High KPNA2 expression predicts poor prognosis in pathological T4 colorectal cancer by importing c-Myc into the nucleus to suppress p53-dependent p21 expression.

backgroundAdvanced colorectal cancer (CRC) is an aggressive subtype with a poor prognosis, highlighting the need for effective biomarkers. Karyopherin alpha 2 (KPNA2), a nuclear transport protein, facilitates the expression of oncogenic transcription factors (e.g. c-Myc). However, the clinical and functional implications of KPNA2 expression in pathological T4 (pT4) CRC in relation to the status of p53, a tumour suppressor, and c-Myc regulation remain unclear.

methodsKPNA2 and p53 expression in 78 surgically resected pT4 CRC samples was assessed using immunohistochemistry. Functional analyses were conducted using short hairpin RNA-mediated KPNA2 knockdown in p53-mutant, wild-type p53 and p53-null CRC cell lines.

resultsHigh KPNA2 expression significantly associated with aggressive tumour characteristics and poor prognosis, particularly in the wild-type p53 patient subgroup. Clinically, elevated KPNA2 levels correlated with increased distant metastasis rates and reduced disease-free survival, especially in patients with wild-type p53 receiving adjuvant chemotherapy. KPNA2 suppression reduced cell proliferation, inhibited xenograft tumour growth and selectively enhanced 5-FU and oxaliplatin sensitivity in wild-type p53 CRC cells. KPNA2 knockdown impaired nuclear c-Myc transport and induced p53-dependent p21 expression; however, these effects were not observed in p53-mutant or p53-null CRC.

conclusionsKPNA2 expression may serve as an important prognostic biomarker and therapeutic target in patients with locally advanced wild-type p53 CRC.