Int J Biol Sci 2022; 18(5):2032-2046. doi:10.7150/ijbs.68960 This issue
1. Department of breast surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
2. Department of medical oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
3. Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
4. Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
*These authors contributed equally to this paper.
Background: The progressive, multifactorial and multistep dynamic process of metastasis is the primary cause of breast cancer (BC) lethality. PROX1 (Prospero-related homeobox 1), as a type of transcription factor that plays a key role in the formation of lymphatic vessels in animal embryonic development, has been proven to promote or suppress cancer in a variety of malignant tumors. However, molecular mechanisms behind PROX1 induced breast cancer metastases remain elusive.
Methods: Changes of PROX1 expression and clinical significance of PROX1 in BC were evaluated by BC tissue, as well as public database. The functional role of PROX1 in metastases BC was analyzed by transwell assay in vitro, and by lung metastases model of nude mice in vivo via lentivirus mediated knockdown assays. Mechanism studies were performed by public database screening, western blot and PCR assay, immunoprecipitation, immunofluorescence staining and luciferase promoter assays.
Results: In this study, we found that PROX1 was upregulated in breast cancer tissues; increased PROX1 expression in breast cancer was associated with tumor size, lymph node metastasis, ER and PR status. Meanwhile, PROX1 can promote breast cancer invasion and metastasis in vitro and in vivo. Furthermore, PROX1 can interact with hnRNPK to activate WNT/β-catenin signaling in breast cancer cells. Moreover, the interaction of PROX1 and hnRNPK inhibits the ubiquitination of hnRNPK, and subsequently activates WNT pathway to promote the invasion and metastasis of breast cancer.
Conclusions: In conclusion, our findings indicated PROX1 contributes to breast cancer EMT and metastasis and serves as a candidate diagnostic biomarker and promising therapeutic target for breast cancer.
Keywords: PROX1, breast cancer, EMT, WNT signaling, hnRNPK