Article ID: 2025.01036
The pre-mRNAs splicing is important mechanisms of hepatocellular carcinoma (HCC) progression. Hence, this study aimed to explore the function and corresponding mechanisms of small nuclear ribonucleoprotein polypeptide A (SNRPA), a vital RNAs splicing molecule, in HCC. Here, the University of Alabama at Birmingham CANcer data analysis portal (UALCAN), western blotting, and immunohistochemistry indicated that SNRPA levels were elevated in HCC tissues. Moreover, high expression of SNRPA was correlated with unfavorable clinicopathologic features and poor survival in HCC patients. A series of in vitro and in vivo gain/loss-of-function experiments reported that SNRPA promoted the proliferation of HCC cells. Integrated nanopore full-length cDNA sequencing and RNA-binding protein immunoprecipitation sequencing revealed that B7 homologue 6 (B7-H6) was a potential target of SNRPA. Subsequently, western blotting and flow cytometry showed that SNRPA activated B7-H6-STAT3/AKT signaling axis in HCC cells with promotion of G1-S transition in the cell cycle and inhibition of cell apoptosis. Mechanistically, RNA-binding protein immunoprecipitation and polymerase chain reaction with using exon-exon and exon-intron junction primers revealed that SNRPA facilitated B7-H6 pre-mRNA maturation by binding to it directly and contributing to its intron 2 splicing. Moreover, drug sensitivity test found that SNRPA induced HCC cell resistance to lenvatinib. Finally, restoration experiments demonstrated that the effects of SNRPA on HCC cells relied on B7- H6 expression. Taken together, SNRPA promotes HCC growth and lenvatinib resistance via B7-H6-STAT3/AKT axis through facilitating B7-H6 pre-mRNA maturation by maintaining its intron 2 splicing. Thus, SNRPA may be a promising target for HCC therapy and lenvatinib resistance reversion.
