The TβRI promotes migration and metastasis through thrombospondin 1 and ITGAV in prostate cancer cells

• Published in: Oncogene 2024-11, Vol.43 (45), p.3321-3334
• Main Authors: Mu, Yabing, Wallenius, Anders, Zang, Guangxiang, Zhu, Shaochun, Rudolfsson, Stina, Aripaka, Karthik, Bergh, Anders, Mateus, André, Landström, Maréne
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 13/95; 14/105; 14/63; 631/67/1857; 692/53/2423; Animal research; Animals; Apoptosis; Castration; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Clonal deletion; CRISPR; Down-regulation; Extracellular matrix; Gene Expression Regulation, Neoplastic; Human Genetics; Humans; Internal Medicine; Male; Malignancy; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Neoplasm Metastasis; Oncology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Proteins; Proteomics; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Signal Transduction; siRNA; Thrombospondin; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Transforming growth factor-b1
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-03165-3

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.