umeå, Sweden.
Department of Chemistry, Umeå University, Umeå, Sweden.
Oncogene. 2024 Nov;43(45):3321-3334. doi: 10.1038/s41388-024-03165-3. Epub 2024 Sep 20.
TGFβ potently modifies the extracellular matrix (ECM), which is thought to favor tumor cell invasion. However, the mechanism whereby the cancer cells employ the ECM proteins to facilitate their motility is largely unknown. In this study we used RNA-seq and proteomic analysis to examine the proteins secreted by castration-resistant prostate cancer (CRPC) cells upon TGFβ treatment and found that thrombospondin 1 (THBS1) was observed to be one of the predominant proteins. The CRISPR Cas9, or siRNA techniques was used to downregulate TGFβ type I receptor (TβRI) to interfere with TGFβ signaling in various cancer cells in vitro. The interaction of ECM proteins with the TβRI in the migratory prostate cancer cells in response to TGFβ1 was demonstrated by several different techniques to reveal that THBS1 mediates cell migration by interacting with integrin subunit alpha V (ITGAV) and TβRI. Deletion of TβRI or THBS1 in cancer cells prevented their migration and invasion. THBS1 belongs to a group of tumorigenic ECM proteins induced via TGFβ signaling in CRPC cells, and high expression of THBS1 in human prostate cancer tissues correlated with the degree of malignancy. TGFβ-induced production of THBS1 through TβRI facilitates the invasion and metastasis of CRPC cells as shown in vivo xenograft animal experiments.
TGFβ 能强烈地修饰细胞外基质（ECM），这被认为有利于肿瘤细胞的侵袭。然而，癌细胞利用 ECM 蛋白来促进其运动的机制在很大程度上尚不清楚。在这项研究中，我们使用 RNA-seq 和蛋白质组学分析来检查去势抵抗性前列腺癌（CRPC）细胞在 TGFβ 处理后分泌的蛋白质，发现血小板反应蛋白 1（THBS1）被观察到是主要蛋白质之一。CRISPR Cas9 或 siRNA 技术被用于下调 TGFβ 型 I 受体（TβRI），以干扰体外各种癌细胞中的 TGFβ 信号。通过几种不同的技术证明了 ECM 蛋白与迁移的前列腺癌细胞中的 TβRI 相互作用，以响应 TGFβ1，表明 THBS1 通过与整合素亚基 alpha V（ITGAV）和 TβRI 相互作用来介导细胞迁移。在癌细胞中删除 TβRI 或 THBS1 可阻止其迁移和侵袭。THBS1 属于一组通过 TGFβ 信号在 CRPC 细胞中诱导的致瘤性 ECM 蛋白，并且在人类前列腺癌组织中 THBS1 的高表达与恶性程度相关。TGFβ 通过 TβRI 诱导 THBS1 的产生，促进了 CRPC 细胞的侵袭和转移，如体内异种移植动物实验所示。
