Centromere protein I promotes hepatocellular carcinoma progression by activating PI3K/AKT/mTOR-CDK2 cascade.

BACKGROUND

Hepatocellular carcinoma (HCC) is characterized by high recurrence rates and limited targeted therapies. Centromere protein I (CENPI), a core kinetochore component linked to chromosomal instability, is dysregulated in multiple malignancies, yet its role and mechanism in HCC progression remain incompletely elucidated.

METHODS

CENPI expression was quantified in paired human HCC tissues and orthotopic rat HCC models via immunohistochemistry (IHC) and western blot (WB). Gain- and loss-of-function assays were performed in HepG2 cells and validated in Hep3B cells to evaluate the effects of CENPI modulation on cell proliferation, migration, invasion, apoptosis, and cell cycle dynamics. Mechanistic analyses included pathway enrichment and WB, with validation via rapamycin in HepG2 cells and LY294002 in Hep3B cells. In vivo tumor growth and signaling alterations were assessed in orthotopic HCC models following CENPI silencing.

RESULTS

CENPI was upregulated in HCC tissues and orthotopic tumors, correlating with poor survival. CENPI depletion suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while enhancing apoptosis and inducing G1 arrest; overexpression was pro-oncogenic. Mechanistically, CENPI activated the PI3K/AKT/mTOR-CDK2 axis, upregulating CDK2, and modulating EMT markers. Rapamycin abrogated CENPI-induced oncogenic signaling in vitro, and CENPI silencing reduced in vivo tumor burden by 65% while suppressing the pathway and EMT.

CONCLUSION

CENPI may function as an oncogenic regulator in HCC through activation of the PI3K/AKT/mTOR-CDK2 cascade, linking cell cycle progression to EMT-associated invasiveness. These findings provide a preclinical rationale for further evaluating CENPI and its related signaling axis as potential prognostic and therapeutic targets in broader HCC models and clinical cohorts.