Harada-Kagitani Sakurako, Kouchi Yusuke, Shinomiya Yoshiki, Kodama Makoto, Ohira Gaku, Matsubara Hisahiro, Ikeda Jun-Ichiro, Kishimoto Takashi
Department of Molecular Pathology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Pathology, Chiba University Hospital, Chiba, Japan.
Department of Pathology, Tokyo Yamate Medical Center, Tokyo, Japan.
Lab Invest. 2024 Jul;104(7):102075. doi: 10.1016/j.labinv.2024.102075. Epub 2024 May 9.
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.
角蛋白（KRTs）是上皮细胞中的中间丝蛋白，对细胞骨架组织很重要。KRT6A被归类为II型角蛋白，通常在复层鳞状上皮和鳞状细胞癌中表达。关于KRT6A在腺癌中的表达和作用知之甚少。我们研究了KRT6A在结直肠癌中的临床病理和分子生物学意义。对在我们机构接受治疗的结直肠癌病例进行免疫染色显示，KRT6A在浸润前沿的表达明显强于肿瘤中心（P <.0001）。高KRT6A表达病例（n = 47）往往具有较高的芽生分级，预后明显较差。多变量分析显示，KRT6A表达状态是总生存期（P =.0004）、疾病特异性生存期（P =.0097）和无进展生存期（P =.0033）的独立预后因素。KRT6A与患者预后之间的相关性也在一个已发表数据集中的外部队列中得到验证。为了在体外确定KRT6A的功能，在3种结肠癌细胞系（DLD-1、SW620和HCT 116）中过表达KRT6A。KRT6A过表达增加了DLD-1细胞的迁移和侵袭能力，但在SW620和HCT116细胞中没有。在三维球状体形成培养中，KRT6A的表达增强了DLD-1细胞球状体周围的不规则突起。我们在本研究中的发现表明，KRT6A表达是结直肠癌的一个有价值的预后标志物，并且KRT6A可能参与了结直肠癌侵袭区域进展的分子机制。
