Open Access

Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential

  • Authors:
    • Yuhei Endo
    • Koichi Suzuki
    • Yasuaki Kimura
    • Sawako Tamaki
    • Hidetoshi Aizawa
    • Iku Abe
    • Fumiaki Watanabe
    • Takaharu Kato
    • Masaaki Saito
    • Kazushige Futsuhara
    • Hiroshi Noda
    • Fumio Konishi
    • Toshiki Rikiyama
  • View Affiliations

  • Published online on: April 7, 2022     https://doi.org/10.3892/ijo.2022.5351
  • Article Number: 61
  • Copyright: © Endo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Genome‑wide DNA hypomethylation is the most common molecular feature in human cancers associated with chromosomal instability (CIN), which is involved in the mechanisms that regulate pancreatic cancer (PC) metastasis. It was investigated whether genome‑wide DNA hypomethylation affects the phenotype in PC via CIN in vitro, and its significance on the biological behavior of PC was verified. The relative demethylation level (RDL) of long interspersed nucleotide element‑1 (LINE‑1) in human PC cell lines was used to characterize DNA hypomethylation using methylation‑specific quantitative (q)PCR. CIN was estimated by changes in chromosomal copy number using comparative genomic hybridization analysis. Abnormal segregation of chromosomes was assessed by immunocytochemistry, and the DNA damage response was evaluated using the number of anti‑γH2AX positive cells. Invasion ability was assessed using a Matrigel invasion assay. Clinical specimens from 49 patients with PC who underwent curative surgery were evaluated for a correlation of DNA hypomethylation with clinical outcome. Successful induction of genome‑wide DNA hypomethylation in PC cells led to copy number changes in specific chromosomal regions. The number of cells with abnormal segregation of chromosomes significantly increased with the number of anti‑γH2AX positive cells. The invasive potential of these cells also significantly increased. The occurrence of occult distant metastasis in the clinical specimens and receiver operating characteristic analysis clearly identified those who were and were not likely to have occult distant metastasis, with high LINE‑1 RDL significantly correlated with the presence of occult distant metastasis (P=0.035) and poor prognosis (P=0.048). The significance of genome‑wide DNA hypomethylation on the biological behavior of PC, which promotes a more invasive phenotype via CIN in vitro and predicts the susceptibility to occult distant metastasis and poor prognosis in patients with PC was revealed.
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June-2022
Volume 60 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Endo Y, Suzuki K, Kimura Y, Tamaki S, Aizawa H, Abe I, Watanabe F, Kato T, Saito M, Futsuhara K, Futsuhara K, et al: Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential. Int J Oncol 60: 61, 2022.
APA
Endo, Y., Suzuki, K., Kimura, Y., Tamaki, S., Aizawa, H., Abe, I. ... Rikiyama, T. (2022). Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential. International Journal of Oncology, 60, 61. https://doi.org/10.3892/ijo.2022.5351
MLA
Endo, Y., Suzuki, K., Kimura, Y., Tamaki, S., Aizawa, H., Abe, I., Watanabe, F., Kato, T., Saito, M., Futsuhara, K., Noda, H., Konishi, F., Rikiyama, T."Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential". International Journal of Oncology 60.6 (2022): 61.
Chicago
Endo, Y., Suzuki, K., Kimura, Y., Tamaki, S., Aizawa, H., Abe, I., Watanabe, F., Kato, T., Saito, M., Futsuhara, K., Noda, H., Konishi, F., Rikiyama, T."Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential". International Journal of Oncology 60, no. 6 (2022): 61. https://doi.org/10.3892/ijo.2022.5351