p15INK4B is an alternative marker of senescent tumor cells in colorectal cancer

Soon Sang Park; Young-Kyoung Lee; So Hyun Park; Su Bin Lim; Yong Won Choi; Jun Sang Shin; Young Hwa Kim; Jang-Hee Kim; Tae Jun Park

doi:10.1016/j.heliyon.2023.e13170

p15^INK4B is an alternative marker of senescent tumor cells in colorectal cancer

Heliyon. 2023 Jan 24;9(2):e13170. doi: 10.1016/j.heliyon.2023.e13170. eCollection 2023 Feb.

Authors

Soon Sang Park^{1

2

3}, Young-Kyoung Lee^{1

3}, So Hyun Park^{3

4}, Su Bin Lim^{1

2

3}, Yong Won Choi^{3

5}, Jun Sang Shin⁶, Young Hwa Kim³, Jang-Hee Kim^{3

4}, Tae Jun Park^{1

2

3}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 16499, South Korea.
² Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 16499, South Korea.
³ Inflamm-Aging Translational Research Center, Ajou University Medical Center, Suwon, 16499, South Korea.
⁴ Department of Pathology, Ajou University School of Medicine, Suwon, 16499, South Korea.
⁵ Department of Hematology and Oncology, Ajou University School of Medicine, Suwon, 16499, South Korea.
⁶ Department of Surgery, Ajou University School of Medicine, Suwon, 16499, South Korea.

Abstract

Senescent tumor cells are nonproliferating tumor cells which are closely related to cancer progression by secreting senescence-related molecules, called senescence-associated secreting phenotypes. Therefore, the presence of senescent tumor cells is considered a prognostic factor in various cancer types. Although senescence-associated β-galactosidase staining is considered the best marker for detection of senescent tumor cells, it can only be performed in fresh-frozen tissues. p16^INK4A, a cyclin-dependent inhibitor, has been used as an alternative marker to detect senescent tumor cells in formalin-fixed paraffin-embedded tissues. However, other reliable markers to detect senescent tumor cells is still lacking. In the present study, using public single-cell RNA-sequencing data, we found that p15^INK4B, a cyclin-dependent kinase inhibitor, is a novel marker for detection of senescent tumor cells. Moreover, p15^INK4B expression was positively correlated with that of p16^INK4A in colorectal cancer tissues. In in vitro studies, mRNA expression of p15^INK4B was increased together with that of p16^INK4A in H₂O₂- and therapy-induced cancer senescence models. However, the mRNA level of p15^INK4B did not increase in the oncogene-induced senescence model in primary colonic epithelial cells. In conclusion, p15^INK4B is a potential alternative marker for detection of senescent tumor cells together with conventional markers in advanced stages of colorectal cancer.

Keywords: CDK, cyclin dependent kinase; CRC, colorectal cancer; Cellular senescence; Colorectal cancer; FBS, fetal bovine serum; FFPE, formalin-fixed paraffin-embedded; GSEA, gene set enrichent analysis; H3K9me3, histone H3 lysine 9 trimethylation; IHC, immunohistochemistry; SA-β-Gal, senescence-associated β-galactosidase; STC, senescent tumor cell; Senescence marker; Senescent tumor cells; p15INK4B; p16INK4A; scRNA-seq, single cell RNA sequencing.