Abstract
Background & Aims: There are notable gender disparities in the incidence and mortality rates of hepatocellular carcinoma (HCC). Women have comparatively lower incidence and mortality rates of HCC than men. Circular RNAs (circRNAs) have emerged as pivotal regulators in HCC biology, yet their functions in patients of different genders remain unexplored. In this investigation, we aimed to identify the significant circRNA between male and female patients, and to explore its functional implications and underlying molecular mechanisms in the progression of HCC.
Methods: First, we used microarray and found circRNA transcripts that are differently expressed in men and women patients with HCC. Then, through bioinformatics analysis, we identified a significant circular RNA KIF18A, and validated its expression in cells. And we analyzed the differentially expressed transcriptome genes between HCC cells with circKIF18A knockout and normal cells. Using bioinformatics methods, we identified pathways and proteins that may be associated with circKIF18A regulation. Meanwhile, we performed cell behavioral experiments to demonstrate the knockdown of circRNAs’ implication on HCC.
Results: A novel circRNA named circKIF18A was found upregulated in males with HCC compared with females, promoting cell proliferation and migration, while inhibiting apoptosis. We performed extensive bioinformatic analyses, we discovered that the estrogen receptor pathway might be involved in KIF18A regulation of hepatocellular carcinoma. Within this pathway, KPNA2 was identified as the most significantly differentially expressed protein, and it is associated with the prognosis of hepatocellular carcinoma.
Conclusions: Our working hypothesis suggests that circKIF18A may orchestrate KPNA2 through the estrogen signaling pathway, demonstrating their combined significance as promoting roles in the initiation and progression of HCC. Meanwhile, this finding may provide potential evidence for the observed disparities in incidence and mortality rates of HCC between male and female patients; however, further experimental validation is required.