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

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Laboratory Investigation Pub Date : 2024-05-09 DOI:10.1016/j.labinv.2024.102075

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

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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.

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角蛋白 6A 在侵袭前沿表达，并促进结直肠癌的进展。

角蛋白是上皮细胞的中间丝蛋白，对细胞骨架组织非常重要。角蛋白 6A（KRT6A）被归类为 II 型角蛋白，通常在分层鳞状上皮和鳞状细胞癌中表达。人们对 KRT6A 在腺癌中的表达和作用知之甚少。我们研究了 KRT6A 在结直肠腺癌中的临床病理学和分子生物学意义。对我院结直肠腺癌病例的免疫染色显示，KRT6A在浸润前沿的表达明显强于肿瘤中心（p < 0.0001）。高 KRT6A 表达的病例（n = 47）往往具有较高的萌芽分级，预后明显较差。多变量分析显示，KRT6A表达状态是总生存期（p = 0.0004）、疾病特异性生存期（p = 0.0097）和无进展生存期（p = 0.0033）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的外部队列中得到了验证。为了确定 KRT6A 在体外的功能，KRT6A 在三种结肠癌细胞系 DLD-1、SW620 和 HCT 116 中过度表达。过表达 KRT6A 增加了 DLD-1 的迁移和侵袭，但没有增加 SW620 和 HCT116 的迁移和侵袭。在三维球形培养中，KRT6A的表达增强了DLD-1球体周围的不规则突起。本研究结果表明，KRT6A 的表达是结直肠癌有价值的预后标志物，KRT6A 可能参与了结直肠癌浸润区进展的分子机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Laboratory Investigation 医学-病理学

CiteScore

8.30

自引率

0.00%

发文量

125

审稿时长

2 months

期刊介绍： Laboratory Investigation is an international journal owned by the United States and Canadian Academy of Pathology. Laboratory Investigation offers prompt publication of high-quality original research in all biomedical disciplines relating to the understanding of human disease and the application of new methods to the diagnosis of disease. Both human and experimental studies are welcome.