Keratin 6A Is Expressed at the Invasive Front and Enhances the Progression of Colorectal Cancer

Sakurako Harada-Kagitani; Yusuke Kouchi; Yoshiki Shinomiya; Makoto Kodama; Gaku Ohira; Hisahiro Matsubara; Jun-Ichiro Ikeda; Takashi Kishimoto

doi:10.1016/j.labinv.2024.102075

Keratin 6A Is Expressed at the Invasive Front and Enhances the Progression of Colorectal Cancer

Lab Invest. 2024 May 9;104(7):102075. doi: 10.1016/j.labinv.2024.102075. Online ahead of print.

Authors

Sakurako Harada-Kagitani¹, Yusuke Kouchi¹, Yoshiki Shinomiya¹, Makoto Kodama², Gaku Ohira³, Hisahiro Matsubara³, Jun-Ichiro Ikeda⁴, Takashi Kishimoto⁵

Affiliations

¹ Department of Molecular Pathology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Pathology, Chiba University Hospital, Chiba, Japan.
² Department of Pathology, Tokyo Yamate Medical Center, Tokyo, Japan.
³ Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
⁴ Department of Pathology, Chiba University Hospital, Chiba, Japan; Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
⁵ Department of Molecular Pathology, Chiba University Graduate School of Medicine, Chiba, Japan. Electronic address: tkishi@faculty.chiba-u.jp.

PMID: 38729352
DOI: 10.1016/j.labinv.2024.102075

Abstract

Keratins (KRTs) are intermediate filament proteins in epithelial cells, and they are important for cytoskeletal organization. KRT6A, classified as a type II KRT, is normally expressed in stratified squamous epithelium and squamous cell carcinomas. Little is known about the expression and role of KRT6A in adenocarcinomas. We investigated the clinicopathologic and molecular biological significance of KRT6A in colorectal adenocarcinoma. Immunostaining of colorectal adenocarcinoma cases treated at our institution demonstrated that KRT6A showed significantly stronger expression at the invasive front than that at the tumor center (P < .0001). The high KRT6A-expression cases (n = 47) tended to have a high budding grade associated with significantly worse prognoses. A multivariate analysis revealed that the KRT6A expression status was an independent prognostic factor for overall survival (P = .0004), disease-specific survival (P = .0097), and progression-free survival (P = .0033). The correlation between KRT6A and patient prognoses was also validated in an external cohort from a published data set. To determine the function of KRT6A in vitro, KRT6A was overexpressed in 3 colon cancer cell lines: DLD-1, SW620, and HCT 116. KRT6A overexpression increased migration and invasion in DLD-1 but did not in SW620 and HCT116. In 3-dimensional sphere-forming culture, KRT6A expression enhanced the irregular protrusion around the spheroid in DLD-1. Our findings in this study indicated that KRT6A expression is a valuable prognostic marker of colorectal cancer and KRT6A may be involved the molecular mechanism in the progression of invasive areas of colorectal cancer.

Keywords: 3D culture; KRT6A; colorectal cancer; spheroid formation; tumor budding.