PRRX1 Regulates Cellular Phenotype Plasticity and Dormancy of Head and Neck Squamous Cell Carcinoma Through miR-642b-3p

Abstract

BACKGROUND: Dormancy is one characteristic of cancer cells to make patients remain asymptomatic before metastasis and relapse, which is closely related to the survival rate of cancer patients, including head and neck squamous cell carcinoma (HNSCC). PRRX1 has previously been implicated in the invasion and metastasis of the epithelial-mesenchymal transition (EMT) process in different types of human carcinoma. However, whether PRRX1 can regulate cancer dormancy and its reactivation, leading to the migration and invasion of HNSCC cells, remains elusive. The aim of this study was to determine the role of PRRX1 in cellular phenotype plasticity and cancer dormancy of HNSCC cells and its association with miRNAs in HNSCC. METHODS: The expression of PRRX1 was detected by immunohistochemical staining in primary HNSCC samples and the metastatic lymph nodes. Meanwhile, the role of PRRX1 and its relationship with miR-642b-3p and EMT in cellular phenotype plasticity and cancer dormancy of HNSCC were investigated in vitro and in vivo. RESULTS: PRRX1 was significantly higher at the invasive front of HNSCC samples compared with the metastatic lymph nodes, and such switch process was accompanied by the cellular phenotype plasticity and cell dormancy activation. In HNSCC cell lines, PRRX1 positively promoted the expression of known EMT inducers and cooperated with activated TGF-β1 to contribute to EMT and migration and invasion of HNSCC cells. Then, we found that overexpression of miR-642b-3p, one of the most significantly downregulated miRNAs in PRRX1-overexpressed cells, significantly reduced the migration and invasion, and increased cell proliferation and apoptosis. And miR-642b-3p restoration reversed PRRX1-induced cell dormancy and EMT of HNSCC cells through TGF-β2 and p38. Finally, we demonstrated that overexpressed PRRX1 was closely correlated with miR-642b-3p downregulation and the upregulation of TGF-β2 and p38 in a xenograft model of HNSCC. CONCLUSIONS: Our findings showed that PRRX1 may be one of the main driving forces for the cellular phenotype plasticity and tumor dormancy of HNSCC. Therefore, we can raise the possibility that EMT may help to keep cancer cell in dormant state and mesenchymal-epithelial transition may resurge dormancy in HNSCC.

Aberrant expression of vasculogenic mimicry, PRRX1, and CIP2A in clear cell renal cell carcinoma and its clinicopathological significance

“…Expression of the transcription factor PRRX1 as a transcription factor is related to embryonic limb development, vascular differentiation and skeletal muscle development, [30,31] and it has been suggested that transforming growth factor-b and microRNA regulate expression of PRRX1. [32–34] However, details are lacking and further analysis is required to uncover the signaling network regulating PRRX1. In this study, we observed that the level of PRRX1 expression was lower in CCRCC tissues than in adjacent tissues.…”

The rs7911488-T allele promotes the growth and metastasis of colorectal cancer through modulating miR-1307/PRRX1

“…In gastric cancer, PRRX1 stimulates translocation of β-catenin into the nucleus upon Wnt pathway activation, thereby inducing c-Myc and consequent EMT of tumor cells 39 . In head and neck squamous cell carcinoma cells, PRRX1 has a synergistic effect with the activated TGF-β1 on the promotion of the migration and invasion of cancer cells, and regulates the phenotypic plasticity and dormancy of tumor cells 40 . These findings suggest that PRRX1 plays divergent roles in different types of tumors.…”

“…In squamous cell carcinoma, PRRX1 expression is evidently negatively correlated with miR-642b-3p, which is downregulated in PRRX1-overexpressed cells. Reinforced expression of miR-642b-3p can reverse the PRRX1-promoted EMT and cell proliferation 40 . In lung cancer, PRRX1 knockdown inhibits the expression of Caspase 3, caspase 9, Apaf-1, and cytochrome C, leading to enhanced anti-apoptotic capacity and resistance to cisplatin in lung cancer cells 41 .…”

Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy

“…One such strategy takes advantage of the fact that TGFβ is synthesized as a latent form that can be activated by binding to specific integrin receptors that are restricted in where and when they perform this function, and that can only activate TGFb1 and 3 (Robertson et al, 2015). Blockade of integrins, that do not affect activation of TGFβ2 homodimers, may be advantageous in avoiding possible outgrowth of dormant metastatic tumor cells that are growth inhibited by TGFβ2 in bone and lymph nodes (Bragado et al, 2013;Jiang et al, 2019;Yumoto et al, 2016).…”