Katase Naoki, Nagano Kenichi, Fujita Shuichi
Department of Oral Pathology, Institute of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8588, Japan.
Department of Oral Pathology, Institute of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8588, Japan.
J Oral Biosci. 2020 Mar;62(1):9-15. doi: 10.1016/j.job.2020.01.008. Epub 2020 Feb 4.
Cancer arises from cumulative genetic or epigenetic aberrations, or the destabilization of central signaling pathways that regulate cell proliferation, differentiation, cell cycle, gene transcription, migration, angiogenesis and apoptosis. Investigating the cancer-specific genetic background is important to get deeper apprehension of cancer biology. In this review, we aimed to identify head and neck squamous cell carcinoma (HNSCC)-specific genes and identified DKK3 gene as a candidate.
DKK3 belongs to the DKK family (DKK1, DKK2, DKK3 and DKK4), which codes for an evolutionally conserved secreted glycoprotein that is characterized by two distinct cysteine rich domains and functions as an antagonist of the oncogenic Wnt signaling pathway. It has been reported that DKK3 expression is decreased in many kinds of cancers, and it is thus thought to be a tumor suppressor gene. However, our investigations have demonstrated unique expression and function of DKK3 in HNSCC. DKK3 protein expression is predominantly positive in HNSCC, and DKK3-positive patients show significantly shorter disease-free survival rates, whereas DKK3-negative cases do not show metastasis. Molecular biological analyses demonstrated that DKK3 over expression significantly increased HNSCC cell proliferation, migration, and invasion via increased phosphorylation of AKT. Moreover, DKK3 knockdown in HNSCC cells significantly decreased these malignant potentials through decreased AKT phosphorylation.
Our previously published data, alongside those from other reports, indicate that DKK3 may have an additional oncogenic function other than tumor suppression.
癌症源于累积的遗传或表观遗传畸变，或调控细胞增殖、分化、细胞周期、基因转录、迁移、血管生成和凋亡的核心信号通路的不稳定。研究癌症特异性遗传背景对于更深入理解癌症生物学至关重要。在本综述中，我们旨在鉴定头颈部鳞状细胞癌（HNSCC）特异性基因，并将DKK3基因确定为候选基因。
DKK3属于DKK家族（DKK1、DKK2、DKK3和DKK4），该家族编码一种进化上保守的分泌糖蛋白，其特征在于两个不同的富含半胱氨酸结构域，并作为致癌性Wnt信号通路的拮抗剂发挥作用。据报道，DKK3在多种癌症中表达降低，因此被认为是一种肿瘤抑制基因。然而，我们的研究表明DKK3在HNSCC中具有独特的表达和功能。DKK3蛋白表达在HNSCC中主要呈阳性，DKK3阳性患者的无病生存率显著缩短，而DKK3阴性病例未出现转移。分子生物学分析表明，DKK3过表达通过增加AKT磷酸化显著增加HNSCC细胞的增殖、迁移和侵袭。此外，HNSCC细胞中DKK3基因敲低通过降低AKT磷酸化显著降低了这些恶性潜能。
我们之前发表的数据以及其他报告的数据表明，DKK3可能除了具有肿瘤抑制作用外还具有额外的致癌功能。
