High extracellular matrix stiffness promotes the metastasis of nasopharyngeal carcinoma through STAT3/FGF1 positive feedback regulation activated by JAK2

The stiffness of the extracellular matrix (EM) is known to be associated with tumor metastasis. This study aims to clarify the function and mechanisms of EM stiffness in nasopharyngeal carcinoma (NPC) and to provide a potential therapeutic target for patients with NPC. The NPC cell lines were cultured under varying stiffnesses. Plate cloning, Transwell assays and scratch tests were conducted to compare the phenotypes. Transcriptome sequencing and enrichment analysis were performed to explore the key molecules and the downstream signaling pathways, which were verified via in vitro and in vivo experiments. Our study showed that the NPC cells cultured on a stiff substrate (50 ​kPa) had greater colony formation, invasion and migration abilities than those cultured on a soft substrate. Transcriptome sequencing showed that a stiff environment induced high expression of fibroblast growth factor 1 (FGF1), which suggested a poor prognosis in various malignancies. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway played an important role in NPC metastasis activated by the FGF1 autocrine pathway in a stiff environment. The increased FGF1 expression was regulated by the transcription factor STAT3, and a positive feedback regulation between them was observed. The use of the JAK inhibitor Ruxolitinib and JAK2 interference inhibited the activation of STAT3. In conclusion, JAK2 activates STAT3/FGF1 positive feedback regulation and promotes NPC metastasis via the PI3K/Akt signaling pathway in a high-stiffness environment. Hence, FGF1 can be used as a potential therapeutic target for patients with NPC.