British journal of cancer · 2026
High KPNA2 expression predicts poor prognosis in pathological T4 colorectal cancer by importing c-Myc into the nucleus to suppress p53-dependent p21 expression.
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Dorjkhorloo Gendensuren, Erkhem-Ochir Bilguun, Shiraishi Takuya, Okami Haruka, Yamaguchi Arisa, Shioi Ikuma, Hosoi Nobuhiro, Komine Chika, Nakazawa Nobuhiro, Shibasaki Yuta, Okada Takuhisa, Osone Katsuya, Sano Akihiko, Sakai Makoto, Shibata Atsushi, Yokobori Takehiko, Shirabe Ken, Saeki Hiroshi
Аннотация
BACKGROUND: Advanced 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.
METHODS: KPNA2 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.
RESULTS: High 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.
CONCLUSIONS: KPNA2 expression may serve as an important prognostic biomarker and therapeutic target in patients with locally advanced wild-type p53 CRC.
METHODS: KPNA2 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.
RESULTS: High 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.
CONCLUSIONS: KPNA2 expression may serve as an important prognostic biomarker and therapeutic target in patients with locally advanced wild-type p53 CRC.