PRRX1 isoform PRRX1A promotes hepatocellular carcinoma progression through the ANTXR1–PI3K/AKT/mTOR signaling

Abstract Proteomic analysis of hepatocellular carcinoma (HCC) and paired adjacent non-tumor tissues revealed a significant increase in ANTXR1 phosphorylation in HCC samples. Using the GEPIA online tool, we identified a strong positive correlation between ANTXR1 and PRRX1 in HCC tissues. Moreover, the transcriptional level of PRRX1 was closely associated with overall survival in HCC patients. PRRX1, a homeodomain transcription factor, exists in two subtypes: PRRX1A and PRRX1B. These subtypes have been implicated in several malignancies, including pancreatic, breast, and lung cancers; however, their roles in HCC remain unclear.Immunohistochemical (IHC) analysis of 175 paired clinical samples demonstrated significant PRRX1 overexpression in HCC tissues compared to adjacent tissues. IIndividual overexpression of PRRX1 isoforms demonstrated that PRRX1A, but not PRRX1B, markedly promoted hepatocellular carcinoma cell proliferation.Furthermore, knockdown of PRRX1 resulted in significant downregulation of ANTXR1 protein levels in both Huh-7 and SK-HEP-1 cell lines, suggesting that PRRX1 positively regulates ANTXR1. Notably, only PRRX1A overexpression rescued the suppressed ANTXR1 transcription and altered its subcellular localization following PRRX1 knockdown.Mechanistic investigations revealed that both PRRX1 and ANTXR1 contribute to tumor progression through activation of the PI3K/Akt/mTOR signaling pathway. In summary, our results indicate that PRRX1, particularly the PRRX1A subtype, acts as a critical promoter in hepatocellular carcinoma progression.